Azienda ospedaliera "Ospedali Riuniti Marche Nord" Presidio S. Salvatore via Lombroso 61121 Pesaro (Italy)
d.rossi63@libero.it
CURRICULUM VITAE DAVID ROSSI M.D.
Born in Senigallia (Ancona) 16th september 1963 and living in Senigallia.
1989: degree in Medicine at State University of Ancona (110/110 cum Laude)
1994 - 1995: degree in Medical Oncology at State University of Ancona (50/50).
1998 - 2012: Senior Assistant of Medical Oncolgy Unit in S. Salvatore Hospital (Pesaro).
First author and co-author of original articles concerning lung, breast and gastrointestinal cancer. Coordinator of Lung Cancer Unit at "Ospedali Riuniti Marche Nord" in Pesaro. Member of AIOM (Italian Medical Oncology Association) and AIOT (Italian Society of Thoracic Oncology). Reviewer of International Cancer Journals. Lead Faculty of "WebMed Central". Advisory Board Member of "The Scientific World Journal".
Abstract: BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50Â mg/m(2) as a 30-min infusion on day 1, leucovorin 200Â mg/m(2) in a 2-h infusion, and 5-FU 2,800Â mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75Â mg/m(2), every 3Â weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64Â years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6Â months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.
Abstract: Catalano V, Mellone P, d'Avino A, Shridhar V, Staccioli M P, Graziano F, Giordani P, Rossi D, Baldelli A M, Alessandroni P, Santini D, Lorenzon L, Testa E, D'Emidio S, De Nictolis M, Muretto P, Fedeli S L & Baldi A (2011) Histopathology HtrA1, a potential predictor of response to cisplatin-based combination chemotherapy in gastric cancer Aims:â HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer. Methods and results:â HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64âyears (range 32-82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7-88.2], 66.7% (95% CI 47.8-85.5) and 28.6% (95 CI 11.8-45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (Pâ=â0.002). The median overall survival for patients with high/medium expression was 17âmonths compared to 9.5âmonths for patients with low HtrA1 expression (Pâ=â0.037). Conclusions:â Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.
Abstract: BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (nâ=â178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.
Abstract: Visceral metastases of breast cancer have been commonly treated with "aggressive" anthracyclines/taxanes-based chemotherapy. In contrast, this case report concerns an elderly patient with advanced breast cancer (pleural effusion, peritoneal carcinosis, and bone metastases) who firmly declined intravenous chemotherapy and was treated for a long time (28 months) with oral vinorelbine. The oral formulation of this drug had activity and a high safety profile, enabling the patient's wishes to be respected.
Abstract: The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites > or =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.
Abstract: No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin </=11.5 g l(-1) (HR, 1.48; 95% CI, 1.06-2.05; P=0.019), CEA level >50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy </=6 months (HR, 1.97; 95% CI, 1.39-2.80; P<0.0001). A prognostic index was constructed dividing patients into low- (no risk factor), intermediate- (one to two risk factors), or high- (three to five risk factors) risk groups, and median survival times for each group were 12.7 months, 7.1 months, and 3.3 months, respectively (P<0.001). In the absence of data deriving from randomised trials, this analysis suggests that some easily available clinical factors may help to select patients with advanced gastric cancer who could derive more benefit from second-line chemotherapy.
Abstract: PURPOSE: Paclitaxel and platinum-based chemotherapy is considered to be a standard approach for locally advanced and metastatic non-small-cell lung cancer (NSCLC). In recent years, weekly paclitaxel has been widely used for its safety profile, especially in breast and ovarian cancer. Otherwise, only a few studies are available in NSCLC. The aim of our study was to investigate the activity and safety of weekly paclitaxel in elderly patients with locally advanced (stage IIIB) and metastatic (stage IV) NSCLC. PATIENTS AND METHODS: Twenty-seven patients entered the study; 10 had stage IIIB disease (5 "wet" and 5 "dry"), and 17 had stage IV disease. Median age was 73 years (range, 70-83 years). Sixteen patients (59%) presented with comorbidities. The schedule was weekly paclitaxel 80 mg/m2 for 6 weeks with 2 weeks of rest (1 cycle). RESULTS: All patients were evaluable for response and toxicity; a median of 1 cycle was administered (range, 1-5 cycles). Partial responses were recorded in 9 patients (37.5%; 33.3%, according to intention-to- treat analysis; 95% CI, 15.5%-51.1%); 7 had stable disease (29%), and 8 had progressive disease (33.5%). Median time to progression was 5 months (range, 1-23 months), and median survival was 12 months (range, 1-36 months). Grade 2/3 asthenia was the main toxicity in 7 patients (29%); a hypersensitivity reaction presented in 1 patient. No other episode of grade 3/4 toxicity was recorded. CONCLUSION: Our study confirmed that paclitaxel 80 mg/m2 weekly is active in patients with locally advanced and metastatic NSCLC with a good safety profile; this schedule might be considered an alternative choice to gemcitabine or vinorelbine as first-line treatment in elderly patients, particularly patients with comorbidities. Phase III studies that compare these third-generation drugs are warranted to draw definitive conclusion about the best approach in these patients.
