A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer.

Our purpose was to determine the response rate and median and overall survival of gemcitabine as monotherapy versus gemcitabine plus irinotecan in advanced or metastatic pancreatic cancer. Patients with histologically or cytologically confirmed adenocarcinoma who were chemotherapy and radiotherapy naive were enrolled. Patients were centrally randomised at a one-to-one ratio to receive either gemcitabine monotherapy (900 mg m(-2) on days 1, 8 and 15 every 4 weeks (arm G), or gemcitabine (days 1 and 8) plus irinotecan (300 mg m(-2) on day 8) (arm IG), repeated every 3 weeks. The total number of cycles administered was 255 in the IG arm and 245 in the G arm; the median number of cycles was 3. In all, 145 patients (71 in arm IG and 74 in arm G) were enrolled; 60 and 70 patients from arms IG and G, respectively, were evaluable. A complete clinical response was achieved in three (4.3%) arm G patients; nine (15%) patients in arm IG and four (5.7%) in arm G achieved a partial response. The overall response rate was: arm IG 15% and arm G 10% (95% CI 5.96-24.04 and 95% CI 2.97-17.03, respectively; P=0.387). The median time to tumour progression was 2.8 months and 2.9 months and median survival time was 6.4 and 6.5 months for the IG and G arms, respectively. One-year survival was 24.3% for the IG arm and 21.8% for the G arm. No statistically significant difference was observed comparing gemcitabine monotherapy versus gemcitabine plus irinotecan in the treatment of advanced pancreatic cancer, with respect to overall and 1-year survival.

Methotrexate, etoposide, ifosfamide and cisplatin (MVIP): an effective first-line therapy for IGCCC intermediate / poor prognosis patients with germ-cell tumors. Single institution experience.

PURPOSE: To evaluate the antitumor activity and toxicity of methotrexate (M), etoposide (V), ifosfamide (I) and cisplatin (P) combination chemotherapy (MVIP) administered to chemotherapy-naive patients with intermediate / poor prognosis germ-cell tumors (GCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) consensus classification system (IGCCC). PATIENTS AND METHODS: From 1992 to 2001 24 consecutive intermediate (n=14)/poor prognosis (n=10) GCT male patients entered prospectively this phase II trial. Patients received methotrexate 250 mg/m(2), day 1, with folinic acid rescue; cisplatin 100 mg/m(2) with appropriate hydration, day 3; ifosfamide 5 g/m(2) with mesna uroprotection, day 3; and etoposide 100 mg/m(2)/day, days 3-5. MVIP was repeated every 3 weeks. RESULTS: After 120 cycles of MVIP (median 5, range 2- 7) 18 (75%) patients achieved complete remission (CR). CR was attained by 12 out of 14 (86%) intermediate prognosis and 6 out of 10 (60%) poor prognosis patients. Three CR patients (2 intermediate, 1 poor prognosis) of out 18 (16.7%) relapsed after a median of 6 months and 1 of them (poor prognosis) achieved a durable CR with second-line chemotherapy. After a median follow-up of 37 months (range 5-115 months) 16 patients (10, 71% intermediate and 6, 60% poor prognosis) are long-term survivors with no evidence of disease (NED), and 2 (one of each group) are alive with disease. Actuarial overall survival at 3 and more years is 75% and NED survival is 67%. Hematologic toxicity was most common and easily manageable (grade 3-4 neutropenia 46% of the cycles and thrombocytopenia 25% of the cycles). There were no deaths, withdrawals or delays in chemotherapy administration because of toxicity. CONCLUSION: MVIP conventional chemotherapy proved very effective in terms of CR rate, overall survival and longterm NED survival in these unfavorable groups of GCT patients. The results obtained are encouraging and compare favorably with those taken by more intensive regimens including high-dose chemotherapy. We believe that MVIP justifies further studies.

Methotrexate, etoposide, ifosfamide and cisplatin (MVIP): An effective salvage therapy for patients with refractory or relapsed germ-cell tumors.

