Abstract: BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. Apart from supportive care and palliative radiation to localized (e.g. bone) metastasis, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the efficacy of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to March 2009, reference lists of studies, and contacted pharmaceutical companies and national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Thirty five trials, with a total of 5726 patients, have been included in the meta-analysis of overall survival. The comparison of chemotherapy versus best supportive care consistently demonstrated a significant benefit in overall survival in favour of the group receiving chemotherapy (hazard ratios (HR) 0.37; 95% confidence intervals (CI) 0.24 to 0.55, 184 participants). The comparison of combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.82; 95% CI 0.74 to 0.90, 1914 participants). The price of this benefit is increased toxicity as a result of combination chemotherapy. When comparing 5-FU/cisplatin-containing combination therapy regimens with versus without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95, 501 participants) and 5-FU/anthracycline-containing combinations with versus without cisplatin (HR 0.82; 95% CI 0.73 to 0.92, 1147 participants) there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. Both the comparison of irinotecan versus non-irinotecan (HR 0.86; 95% CI 0.73 to 1.02, 639 participants) and docetaxel versus non-docetaxel containing regimens (HR 0.93; 95% CI 0.75 to 1.15, 805 participants) show non-significant overall survival benefits in favour of the irinotecan and docetaxel-containing regimens. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU. All patients should be tested for their HER-2 status and trastuzumab should be added to a standard fluoropyrimidine/cisplatin regimen in patients with HER-2 positive tumours. Two and three-drug regimens including 5-FU, cisplatin, with or without an anthracycline, as well as irinotecan or docetaxel-containing regimens are reasonable treatment options for HER-2 negative patients.
Abstract: Biomarkers and surrogate end points have great potential for use in clinical oncology, but their statistical validation presents major challenges, and few biomarkers have been robustly confirmed. Provisional supportive data for prognostic biomarkers, which predict the likely outcome independently of treatment, is possible through small retrospective studies, but it has proved more difficult to achieve robust multi-site validation. Predictive biomarkers, which predict the likely response of patients to specific treatments, require more extensive data for validation, specifically large randomized clinical trials and meta-analysis. Surrogate end points are even more challenging to validate, and require data demonstrating both that the surrogate is prognostic for the true end point independently of treatment, and that the effect of treatment on the surrogate reliably predicts its effect on the true end point. In this Review, we discuss the nature of prognostic and predictive biomarkers and surrogate end points, and examine the statistical techniques and designs required for their validation. In cases where the statistical requirements for validation cannot be rigorously achieved, the biological plausibility of an end point or surrogate might support its adoption. No consensus yet exists on processes or standards for pragmatic evaluation and adoption of biomarkers and surrogate end points in the absence of robust statistical validation.
Abstract: PURPOSE OF REVIEW: The vascular endothelial growth factor (VEGF) system is a critical regulator of angiogenesis and known to promote tumor growth and invasion in colorectal cancer (CRC). Bevacizumab is currently the only VEGF inhibitor with clear proof of efficacy in CRC, but optimal use of this agent at various stages of the disease is still under investigation. Additionally, there are numerous other angiogenesis agents targeting VEGF and other proangiogenic systems in clinical development. RECENT FINDINGS: Although bevacizumab has been shown to improve outcomes in terms of progression-free and overall survival in the setting of metastatic CRC (mCRC), it does not appear to provide long-term benefit in the adjuvant setting. The combination of VEGF inhibition with epidermal growth factor inhibition with chemotherapy does not improve survival for patients with mCRC, and may potentially be harmful in the first-line setting. Tyrosine kinase inhibitors in combination with other therapies show promise in early clinical trials in mCRC. SUMMARY: Current evidence suggests that the benefit of VEGF inhibition with bevacizumab in CRC is limited to the metastatic setting. Dual antibody therapy with bevacizumab and an epidermal growth factor inhibitor (cetuximab or panitumumab) should not be used in mCRC. Results of ongoing trials involving tyrosine kinase inhibitors may result in an expansion of treatment options for patients with CRC.
Abstract: PURPOSE To improve the understanding of the appropriate design of phase II oncology clinical trials, we compared error rates in single-arm, historically controlled and randomized, concurrently controlled designs. PATIENTS AND METHODS We simulated error rates of both designs separately from individual patient data from a large colorectal cancer phase III trials and statistical models, which take into account random and systematic variation in historical control data. RESULTS In single-arm trials, false-positive error rates (type I error) were 2 to 4 times those projected when modest drift or patient selection effects (eg, 5% absolute shift in control response rate) were included in statistical models. The power of single-arm designs simulated using actual data was highly sensitive to the fraction of patients from treatment centers with high versus low patient volumes, the presence of patient selection effects or temporal drift in response rates, and random small-sample variation in historical controls. Increasing sample size did not correct the over optimism of single-arm studies. Randomized two-arm design conformed to planned error rates. CONCLUSION Variability in historical control success rates, outcome drifts in patient populations over time, and/or patient selection effects can result in inaccurate false-positive and false-negative error rates in single-arm designs, but leave performance of the randomized two-arm design largely unaffected at the cost of 2 to 4 times the sample size compared with single-arm designs. Given a large enough patient pool, the randomized phase II designs provide a more accurate decision for screening agents before phase III testing.
Abstract: Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5-FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes.
Abstract: Colorectal cancer metastatic to the liver is a common oncologic problem, and carefully selected patients can be successfully treated with surgical resection of liver metastases. Perioperative chemotherapy has been shown to increase progression-free survival in patients with resectable liver metastases and can currently be considered a standard therapy for eligible patients. Preoperative chemotherapy can downstage unresectable liver metastases and allow a complete resection. More aggressive chemotherapy as well has the incorporation of targeted agents such as cetuximab and bevacizumab into modern chemotherapy regimens has resulted in higher response rates, which may translate into improved survival. Preoperative chemotherapy can increase postoperative complications after hepatic resection, and the decision to use such therapy should be made in a multidisciplinary setting.
Abstract: PURPOSE: We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. METHODS: The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. RESULTS: Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R(2) = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R(2) = 0.67 for both 2- and 3-year DFS) and 7-year OS (R(2) = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. CONCLUSION: Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.
Abstract: The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.
Abstract: PURPOSE With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. PATIENTS AND METHODS Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. CONCLUSION This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.
Abstract: PURPOSE Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. METHODS MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). Results Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). CONCLUSION Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
Abstract: Angiogenesis--one of the hallmarks of cancer--has emerged as a valid therapeutic target in oncology. The VEGF system represents a key mediator of tumor-initiated angiogenesis and the first target of antiangiogenesis agents introduced in clinical practice. Although anti-VEGF therapies have clearly demonstrated antitumor efficacy in various malignancies, especially when combined with conventional cytotoxic chemotherapy, their mechanism of action is not fully understood. This Review will discuss the rationale for using antiangiogenic compounds and will focus on large molecules, such as antibodies, that target the VEGF system. Clinical data on bevacizumab is discussed in detail. Predictive markers for anti-VEGF agents have not yet been identified and questions regarding the usefulness of bevacizumab in the adjuvant setting as well as its continued use beyond progression remain unanswered, in spite of negative data on bevacizumab in treating patients with adjuvant colon cancer. Nonetheless, anti-VEGF therapy has enhanced the arsenal of anticancer therapies and has provided new insights into the biology of malignancy.
Abstract: To assess whether prechemotherapy quality of life (QoL) factors and certain coping strategies are associated with postchemotherapy nausea and vomiting (PCNV). A total of 43 chemotherapy-naïve patients scheduled to receive anti-emetic prophylaxis were enrolled in this study. QoL parameters were measured by a modified EORTC Quality of Life Questionnaire (QLQ-30). In addition, questions regarding active or passive coping strategies were asked 1 day before chemotherapy. Prechemotherapy QoL factors, coping strategies as well as other patient, disease and treatment variables were compared between the groups of patients with or without PCNV. The univariate analysis identified four QoL parameters, 'tiredness', 'impairment of daily life by pain', 'sensation of abdominal pressure and fullness' and 'impairment of social activities' as associated with PCNV. No association was found between coping strategies and PCNV. In the multivariate analysis, the factors 'impairment of social activities' and 'sensation of abdominal pressure and fullness' remained significant. Specific pretreatment QoL parameters are associated with the risk to develop PCNV. Thus, in addition to other established risk factors for PCNV, patients should be screened for these QoL factors in order to improve the control of PCNV and facilitate the selection of appropriate, individualised anti-emetic prophylaxes.
Abstract: PURPOSE: Performance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain. PATIENTS AND METHODS: Individual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade > or = 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy. RESULTS: Compared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade > or = 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients. CONCLUSION: In clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.
Abstract: BACKGROUND: Angiogenesis inhibitors have been developed to block tumour angiogenesis and target vascular endothelial cells. While some of them have already been approved by the health authorities and are successfully integrated into patient care, many others are still under development, and the clinical value of this approach has to be established. OBJECTIVES: To assess the efficacy and toxicity of targeted anti-angiogenic therapies, in addition to chemotherapy, in patients with metastatic colorectal cancer. Primary endpoints are both progression-free and overall survival. Response rates, toxicity and secondary resectability were secondary endpoints. Comparisons were first-line chemotherapy in combination with angiogenesis inhibitor, to the same chemotherapy without angiogenesis inhibitor; and second-line chemotherapy, to the same chemotherapy without angiogenesis inhibitor. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, as well as proceedings from ECCO, ESMO and ASCO until November 2008. In addition, reference lists from trials were scanned, experts in the field and drug manufacturers were contacted to obtain further information. SELECTION CRITERIA: Randomized controlled trials on targeted anti-angiogenic drugs in metastatic colorectal cancer (MCRC). DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed, according to a previously published protocol. Because individual patient data was not provided, aggregate data had to be used for the analysis. Summary statistics for the primary endpoints were hazard ratios (HR's) and their 95% confidence intervals. MAIN RESULTS: At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS. AUTHORS' CONCLUSIONS: The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.
Abstract: BACKGROUND: The Bevacizumab Regimens' Investigation of Treatment Effects (BRiTE) study is a prospective, observational cohort study designed to elucidate safety and effectiveness outcomes associated with bevacizumab combined with chemotherapy as used in clinical practice for first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Baseline characteristics, prespecified bevacizumab-related adverse events, and effectiveness data were collected from 1,953 mCRC patients who were receiving first-line treatment including bevacizumab at 248 U.S. sites. RESULTS: At database lock, the median follow-up was 20.1 months. At baseline, 46% of patients were aged >or=65 years and 49% had an Eastern Cooperative Oncology Group performance status score >or=1. Fluorouracil, leucovorin, and oxaliplatin was the most common first-line chemotherapy regimen (56%). Overall rates of bevacizumab-related adverse events in the BRiTE study, such as gastrointestinal perforation (1.9%), arterial thromboembolic events (2%), grade 3-4 bleeding (2.2%), and de novo hypertension requiring medication (22%), were consistent with those reported in randomized clinical trials (RCTs) of bevacizumab in first-line mCRC treatment. The median progression-free survival (PFS) and overall survival (OS) times were 9.9 (95% confidence interval [CI], 9.5-10.3) months and 22.9 (95% CI, 21.9-24.4) months, respectively. CONCLUSION: The median PFS and OS durations and safety profile of bevacizumab in the BRiTE study were similar to those in RCTs of bevacizumab plus chemotherapy in first-line mCRC patients. The observations from the BRiTE study complement and expand upon RCT data, providing clinical information in a large cohort of bevacizumab-treated patients and subgroups such as the elderly.
Abstract: PURPOSE: Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified. METHODS: We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005. RESULTS: Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period. CONCLUSION: Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).