Abstract: PURPOSE: Capecitabine is an orally administered precursor of 5'-deoxy-5-fluorouridine that was rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue. The drug enables chronic dosing that mimics continuous infusion of 5-FU. Phase II trials of capecitabine at 1250 mg/m2 twice daily for 14 days followed by 7 days of rest, is active in anthracycline- and taxane-pretreated patients; the main toxicity is palmar-plantar erythrodysesthesia, diarrhea, and nausea. To overcome these side effects, the dose has been reduced to 1000 mg/m2 twice daily with a better therapeutic profile and encouraging efficacy. The aim of our study was to confirm safety and activity of capecitabine at lower doses in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-seven patients with advanced breast cancer entered the study. The first 7 patients were treated with capecitabine 1250 mg/m2 twice daily (for 14 days followed by 7 days of rest) and the next 30 patients with capecitabine 1000 mg/m2. The median age was 62 years (range, 38-87 years). Thirteen patients were chemotherapy naive and 24 were pretreated with chemotherapy (9 patients, 1 line; 15 patients, > or = 2 lines). Anthracyclines and/or taxane schedules were administered in 22 patients. Soft tissue metastases were documented in 36 patients; visceral metastases in 24 patients; visceral and soft tissue metastases in 23 patients. RESULTS: Thirty patients were evaluable for response (5 at "higher" dose and 25 at "lower" dose) and all for toxicity. Overall objective response rate was 57% (5 complete responses and 12 partial responses); 95% CI, 39%-74%; stable disease 20% and progressive disease 23%. Eight of 13 chemotherapy-naive patients (61.5%) and 9 of 24 pretreated patients (37.5%) responded to capecitabine, according to the intent-to-treat principle (6 of 9 responses were obtained at a lower dose). Three responses at the "higher" dose and 14 at the "lower" dose were reported. Median time to progression was 7 months (range, 1-38 months) and median overall survival was 19 months (range, 2-47 months). Toxicity was as follows: grade 2/3 palmar-plantar erythrodysesthesia in 9 patients (24%), grade 2/3 asthenia in 7 patients (19%), grade 2 vomiting in 4 patients (11%), grade 2 renal toxicity in 1 patient, grade 2 skin reaction in 1 patient, and suspected cardiac toxicity in 1 patient. CONCLUSION: Our study confirmed that a lower dose of capecitabine has a good toxicity profile and is active in patients with MBC.
Abstract: PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m(2) once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m(2) once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m(2) weekly are warranted.