PURPOSE: To study the efficacy and toxicity of a combination of methotrexate, etoposide, ifosfamide and cisplatin (MVIP) in patients with germ-cell tumors (GCTs) refractory to or relapsed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Between 1989 and 2001 22 male patients with GCTs refractory (n=7) or relapsed (n=15) after first-line platinum-based chemotherapy entered prospectively the study. Their median age was 29 years. Methotrexate 250 mg/m(2) as 4-hour infusion plus folinic acid were administered on day 1. On day 3 cisplatin 100 mg/m(2) with pre and posthydration was given as 30-min infusion; and ifosfamide 5 g/m(2) with mesna as 24-hour infusion. Etoposide 100 mg/m(2)/day as 1-hour infusion was administered on days 3-5. Cycles were repeated every 3 weeks. Granulocyte colony stimulating factor (GCSF) was administered either therapeutically (grade 3-4 neutropenia-/+antibiotics) or prophylactically (nadir grade 3-4 neutropenia in the previous chemotherapy cycle). RESULTS: All patients were evaluable for response, toxicity and survival. A total of 95 cycles (median 4 cycles per patient) of MVIP were administered. Fourteen (63.6%) patient achieved complete response (CR), and 8 (36.4%) were treatment failures. Long-term disease-free survival (DFS) with MVIP was achieved in 11 out of 14 (78.6%) CR patients or 50% of all patients. After a median follow-up period of 55.04(+) months (range 4-147(+) months) overall survival is 59.09%. Good performance status (PS) was the only significant predictor for survival. Toxicity was easily manageable with no deaths or therapy delays. CONCLUSION: MVIP conventional chemotherapy proved particularly effective in terms of CR rate, overall survival and long-term DFS in this very poor prognosis patient population. Toxicity was tolerable. The results obtained are equal or even superior compared with those taken by more intensive regimens, including high-dose chemotherapy. MVIP justifies further studies in patients with refractory/ relapsed GCTs.

Paclitaxel in cisplatin or carboplatin-pretreated ovarian cancer. Phase II study.

A phase II trial was conducted in order to assess the efficacy and toxicity of paclitaxel given at a dose of 175 mg/m2 in a 3-hour infusion every 3 weeks in patients with recurrent or cisplatin (CDDP) carboplatin-refractory ovarian cancer. Forty-two patients with a median age of 61 years (range 34-76 years) entered the study. Most patients had bulky disease. Thirty-three patients (78.5 %) presented with stage III and IV diseases. Twenty-two patients (52.3%) had previously been treated with only 1 regimen and 20 patients (47.7%) with > or = 2 regimens. The median treatment interval from the last previous therapy was 4.5 months (range 2-26 months). From 41 patients evaluable for response, 3 (7.3%) achieved a complete and 4 (9.8%) a partial response. All 3 complete and 2 out of the 4 partial responders had previously received > or = 2 chemotherapeutic regimens. Grade 3-4 toxicities included granulocytopenia (35%), which was of short duration, neurotoxicity (9.75%) and alopecia (60.9%). Two patients with grade 4 neutropenia were hospitalized due to pneumonia, which was successfully treated by broad-spectrum antibiotics and administration of G-CSF. A severe hypersensitivity reaction occurred in 1 patient early during the first cycle, resulting in discontinuation of treatment. Median relapse-free survival was 6.9 months, median time to progression 6.2 months and median survival 13.2 months. In conclusion, paclitaxel given at a dose of 175 mg/m2 as a 3-hour infusion every 3 weeks appears to be an efficacious and well-tolerated treatment in patients with recurrent or CDDP/carboplatin-refractory ovarian cancer.

Chemotherapy with methotrexate, carboplatin, mitoxantrone (Novantrone) and vincristine (Oncovin) in transitional-cell urothelial cancer.