Abstract: Oral capecitabine has been shown to be a convenient and well tolerated alternative to intravenous 5-fluorouracil (5-FU) in the treatment of colorectal cancer. The question of whether capecitabine is an adequate and equally effective substitute for infusional 5-FU in combination with oxaliplatin for the treatment of advanced colorectal cancer has long been unanswered. On the basis of results from the randomized, phase III trial by Cassidy et al., capecitabine in combination with oxaliplatin has emerged as a valid treatment alternative to infusional 5-FU in combination with oxaliplatin in patients with advanced colorectal cancer. For patients treated in the US, however, questions about the most appropriate dosage and schedule of capecitabine have not yet been completely resolved. Oncologists will probably have to use a lower starting dose of capecitabine in combination therapies that include oxaliplatin, than that used in this study.
Abstract: PURPOSE: Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. METHODS: The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. RESULTS: A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. CONCLUSION: Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value.
Abstract: Genomics and proteomics have held out the promise of individualized medicine for the last 10 or 20 years, but clinical medicine has not yet delivered on this promise. Some cancers, such as breast cancer and some hematologic malignancies, have been at the forefront of individualized therapeutic approaches by integrating molecular biomarkers into treatment decision algorithms. Until recently, the treatment of colorectal cancer (CRC) has lagged behind these other cancers in this regard and therapeutic decisions have been solely empirical. Data from various clinical trials and translational studies have now opened the door for individualized treatment approaches by identifying patients with metastatic CRC who are most likely to benefit from antibodies against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab. Activating mutations of KRAS, a downstream mediator of EGFR signaling, has been shown to render EGFR antibodies ineffective, such that analyzing tumors for these mutations has become mandatory before the use of EGFR antibodies is considered in CRC. Beyond KRAS, several additional biomarkers are currently being investigated as potential positive or negative predictors for the efficacy of EGFR-targeted therapy. Most of these markers are alterations of molecules integrated in the EGFR pathway. This review will focus on the type and quality of evidence that has been gathered to date to predict resistance to monoclonal antibodies against EGFR in CRC. (Clin Cancer Res 2009;15(24):7492-501).
Abstract: BACKGROUND: This phase 2 trial was designed to evaluate the efficacy and toxicity of a combination of docetaxel, gemcitabine, and oxaliplatin for platinum- and paclitaxel-pretreated epithelial ovarian cancer. PATIENTS AND METHODS: Heavily pretreated patients (N = 30; median age, 61 years) received docetaxel, 55 mg/m2; gemcitabine, 500 mg/m2 (day 1); and oxaliplatin, 70 mg/m2 (day 2) biweekly. Twelve patients had platinum-sensitive disease, and 18 patients had platinum-resistant disease. RESULTS: Median follow-up was 18.6 months. No differences in patient characteristics were observed between patients with carboplatinum-sensitive and carboplatinum-resistant disease. In patients with carboplatin-sensitive disease, an overall response (OR) of 83.3%, a progression-free survival of 10.6 months, and an overall survival of 18.9 months were observed. In patients with carboplatinum-resistant disease, an OR was seen in 38.9% with a progression-free survival of 5.3 months and an overall survival of 16.3 months. Patients with platinum-refractory disease (progression under previous carboplatinum therapy, n = 13) had an OR of 23%, whereas patients with objective response but relapse less than 6 months after carboplatinum therapy had an OR of 80.0%. Grade 3 and 4 toxicities were only observed for anemia (6.7%), neutropenia (20.0%), thrombopenia, peripheral neuropathy, and diarrhea (16.7%). No neutropenic fever or treatment-related death occurred. CONCLUSIONS: In comparison with current standard protocols, a combination of docetaxel, gemcitabine, and oxaliplatin showed considerably higher efficacy without remarkable increased toxicity; particularly for patients with early relapse after a platinum-containing therapy.
Abstract: The human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, panitumumab, represents a significant advance in the treatment of colorectal cancer. The strategy to target this receptor is based on sound cancer biology demonstrating its essential role in colorectal carcinogenesis. Panitumumab, unlike its predecessor, cetuximab, is fully human and thus reduces the incidence of hypersensitivity reactions. But, in several clinical trials, unexpected toxicities have become more apparent, raising concerns of how readily panitumumab can succeed cetuximab. This paper reviews the development of this agent and the pivotal clinical trials that help our understanding of its optimal use in colorectal cancer treatment.
Abstract: PURPOSE: Angiogenesis, one of the hallmarks of cancer, has recently become the target of therapeutic approaches in oncology. Among the complex system of pro- and antiangiogenic factors, the vascular endothelial growth factor system stands out as key mediator of tumor-initiated angiogenesis and as target of antiangiogenesis agents introduced in clinical practice. Although antivascular endothelial growth factor therapies, and in particular, bevacizumab as monoclonal antibody against vascular endothelial growth factor has clearly demonstrated antitumor efficacy, its mechanism of action is not fully understood. DESIGN: This review will discuss the rationale for using antiangiogenesis as anticancer therapy with focus on antibody-based approaches toward the vascular endothelial growth factor-system. Results of clinical trials using bevacizumab will be discussed in detail. RESULTS: Bevacizumab has well-documented efficacy as part of first-line therapy in various malignancies ranging from colorectal to breast and lung cancer. Although it mainly exerts its efficacy in conjunction with conventional cytotoxic chemotherapy, several, apparently vascular endothelial growth factor-dependent malignancies such as renal cell cancer, ovarian cancer, and glioblastoma have shown to be susceptible to single-agent bevacizumab. DISCUSSION: Antiangiogenesis therapy with antibodies, namely bevacizumab as antivascular endothelial growth factor agent, has demonstrated efficacy in various human malignancies. The mechanism of action of antivascular endothelial growth factor therapy in general and bevacizumab in particular, however, is not fully understood. Predictive markers have not yet been identified and questions regarding bevacizumab's usefulness in the adjuvant setting as well as its value as continued therapy beyond progression are still unanswered. It is indisputable, though, that antiangiogenesis has greatly enhanced the therapeutic arsenal of anticancer therapies and has changed oncology forever.
Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs, taxanes, epothilones and vinca alkaloids, and also newer agents such as bortezomib and lenolidamide. Symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. This manuscript provides a review of studies directed at both of these areas. New evidence strongly suggests that intravenous calcium and magnesium therapy can attenuate the development of oxaliplatin-induced CIPN, without reducing treatment response. Accumulating data suggest that vitamin E may also attenuate the development of CIPN, but more data regarding its efficacy and safety should be obtained prior to its general use in patients. Other agents that look promising in preliminary studies, but need substantiation, include glutamine, glutathione, N-acetylcysteine, oxcarbazepine, and xaliproden. Effective treatment of established CIPN, however, has yet to be found. Lastly, paclitaxel causes a unique acute pain syndrome which has been hypothesised to be caused by neurologic injury. No drugs, to date, have been proven to prevent this toxicity.
Abstract: PURPOSE: This study was undertaken to examine five possible prognostic factors in patients with recurrent stage II and III colon cancer: time from randomization on an adjuvant therapy clinical trial to tumor recurrence (< 1 year, 1 to 2 years, 2 to 3 years, 3 to 4 years, > 4 years), initial stage (II v III), initial adjuvant treatment (fluorouracil [FU]-based v surgery alone), the era in which the patient entered an adjuvant therapy clinical trial (1978 to 1985, 1986 to 1992, 1993 to 1999), and patient age at recurrence. METHODS: The Adjuvant Colon Cancer End Points (ACCENT) data set was analyzed using univariate and multivariate Cox proportional hazards models, stratified by study. RESULTS: 5,722 (32.9%) of 17,381 patients experienced recurrence. Median survival following recurrence was 13.3 months. Time from randomization to recurrence was highly prognostic of survival following recurrence (P < .0001). Longer survival following recurrence was seen in patients with initial stage II versus III disease (P < .0001; 14.3% 6-year overall survival after recurrence in initial stage II patients), patients entered more recently onto trials (P < .0001), and patients initially treated with surgery alone versus FU adjuvant treatment (P = .0005). All relationships were maintained in multivariate models. CONCLUSION: Time from initial treatment to recurrence and initial stage are important prognostic factors in patients with recurrent colon cancer. Survival following recurrence increased modestly from 1978 to 1999. Patients who had a recurrence following adjuvant therapy had poorer prognosis than those who progressed after surgery alone. These prognostic factors may be useful for clinical trial design and treatment decisions in patients with recurrent colon cancer.
Abstract: Rexin-G is a pathotropic retroviral vector displaying a von Willebrand factor-targeting motif and expressing a dominant negative cyclin G1 gene. We undertook a phase I trial of intravenous (i.v.) administration of Rexin-G in patients with gemcitabine refractory, metastatic pancreatic adenocarcinoma. Twelve patients were treated. Dose escalation was performed from a dose of 1 x 10(11) colony forming units (CFU) per cycle to 6 x 10(11) CFU per cycle. The treatment was well tolerated. One dose-limiting toxicity (DLT) at dose level 2 (1.5 x 10(11) CFU per cycle) was observed, consisting of grade 3 transaminitis. There was no detection of replication-competent virus in patients' peripheral blood mononuclear cells (PBMCs) or viral integration in DNA obtained from PBMCs, and no development of neutralizing antibodies. No evidence of antitumor activity was observed. The best objective response was progressive disease in 11 of the 12 study patients, while 1 patient showed radiographically stable disease with clinical deterioration and increase in the CA19.9 tumor marker. Median time to progression was 32 days. The median duration of survival of the study patients was 3.5 months from treatment initiation. Rexin-G is well tolerated in doses up to 6 x 10(11) CFU in patients with recurrent pancreatic cancer, but there was no evidence of clinical antitumor activity.
Abstract: PURPOSE: In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. PATIENTS AND METHODS: For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. RESULTS: Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. CONCLUSION: In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.
Abstract: BACKGROUND: We evaluated the outcome of 140 patients aged > or = 70 years of age who received first-line treatment for metastatic colorectal cancer within the German phase III trial of FUFOX (5-fluorouracil/leucovorin/oxaliplatin) versus CAPOX (capecitabine/oxaliplatin). PATIENTS AND METHODS: One hundred forty (30%) elderly patients of 476 total patients were identified, and 138 patients received the CAPOX or FUFOX treatment. RESULTS: Overall, treatment was well tolerated, and grade 3/4 toxicities were similar in both groups, with more gastrointestinal side effects in the elderly group but less neurosensory side effects. The response rate (RR) was comparable between both cohorts (49% in elderly patients vs. 52% in patients aged < 70 years). Median progression-free survival (PFS) was 7.7 months for patients aged > or = 70 years and 7.5 months for patients aged < 70 years (hazard ratio [HR], 1.07; 95% CI, 0.86-1.34). With regard to the chemotherapy regimen, there was no inferiority between FUFOX and CAPOX in patients aged > or = 70 years (7.9 months vs. 7.6 months). The median overall survival (OS) between FUFOX and CAPOX was comparable in patients aged > or = 70 years (14.4 months vs. 14.2 months). However, when compared with patients aged < 70 years, the median OS was significantly shorter (18.8 months vs. 14.4 months; P = 0.013; HR, 1.37; 95% CI, 1.07-1.76). This was consistent with our multivariate analysis, which revealed that age > or = 70 years was a negative factor for OS. CONCLUSION: Oxaliplatin combined with 5-FU/leucovorin or capecitabine was generally well tolerated in elderly patients. Elderly patients had similar PFS and overall RRs compared with the population aged < 70 years, but the OS was shorter.
Abstract: The administration of adjuvant chemotherapy after resection of stage III colon cancer to prolong disease-free survival (DFS) and increase overall survival (OS) has been clinical standard since the early 1990s. Recently, 3-year DFS was recognized as surrogate endpoint for OS based on a meta-analysis of trials utilizing 5-fluorouracil as only active chemotherapy component. The standard of care in adjuvant therapy, however, has moved on to modern combination regimens including oxaliplatin, and novel targeted agents such as angiogenesis inhibitors and antibodies against epidermal growth factor receptor are currently undergoing rigorous testing in phase III adjuvant trials. For the practicing clinician, the use of surrogate endpoints to appreciate the efficacy of a specific adjuvant therapy contains various challenges, in particular, in discussions with patients. It is questionable whether 3-year DFS can still be considered an appropriate predictor of OS in complex clinical scenarios with continuous change in treatment standards in the adjuvant and palliative situation. Thus, the practicing oncologist needs to be aware of the limitations in the definition of surrogate endpoints in the adjuvant setting.