Abstract: Abstract : Background: Neurotoxicity is a frequent side effect of chemotherapy. There are few drugs (GSH, amifostine) that are effective for the prevention of this toxicity, especially for platinum-derivates and a number of other drugs have been used for therapy. However, there is no standard treatment. Over the last few years gabapentin has shown its efficacy for neuropathic pain. The aim of this study was to demonstrate the activity of gabapentin for peripheral sensorial neurotoxicity Patients and methods: 25 patients with peripheral sensorial neurotoxicity = 2 according to the NCI scale and treated with potentially neurotoxic drugs entered the study. Treatment was: gabapentin 400 mg/die for two days, 400 mg bid for a further two days and then 400 mg tid as maintenance. Response was evaluated with a Zero to 10 Numerical Scale before treatment (T0) and after 30 days (T1). The median age was 66 (range 41 â 75); 16 females and 9 males. 10 breast cancer patients, 5 colon cancer patients, 3 lung cancer patients, 2 bladder cancer patients, 1 gastric cancer patient, 1 ovarian cancer patient, 1 melanoma patient, 1 laryngeal cancer patient and 1 oral cavity cancer patient. Previous treatments included: paclitaxel in 6 patients; cisplatin/paclitaxel in 5 patients; oxaliplatin in 5 patients; vinorelbine/oxaliplatin/paclitaxel in 2 patients; docetaxel in 2 patients; vinorelbine/paclitaxel in 1 patient; docetaxel/vinorelbine/oxaliplatin in 1 patient; cisplatin/oxaliplatin in 1 patient.; vinorelbine in 1 patient and cisplatin in 1 patiemt. Results: 19 patients were eligible for evaluation response. 11 out of 19 (60%) patients responded with an improvement to sensorial neurotoxicity, documented by a median reduction of 3 points in numerical scale (range 1 â 5). The main toxicity was lethargy for 8 patients (32%); and for 5 this was associated with mental clouding. 1 patient reported agitation. Conclusion: Our study seems to provide evidence that gabapentin is a promising drug for sensorial neurotoxicity induced by chemotherapy, although it requires further investigation in a randomised phase III study.
Abstract: INTRODUCTION: Single-agent docetaxel is active as second-line chemotherapy in non-small cell lung cancer (NSCLC) pretreated patients; seven phase II studies have shown response rates of about 20% and 9 months of median survival. Two phase III studies documented a survival benefit at 1 year compared to BSC and vinorelbine or ifosfamide. Recent trials indicate acceptable activity and a good safety profile of weekly docetaxel with doses of 25-43 mg/m2. The aim of our study was to confirm this evidence and to evaluate activity and toxicity of weekly docetaxel at the dose of 40 mg/m2. PATIENTS ATND METHODS: Twenty-one patients with NSCLC entered the study (7 stage IIIB and 14 stage IV): 13 males and 8 females. Median age was 66 years (range, 53-75). ECOG was O in 6, 1 in 9 and 2 in 6 patients. All patients were pretreated with a first-line chemotherapy (13 patients progressed soon after the first line); 6 of them received palliative radiotherapy on the chest. The treatment consisted of weekly docetaxel, 40 mg/m2 in 1 hr for six weeks with two weeks of rest (1 cycle). A total of 87 administrations was delivered (median, 4; range, 1-12). RESPONSES: All patients were assessable for response (according to the "intent-to-treat principle") and for toxicity. No complete or partial remission was observed; 2 minor responses (9.5%), 1 stable disease (5%), 8 progressive diseases (38%) were documented. Seven patients dropped out the study due to severe toxicity (33.5%) and 3 due to early death (14%). Median survival was 3 months (range, 1-17), and 1-year survival was 9.5%. Toxicity was as follows: grade 4 diarrhea in 1; grade 3 asthenia in 8 (38%), grade 3 stomatitis in 2; grade 3 neutropenia in 1; allergic reactions in 2. No treatment-related death was recorded. CONCLUSIONS: The trial showed only very modest activity of weekly docetaxel, with severe side effects that induced us to stop the accrual in order to prevent other worse toxicities. We therefore concluded that a dose of 40 mg/m2 of weekly docetaxel is not manageable and does not seem to provide a real benefit in terms of response and quality of life.