Forty-four patients with either metastatic or locally advanced transitional cell carcinoma of the bladder were treated with the MCNO regimen (methotrexate 300 mg/m2 in 1,000 ml normal saline as a 4-hour infusion on days 1 and 14 with leucovorin rescue 15 mg 6-hourly for 6 doses; carboplatin 300 mg/m2 in 250 ml 5% distilled water as a 1-hour infusion on day 1; mitoxantrone (Novantrone) 10 mg/m2 in 100 ml 5% distilled water as a 30-min infusion on day 1, and vincristine (Oncovin) 1 mg/m2 as an intravenous bolus on days 1 and 14. Patients with metastatic disease were treated with 6 cycles, while patients with locally advanced disease were treated with 4 cycles of induction chemotherapy followed by cystectomy or radiotherapy. The overall response rate was 40%, with 15% complete response (CR). The responses were better for patients with locally advanced disease (CR 25%, partial response, PR, 31.25%, response rate, RR, 56.25%) than for those with metastatic disease (CR 8.3%, PR 20.83%, RR 29.1 %). The differences in these results were probably due to the bad performance status and the presence of visceral metastases in patients with generalized disease. The overall median survival was 14 months, with responders living longer (median survival 28.8 months in patients with locally advanced disease and 22.9 months in patients with metastatic disease) than non-responders (median survival 16 months in patients with locally advanced disease and 8.9 months in patients with metastatic disease). The difference in survival between responders and non-responders was statistically significant in both groups of patients. Toxicity was moderate, but manageable. The MCNO regimen appears to have a lower efficacy than that obtained with cisplatin-based regimens for the treatment of metastatic disease and rather similar efficacy for the treatment of locally advanced urothelial-cell cancer. Therapy with this regimen, though less toxic, may not be a reliable alternative in elderly patients with visceral metastases and a performance status of > or = 2.

An outpatient phase II study of subcutaneous interleukin-2 and interferon-alpha-2b in combination with intravenous vinblastine in metastatic renal cell cancer.

A prospective phase II trial was carried out to define the activity of a low-dose subcutaneous regimen of interleukin-2 (IL-2) and interferon alpha-2b (IFN-alpha) in combination with intravenous administration of vinblastine (VLB) in patients with metastatic renal cell cancer (RCC). Thirty-one patients with advanced RCC who had received no prior biochemotherapy were treated with IL-2 4.5 MU x 2/24 h thrice weekly for 2 weeks, IFN-alpha 3 MU/24 h thrice weekly (alternating days) for 2 consecutive weeks and VLB 4 mg/m2 every 3 weeks. Patients were to have a 1-week rest period after each 2 weeks of therapy with cytokines. Treatment was repeated every 3 weeks. Maximum duration of treatment was 1 year. Treatment was administered on an outpatient basis. There were 4 complete (12.9%) and 8 partial responses (25.8%), with an overall response rate of 38.7%. The median duration of response was 6.5 months. Responses were seen in lung, lymph nodes, bones, liver and other tumor metastases. Toxicity was mild to moderate, consisting of fever, anorexia, malaise and nausea-vomiting in > 80% of patients. Hypotension and transient alopecia occurred in > 20% of patients. Liver enzyme elevation was frequently observed. Treatment-induced eosinophilia occurred in the majority of patients, while in 52% of patients granulocytopenia grade II and grade III did not require dose modification of drugs. Transient inflammation and local induration at the injection sites was observed in the majority of patients. None of the patients experienced major VLB-related toxicity and no toxic deaths occurred. This three-drug combination immunochemotherapy may be a promising regimen with modest toxicity in advanced RCC.

CEA, CA 19-9, and CA-50 in monitoring gastric carcinoma.