Abstract: PURPOSE: Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX. PATIENTS AND METHODS: This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity. RESULTS: The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested similar outcome within the range of noninferiority. Grade 3/4 toxicities (thrombocytopenia-HR = 2.07, 95% CI, 1.42 to 3.03; P < .0002; diarrhea-HR = 1.34; 95% CI, 1.08 to 1.66; P < .0009; and grade 2/3 hand-foot-syndrome [HFS]-HR = 3.54; 95% CI, 2.07 to 6.05; P < .00001) were less prominent with FU-based regimens whereas neutropenia (HR = 0.15; 95% CI, 0.11 to 0.19; P < .00001) was lower in the CAP regimens. CONCLUSION: The combination of CAP and OX resulted in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and HFS consistently more prominent in the CAP regimens.
Abstract: PURPOSE: Bevacizumab provides a survival benefit in first- and second-line metastatic colorectal cancer (mCRC). In a large, observational, bevacizumab treatment study (Bevacizumab Regimens: Investigation of Treatment Effects and Safety [BRiTE]) in patients who had mCRC, a longer-than-expected overall survival (OS) of 25.1 months was reported. The association between various pre- and post-treatment factors (including the use of bevacizumab beyond first progression [BBP]) and survival was examined. PATIENTS AND METHODS: The 1,445 of 1,953 previously untreated patients with mCRC who were enrolled in BRiTE and who experienced disease progression (PD) were classified into three groups: no post-PD treatment (n = 253), post-PD treatment without bevacizumab (no BBP; n = 531), and BBP (n = 642). Relevant baseline and on-study variables, including BBP, were analyzed with a Cox model with respect to their independent effect on survival beyond first PD. RESULTS: Median OS was 25.1 months (95% CI, 23.4 to 27.5 months), and median progression-free survival was 10.0 months in the overall BRiTE population. Baseline and postbaseline factors were well balanced between the BBP and no-BBP groups. Median OS rates were 12.6, 19.9, and 31.8 months in the no post-PD treatment, no-BBP, and BBP groups, respectively. In multivariate analyses, compared with no BBP, BBP was strongly and independently associated with improved survival (HR, 0.48; P < .001). Hypertension that required medication was the only bevacizumab-related safety event that occurred more frequently in the BBP group (24.6% v 19.2%). CONCLUSION: These results from a large, prospective, observational study suggest that continued vascular endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important role improving the overall success of therapy for patients who have mCRC.
Abstract: As with many malignancies, cytogenetic information has become increasingly important to the diagnosis and proper treatment of colorectal cancer. In particular, several recent studies have confirmed that KRAS is not only one of the most commonly mutated genes in colorectal cancer, but also essential to treatment decision-making. Several key studies have demonstrated that patients with mutant KRAS do not respond to treatment with epidermal growth factor inhibitors. This finding has several implications for clinicians who treat patients with metastatic colorectal cancer. The following monograph includes discussions on the key issues surrounding the integration of recent data on KRAS status into the care of patients with this disease.
Abstract: The North Central Cancer Treatment Group (NCCTG) was founded in 1977 as a regional cooperative group to allow cancer patients in the upper Midwest of the United States to gain access to clinical trials in oncology by establishing a network of community oncology practices with one academic research base, the Mayo Clinic. Since then, the NCCTG has grown into an international cooperative group with 43 members in 33 US states and Canada. This article details 30 years of achievements of the NCCTG, including important scientific contributions from disease-specific and treatment modality committees, the cancer control program, patient-reported outcomes and quality-of-life research, and biostatisticians that support the NCCTG's specific aims: to improve the duration and quality of life of cancer patients, to enhance our understanding of the biological consequences of cancer and its treatment, and to improve methods for clinical trial conduct.
Abstract: PURPOSE: To compare the use of capecitabine plus oxaliplatin (CAPOX) with infusional fluorouracil (FU)/folinic acid plus oxaliplatin (FUFOX) as first-line therapy for patients with metastatic colorectal cancer (MCRC). PATIENTS AND METHODS: A total of 474 patients with MCRC received either CAPOX (capecitabine 1,000 mg/m2 bid, days 1 to 14 plus oxaliplatin 70 mg/m2 days 1 and 8, repeated every 22 days) ) or FUFOX (oxaliplatin 50 mg/m2 followed by leucovorin 500 mg/m2 plus FU 2,000 mg/m2 as a 22-hour infusion days 1, 8, 15, and 22, repeated every 36 days). The primary end point was progression-free survival (PFS). Secondary end points were response rate (RR), overall survival (OS), time to treatment failure, and toxicity. The study was designed to determine noninferiority for the CAPOX regimen. RESULTS: Median PFS was 7.1 months in the CAPOX arm and 8.0 months in the FUFOX arm (hazard ratio [HR], 1.17; 95% CI, 0.96 to 1.43; P = .117). Median OS was 16.8 months (CAPOX) and 18.8 months (FUFOX; HR, 1.12; 95% CI, 0.92 to 1.38; P = .26). Overall RRs were 48% for CAPOX (95% CI, 41% to 54%) and 54% for FUFOX (95% CI, 47% to 60%). Both regimens were generally well tolerated, although there was a significantly higher incidence of grade 2/3 hand-foot syndrome (HFS) in the CAPOX arm (P = .028). CONCLUSION: CAPOX resulted in a slightly inferior efficacy than FUFOX. With respect to PFS, the best estimate of the HR of 1.17 was within the prespecified equivalence range. However, a relevant inferiority cannot be excluded. Both regimens were generally well tolerated but there was a significantly higher rate of grade 2/3 HFS in the CAPOX arm.
Abstract: BACKGROUND: Efficacy and toxicity of oxaliplatin (Eloxatin; Sanofi-Aventis, Paris, France) combined with irinotecan (IROX) were examined in 383 patients enrolled on the IROX arm of Intergroup Study N9741. METHODS: This IROX regimen was oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2) administered every 3 weeks. The relation between adverse events on IROX to selected characteristics was analyzed. Time to progression (TTP), response rate, and overall survival for patients treated with IROX compared with patients treated with oxaliplatin with 5- fluorouracil (FOLFOX) were updated in this article. RESULTS: Grade >or=3 gastrointestinal and hematologic toxicities were common with 39% patients experiencing neutropenia, 28% diarrhea, and 21% vomiting. Patients ages >70 years experienced higher rates of grade >or=3 toxicity, with significantly higher rates of grade >or=3 hematologic toxicities (P = .02). Long-term toxicity was uncommon, and nearly all cases of grade >or=3 neurotoxicity resolved within 10 months. Fifty-two percent of patients required dose reductions for adverse events, and 26% experienced 119 hospitalizations related to complications of treatment or their disease, with 5 treatment-related deaths. This analysis confirmed prior findings that FOLFOX is superior to IROX in terms of response rate (43% vs 36%, p = 0.002), TTP (9.2 months vs 6.7 months, P < .0001), and overall survival (19.5 months vs 17.3 months, P = .0001). CONCLUSIONS: IROX was found to be less active than FOLFOX but with a similar toxicity profile except in patients ages >70 years. Although IROX may be considered in patients intolerant of 5-FU or in patients known to have a dihydropyrimidine dehydrogenase (DPD) deficiency, it should be used with caution in older patients.
Abstract: Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.
Abstract: New agents for the treatment of metastatic colorectal cancer have extended median overall survival to more than 20 months, an increase that has changed the view of advanced colorectal cancer from an acute to a chronic condition. This article proposes a shift in treatment strategy from the concept of successive "lines" of therapy, in which chemotherapy is continued until disease progression, to that of a continuum of care, in which the use of chemotherapy is tailored to the clinical setting and includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays," and surgical resection of metastases in selected patients. In this approach, the distinction between lines of therapy is no longer absolute. This represents a paradigm shift in the management of metastatic colorectal cancer to that of a continuum of care approach that includes individualized planning, in which patients are given the opportunity to benefit from exposure to all active agents and modalities while minimizing unnecessary treatment and toxicity, with the ultimate goal of improving survival as well as quality of life.
Abstract: GOALS OF WORK: Comparing antiemetic efficacy of different 5-HT(3)-receptor antagonists (5-HT(3)RAs) is difficult due to inter-study variability. Therefore, a meta-analysis was performed to comparatively evaluate dolasetron, granisetron, ondansetron and tropisetron for acute chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Comparisons between 5-HT(3)RAs were based on 44 randomized studies (including 12,343 patients) identified by MEDLINE, CANCERLIT or EMBASE searches and subcategorized by chemotherapy type (cisplatin- or non-cisplatin-based). MAIN RESULTS: When all studies were combined, granisetron was equivalent to ondansetron (n = 27), and showed an advantage vs tropisetron (p = 0.018; n = 12). Ondansetron vs tropisetron (n = 11) and ondansetron vs dolasetron (n = 3) revealed equivalence in each comparison. An advantage for 3 mg granisetron vs 8 mg ondansetron was found in non-cisplatin-based studies (p = 0.015; n = 6). Overall equivalence was seen between ondansetron, 24 or 32 mg, and granisetron, 2 or 3 mg, for all studies (n = 13). There was a possible advantage for higher (24 or 32 mg) vs lower (8 mg) ondansetron dose regimens with cisplatin-based trials (n = 6). No differences were seen between 3 and 1 mg granisetron doses (n = 6). CONCLUSIONS: Efficacy of 5-HT(3)RAs for preventing CINV following cisplatin- and non-cisplatin-based chemotherapy is comparable, with the exception of granisetron vs tropisetron. Some differences were noted in dosing subanalyses.
Abstract: Symptoms related to cancer and/or cancer therapy are a prominent consideration in cancer patients; multiple options have been proposed to alleviate these problems. The US National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) has mandated that CCOP participant institutions be involved with cancer control trials in addition to cancer treatment trials. Through such efforts, scientifically sound symptom control clinical trials are being conducted to determine the effectiveness of promising agents. In this article, the authors provide an update of clinical trial outcomes regarding 13 symptom and symptom complexes related to cancer and/or cancer therapy, emphasizing that publication of both positive and negative study results is important to separate what works from what does not.
Abstract: For nearly two decades, adjuvant chemotherapy has been the standard of care in patients with early-stage colon cancer at high risk of recurrence. Until now, treatment has been based on the use of cytotoxic drugs that have well-demonstrated efficacy in advanced colorectal cancer. Most recently, targeted biological agents [i.e., antibodies against the epidermal growth factor receptor and vascular endothelial growth factor] have become essential components of the palliative medical treatment of colorectal cancer. Proof of efficacy of these agents in advanced disease has led to the initiation of several trials testing epidermal growth factor receptor and vascular endothelial growth factor antibodies in the adjuvant setting. Although definitive results of ongoing adjuvant studies will not be available for 2 to 3 years, some oncologists might already inappropriately consider the use of these targeted agents as a component of adjuvant therapy in selected patients. Whether the results obtained in advanced colorectal cancer can be readily translated into a projected efficacy in early-stage colon cancer, however, is unclear. In addition, the long-term safety of biological agents in potentially surgically cured patients has not yet been established. This review discusses the potential caveats and concerns associated with the uncritical use of targeted agents as adjuvant therapy before their safety and efficacy in this setting has been indisputably established in definitive phase III trials.
Abstract: PURPOSE: The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. METHODS: Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. RESULTS: DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. CONCLUSION: DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.
Abstract: The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.