Abstract: BACKGROUND: Cisplatin/gemcitabine are one of the "standard" chemotherapy schedules in locally advanced and metastatic NSCLC cancer. A number of trials documented that omission of gemcitabine on day 15 and reduction of cisplatin up to 70 mg/mq are equivalent in term of response rates to "classic" administrations on days 1, 8 and 15 with cisplatin 100 mg/mq. The aim of this study was to confirm this evidence and to demonstrate that a further reduction of gemcitabine dose-intensity may be performed with the same efficacy on response. PATIENTS AND METHODS: Fifty untreated patients with locally advanced and metastatic NSCLC entered the study: 24 stage IIIB and 26 stage IV. The median age was 65 years (range 32-76); 44 males and 6 females Genicitabine was administered 1000 mg/mq weekly on days 1 and 8 followed by a 2-week rest and cisplatin 80 mg/mq on day 2 of each 28-day-cycle. RESULTS: Forty-five patients were evaluable for response and all for toxicity. The overall response rates were 35.5% with 16 partial responses (95% Confidence Interval: 32%-61%). Most of the objective responses were seen in IIIB patients (56% of the stage IIIB and 44% of the stage IV patients responded). According to the intent-to-treat-principle, the response rates were 32% (16 out of 50 patients). The median dose-intensity of gemcitabine and cisplatin was respectively 477.6 mg/mq/week (481.4 for responders) and 19.5 mg/mq/week (19.9 mg/mq for responders). The median response duration was 5 months (range 1-18) and the median time to progression was 5 months (1-21); median survival was 9 months (range 2-31). The main toxicity was haematological: thrombocytopenia grade IV in 5 patients (10%) and grade III in 11 patients (22%); neutropenia grade III-IV in 4 patients (8%); grade III anemia in 3 (6%). Asthenia was the most significant non-haematological toxicity and was observed in 19 patients (38%). CONCLUSION: This trial confirmed the efficacy of a schedule with 2 administrations of gemcitabine (on days 1, 8) and a cisplatin dose on day 2 lower than 100 mg/mq. Moreover, the same efficacy was obtained with a median-dose intensity of cisplatin and gemcitabine lower than planned in a 21-day-schedule. For safety and low toxicity, we think that this schedule provides another chance to treat patients with non-small cell lung cancer, especially the elderly or patients with coexistent medical illnesses.
Abstract: BACKGROUND: Anthracyclines combined with paclitaxel are one of the most active schedules in patients with advanced breast cancer: response rates range from 40 to 80%, considering all metastatic sites (visceral and soft tissues). We performed a non-randomized phase II trial with anthracyclines/paclitaxel combination to evaluate response and toxicity only in patients with visceral metastases. METHODS: Twenty-seven patients (median age 50 years; range 30-72) with visceral metastases of breast cancer were enrolled in this study. Overall, 11 patients had lung metastases (41%), 10 liver (37%), 4 liver-lung metastases (15%) and 2 peritoneal carcinosis (7%). 7 patients had received adjuvant anthracycline-based chemotherapy (26%) and 10 patients adjuvant CMF combination chemotherapy (37%); 10 patients (37%) received hormonal therapy for advanced disease. Treatment schedules were: group A) 17 patients, Adriamicyn 50 mg/m2 on day 1 i.v. bolus and Paclitaxel 175 mg/m2 on day 2 i.v. 3 hours infusion, every 3 weeks; group B) 10 patients, epirubicin 90 mg/m2 on day 1 i.v. bolus and paclitaxel 200 mg/m2 on day 2 i.v., 3 hours infusion, every 3 weeks. The number of cycles administered was 141 with a median of 5 (range 3-9). RESULTS: All patients were evaluable for response and toxicity. The objective response rate was 59% - 16 patients - (15% complete and 44% partial remission), 95% C.I. 40.7-77%; 10/17 in group A and 7/10 in group B. Stable disease 30% (8 patients) and progressive disease 11% (3 patients). The median duration of response was 5 months (range 1-16); median time to progression 13 months (range 3-18) and median survival 17 months (range 4-24). The main toxicity was neutropenia, occurred in 16 patients (59%; grade IV in 7 patients, of whom 2 febrile neutropenia, and grade III in 9 patients); grade III gastrointestinal toxicity in 2 patients; grade III neurological toxicity in 1 patient; grade III stomatitis in 2 patients. No congestive hearth failure or treatment death related was observed. CONCLUSIONS: These schedules of anthracyclines and paclitaxel confirmed their efficacy in metastatic breast cancer even in patients with visceral disease. Neutropenia was the main toxicity; grade IV neutropenia was more frequently observed in epirubicin/paclitaxel arm.
