Abstract: BACKGROUND: Health-related quality of life (HRQOL) parameters are often used as end points in phase III trials in advanced breast cancer. The frequency and correlates of significant gains in HRQOL have not been assessed. METHODS: To evaluate the contemporary role for HRQOL assessment in advanced breast cancer, we searched PubMed for the main and companion papers reporting the results of phase III trials on systemic antineoplastic therapies published between 1/98 and 7/09 in 11 leading journals. RESULTS: The search yielded 87 trials that enrolled a total of 33,669 patients. HRQOL was mentioned/reported in the main paper in 34 trials, reported in a companion paper in one (a total of 35/87=40%), and mentioned in the abstract of the main paper in 19/34 cases (56%). There was no temporal trend for reporting on HRQOL in the two 6-year periods. Although formal statistical comparisons were reported in 31/35 cases (89%), a significant difference was found in only 4/31 (13%) trials, always favoring the experimental arm. Given the small number of studies with a significant HRQOL finding, we could not assess correlates of gain in HRQOL. CONCLUSIONS: HRQOL is one of the key indicators of treatment benefit in advanced breast cancer, but contemporary systemic therapies in this setting do not appear to affect HRQOL differentially.
Abstract: The American Society of Clinical Oncology Annual Meeting is the largest forum for presentation of clinical research in oncology. We quantified the contribution of countries and assessed correlates of their presence at such meetings.
Abstract: Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.
Abstract: With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression.
Abstract: The 21-gene expression assay may support the decision regarding use of chemotherapy in early breast cancer. We sought to investigate the potential impact of incorporating the 21-gene expression assay into private practice in Brazil, from the perspective of third party payers.
Abstract: We and others have previously suggested that pretreatment levels of CA 19-9 correlate with overall survival (OS) among patients with advanced pancreatic cancer treated with gemcitabine. We sought to confirm the prognostic role of the pretreatment level of CA 19-9 in patients with advanced pancreatic cancer treated with chemotherapy.
Abstract: Background: The growing availability of active agents makes the development of novel therapies increasingly complex and the choice of end points critical. We assessed the frequency of use of efficacy end points in advanced breast cancer.
Abstract: Breast cancer, a leading type of cancer in many developing countries, is the most frequent non-cutaneous tumor in Brazil. Hormone therapy is the standard of care in the adjuvant treatment of early-stage, hormone-receptor-positive disease, and both tamoxifen and third-generation aromatase inhibitors are options in postmenopausal women. The comparative cost-effectiveness of different treatment strategies is of considerable interest in societies facing limited resources.
Abstract: Invasive lobular carcinoma is the second most frequent histological type of breast cancer and its incidence is increasing. It has unique clinical, biological, and molecular features. Invasive lobular carcinoma is almost invariably positive for the oestrogen receptor and, when compared with invasive ductal carcinoma, it is typically of a lower grade. Even though invasive lobular carcinoma represents a distinct clinical entity, the same criteria used for invasive ductal carcinoma are currently applied to establish the need for primary or adjuvant systemic chemotherapy. We reviewed randomised trials of neoadjuvant and adjuvant chemotherapy and noted that insufficient evidence is available to support or withhold use of chemotherapy in patients with invasive lobular carcinoma. Thus, the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear. Invasive lobular carcinoma deserves to be investigated separately in prospective clinical trials to define the best treatment and prevention strategies.
Abstract: Cancer patients receive numerous medications, including antineoplastic agents, drugs for supportive care, and medications for comorbid illnesses. Therefore, they are at risk for drug interactions and duplicate prescribing.
Abstract: To quantify the frequency of potential drug interactions unrelated to chemotherapy in cancer patients admitted to our institution, and to define risk factors for such interactions.
Abstract: Over the past decade, metastatic colorectal cancer has evolved from a relatively resistant disease to one that is sensitive to a variety of chemotherapeutic drugs and combinations of drugs. During the same period, the median survival of patients with metastatic colorectal cancer increased from approximately 14 months to almost 20 months. First-line chemotherapy prolongs survival and delays the appearance of symptoms and should be considered in patients who are still asymptomatic. Patients with metastatic colorectal cancer and adequate performance status should be treated with a combination of fluorouracil (5-FU) and either oxaliplatin or irinotecan. Bevacizumab, the monoclonal antibody against the vascular endothelial growth factor, has been shown to prolong survival with acceptable toxicity and may be added when available. When the disease recurs, second-line chemotherapy may also prolong survival in appropriately selected patients. Typically, treatment includes 5-FU and one of the drugs not used in the first-line therapy (oxaliplatin or irinotecan). Several oral prodrugs of 5-FU are currently available. Capecitabine, approved in the United States, may be safely substituted for 5-FU in the majority of settings and combinations. Cetuximab is a monoclonal antibody against the epidermal growth factor receptor and is approved both as a single agent and in combination with irinotecan for patients with recurrent disease. This treatment may represent a second-line or third-line option in selected patients. Treatment of patients with isolated liver metastases may also include surgical or other ablative procedures. In carefully selected patients, these modalities add to the efficacy of chemotherapy and may be used with potentially curative intent. However, for the vast majority of patients with metastatic colorectal cancer treatment is palliative.