Abstract: PURPOSE: This systematic review and meta-analysis were performed to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer. METHODS: Randomized phase II and III clinical trials on first-line chemotherapy in advanced gastric cancer were identified by electronic searches of Medline, Embase, the Cochrane Controlled Trials Register, and Cancerlit; hand searches of relevant abstract books and reference lists; and contact to experts. Meta-analysis was performed using the fixed-effect model. Overall survival, reported as hazard ratio (HR) with 95% CI, was the primary outcome measure. RESULTS: Analysis of chemotherapy versus best supportive care (HR = 0.39; 95% CI, 0.28 to 0.52) and combination versus single agent, mainly fluorouracil (FU) -based chemotherapy (HR = 0.83; 95% CI = 0.74 to 0.93) showed significant overall survival benefits in favor of chemotherapy and combination chemotherapy, respectively. In addition, comparisons of FU/cisplatin-containing regimens with versus without anthracyclines (HR = 0.77; 95% CI, 0.62 to 0.95) and FU/anthracycline-containing combinations with versus without cisplatin (HR = 0.83; 95% CI, 0.76 to 0.91) both demonstrated a significant survival benefit for the three-drug combination. Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly FU/cisplatin) resulted in a nonsignificant survival benefit in favor of the irinotecan-containing regimens (HR = 0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination. CONCLUSION: Best survival results are achieved with three-drug regimens containing FU, an anthracycline, and cisplatin. Among these, regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.
Abstract: Monoclonal antibodies against the epidermal growth factor receptor have proven efficacy as monotherapy and in combination with chemotherapy in patients with metastatic colorectal cancer (CRC: mCRC). Initial clinical trials in CRC used the human-murine chimeric monoclonal antibody cetuximab. Ongoing studies are being conducted to evaluate the efficacy and safety of the fully human anti-epiderman growth factor receptor monoclonal antibody panitumumab. The results of a phase III trial which compared panitumumab as a single agent to best supportive care in patients with previously treated metastatic CRC have recently been reported Pantitumumab therapy resulted in a 46% reduction in the risk of tumor progression and a partial response rate of 8%. Rash was reported in 90% of patients with increased severity significantly correlated with improved medium overall survival (OS). Further clinical studies re ongoing and planned to test panitumumab in combination with chemotherapy in first-line therapy of advanced-stage CRC and adjuvant treatment of colon cancer.
Abstract: In the USA, colorectal cancer is the fourth most prevalent cancer and is the second leading cause of cancer death after lung cancer. In 2006, 148,610 colorectal cancer cases are expected in the USA, with 55,170 deaths expected from this disease. After years of stagnation, the treatment of metastatic colorectal cancer has recently made dramatic advances. The previous standard of care, 5-fluorouracil, is the now the backbone of combination regimens with oxaliplatin or irinotecan. The addition of biological agents, such as the vascular endothelial growth factor inhibitor, bevacizumab, and the epidermal growth factor receptor inhibitors, cetuximab and panitumumab, have further enhanced the activity of conventional chemotherapy. These advances have increased the overall survival of advanced colorectal cancer patients, which was once 6 months with best supportive care, to over 2 years if all active agents are used in the course of the disease.
Abstract: Selection of third-line treatment in metastatic colorectal cancer depends on the agents that have been used in prior therapy. A principle in treatment is to use all five of the active drugs in this setting (5-fluorouracil [5-FU], oxaliplatin, irinotecan, cetuximab, and bevacizumab) during the patient's overall treatment course for metastatic disease because cumulative use of available active drugs appears to increase overall survival. Currently, 5-FU/leucovorin (5-FU/LV)/oxaliplatin (FOLFOX) or 5-FU/LV plus irinotecan (FOLFIRI) can be considered standard therapy in first-line treatment, with cross-over irinotecan or oxaliplatin-containing regimens as a component of several possible second-line regimens. On this scenario, third-line treatment can include the combination of irinotecan with cetuximab or bevacizumab or both or the use of cetuximab and bevacizumab in combination. Data from randomized trials on third-line treatment are needed.
Abstract: The question of continuous versus intermittent chemotherapy for patients with metastatic colorectal cancer has been an ongoing issue of debate for determining the optimum duration of treatment. The results from 2 major trails addressing this issue were recently presented at the 2006 Annual Meeting of the American Society of Clinical Oncology. The OPTIMOX2 trial evaluated the efficacy and safety of oxaliplatin reintroduction after a complete chemotherapy-free interval or maintenance therapy in patients with previously untreated disease. The GISCAD (Italian Group for the Study of Digestive Tract Cancer) study investigated the utility of intermittent versus continuous irinotecan-based chemotherapy. Both studies demonstrated that chemotherapy can be administered intermittently without affecting the overall efficacy of treatment.
Abstract: Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.
Abstract: Traditional therapeutic concepts and treatment regimens for colorectal cancer are currently changing with the demonstration of the efficacy of biologic agents in this disease setting. The addition of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to conventional chemotherapy in the first- and second-line settings has shown a survival benefit; this outcome has helped to rapidly change the standard of care. Other targeted agents, such as anti-epidermal growth factor receptor (EGFR) antibodies, have shown proof of efficacy in colorectal cancer as well. The molecular targeted therapies are associated with toxicity profiles that are distinctly different from those seen with conventional chemotherapy. A notable difference is the absence of high risk for myelosuppression, diarrhea, or alopecia, which are common side effects of cytotoxic chemotherapy. This article will explore the toxicities associated with targeted therapies in detail in an attempt to provide assistance to the practicing oncologist in detecting and managing these side effects in their patients. In particular, the article will focus on the side effects associated with the three currently approved targeted drugs: the anti- VEGF monoclonal antibody bevacizumab and the anti-EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix).
Abstract: Bevacizumab, the first approved vascular endothelial growth factor (VEGF)-targeted agent for metastatic colorectal cancer, continues to be developed in phase III trials in other tumor types. Its use is being explored not only in advanced disease, but also in earlier-stage disease in the adjuvant setting. Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other VEGF-targeted agents, including (1) dual inhibition of VEGF and platelet-derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature; (2) combining VEGF-targeted agents with other targeted agents, such as inhibitors of HER2 or epidermal growth factor receptor signaling, which affect several angiogenic pathways; and (3) combining VEGF-targeted agents with low-dose, metronomic chemotherapy. The optimal dose and schedule of VEGF-targeted agents is another unanswered question. Further investigation of the mechanism of action and vascular effects of VEGF-targeted agents in humans will help to address these questions. Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors, using imaging studies.
Abstract: BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after apparently curative operation. Apart from supportive measures, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the effect of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE and EMBASE up to February 2004 and reference lists of articles. We also contacted pharmaceutical companies as well as national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Chemotherapy versus best supportive care consistently demonstrated a significant benefit in terms of overall survival in favour of the group receiving chemotherapy (Hazard Ratios (HR) 0.39; 95% confidence intervals (CI) 0.28 to 0.52). Combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.85; 95% CI 0.76 to 0.96). Numbers included in these comparisons were 184 and 1338 participants respectively. This benefit is achieved at the price of increased toxicity in the combination chemotherapy arms. When comparing 5-FU/cisplatin-containing combination therapy regimens with anthracyclines versus those without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95 based on 501 participants) and 5-FU/anthracycline-containing combinations with cisplatin versus those without cisplatin (HR 0.83; 95% CI 0.76 to 0.91 based on 1147 participants), there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU, but the effect size is much smaller. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5-FU, anthracyclines and cisplatin. In this category, ECF (epirubicin, cisplatin and continuous infusion 5-FU) is tolerated best.
Abstract: In recent years, oxaliplatin-based chemotherapy protocols, particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX or FUFOX), have emerged as the standard of care in first- and second-line therapy of advanced-stage colorectal cancer. Although oxaliplatin by itself has only mild hematologic and gastrointestinal side effects, its clinically dominating toxicity affects the peripheral sensory nervous system in the form of 2 distinct types of neurotoxicity: (1) a unique, frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but at the same time is rapidly reversible without persistent impairment of sensory functions; (2) the dose-limiting toxicity of oxaliplatin, a cumulative, chronic sensory neurotoxicity that resembles that of cisplatin with the important difference of its being more rapidly and completely reversible. This chronic sensory neurotoxicity is highly predictable, being closely associated with the cumulative dose of oxaliplatin that is administered. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The stop-and-go concept uses the predictability and reversibility of neurologic symptoms to allow patients to stay on an oxaliplatin-containing first-line therapy for a prolonged period. Several neuromodulatory agents such as calcium-magnesium infusions; antiepileptic drugs like carbamazepine, gabapentin, and venlafaxine; amifostine; a-lipoic acid; and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatin-induced acute neuropathy. However, randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatin's cumulative neurotoxicity are still lacking. The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow patients and doctors to develop strategies to manage this side effect in view of the individual patient's clinical situation. This is of increasing importance, because the addition of bevacizumab to FOLFOX will conceivably further prolong the progression-free survival achieved with FOLFOX so that neurotoxicity and not tumor progression could become the dominating treatment-limiting issue in the first-line therapy of advanced colorectal cancer.
Abstract: AIMS: 1) to identify the treatment costs of different standard fluoropyrimidine-based therapies, i. e., the Mayo-Clinic and AIO/Ardalan regimens, under real-life conditions in settings routinely used for chemotherapy administration in Germany (inpatient, day-clinic or office-based oncologists) and 2) to investigate the cost implications of the routine use of capecitabine, an oral alternative for the treatment of metastatic colorectal cancer. METHODS: We analysed the actual fee-listings of office based oncologists and projected the results to several hospital-based treatment settings and to oral treatment with capecitabine from the perspective of statutory sickness funds. RESULTS: Office-based setting: the highest quarterly treatment costs of 9.874 were found for the AIO/Ardalan-regimen, followed by the Mayo-Clinic regimen, which incurred costs of 2.497. The cheapest treatment option was capecitabine with quarterly costs of 1.610. Day-clinic setting: the costs of the Mayo-Clinic protocol amounted to 2.036 in a municipal hospital and 8.455 in a university hospital. The respective costs for the AIO/Ardalan regime were 1.294 and 5.374. In-patient setting: the Mayo-Clinic protocol costs were 3.143 in a municipal hospital and 10.5609 in a university hospital. The respective costs found for the AIO/Ardalan-regimen were 1.998 and 6.717. CONCLUSION: From a health economic perspective, substantial cost savings for health insurance may be realised if patients with colorectal carcinoma were treated in the office-based setting with capecitabine instead of a hospital-based treatment. Economic consequences would be positive for municipal hospitals (avoided losses) and negative for university hospitals. Further savings could be realised if drug prices in hospital and retail pharmacies were harmonized.
Abstract: OBJECTIVES: To assess the antiemetic efficacy of an oral suspension of granisetron/dexamethasone in patients receiving chemotherapy and to determine whether quality-of-life parameters influence the risk for postchemotherapy nausea and vomiting (PCNV). PATIENTS AND METHODS: In an open monocentric study, an oral suspension containing 2 mg granisetron and 16 mg (4 mg for moderately emetogenic chemotherapy) dexamethasone was administered to 43 chemotherapy-naive patients before highly (n = 16) or moderately (n = 27) emetogenic chemotherapy and on the 3 subsequent days (2 for moderately emetogenic chemotherapy). Emetic episodes were recorded and quality of life was assessed prior to each cycle with a questionnaire based on EORTC QLQ-30. RESULTS: In the group undergoing highly (moderately) emetogenic chemotherapy, complete control of acute vomiting was achieved in 60-72.7% (92.6-95.0%), and complete control of delayed vomiting in 37.5-40.0% (75.0-92.2%), of patients within the first 3 (5) cycles. The following quality-of-life parameters were significantly associated with PCNV: tiredness (RR = 1.3, p < 0.05), pain (RR = 1.5), impairment of daily life by pain (RR = 1.7), sensation of abdominal pressure and fullness (RR = 2.5), impairment of social activities (RR = 2.9). CONCLUSIONS: Once-daily oral administration of a suspension of granisetron/dexamethasone is an active prophylaxis of nausea and vomiting and compares favorably with data reported on intravenous administration. Quality-of-life parameters assessed pre-treatment could help to identify patients at high risk for nausea and vomiting so that antiemetic therapy can be tailored to individual patient risk.