Abstract: Questo «case report» riguarda un paziente con metastasi ossee ed epatiche da carcinoide atipico polmonare trattato con successo per oltre 2 anni con octreotide LAR. Il paziente era stato sottoposto a bilobectomia destra e linfoadenectomia mediastinica nel 1996. Nel gennaio 2000, una rivalutazione strumentale di malattia ha documentato una progressione a livello epatico ed osseo. Dopo un solo ciclo con cisplatino ed etoposide, il paziente ha interrotto la chemioterapia ed ha iniziato la somministrazione di octreotide LAR (1 iniezione i.m. al mese) per un episodio di dolore retrosternale sospetto per angina pectoris. Fino ad oggi il farmaco ha consentito di tenere sotto controllo la malattia senza effetti collaterali e con un ottimo impatto sulla qualità di vita del paziente. L'octreotide LAR è un farmaco altamente maneggevole e dovrebbe essere utilizzato come primo approccio terapeutico in questo tipo di neoplasia, soprattutto nei pazienti anziani o con una situazione clinica compromessa.
Abstract: BACKGROUND: The combination of gemcitabine and cisplatin has proven effective in the treatment of advanced non-small-cell lung cancer (NSCLC). However, the optimal schedule for administration of the two drugs has not yet been determined. In this study we evaluated the activity and toxicity of a weekly gemcitabine and cisplatin schedule. PATIENTS AND METHODS: Thirty-six untreated patients with stage IIIB IV NSCLC entered the study. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on day 1,8, and 15, followed by one week of rest. RESULTS: Ninety-seven courses (273 weekly administrations) were delivered. The median dose-intensity was 612 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All 36 of the patients were evaluable for toxicity, and 30 for response. Partial remissions were observed in 12 patients, for an overall response rate of 40% (95% confidence interval (95% CI): 22.5%-57.5%). Most of the partial remissions were seen in IIIB patients (54% of the stage IIIB and 22% of the stage IV patients responded). According to the intent-to-treat principle, the response rate was 33.3% (12 of 36 patients). The median response duration was 9.9 months (range 4-23) and the median survival time 11.8 months (range 1-24). World Health Organization (WHO) grade 3-4 myelotoxicity was: thrombocytopenia in nine patients (25%), neutropenia in six (16.6%) and anemia in six (16.6%); there was very little additional major toxicity. CONCLUSIONS: This regimen appears to be active and to have a favourable toxicity profile.
Abstract: Cancer patients with painful osteolytic bone metastases who had failed initial treatment with hormones and/or chemotherapy were each randomized to receive one of three pamidronate doses as outpatients: 45, 60, 90 mg given every 3 weeks for 12 weeks. Seventy patients were enrolled in this study, for a total of 265 infusions. There were 64 patients who completed 12 weeks of therapy. Forty-eight patients took nonsteroidal antinflammatory drugs, while 22 patients received morphine before pamidronate treatment. A reduction in bone pain and mobility scores was observed in all three different dose groups: in 11 of 23 patients (47%) at 45 mg; in 12 of 24 patients (50%) at 60 mg; and in 16 of 23 patients (69%) at 90 mg. However, while for patients receiving pamidronate at 90 mg median changes in pain and mobility were statistically significant at the 6th week, for patients receiving 45 mg they were not significant until the 12th week and for patients receiving 60 mg, until the 9th week. In weeks 0-6, the daily consumption of analgesics was reduced in 3 patients in the 45-mg arm, in 4 patients in the 60-mg arm, and in 7 patients in the 90-mg arm. In weeks 7-12, the daily consumption of analgesics was reduced in 8 patients receiving 45 mg, in 8 patients receiving 60 mg, and in 7 patients receiving 90 mg. No significant toxicity was recorded. In 2 patients (45 and 90 mg) fever (> 38 degrees C) and myalgia were observed after the first administration. In conclusion, our results seem to confirm the utility of higher doses of pamidronate in patients with painful bone metastases, because of the faster symptom relief achieved.
Abstract: A total of 26 patients with advanced colorectal cancer received 60 mg/m2 methotrexate i.v. on days 1-4; 400 mg/m2 5-fluorouracil i.v. on days 2, 3, 5, and 6; and 100 mg/m2 6S-leucovorin i.v. on days 2, 3, 5, and 6. Interferon-alpha 2b at a dose of 3 million U was given i.m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2-28%): In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5-fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity.
Abstract: Background: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression).
Methods: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m² every three weeks for 3 courses and weekly paclitaxel 80 mg/m² for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations.
Results: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or âin situâ) on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 âminimalâ responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) less than 50% were recorded (with a median reduction of 8%).