Abstract: Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer (MCC). There is a strong preclinical rationale for combining these two agents. We sought to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combined irinotecan and oxaliplatin given every three weeks.
Abstract: Despite the acceptance of gemcitabine as the standard first-line agent for the treatment of advanced pancreatic cancer as well as the improved response rates seen with gemcitabine combinations, novel therapies are needed for this disease, which has one of the lowest survival rates. The growing understanding of the molecular basis of pancreatic cancer and the recent introduction of targeted therapeutic agents have initiated novel studies that have the potential to improve on existing treatments.
Abstract: Our purpose in the study was to determine the maximum tolerated dose and dose-limiting toxicity and investigate the clinical pharmacology of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate.
Abstract: UFT is the combination of the fluorouracil (5-FU) prodrug tegafur, and the dihydrophyrimidine dehydrogenase inhibitor uracil. UFT and leucovorin have been used in the oral treatment of a variety of malignancies. Given the radiosensitizing properties of UFT, its combination with radiation therapy is a logical step in the development of novel strategies for the treatment of gastrointestinal malignancies. Several phase I and phase II studies, described in this review, have attempted to substitute UFT for 5-FU in chemoradiation strategies for the treatment of patients with esophageal, pancreatic and rectal cancer. The results thus far suggest that this approach has acceptable toxicity and promising efficacy. Given the availability of the novel oral fluorinated pyrimidines and their efficacy in metastatic diseases, it remains to be determined whether 5-FU will eventually be substituted by oral fluorinated pyrimidines in the adjuvant and chemoradiation settings.
Abstract: The molecular mechanisms of action, clinical development, and efficacy and safety of targeted antineoplastic drugs are discussed. Recently introduced mechanism-based systemic therapies for cancer may be more specific, less toxic, and more effective and represent a paradigm shift in treatment. Currently, receptor tyrosine kinases (RTKs), nonreceptor kinases, the angiogenic molecules, the enzymes involved in extracellular matrix degradation, and the enzymes responsible for protein anchorage to the cytoplasmic membrane are among the targets against which specific interventions have been developed. Monoclonal antibodies against the extracellular portion of RTKs and small-molecule inhibitors of their tyrosine kinase activity are strategies in more advanced phases of clinical development. Over the next few years, one can expect to see the results of many studies of such new pharmacologic agents or combinations. It seems likely, at this point, that targeted drugs will be used in association with existing medical, surgical, and radiotherapeutic modalities and will play an important role in the ultimate goal of reducting the burden of cancer. Targeting of molecular abnormalities that are differentially expressed in tumors may represent a more specific and less toxic way of treating cancer.
Abstract: Hand-foot syndrome (HFS) has been previously reported as a side effect in 45-56% of patients treated with capecitabine. However, the natural history of HFS has not been fully characterized. In this study, we investigate the incidence, severity, and time course of HFS.
Abstract: High-dose chemotherapy has been advocated by some investigators as a means to circumvent drug resistance, thereby improving treatment results in patients with solid tumors. For patients with unknown primary tumors, this hypothesis has only recently undergone limited testing. Two groups (one from the USA and one from Europe) have published their experience with higher doses of chemotherapy in the treatment of UPC. The results are not superior to those reported by other investigators using more standard doses of chemotherapy. Most importantly, chemotherapy trials for UPC are usually conducted in small populations made up of heterogeneous patient subsets with varying sensitivity to chemotherapy. It seems likely that progress in the management of patients with unknown primary cancers will occur as a result of efforts to improve the understanding of the natural history of this disease coupled with the assessment of novel agents targeted against specific biochemical abnormalities that will be demonstrated to be important in the development and maintenance of these malignancies.
Abstract: Dolastatin-10 is a potent inhibitor of microtubule assembly derived from the sea hare, which displayed significant antitumor activity in preclinical models. We conducted a phase II study of dolastatin-10 in patients with advanced colorectal cancer and no prior chemotherapy for metastatic disease. Fourteen patients received doses ranging from 300 microg/m(2) to 450 microg/m(2) as an intravenous push every 21 days. There were no major objective responses. Toxicity was mainly hematologic, with grade III or IV granulocytopenia occurring in 9 of 42 treatment courses. Other toxic effects were generally mild. Dolastatin-10 lacks clinically significant activity in advanced colorectal cancer when used in this dose and schedule.