Abstract: This analysis compares the antiemetic efficacy of the 5-HT3-receptor antagonists granisetron and tropisetron in acute chemotherapy-induced nausea and vomiting (CINV). All published randomized studies comparing granisetron with tropisetron in conventionally-dosed, emetogenic chemotherapy are included in this pooled analysis. The target criterion for antiemetic success was 'acute complete response' (complete absence of vomiting in the 24 h after the start of chemotherapy) and the rate of successful treatment reported as 'response rate' (acute complete response rate per patient). Twelve studies were used comprising 810 patients. Comparison between granisetron and tropisetron in patients receiving cisplatin-based therapy showed superiority of granisetron (odds ratio above 1.0) in six out of seven studies. However, this difference did not reach statistical significance. In patients receiving noncisplatin-based therapies, four out of five studies showed an advantage of granisetron over tropisetron with one study showing a significant advantage. Pooled analysis of all studies demonstrated a significant overall advantage for granisetron over tropisetron (p=0.042). This is supported by the individual studies: overall, ten out of the 12 studies analyzed showed an advantage for granisetron, with a 6.4% difference in response rate. This advantage was more pronounced in noncisplatin-based therapy (7.3%), whereas in cisplatin-based therapy, the difference was 5.4%. The overall results of this pooled analysis of cisplatin and noncisplatin-based studies suggest that granisetron has a marginal but clinically potentially relevant statistically significant advantage in efficacy over tropisetron for the control of acute CINV.
Abstract: Lymphomatoid granulomatosis is a rare Epstein-Barr virus (EBV)-positive-B-cell lymphoproliferative disorder. Treatment options include corticosteroids, antiviral therapy, interferon-alpha and chemotherapy. However, long-term prognosis is poor and no therapeutic standard has been established yet. In a 21-year-old woman, a biopsy of mediastinal mass revealed lymphomatoid granulomatosis. Combined therapy with valganciclovir and interferon-alpha proved ineffective. In view of the CD20 expression of the tumor cells, monotherapy with rituximab was intiated. After 3 months a complete remission was achieved. Rituximab was continued for another 6 months with subsequent consolidation radiotherapy. This is the first report of an enduring complete remission (20 months) of a non-CNS lymphomatoid granulomatosis treated with rituximab.
Abstract: BACKGROUND: Long-term survival is reported in patients with liver metastases of colorectal cancer. Recently, an increased number of reports on liver resection following neoadjuvant chemotherapy in patients with initially unresectable liver metastases has been published. METHODS: We analysed all published or presented trials and retrospective studies that report the rate of objective response and the rate of resection of initially unresectable metastases to correlate objective response and the rate of resection of metastases. RESULTS: In studies that enrolled patients with metastases confined to the liver, 24-54% of patients were resected following chemotherapy, compared to 1-26% of patients in trials that included non-selected patients with metastatic colorectal cancer. A strong correlation was found between response rates and the resection rate in studies with patients with isolated liver metastases (r = 0.96, P=0.002). Likewise, in studies with non-selected patients, the resection rate of metastases also was associated with the objective response rate (r = 0.74, P <0.001). CONCLUSIONS: Patient selection and efficacy of pre-operative chemotherapy are both strong predictors for resectability of liver metastases. Resectability is a novel endpoint focusing on the curative potential of treatment compared with classical endpoints of response or progression-free survival that are important if palliation is the aim. Therefore, patients with potentially resectable liver metastases should be investigated in special trials and interdisciplinary teams.
Abstract: PURPOSE: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.
Abstract: In the past several years, significant advances in the treatment of colorectal cancer (CRC) have been made. With the introduction of irinotecan and oxaliplatin combined with infusional 5-fluororuracil, survival times for patients with metastatic CRC have nearly doubled. With the incorporation of biologic agents that target the vascular endothelial growth factor and epidermal growth factor (EGF) pathways, additional improvements in response, progression-free survival, and overall survival have been seen in patients with advanced, metastatic disease. This article reviews the impact of EGF receptor inhibitors on improving survival in CRC when combined with oxaliplatin-containing regimens.
Abstract: Traditionally, anatomic staging systems have been used to determine predictions of individual patient outcome and, to a lesser extent, guide the choice of treatment in patients with cancer. With new targeted therapies, the role of biomarkers is increasingly promising, suggesting an integrated approach using the genetic make-up of the tumor and the genotype of the patient for treatment selection and patient management. Specifically, biomarkers can aid in patient stratification (risk assessment), treatment response identification (surrogate markers), or in differential diagnosis (identifying individuals who are likely to respond to specific drugs). To be clinically useful, a marker must favorably affect clinical outcomes such as decreased toxicity, increased overall and/or disease-free survival, or improved quality of life. This paper focuses on possible clinical trial designs for assessing the utility of a predictive marker(s) for toxicity or clinical efficacy. We consider the scenario of single and multiple markers as well as present alternative solutions based on the prevalence of a marker. Our designs rest on the assumption that the methods for assessment of the biomarker are established and the initial results show promise with regard to the predictive ability of a marker. Additional research is clearly warranted to achieve the goal of 'predictive oncology'.
Abstract: PURPOSE: Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. MATERIALS AND METHODS: We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. RESULTS: The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P =.0008) but not with the percentage of patients who received any second-line therapy (P =.19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P =.0083). CONCLUSION: Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.
Abstract: Combination protocols of 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan or oxaliplatin have demonstrated high activity in metastatic colorectal cancer. Capecitabine, an oral 5-FU prodrug, may replace infusional 5-FU/LV in combination protocols with irinotecan or oxaliplatin. We therefore initiated a phase II study with capecitabine plus either irinotecan or oxaliplatin to determine the efficacy and toxicity of specific combination protocols in patients with advanced gastrointestinal (GI) tumors. Capecitabine 1000 mg/m(2) taken orally twice a day on days 1-14, plus oxaliplatin 70 mg/m(2) on days 1 and 8, or irinotecan 100 mg/m(2) on days 1 and 8; repeated every 3 weeks in an outpatient setting. Patient and tumor characteristics were as follows: median age, 68 years (range, 34-77 years); sex: 10 women, 33 men; tumor types: 35 colorectal cancer; 8 other GI tumors including 5 gastric, 2 pancreatic, and 1 duodenal cancer. All 43 patients treated were evaluable for toxicity (capecitabine/oxaliplatin, 24 patients; capecitabine/irinotecan, 19 patients), and 39 were evaluable for efficacy (capecitabine/oxaliplatin, 22; capecitabine/irinotecan, 17). Grade 3/4 toxicities (National Cancer Institute Common Toxicity Criteria Version 2.0) were limited to diarrhea, 9 patients (capecitabine/irinotecan, n = 5; capecitabine/oxaliplatin, n = 4); hand-foot syndrome, 1 patient (capecitabine/irinotecan); nausea, 2 patients (capecitabine/oxaliplatin); vomiting, 1 patient (capecitabine/oxaliplatin); and peripheral neuropathy, 1 patient (capecitabine/oxaliplatin). No grade 3/4 myelosuppression was noted for either protocol. Capecitabine/irinotecan and capecitabine/oxaliplatin demonstrated significant clinical activity in colorectal cancer and other GI cancers as first-line and salvage therapy. Capecitabine/oxaliplatin and capecitabine/irinotecan show an excellent safety profile and clinical activity in colorectal cancer and other advanced GI tumors. The main toxicity in both arms was manageable diarrhea. This trial served as basis for a randomized multicenter phase II study comparing capecitabine/oxaliplatin and capecitabine/irinotecan as first-line therapy in patients with advanced colorectal cancer.
Abstract: The medical treatment of colorectal cancer (CRC) has rapidly evolved in recent years with the introduction of novel cytotoxic drugs into clinical practice such as irinotecan, oxaliplatin, and capecitabine. Combination regimens using infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus either oxaliplatin or irinotecan have demonstrated clinically meaningful, high efficacy in advanced CRC. Based on the results of the Intergroup trial N9741, FOLFOX4, a combination of infusional plus bolus 5-FU/LV and oxaliplatin, has emerged as the standard first-line therapy in the palliative setting. However, infusional 5-FU-based regimens carry the need for use of central venous lines and implantable ports to allow treatment on an outpatient basis and are thus inconvenient and expensive. The use of oral fluoropyrimidines (capecitabine or uracil/tegafur [UFT] plus LV) as substitutes for infusional 5-FU in combination protocols with oxaliplatin offers greater convenience, at the same time conceivably maintaining the high efficacy and tolerability observed with intravenous protocols. Various phase I/II trials have recently been reported that investigated oxaliplatin in combination with either capecitabine or UFT/LV in patients with advanced CRC. This review will detail the results of these trials focused on capecitabine-based combinations.
Abstract: As capecitabine (Xeloda) is converted to 5-FU within tumours it can produce 5-FU-like side effects. However, diarrhoea, stomatitis, nausea, alopecia and neutropenia are significantly less frequent than with i.v. 5-FU. Hand-foot syndrome (HFS) is the only clinical adverse event occurring more often during capecitabine treatment. These findings in MCRC have also been confirmed in a large phase III trial in early stage colon cancer (X-Act adjuvant study) and phase II clinical trials in metastatic breast cancer. Because capecitabine is taken in the outpatient setting, the nurse and/or supervising clinician are responsible for educating patients how to use it correctly and on the nature/recognition/severity of adverse events. Patients need to be aware that temporary interruptions/dose modifications do not reduce the overall efficacy of capecitabine and will most likely lead to a resolution of side effects. Consequently, oncology nurses will be assuming a more significant and pivotal role in the efficient education and support of patients during home-based therapy with capecitabine.
Abstract: The objective of this study was to evaluate the cost implications of different settings (inpatient, outpatient/day clinic, or office-based oncologists) for the administration of standard fluoropyrimidine therapies, i.e., Mayo Clinic and Arbeitsgemeinschaft Internistische Onkologie (AIO)/Ardalan regimen, and to compare the results with the cost of oral capecitabine in Germany. In total, 89 quarterly fee-listings from 26 patients provided by 5 office-based oncologists were analyzed. Physician's services, drug costs, pharmacy costs, and costs for implantable venous port systems and single-use pumps were considered. Findings were transferred to the hospital setting. A third-party payer perspective was applied. Quarterly treatment costs for the Mayo Clinic regimen varied between <euro> 2,036 and <euro> 10,569, and between <euro> 1,294 and <euro> 10,179 for the AIO/Ardalan regimen depending on the treatment setting. Projected costs for capecitabine were <euro> 2,338. No hospitalization was considered to be necessary for capecitabine due to its oral administration route. The most expensive treatment options were the AIO/Ardalan protocol in the office-based setting and the Mayo Clinic protocol in the hospital setting. Capecitabine emerged as the cheapest option in the office-based setting. Overall, the cheapest option was the AIO/Ardalan protocol in municipal hospitals. However, municipal hospitals are unlikely to cover their costs in this situation. Substantial cost savings without incurring losses to providers may be realized if patients are transferred from the hospital setting to the office-based setting and treated with capecitabine.
Abstract: Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.
Abstract: In the last 5 years, major advances have occurred in the treatment of colorectal cancer. Following a period of over 30 years in which 5-fluorouracil was the only proven treatment for colorectal cancer, survival for patients with metastatic colorectal cancer has nearly doubled following the introduction of irinotecan (Campto, Aventis) and oxaliplatin (Eloxatin, Sanofi-Synthelabo). Furthermore, recent studies have demonstrated additional improvements in response and survival when combination chemotherapy drugs are administered with biologic agents that target angiogenesis and tumor growth pathways. The benefit of these newer drugs is now being realized in the adjuvant setting, where the addition of oxaliplatin to infusional 5-fluorouracil/leucovrin has led to improvements in disease-free survival. Further adjuvant studies are testing the benefit of the addition of biologic therapies to oxaliplatin and irinotecan-based combination chemotherapy.