This study was conducted to investigate the clinical utility of CEA, CA 19-9, and CA-50 in the diagnosis, monitoring, and prognosis of 62 gastric carcinoma patients having either adjuvant or palliative chemotherapy. Patients were divided in two groups: group A included patients treated on an adjuvant basis following a curative resection of gastric cancer, and group B included patients with residual disease post surgery or patients with inoperable tumor or generalized disease. Serum marker levels were measured in a prospective study just before the initiation of chemotherapy and before each course during chemotherapy. In group A, CEA was positive in 2/25 (8%) patients, CA 19-9 in 1/25 (4%), and CA-50 in 1/25 (4%). In group B the sensitivity of CEA was 48.6% (18/37 patients), of CA 19-9 64.9% (27/37 patients), and of CA-50 70.3% (26/37) patients. There was a significant correlation between the CA 19-9 and CA-50 levels in both groups. No correlation was found between the sensitivity or the absolute initial marker levels and the tumor's differentiation or extent of disease. In group A the only patient with initially elevated CA 19-9 and CA-50 values relapsed early while he was on adjuvant chemotherapy. It was also found that the rising final CA 19-9 and CA-50 values at the end of chemotherapy were correlated with an increased incidence of relapse, but not with the disease-free interval. In group B the initially low marker levels showed a trend to predict a favorable outcome of treatment. There was no statistically significant correlation between the marker titers before each course and response to chemotherapy. It is concluded that the comeasurement of CA 19-9 and CA-50, and to some degree of CEA, is justifiable for gastric cancer. The estimation of CA 19-9 and CA-50 may be useful for early detection of recurrence after curative surgery and adjuvant chemotherapy. In advanced or recurrent gastric cancer, the estimation of either CA 19-9 or CA-50 and CEA serum values may help in checking the prognosis, determining the efficacy of palliative treatment modalities, and recognizing recurrences.

Comparison of two different doses of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced emesis.

This study was conducted to evaluate the efficacy of two different doses of ondansetron (8 mg vs. 24 mg) plus dexamethasone in the prevention of cisplatin (CDDP)-induced emesis and nausea (acute and delayed). The persistence of the anti-emetic efficacy during the second cycle of chemotherapy was also assessed. Eighty patients receiving high-dose CDDP (>80 mg/m2) were randomized to have either ondansetron 8 mg plus dexamethasone 20 mg (8 mg group) or ondansetron 24 mg plus dexamethasone 20 mg (24 mg group), given intravenously as a single dose before the CDDP infusion. From days 2-5, all patients received oral ondansetron 8 mg twice daily. Seventy-five patients (38 in the 8 mg group and 37 in the 24 mg group) were evaluable for analysis. Among these, there were 24 patients who received ifosfamide (IFO) on the 2nd day of treatment; these patients were evaluated separately for delayed emesis. Complete protection from acute emesis was obtained in 26 (68.4%) and 26 (70.3%) patients, in the two groups, respectively. Complete protection against acute nausea was achieved in 23 (60.5%) and 24 (64.9%) patients, respectively. With respect to the delayed emesis, complete protection was achieved in 14 (56%) and 13 (50%) patients not receiving IFO and in 4 (30.8%) and 3 (27.3%) of those receiving IFO. The figures for the delayed nausea were: 12 (48%) and 13 (50%), 2 (15.4%) and 2 (18.2%), respectively. Similar protection against emesis and nausea was recorded during the second cycle of chemotherapy. Both regimens have the same efficacy and thus, taking into account the cost-effectiveness, 8 mg of ondansetron plus dexamethasone in a single intravenous dose should be used for the prevention of high-dose CDDP-induced emesis.

Superiority of carboplatin monochemotherapy over carboplatin-based polychemotherapy in ovarian cancer.

Forty patients with previously untreated epithelial ovarian cancer (OC), with FIGO stages Ic-IV, were randomly allocated to receive intravenously either carboplatin (C) 400 mg/m2 every three weeks (C arm, 20 patients) or a combination of C 350 mg/m2, ifosfamide (I) 5 g/m2 with mesna every three weeks, vincristine (V) 1.4 mg/m2 (maximum total dose 2 mg) and bleomycin (B) 30 mg every ten days (CIVB arm, 20 patients). Responding patients received 6 courses of chemotherapy and all 40 patients were evaluable for toxicity, response and survival. Clinical characteristics of patients were similar in both arms. Clinico-imaging results with chemotherapy were as follows: in C arm, clinical complete remission (cCR) 11 (55%) and partial remission (cPR) five (25%) patients for an overall response rate (ORR) 80%. For CIVB arm, cCR ten (50%) and cPR four (20%) patients for an ORR 70%. Second look operation (SLO) was performed in three of the 11 cCR patients in the C arm and six of the ten cCR patients in the CIVB arm. Pathological CR (pCR) was confirmed in two of the three cCR C arm patients and two of the six in the CIVB patients. In the first interim analysis statistically significant differences, all favoring monochemotherapy, were seen in response duration, time to progression, disease-free and overall survival. These results along with the severe myelotoxicity resulting in dose reductions in the CIVB patients led us to stop enrolling new patients and follow this population closely for long-term results. These confirmed the first observations of the superiority of single-agent carboplatin in response duration (p = 0.034), time to progression (p = 0.028), disease-free survival (p = 0.010) and overall survival (p = 0.043). Because of the above reasons we have concluded that monochemotherapy with carboplatin is to be preferred over carboplatin in combination with other drugs.