Abstract: Serum levels of CA 19-9 correlate with survival among patients with pancreatic cancer treated with surgery or radiation therapy. In addition, CA 19-9 responses have been shown to predict for a better prognosis among patients with advanced disease treated with chemotherapy. The present study evaluates the predictive role of CA 19-9 pretreatment levels and response among patients treated with gemcitabine.
Abstract: Hand-foot syndrome (HFS) is a relatively common side effect of fluorouracil (5-FU) chemotherapy that has also been associated with the oral fluoropyrimidine capecitabine. Interestingly, HFS is virtually unknown to result from treatment with UFT, a combination of tegafur and uracil. Tegafur is a prodrug of 5-FU and is a component of S-1, another oral fluoropyrimidine active in a variety of solid tumors. We know of only one previously described case of S-1-induced HFS and the case reported here is the first to provide full documentation of this occurrence. The pathophysiology of chemotherapy-induced HFS remains unknown and very little pathological information is available. Treatment consists of topical emollient therapy, although pyridoxine has occasionally been beneficial. The study of HFS may provide an important insight into the pharmacology of fluoropyrimidines and allow for effective preventive strategies for this side effect of chemotherapy.
Abstract: Researchers, primarily in Japan, Europe, and the United States, have evaluated several new fluorinated pyrimidines in recent years. Most of these drugs are orally active prodrugs of fluorouracil (5-FU), and some also contain modulators of its pharmacological properties. S-1 is a rationally developed combination of tegafur, a prodrug of 5-FU; CDHP, an inhibitor of 5-FU catabolism; and potassium oxonate, an inhibitor of 5-FU-induced diarrhea. S-1 underwent phase I and II trials in Japan, where it is now approved for use in the treatment of advanced gastric cancer. Two phase I studies conducted recently in Europe and the United States identified diarrhea as the dose-limiting toxicity of S-1. BOF-A2, which contains a 5-FU prodrug and CNDP, an inhibitor of 5-FU catabolism, demonstrated clinical activity in preliminary studies in Japan. This article summarizes the preclinical and clinical development of S-1 and BOF-A2.
Abstract: Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four other patients had grade 1 ototoxicity. Grade 1 and 2 muscle cramps were observed at all dose levels. Other toxic effects observed included fatigue, nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase. Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support, the recommended doses of tirapazamine and cyclophosphamide when administered in this schedule are 260 and 1000 mg/m(2), respectively.
Abstract: Progressive multifocal leukoencephalopathy (PML) is a demyelinating infectious disease caused by the JC virus. It was originally described in patients with chronic lymphocytic leukemia (CLL). Richter's syndrome, or transformation to large cell Lymphoma, occurs in approximately 3% of patients with CLL, and carries a poor prognosis. We report a patient with documented PML and concurrent Richter's transformation outside the central nervous system. Before establishing a definitive diagnosis of PML, radiation therapy to the presumed lymphomatous brain lesion had been considered, raising the issue of whether stereotactic brain biopsy should be considered in every patient in a similar situation. Although this is likely a rare occurrence, patients with Richter's transformation documented at an extra-neural site and a brain lesion may benefit from the establishment of an infectious diagnosis which would influence therapy.
Abstract: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting.
Abstract: The use of combined modality regimens has been well established in the treatment of stages II and III rectal cancer. The most common chemotherapy regimens used include continuous-infusion 5-FU delivered with the help of a central venous catheter and the use of portable pumps. These regimens are expensive and can potentially develop line problems. The availability of the oral agent UFT in combination with oral leucovorin prompted the development of an all-oral chemotherapy regimen that could be combined with radiotherapy. At The University of Texas M. D. Anderson Cancer Center, we routinely use combined chemotherapy and radiotherapy preoperatively for the treatment of rectal cancers, and decided to conduct a phase I trial in which UFT and leucovorin was used instead of the conventional 5-FU. The preliminary results are encouraging and seem to demonstrate the feasibility of this approach.
Abstract: Evidence-based medicine has been described as a new approach to teaching and practicing clinical medicine. Although the search for evidence is an established practice among physicians, what is being proposed is the systematic gathering and critical interpretation of data, which can then be used in the appropriate context. The main objective is to provide better care for patients. This is accomplished by transforming clinical problems in specific questions to be answered by searching the literature for the levels of evidence favoring the possible interventions for one particular case. This has to be done in a systematic and conscientious fashion. Through its method, evidence-based medicine places less value on clinical experience, the study understanding of pathophysiology, and common sense; instead, it emphasizes observation, levels of evidence, and critical interpretation of original literature. In this manner, evidence-based medicine may be seen by the authoritarian physician as a threat. Other obstacles to the acceptance of the method include lack of time and lack of familiarity with computers. One important limitation of evidence-based medicine is the incomplete or contradictory evidence available in many areas of clinical medicine, or the so-called "grey zones". We outline the main aspects of evidence-based medicine, expecting a growing interest among brazilian physicians for this useful clinical tool.