Conclusions: A âshort courseâ of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this âshort courseâ schedule, the result in term of clinical responses didn't turn into complete pathological responses.
Abstract: Lâimpiego di peg-filgrastim a scopo profilattico trova oggi indicazione elettiva nelle pazienti sottoposte a chemioterapia con rischio elevato (>20%) di neutropenia febbrile. A questo proposito, i migliori risultati sono stati documentati nelle pazienti trattate con schema TAC adiuvante (docetaxel, adriamicina, ciclofosfamide), in associazione alla somministrazione di ciprofloxacina (1). Lo studio di Von Minckwitz et al. ha mostrato come tale associazione sia in grado di ridurre in maniera statisticamente significativa lâincidenza di neutropenia febbrile rispetto a filgrastim/lenograstim e ciprofloxacina o alla sola ciprofloxacina. Del resto, Lo studio di Vogel et al. (2) aveva già evidenziato come lâutilizzo della formulazione pegilata di filgrastim era in grado di ridurre significativamente, rispetto al placebo, la percentuale di neutropenia febbrile, gli episodi di ospedalizzazione e lâuso di antibiotici e.v. nelle pazienti trattate con docetaxel 100 mg/mq.
Ulteriori studi hanno confermato l'efficacia di peg-filgrastim nel ridurre l'incidenza di neutropenia febbrile, permettendo in tal modo di riciclare nei tempi previsti e quindi, di mantenere un'adeguata dose-intensity. Nello studio di Burstein et al (3), sono state arruolate 135 pazienti affette da carcinoma mammario (stadio I-III), che sono state sottoposte ad un regime âintensivoâ (dose-dense) neoadiuvante o adiuvante AC, seguito da Paclitaxel ogni 2 settimane, con il supporto di peg-filgrastim al giorno 2; l'incidenza di neutropenia febbrile è stata del 1,5 % (2 pazienti). L' 83% delle pazienti ha completato i programmati 8 cicli di chemioterapia e solo in 2 pazienti si è resa necessaria una riduzione di dose.
La stessa efficacia del peg-filgrastim in uno studio dose-dense è stata documentata da Piedbois et al. (4). In tale studio 100 pazienti sono stati randomizzati a ricevere 6 cicli TEC (docetaxel, epi, ciclofosfamide) o 4 cicli EC, seguiti da 4 cicli docetaxel (ogni 2 settimane) o 4 cicli docetaxel, seguiti da 4 cicli EC (ogni 2 settimane) con il supporto di peg-filgrastim al giorno 2 di ogni ciclo. L'incidenza di neutropenia febbrile è stata rispettivamente del 14%, del 5% e dello 0% nei 3 bracci.
Wenzel et al. (5) hanno documentato la fattibilità e l'efficacia in neo-adiuvante di uno schema a 3 farmaci, comprendente epirubicina, docetaxel e capecitabina, utilizzando il supporto di peg-filgrastim.
Il particolare profilo di efficacia ha stimolato lâimpiego del peg-filgrastim anche nelle pazienti anziane.
Nello studio di Romieu et al. (6) sono state inserite 31 pazienti âelderlyâ (età >65 anni) affette da carcinoma mammario in stadio II-III trattate con FEC 100, randomizzate a ricevere peg-filgrastim al primo ciclo o dopo il primo episodio di neutropenia. L'incidenza di neutropenia febbrile è stata del 7% nelle pazienti trattate con peg-filgrastim sin dal primo ciclo, rispetto al 27% di quelle in cui il farmaco è stato utilizzato dopo un primo episodio neutropenico; ciò si è tramutato anche in una minor incidenza di eventi avversi (41% versus 10%). Nello stesso studio, l'87% delle pazienti nel braccio con peg-filgrastim profilattico e il 69% di quelle nel braccio di confronto, hanno completato 4 cicli di chemioterapia. Partendo da questi presupposti, abbiamo deciso di impiegare il peg-filgrastim proprio nelle pazienti anziane affette da carcinoma mammario, trattate con schemi di chemioterapia a rischio intermedio â elevato di neutropenia febbrile. Tale scelta è supportata anche dalle linee guida ASCO e NCCN: in entrambi i casi si pone indicazione alla profilassi con fattori di crescita nel caso di rischio elevato di neutropenia febbrile (>20%), ma si considera il loro utilizzo anche nei casi di rischio intermedio (10-20%), quando vi siano particolari condizioni, tra cui lâetà avanzata (>65 anni).