TPA, TATI, CEA, AFP, beta-HCG, PSA, SCC, and CA 19-9 for monitoring transitional cell carcinoma of the bladder.

A total of 76 patients with transitional cell carcinoma of the bladder were prospectively monitored with simultaneous serum value estimations of tumor polypeptide antigen (TPA), tumor-associated trypsin inhibitor (TATI), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-HCG), prostatic specific antigen (PSA), squamous cell carcinoma antigen (SCC), and CA 19-9 in different stages and phases of their disease. In locally advanced disease positive values were noted for TATI in 22/28 patients (78.5%), for TPA in 17/28 (60.7%), for CA 19-9 in 10/28 (35.7%), for CEA 11/28 (39.2%), for beta-HCG in 3/28 (10.7%), for PSA in 6/28 (21.4%), for SCC in 6/28 (21.4%), and for AFP in 0/28. In metastatic disease elevated levels were observed for TATI in 43/48 patients (89.5%), for TPA in 41/48 (85.4%), for CA 19-9 in 19/48 (39.5%), for CEA in 20/48 (41.6%), for beta-HCG in 6/48 (12.5%), for PSA in 7/48 (14.5%), for SCC in 8/48 (16.6%), and for AFP in 1/48 (2.1%). In metastatic disease TATI and TPA values were significantly modified in patients with complete remission and TATI, TPA, and CA 19-9 in patients with partial remission and nonresponders. In T2-T4-N0M0 tumors, TPA, TATI, CA 19-9, and CEA were significantly increased in nonresponders. In patients with complete remission, a change in serum TATI, TPA, and CA 19-9 levels cannot be evidenced with the available numbers. The concurrent determination of TATI and TPA in T2-T4N0M0 tumors and TATI, TPA, and CA 19-9 in generalized disease could predict the response to chemotherapy. This study indicates that only the determination of TATI and TPA and in some degree the CA 19-9 is a potential tool for monitoring the efficacy of treatment.

Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide.

Merkel cell carcinoma is a rare malignant tumor of the skin. We treated three patients with Merkel call carcinoma with the combination of carboplatin and etoposide, which have been mostly used in the treatment of small cell lung carcinoma. Two patients experienced partial remission of short duration. The third patient received the combination on an adjuvant basis but relapse occurred briefly. Two of these patients failed to respond to second-line chemotherapy with cisplatin, ifosfamide, and epirubicin. The patient who had the first-line treatment on an adjuvant basis, responded completely with the second-line chemotherapy plus radiotherapy and remains disease-free for 5+months. Merkel cell carcinoma appears to be a sensitive tumor to chemotherapeutic regimens used for small cell lung carcinoma, but the responses are often brief.

Treatment of metastatic malignant melanoma with dacarbazine, vindesine and cisplatin.

Twenty-seven patients with disseminated malignant melanoma were treated monthly with cisplatin (CDDP) 120 mg m-2 on day 1, vindesine (VDS) 3 mg m-2 on day 2 and dacarbazine (DTIC) 250 mg m-2 on days 2-6. None of them had received prior chemotherapy. All patients are evaluable for response and toxicity. There were five (19%) complete (CR) and seven (26%) partial (PR) responses for a total response rate of 45%. We conclude that the combination of DTIC, VDS and CDDP is capable of producing a relatively high rate of response in patients with advanced metastatic malignant melanoma, but responses are short.