Abstract: Testicular germ cell cancer is one of the very few cancers that are highly sensitive to and curable by cisplatin-based chemotherapy even in an advanced stage. However, in a few cases resistance to cisplatin occurs and patients subsequently die from progressive disease. The molecular basis for this resistance remains to be determined. Using two cisplatin-sensitive (2102EP and H12.1) and one cisplatin-resistant human testicular germ cell cancer cell line (1411HP), we investigated molecular mechanisms in the induction of apoptosis after cisplatin-treatment focusing on the cleavage and activation of caspase-2, caspase-3, caspase-7, caspase-8, and caspase-9. The cell line 1411HP showed a 3.3-fold cisplatin resistance when compared with the sensitive cell lines 2102EP and H12.1 by IC(90)s, which was treatment schedule independent (2- or 24-h incubation). Cisplatin resistance was associated with substantially decreased apoptosis in vitro and in derived nude mice xenografts as determined by Apo 2.7 detection, DNA-laddering, immunohistochemistry of active caspase-3, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Total DNA platination as assessed by ELISA after cisplatin treatment in equimolar doses did not differ between cisplatin-resistant or -sensitive cells. In separate analysis of cells of early and late apoptotic stages, initiation of cisplatin-induced apoptosis appeared to be rather mediated by caspase-9 than by caspase-8. Resistant 1411HP cells failed to activate caspase-9 during the induction of apoptosis after cisplatin treatment at the IC(90) dose. Interestingly, inhibition of caspase-9 in sensitive H12.1 almost completely blocked apoptosis and induced cisplatin resistance to the same extent as in 1411HP so that apoptosis could only be induced by 3.3-fold higher cisplatin doses. Furthermore, in caspase-9 blocked cells, initiation of apoptosis occurred in a caspase-9 independent manner accompanied by activation of caspase-2 and caspase-3, which are intrinsic characteristics of resistant 1411HP cells. Failure of caspase-9 activation and cisplatin resistance was independent of the expression of p53, Bcl-2 family proteins, Fas receptor, and Fas ligand. In conclusion, failure of activation of the caspase-9 pathway induces a higher cellular threshold for cisplatin-mediated induction of apoptosis in testicular cancer cells. However, this higher threshold can be overcome by higher cisplatin doses, conceivably by using an alternate, caspase-9-independent apoptotic pathway. This supports the current clinical strategy of high-dose chemotherapy in patients with chemorefractory germ cell tumors. However, additional defining and eventually targeting the exact molecular mechanism blocking caspase-9 activation might lead to more selective therapeutic approaches to overcome cisplatin resistance in germ cell cancer.
Abstract: Oxaliplatin has become an integral part of various chemotherapy protocols, and in advanced colorectal cancer in particular. While oxaliplatin has only mild hematologic and gastrointestinal side effects, its dose-limiting toxicity is a cumulative sensory neurotoxicity that resembles that of cisplatin with the important difference of a more rapid and complete reversibility. The reversibility of neurotoxicity has been assured in long-term follow-up of patients who have received adjuvant oxaliplatin-based chemotherapy. In addition, oxaliplatin causes a very unique, but frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but is rapidly reversible, without persistent impairment of sensory function. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The "Stop-and-Go" concept uses the reversibility of neurologic symptoms to aim at delivering higher cumulative oxaliplatin doses as long as the therapy is still effective. Several neuromodulatory agents such as calcium-magnesium infusions, antiepileptic drugs like carbamazepine or gabapentin, amifostine, alpha-lipoic acid, and glutathione have shown promising activity in prophylaxis and treatment of oxaliplatin-induced neurotoxicity. However, larger confirmatory trials are still lacking so that, to date, no evidence-based recommendation can be given for the prophylaxis of oxaliplatin-induced neurotoxicity. The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow patients and doctors to develop strategies to manage this side effect in view of the individual patient's clinical situation.
Abstract: BACKGROUND: Adjuvant chemotherapy for patients with UICC III (Dukes C) colorectal cancer (consensus statements NIH 1990, German Cancer Society 1994) and palliative chemotherapy for metastatic disease have long been recognized to provide a survival benefit in colorectal cancer. However, it remains unclear if these concepts have made inroads into clinical practice. PATIENTS AND METHODS: Therefore, we asked 74 institutions treating colorectal cancer patients in Germany to document the treatment algorithms of all patients with colorectal cancer seen in the third quarter of 1998. Clinical careers of 1,001 patients (m/f 465/536; median age 62.9 years [28-93]; colon 596, rectum 405; UICC I 117, II 206, III 407, IV 218) were documented. RESULTS: Only 63.4% of patients with UICC III colorectal cancer received adjuvant therapy with a significant difference between hospitals with (67.1%) and without (42.6%) oncological departments (p < 0.01). Higher age appeared to be the most important factor for withholding treatment since 196 of 286 (68.5%) patients < 70 years, but only 57 of 121 (47.1%) > 70 years underwent adjuvant therapy. 78.4% of patients with UICC IV colorectal cancer (91.8% university hospitals, 76.8% hospital with, 50% without oncological departments, 66.7% rehabilitation clinics, 82.4% private practices) received palliative chemotherapy (first line: 5-FU/FA bolus 57%, 5-FU/FA infusion 20%, 5-FU mono 15%). CONCLUSION: Considering an annual incidence of colorectal cancer in Germany of 52,000 with 30% UICC III, discounting patients > 80 years or ECOG status > 2, and estimating a survival benefit of 10% after adjuvant chemotherapy, approximately 530 lifes are lost annually in Germany due to insufficient treatment of UICC III colorectal cancer based on our survey. In addition, substantial financial demand is generated by the subsequent palliative treatment of potentially curable patients.--In conclusion, survey-based analysis of treatment algorithms can provide valuable insights into clinical practice in oncology and can disclose deficits in patient care as demonstrated here in colorectal cancer.
Abstract: INTRODUCTION: In patients with advanced colorectal cancer (CRC) refractory to systemic chemotherapy including 5-fluorouracil (5-FU) / folinic acid (FA), oxaliplatin and irinotecan we assessed the feasibility, toxicity and response to hepatic transcatheter arterial chemoembolization (TACE). At the time of treatment, patients had exclusively or dominantly liver metastasis of CRC. PATIENTS AND METHODS: The following protocol was applied via a selective transfemoral hepatic arterial approach: mitomycin C 5 mg/m(2), interferon-alpha2b 4.5 Mio IU, dexamethasone 20 mg mixed with Amilomer DSM 45/25 (Spherex((R))) days 1 and 2 i.a. (bolus), oxaliplatin 50 mg/m(2) (2 h) day 1 i.a., FA 500 mg/m(2) (2 h) day 1 i.v., and 5-FU 1.500 mg/m(2) (24 h) day 1 i.a. Cycles have been repeated at days 15-22. The dose was adjusted according to the pretreatment performance status and elevation of alkaline phosphatase, bilirubin and serum albumin. Treatment was continued until progression or emergence of intolerable toxicity. RESULTS: 11 patients received a total number of 43 TACE, with a range of 2-6 per patient. There was no TACE-related mortality. 4 patients died 5, 8, 10 and 11 months after initiation of treatment due to progression of disease. 7 patients are alive at 4+ (n = 2), 5+ (n = 1), 6+ (n = 1), 7+ (n = 1) and 11+ (n = 2) months after start of treatment. Toxicity (CTC) was mild with grade I-II asthenia (n = 10), grade I-II neurotoxicity (n = 5), grade II nausea and/or vomiting (n = 2) and grade II diarrhea (n = 1). Treatment had to be postponed due to grade I thrombocytopenia in 2 patients. No bleeding episodes or obvious infectious complications occurred during treatment intervals. 1 patient experienced an allergic reaction to oxaliplatin which led to exclusion from further therapy. Arterial catheter dislocation occurred in 3 patients. In 10 patients evaluable for response we observed 3 partial responses, 2 minor responses, and 4 times stable disease. Only 1 patient had further progression of disease under treatment. CONCLUSION: TACE, using a combination of mitomycin C, dexamethasone and interferon-alpha2b mixed with Spherex((R)), followed by oxaliplatin, FA and 5-FU, appears to be an effective and feasible treatment option in the case of liver metastasis of CRC refractory to standard systemic chemotherapy. This treatment is associated with tolerable toxicity, which becomes apparent mainly as asthenia, neurotoxicity or thrombocytopenia. These preliminary data warrant further evaluation for patients with refractory disease and would probably also be of interest for first-line treatment in this patient population.
Abstract: BACKGROUND: Colorectal cancer is usually diagnosed in patients around 70 years of age. With a continuous increase in life expectancy we may expect a higher number of elderly patients in the future. Because patients above 70 or 75 years are often excluded there is uncertainty as to what extent systemic adjuvant and palliative treatment should be offered to elderly patients. METHODS: We reviewed the available literature on adjuvant and metastatic colorectal cancer in order to identify reports on elderly patients treated within chemotherapy trials. RESULTS: Only about 20% of patients entering clinical trials belong to the age group of over 70 years and represent the minority of the very fit patients. Compared to their younger counterparts 5-FU-based treatment appears to be equally effective and more toxic according to some reports. Data regarding raltitrexed, oral fluoropyrimidines, topoisomerase I inhibitors or DACH-platin derivates are limited but suggest no age-specific differences in activity or toxicity. CONCLUSIONS: Elderly patients should not be excluded from clinical trials and studies in unfit elderly patients are warranted. Elderly patients need more attention regarding their functional, social and mental status. Fit elderly patients should be offered adjuvant or palliative chemotherapy.
Abstract: PURPOSE: Mucosal inflammation in the small intestine is a potentially hazardous side effect of abdominal irradiation. In an effort to develop a quantitative method of evaluating mucosal damage, the luminal release of brush border enzymes in response to ionizing radiation was examined using two investigational strategies. METHODS: First, a 20 cm segment of the proximal jejunum was perfused in situ and enzymatic activities within the perfusates were evaluated. In a second approach, enzymatic activities were directly evaluated in isolated brush border membranes from the jejunal mucosa. RESULTS: Most of the peptidase activities measured were increased in the perfusates 1 day after irradiation and had returned to control levels at 4 days. In the brush border membranes, some enzyme activities decreased at 1 day and were, with the exception of leucineaminopeptidase (LAP), similar to control levels at 4 days. CONCLUSIONS: LAP is more strongly affected by radiation than the transmembranously bounded enzymes.
Abstract: Colorectal cancer is one of the leading causes of cancer deaths in the Western world, with approximately 50% of all patients dying from metastatic disease. Until recently, therapeutic options for advanced colorectal cancer were mainly confined to chemotherapy with 5-fluorouracil in various schedules, with or without biochemical modulation with leucovorin. The development of new cytotoxic drugs with substantial activity in this tumor during the past 2 years has dramatically changed treatment strategies and therapeutic goals in metastatic colorectal cancer and has introduced neoadjuvant chemotherapy followed by secondary surgery with the intent of long-term survival. Among these new drugs, oral fluoropyrimidines (tegafur/uracil and capecitabine), irinotecan, and oxaliplatin have already established themselves as part of various treatment approaches. Other novel therapeutics including agents designed to act on molecular targets already show promising activity and will become part of combination protocols with current standard chemotherapy.