Scopo del nostro studio è stato proprio quello di valutare l'efficacia del peg-filgrastim nelle pazienti anziane (età superiore a 65 anni) con carcinoma mammario, sottoposte ad un trattamento antiblastico, pre/post-operatorio o per malattia metastatica (prima linea), con schemi a rischio intermedio-elevato di neutropenia febbrile.
Obiettivi
Gli obiettivi primari sono stati: 1) incidenza di neutropenia febbrile, intesa come associazione di una conta neutrofila assoluta < 500/mm³ e febbre ⥠38 °C, misurata il giorno stesso del controllo dellâemocromo; 2) mantenimento della RDI (Relative Dose Intensity).
Gli obiettivi secondari sono stati: 1) consumo di antibiotici; 2) tasso di ospedalizzazione.
Criteri di inclusione
Sono state ritenute eleggibili per lo studio pazienti di età ⥠a 65 anni con diagnosi di carcinoma della mammella, in trattamento a scopo neoadiuvante/adiuvante o metastatico di prima linea con schemi a rischio intermedio ed elevato di neutropenia febbrile (Adrimicina/ciclofosfamide, Epirubicina 100 mg/m², Adriamicina/paclitaxel, Epirubicina/paclitaxel, adriamicina/docetaxel, etc).
Pazienti e metodi
Tutte le pazienti eleggibili sono state sottoposte ad iniezione di PEG-Filgrastim (Neulasta f 6 mg): 1 fiala sottocute 24 ore dopo il ciclo di chemioterapia, con controllo dell'emocromo al giorno 7; alle pazienti veniva chiesto di misurare la temperatura corporea lo stesso giorno. Nel caso in cui al controllo del giorno 7 si fosse documentata una neutropenia di grado III non febbrile, veniva effettuato un nuovo controllo a 48 ore. Nel caso in cui al controllo del giorno 7 si fosse documentata una neutropenia di grado IV non febbrile, veniva effettuato un nuovo controllo dell'emocromo il giorno successivo; se si confermava la neutropenia dello stesso grado - in assenza di febbre - si effettuava un nuovo controllo a 24 ore. Nel caso in cui al controllo del giorno 7 si fosse documentata una neutropenia di grado III o IV febbrile, il clinico decideva circa lâimpiego di antibioticoterapia, valutando lâeventuale ospedalizzazione nei casi più gravi; i successivi controlli dell'emocromo venivano effettuati a discrezione del clinico.
A distanza di 48 ore, se non si verificava la normalizzazione dei neutrofili (o comunque una tendenza allâincremento della conta neutrofila), il clinico decideva per eventuale somministrazione di antibiotici e/o ospedalizzazione.
Nelle pazienti in trattamento adiuvante, la somministrazione di peg-filgrastim veniva proseguita sino al completamento della chemioterapia prevista con lo schema a rischio intermedio-elevato di neutropenia febbrile (es: le pazienti trattate con lo schema AC seguito da paclitaxel sono state trattate solo per i primi 4 cicli AC); nelle pazienti in trattamento per carcinoma mammario metastatico, la somministrazione di peg-filgrastim veniva proseguita per un massimo di 6 cicli consecutivi.
Risultati
Fino ad oggi sono state incluse nello studio tredici pazienti, con età media di 69,6 anni (range 65-79) e così suddivise:
8 pazienti: sottoposte a chemioterapia adiuvante;
1 paziente: sottoposta a chemioterapia neoadiuvante;
4 pazienti: sottoposte a chemioterapia per malattia metastatica.
Gli schemi di chemioterapia impiegati in neoadiuvante/adiuvante sono stati: epirubicina/paclitaxel; AC (adriamicina/ciclofosfamide); AC seguito da paclitaxel. Gli schemi utilizzati nelle pazienti con malattia avanzata sono stati: epirubicina/paclitaxel, doxorubicina liposomiale non pegilata/ciclofosfamide, doxorubicina liposomiale non pegilata/docetaxel. Il numero medio di cicli somministrati è stato di 5 (range 3 â 7).