Abstract: Epidemiologic studies have documented a 40-50% reduction in incidence of colorectal cancer in individuals taking nonsteroidal antiinflammatory drugs (NSAIDs). Since NSAIDs are known to inhibit cyclooxygenases (COX-1, COX-2), the basic mechanism of their antitumor effects is conceivably the altered metabolism of arachidonic acid and, subsequently, prostaglandins (PGs). Although COX-2, the inducible isoform, is regularly expressed at low levels in colonic mucosa, its activity increases dramatically following mutation of the APC (adenomatous polyposis coli) gene suggesting that beta-catenin/T-cell factor mediated Wnt-signaling activity may regulate COX-2 gene expression. In addition, hypoxic conditions and sodium butyrate exposure may also contribute to COX-2 gene transcription in human cancers. The development of selective COX-2 inhibitors has made it possible to further evaluate the role of COX-2 activity in colorectal carcinogenesis. To date, at least five mechanisms by which COX-2 contributes to tumorigenesis and the malignant phenotype of tumor cells have been identified, including: (1) inhibition of apoptosis; (2) increased angiogenesis; (3) increased invasiveness; (4) modulation of inflammation/immuno-suppression; and (5) conversion of procarcinogens to carcinogens. A clear positive correlation between COX-2 expression and inhibition of apoptosis has been established, associated with increased PGE2 levels resulting in modulation of pro- and anti-apoptotic factors (e.g., bcl-2, MAKs/ras, caspase-3, Par-4). In terms of angiogenesis and invasiveness, COX-2 activity was found to increase the expression of growth factors (e.g., VDEG, PDGF, bFGF) and matrix metalloproteinases (MMPs). Since COX-2 inhibitors have been demonstrated to interfere with tumorigenesis and apoptosis, COX-2 and its gene product may be attractive targets for therapeutic and chemoprotective strategies in colorectal cancer patients. This may lead to new perspectives that by controlling the cancer phenotype, rather than attempting to eradicate all affected cells, may provide significant benefits to the cancer patient.
Abstract: Cisplatin is among the most widely used broadly active cytotoxic anticancer drugs; however, its clinical efficacy is often limited by primary or the development of secondary resistance. Several mechanisms have been implicated in cisplatin resistance, including reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. More recently, additional pathways have been characterized indicating that altered expression of oncogenes that subsequently limit the formation of cisplatin-DNA adducts and activate anti-apoptotic pathways may also contribute to the resistance phenotype. Several lines of evidence suggest that expression of ras oncogenes can confer resistance to cisplatin by reducing drug uptake and increasing DNA repair; however, this is not a uniform finding. Tumor cells, in contrast to normal cells, respond to cisplatin exposure with transient gene expression to protect or repair their chromosomes. The c-fos/AP-1 complex, a master switch for turning on other genes in response to DNA-damaging agents, has been shown to play a major role in cisplatin resistance. In addition, AP-2 transcription factors, modulated by protein kinase A, are also implicated in cisplatin resistance by regulating genes encoding for DNA polymerase beta and metallothionines. Furthermore, considerable evidence indicates that mutated p53 plays a significant role in the development of cisplatin resistance since several genes implicated in drug resistance and apoptosis (e.g. mismatch repair, bcl-2, high mobility group proteins, DNA polymerases alpha and beta, PCNA, and insulin-like growth factor) are known to be regulated by the p53 oncoprotein. Improved understanding of molecular factors for the development of cisplatin resistance may allow the prediction of clinical response to cisplatin-based treatment. Furthermore, the identification of oncogenes involved in cisplatin resistance has already led to in vitro approaches which successfully inactivated these genes using ribozymes or antisense oligodeoxynucleotides, thus restoring cisplatin sensitivity. It is conceivable that these strategies, once transferred to a clinical setting, may have the potential to enhance the efficacy of cisplatin against a great variety of malignancies and thus more fully exploit the antineoplastic and curative potential of this drug.
Abstract: BACKGROUND: A prospective study was conducted to determine whether patients with larger breasts show larger tumors. MATERIALS AND METHODS: 123 patients with primary breast cancer were evaluated (median follow-up 36 months). Breast size was determined as a reflection of cup size. RESULTS: Cup size correlated with tumor diameter at diagnosis (p = 0.0038). On average, cup sizes were larger in postmenopausal than in premenopausal women (p = 0.0011), however, postmenopausal women did not show larger tumors than premenopausal. There was a significant positive correlation between body mass index, body weight and breast size (p < 0.0001). The mode of tumor detection (self vs. not self) was independent of breast size. No correlation was found between breast size and the patient's height, duration of breast feeding, smoking behavior or amount of alcohol consumption, hormone replacement therapy or use of oral contraceptives, number of involved lymph nodes or DFS and OS. CONCLUSION: Patients with larger breasts showed larger tumors. The mode of tumor detection is independent of breast size.
Abstract: Anaplastic thyroid carcinoma (ATC) affects primarily elderly patients, with a median survival of 4-12 months after diagnosis. Presently, under clinical investigation the combination of cisplatin (CDDP) and gemcitabine (GEM) has promising activity in several of human tumor types. To develop new approaches for therapy of ATC, we evaluated the antineoplastic activity of GEM and CDDP alone (1-h and 24-h drug exposure) or in combination in the ATC cell lines SW1736, 8505C, C643, and HTh74. IC50 values were determined by the sulforhodamine B assay, activity was evaluated by the relative antitumor activity (RAA) and drug interaction assessed by isobologram analysis. GEM seemed to be active in ATC, with RAA ranging from 12-114 and CDDP only modestly active (RAA, 0.24-1.4). In four different drug schedules tested, the drug combination was additive when GEM preceded CDDP exposure (combination index, approximately 1), whereas when CDDP preceded GEM exposure the combination was significantly antagonistic (combination index, >1). In SW1736 and 8505C cells, we observed a strong S phase arrest and DNA synthesis inhibition 24 h after a 1-h exposure to an IC50 of CDDP. On the basis of molecular drug targets, cell cycle arrest points, and DNA synthesis inhibition, a model was developed to explain the interaction observed for the combination of GEM and CDDP. In conclusion, GEM shows promising cytostatic activity in ATC. Interaction of GEM and CDDP was schedule and dose dependent, favoring a regime in which GEM is followed by CDDP. Additionally, our model system suggests that DNA-synthesis inhibition and S phase arrest may be important determinants for the drug interaction between GEM and CDDP.
Abstract: Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage stimulating factor (GM-CSF) are currently licensed for use in cancer patients and play a significant role in the management of anemia and neutropenia following myeloblative chemotherapy. EPO was the first recombinant hematopoietic growth factor to be used clinically after a number of clinical trials which demonstrated its effectiveness in treating mild to moderate cancer-associated anemia with or without concomitant chemotherapy (particulary cisplatin). An extensive research has been made for the improvement of the quality of life with EPO therapy, however, when formally assessed, variable effects of this important treatment have been observed. Recently, EPO has been shown to significantly accelerate hematopoietic reconstitution after peripheral blood stem cell transplantation (PBSCT) resulting in reduced infection rates. Both, G-CSF and GM-CSF have been shown, in numerous trials, to shorten the period of chemotherapy-induced neutropenia, with reduction in attendant morbidity and to mobilize PBSC. In addition, administration of both cytokines after PBSCT significantly reduced the use of antibiotics and duration of hospitalization suggesting an economic benefit. The narrower therapeutic window of GM-CSF at higher doses accounts for the fact that it is used much less frequently than G-CSF. To date, none of the growth factors used clinically has been shown to stimulate thrombopoiesis. Although thrombopoietin (TPO) has been found to induce megakaryocyte differentiation in vitro, it is unlikely to enter routine clinical use for treatment of post-chemotherapy thrombocytopenia, since results of clinical trials are not very encouraging, mainly because TPO is difficult to schedule and platelet aggregation may occur. Recently, innovative chimeric growth factor receptor agonists have been synthesized. Synthokine (SC-55494) (a high-affinity human IL-3 receptor ligand analog), myelopoietin (MPO) (activates human IL-3 and G-CSF receptors) and promegapoietin (PMP) (stimulates the human IL-3 and c-mpl receptors) were found to be multilineage hematopoietic growth factors and are currently undergoing clinical trials. Preliminary results suggest that these compounds may have a major impact on the management of myeloablative chemotherapy because of their ability to enhance platelet recovery in addition to their neutrophil restorative activity.
Abstract: Loss of hormone receptor (HR) status in breast carcinomas is associated with increased tumour cell motility and invasiveness. In an immunohistological study of 58 primary breast cancers, oestrogen (ER) and progesterone (PR) receptor levels were inversely correlated with the expression of fascin, an actin-bundling protein associated with cell motility (P< 0.0001 and P = 0.0019, respectively). In addition, fascin was preferentially expressed in non-diploid tumours (P = 0.03). In summary, the upregulation of fascin in HR-negative breast cancers may contribute to their more aggressive behaviour.
Abstract: The over-expression of c-erbB-2/ HER-2, a receptor tyrosine kinase, correlates with poor prognosis in patients with breast and ovarian cancer. In the human breast cancer cell line, MDA-MB-435, c-erbB-2 over-expression results in increased chemoinvasion and higher metastatic properties in nude mice. However, the mechanisms by which c-erbB-2 increases the malignant potential of cells remains unclear. We have determined that over-expression of c-erbB-2 in MDA-MB-435 cells, and in some additional breast cancer cell lines, is associated with graphic increases in mRNA and protein levels of the actin bundling protein fascin. Heightened fascin expression has been observed in other systems to result in greatly increased cell motility, and indeed, our work employing semi-automated time-lapse microscopy demonstrates that MDA-MB-435 cells over-expressing c-erbB-2 exhibit significantly heightened cellular dynamics and locomotion, while visualization of bundled microfilaments within fixed cells revealed enhanced formation of dendritic-like processes, microspikes and other dynamic actin based structures. To address the means by which c-erbB-2 over-expression might result in elevated fascin levels, we identified multiple perfect match TCF and NF-kappaB consensus sites in fascin's promoter and first intron, which appeared consistent with the greater endogenous transcriptional activities of TCF and NF-kappaB in c-erbB-2 over-expressing MDA-MB-435 cells. While such transcriptional modulation may occur in the context of the intact gene/chromatin, subsequent tests using reporter constructs did not support involvement of these signaling pathways. In conclusion, highly increased fascin levels were observed in MDA-MB-435 over-expressing c-erbB-2, likely contributing to these cells' altered actin dynamics, and increased cell motility and malignancy. Studies in progress aim to discern the means by which c-erbB-2 over-expression leads to transcriptional activation of the fascin gene.
Abstract: This study examined the relationship between the expression of E-cadherin or beta-catenin in murine adenocarcinomas and their hematogenous metastatic propensity, assessed by both spontaneous and artificial lung metastasis. Seven different carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4, MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and their cells greatly differ in their ability to form artificial lung nodules when injected i.v. Primary tumors in the leg were assessed for E-cadherin and beta-catenin expression by western blotting. The expression of both proteins showed wide variation among the tumors; however, the expression of E-cadherin correlated well with that of beta-catenin. There was significant inverse correlation between the expression of E-cadherin, as well as beta-catenin, and the incidence of both spontaneous and artificial lung metastases from these tumors. Spontaneous metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were significantly lower in E-cadherin and beta-catenin expression than their corresponding primary tumors were. Thus, the propensity of murine carcinomas for hematogenous spread is highly related to E-cadherin and beta-catenin levels in primary tumors. The inverse correlation between the expression of these molecules and spontaneous and artificial metastases implies that tumor cells with low E-cadherin and beta-catenin content have increased ability to enter the vascular circulation at the primary tumor site and to colonize distant tissues.
Abstract: For nearly four decades, 5-fluorouracil (5-FU) has been the mainstay of treatment for colorectal cancer. Due to the lack of other agents with significant activity, tremendous efforts have been undertaken to increase the efficacy of 5-FU by investigating alternative schedules of delivery and biomodulation. However, bolus 5-FU in combination with folinic acid (FA), either as the Mayo Clinic or Roswell Park protocol, still represents the standard treatment for adjuvant and first-line palliative chemotherapy of colorectal cancer. In a recent meta-analysis, infusional protocols of 5-FU demonstrated increased response rates (14% to 22%) and a marginal, but significant survival benefit of 3 weeks (11.3 to 12.1 months). In view of the much higher costs and complicated management of infusional 5-FU regimens, this marginal survival benefit does not yet allow protracted 5-FU application to be defined as standard therapy. However, protracted 5-FU infusion in combination with radiation can be considered standard therapy as adjuvant treatment of rectal cancer, since it has demonstrated a significant increase in survival. In the future, oral 5-FU prodrugs may be substituted for infusional 5-FU. Furthermore, current data indicate that 5-FU will also be an essential component of combination chemotherapy protocols with the new active agents oxaliplatin, irinotecan, and raltitrexed. Preclinical studies show synergistic antitumor activity of 5-FU with these agents, which corresponds well with clinical response rates of 50% in untreated and 15% to 25% in 5-FU-refractory patients. Moreover, 5-FU-based pro-drug-active drug systems serve as excellent models for tumor-targeted gene therapy.
Abstract: Insulin-like growth factor I (IGF-I) exerts pleiotropic effects on mammalian cells via stimulation of its receptor (IGF-IR), a receptor tyrosine kinase. In vivo, IGF-I acts both as a local tissue growth factor and as a circulating hormone. In oncological research, IGF-I has received increased attention as the activated IGF-I/IGF-IR system displays mitogeneic, transforming, and anti-apoptotic properties in various cell types by stimulating distinct intracellular signaling pathways. Recent data suggest that the anti-apoptotic effect of IGF-I may mediate decreased sensitivity to chemotherapeutic drugs in vitro and in vivo. Thus, targeting the IGF-I/IGF-IR system could serve as an approach to overcome clinical drug resistance in certain tumors.
Abstract: BACKGROUND: Superior vena cava syndrome (SVCS) is the clinical expression of obstruction of blood flow through the superior caval vein. In more than 80% of patients this complication is due to a malignant tumor, and in 60% of cases the first symptom of this tumor. DIAGNOSIS AND TREATMENT: If the clinical course of SVCS represents an absolute emergency, irradiation may have to be started immediately, even before the histologic diagnosis is established. Alternatively, expandable metallic stents have been used with considerable success for treatment of vena caval obstruction since patients respond immediately after stent implantation. For diagnosis, a chest X-ray and a CT scan should be performed. Chemotherapy is the treatment of choice for high-grade lymphomas, germ cell tumors and small-cell lung cancer since this modality is more effective than radiotherapy (response rate: 80%). For less chemotherapy responsive tumors radiotherapy is the primary treatment. Successful experience with thrombolytic agents is limited to treatment of catheter-induced SVCS, in contrast, only 20% of patients respond to thrombolytic therapy in the absence of a central catheter. Surgical resection of SVCS associated tumors has not improved survival rates and should be avoided.
Abstract: Cisplatin is one of the most active and widely used anticancer drugs; however, its clinical efficiacy is often limited by the development of resistance. Since several studies indicated that ras oncogenes may modulate the cellular response to cisplatin or radiation, we investigated the gene-specific repair of the N-ras gene in the human K 562 cell line after exposure to cisplatin using a novel nonradioactive polymerase chain reaction inhibition assay. This assay is based on the fact that DNA lesions can block the Taq polymerase and thereby result in a decreased amplification of a damaged segment compared to the amplification of the same segment in a non-damaged template. The overall genomic repair rate was measured by atomic absorption spectroscopy. Immediately after cisplatin exposure no amplification segment was observed. However, a complete restoration of the N-ras gene (2.4 kb) was seen after 8 h posttreatment incubation. In contrast, only 60% of the overall genome was repaired at this time. Our results clearly indicate that cisplatin-induced DNA lesions are more efficiently removed from transcribed regions within the DNA, suggesting that the efficiency of DNA repair in a given gene may be correlated to its transcriptional activity. Since ras oncogenes control several cellular signal transduction pathways, known to be involved in DNA damage response, preferential repair of the N-ras gene could therefore be an important step to prevent inactivation of cellular defense mechanisms after exposure to genotoxic agents.
Abstract: The expression of the intercellular adhesion molecule-1 (ICAM-1, CD54) seems to have an influence on the metastatic behaviour of tumour cells via immunological mechanisms. Recently, a soluble form of ICAM-1 was identified in physiological fluids. We analysed the serum levels of sICAM-1 in patients with non-small-cell lung cancer (NSCLC) and healthy individuals using a sandwich ELISA technique. Sera from 51 patients with NSCLC were tested for sICAM-1 (46 male, five female; age 38-81 years, median 64 years), 29 of whom presented with localized and 26 with metastatic disease. The control group consisted of 40 healthy individuals (20 smokers, 20 non-smokers). Immunohistochemical analysis of ICAM-1 in tumour cells was performed in 20 cases. Patients with NSCLC had significantly higher serum levels of sICAM-1 compared with healthy non-smokers (P = 0.00001) and smokers (P= 0.0328). Metastatic disease was associated with higher sICAM-1 than localized tumours (P = 0.0013). Only 11 out of 23 patients with localized NSCLC had sICAM-1 levels >300 ng ml(-1), compared with 25 out of 28 patients with metastatic disease. Histological expression of ICAM-1 was positively correlated with serum slCAM-1 (P = 0.0399). No difference was observed between histological tumour types with regard to sICAM-1 or NSCLC expression of ICAM-1. In sequential analysis (13 patients), rising sICAM-1 levels predicted a short-term fatal outcome (P = 0.0054) but, overall, sICAM-1 levels did not correlate with prognosis. In the control group, smokers showed significantly higher levels than non-smokers (P = 0.0016). In contrast to patients with NSCLC, sICAM-1 in the control group was correlated to the leucocyte count (r = 0.580, P = 0.003). In conclusion, serum levels of sICAM-1 seem to be associated with tumour burden and histological expression of ICAM-1 in patients with NSCLC. However, the (patho-) physiological role of ICAM-1 in NSCLC remains to be determined.
Abstract: CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine site, inhibiting the polymerization of microtubules and arresting cellular division in metaphase. Myelosuppression and neurotoxicity were dose-limiting in phase I studies. Sixteen patients with stage III and IV platinum-refractory ovarian cancer received 4.5 mg/m2/day of CI-980 as a continuous i.v. infusion for 72 h, repeated every 3 weeks. Eleven patients had progression and four patients had stable disease. One patient (6%; 95% CI 0-25%) achieved a partial response after 9 months of treatment which lasted for 27 months. The overall median survival was 7 months. Grade 4 granulocytopenia occurred in five patients, with two episodes of neutropenic fever. Neurological toxicity was mild with 12 episodes of transient subclinical recent memory loss documented in four patients by specialized neuropsychological evaluations. One patient each had hallucinations and mild truncal ataxia, and four patients had mild, reversible neurosensory toxicity. One episode of severe hypoxemia and dyspnea occurred in a patient with chronic obstructive pulmonary disease. CI-980 has minimal activity and is tolerable in a population of heavily pretreated patients with platinum refractory ovarian cancer.
Abstract: BACKGROUND AND OBJECTIVE: Up to 60% of all oncological patients use methods of alternative medicine in the course of their illness. In earlier blinded studies demographic characteristics and the patients' motives of using alternative medicine had been recorded, but a correlation with individual illnesses had not been possible. PATIENTS AND METHODS: 142 patients of a oncological outpatient clinic gave their experience with alternative medicine in interviews and non-blinded questionnaires, 103 of them (72.5%; 46 men and 57 women; median age 58 years, range 18-91 years) returning questionnaires that could be evaluated. RESULTS: 46 patients stated that they had used alternative medicine. There was no difference between users and non-users regarding sex; age, profession, education, family status or religion. 58% of all patients with advanced disease used alternative medicine, compared with only 31% with partial remission or stable disease and 41% in complete remission (P = 0.042). Vitamins and mistletoe preparations were the most commonly used substances (50 and 45%, respectively). The predominant purpose was to stimulate the immune system (77%) and strengthen general physical capacity (64.5%). As main stimulus for using alternative medicine the patients came from their family doctor (56%), followed by family and friends (41%). Alternative medicine was used largely as complementary and not an alternative to conventional medicine. Health insurance met all or some of the costs of alternative treatment in 59% of patients. CONCLUSION: A large number of patients treated with conventional oncological regimens also use alternative medicine, most of them because of a polypragmatic attitude to tumor treatment. Family doctors and health insurance companies are playing a more important role than had hitherto been assumed in spreading the use of treatment options without providing scientifically based evidence of their efficacy.
Abstract: Zygomycosis is characterized by a very high lethality, often favoured by rapid fungal growth in blood vessels causing the formation of thrombi and infarcts in several organs, a disease poor in symptoms. A disseminated mycosis normally is a complication of a granulocytopenia which is in our days more frequently observed as localized manifestation, whereas the typical rhinocerebral manifestation complicating diabetic ketoacidosis has become more rare. The diagnosis of zygomycosis can apparently be obtained easier by histology than by culture. The prognosis of zygomycosis can be improved by: 1. an early examination by biopsy, 2. if possible a rapid correction of predisposing factors (e.g. correction of acidosis), 3. an early antimycotic therapy by amphotericin B in risk patients, even if no causative agent can be cultured.
Abstract: Deep fungal infections caused by zygomycetes (so-called mucormycoses) are rare. Whereas in the past rhinocerebral mycosis dominated, today a wide range of clinical manifestations must be expected, especially pulmonary infections and invasion of vessel walls with systemic infarction. On the basis of 10 cases of Mucoraceae mycosis and a review of the literature, the predisposing conditions, clinical symptoms and pathologic-anatomic findings are described. Our observations include 7 patients with leukemia and 2 adults and one newborn without malignant neoplasia. Except for the patient with rhinocerebral mycosis, the diagnosis was not established during the patients' lifetime. 3 patients received systemic antimycotic therapy. Our observations suggest that infarctions of internal organs in immunocompromised patients should direct suspicion towards angio-related mycoses, not only of aspergillosis, but also of zygomycosis.
Abstract: As part of a multicenter trial 12 patients with myelodysplastic syndromes (MDS) were treated with 14-day-cycles of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 250 micrograms/m2 day s.c.). In addition, all patients received 20 mg/m2/day s.c. cytosine-arabinoside (Ara-C) 12 h after GM-CSF except for patients suffering from refractory anemia (RA) according to FAB classification. Courses were repeated after 4 weeks. In 11 evaluable patients, results according to FAB-classified MDS were as follows: RA, 1/2 response (R), 1/2 stable disease (SD); RAEB, 2/3 R, 1/3 SD; RAEB-T, 1/6 CR, 1/6 PR, 2/6 R, 2/6 progression; CMML, 1/2 SD. In 2 patients with RAEB-T, overt acute myeloid leukemia was observed 2 and 10 weeks after initiation of treatment. With few exceptions, treatment resulted in a prompt increase in granulocytes and eosinophiles. This was associated with improvement of infectious complications. Increases in red cells and platelets occurred variably and was apparently associated with responses of the underlying disease. Dose limiting side effects consisted of fever, severe fatigue and dolent local reactions at the site of GM-CSF injection. In addition, nausea and diarrhoea occurred frequently. Less often, respiratory and cardiovascular side effects were encountered. In summary, GM-CSF +/- Ara-C in MDS results in objective remission with manageable toxicity. Conceivably, this regimen will serve as a base for future treatment strategies against MDS.
Abstract: The title compound, designed as a model for the affinity moiety of a cannabinoid affinity gel was synthesized in tritiated form (sp. act. 7.27 mCi/mmole). To validate the affinity approach to isolate the putative THC receptor, the properties of the amide were studied. Upon i.p. injection in mice the amide reaches peak brain levels of 0.13% of the total dose after 15 min. Following i.v. injection, maximal brain concentrations of 1.9% are observed at 5 min. Compared to delta 9-THC, which distributes almost equally between triglyceride and phospholipid phases (51:49) the amide exhibits a strong preference for phospholipids (5:95) that can be interpreted as high relative membrane affinity. In rats trained in a water maze to discriminate between i.p. injections of 3 mg/kg delta 9-THC (ED50 = 1.8 mg/kg) and its vehicle, the amide was generalized to the training drug, being five times less potent (ED50 = 8.7 mg/kg) than delta 9-THC. This demonstration of cannabis-like activity indicates that the amide retains affinity to the postulated receptor and justifies the choice for the affinity ligand.