Una paziente su tredici (8%) ha manifestato neutropenia febbrile (paziente n.4); in tre pazienti su tredici (23%) è stata documentata una neutropenia media di grado IV. (vedi tab. 1)
In due pazienti (15%) è stata utilizzata antibioticoterapia orale (paziente n.2: amoxicillina 1 g ogni 12 ore per 3 giorni, dopo il quarto ciclo; paziente n.4: ciprofloxacina 500 mg, 1 cpr ogni 12 ore per 3 giorni dopo il secondo ciclo e ciprofloxacina 500 mg ogni 12 ore per 5 giorni dopo il terzo, quarto e quinto ciclo).
Nella paziente n.4 si è deciso di ridurre il dosaggio dei chemioterapici (schema AC) al 75% il quarto e quinto ciclo (al 50% il sesto ciclo per una concomitante piastrinopenia di grado III); in tutte le altre pazienti non vi sono stati riduzioni di dose per tossicità midollare o ritardi di somministrazione della chemioterapia, anche se, in altre 4 pazienti è stata necessaria una riduzione del dosaggio dei farmaci al 75% per una tossicità sistemica.
La RDI media è stata complessivamente del 93,5 % (considerando anche le pazienti in cui il dosaggio è stato ridotto per tossicità sistemica) e del 95,2% nelle otto pazienti in trattamento adiuvante. In nessuna paziente è stato necessario impiegare antibiotici parenterali e in nessun caso è stata necessaria lâospedalizzazione. Gli effetti collaterali riferibili alla somministrazione di peg-filgrastim sono stati: malessere generale in due pazienti (in una paziente associato a febbricola) e dolori osteo-muscolari in una terza paziente.
Discussione
I pazienti anziani rappresentano una popolazione particolarmente sensibile allâincidenza di effetti collaterali da chemioterapia, ed in particolare di tossicità midollare. Le stesse linee guida ASCO ed NCCN consigliano lâimpiego di fattori di crescita (G-CSF) nella profilassi primaria da chemioterapia a rischio elevato di neutropenia febbrile (> 20%), ma ne suggeriscono lâuso anche in particolari categorie di pazienti (vedi, età > 65 anni, presenza di co-morbidità , pregressa tossicità midollare) trattati con chemioterapia a rischio intermedio (10-20%). Del resto, recenti evidenze cliniche (6) documentano come un approccio preventivo della neutropenia febbrile con filgrastim peghilato nelle pazienti anziane sia in grado di ridurre lâincidenza, non solo di tale evento collaterale, ma anche di ulteriori eventi avversi.
Scopo del nostro studio è stato proprio quello di valutare lâefficacia in profilassi primaria di PEG-filgrastim nelle pazienti anziane affette da carcinoma della mammella, trattate con schemi a rischio intermedio-elevato di neutropenia febbrile. I risultati preliminari dello studio, disponibili su sole tredici pazienti, sono stati tuttavia molto incoraggianti, tenuto conto di tutti gli obiettivi dello studio, sia primari sia secondari.
Il dato particolarmente interessante, oltre alla bassa incidenza di neutropenia febbrile, è rappresentato dal mantenimento della RDI nelle pazienti trattate in adiuvante (95,2%). Eâ ormai consolidato che il mantenimento di unâadeguata dose-intensity rappresenta un obiettivo fondamentale del trattamento adiuvante, in quanto requisito predittivo di sopravvivenza (7). Visti i promettenti risultati, lo studio è tuttora in corso.
Tab. 1: CAN medio delle pazienti
Bibliografia:
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Abstract: This case report concerns an elderly patient with liver and bone metastases of breast cancer successfully treated for two-years with capecitabine as first line chemotherapy without any side effect.
Abstract: This case report concerns a patient with double synchronous neoplasm, small cell lung and gastric cancer, successfully treated with chemotherapy. The cancers had a good response with complete remission of lung cancer and partial remission of gastric cancer. The management of double neoplasms has been reviewed.
Abstract: Gemcitabine (2'-2'-difluorodeoxycytidine, dFdC) is a novel nucleoside analogue of deoxycytidine recently introduced for the treatment of pancreatic cancer and non-small-cell-lung cancer (NSCLC). We studied the occurrence of thrombocytosis when using this drug.
