Combined chemoimmunotherapy of metastatic melanoma: a single institution experience

The addition of cytokines, such as interferon alpha-2b and interleukin-2, to chemotherapy in metastatic melanoma has produced conflicting results in phase II and III trials. We report our experience with a chemoimmunotherapeutic regimen using subcutaneous cytokines. Twenty-eight patients with advanced melanoma (median age, 45 years; male to female ratio, 19 : 9) were treated. Doses were as follows: cisplatin, 20 mg/m intravenously (iv) days 1-4; vinblastine, 1.6 mg/m iv days 1-4; dacarbazine, 800 mg/m iv day 1; interferon alpha-2b, 5 MIU/m subcutaneously (sc) days 1-5; interleukin-2, 9 MIU/m sc days 1-5 and 8-12. Treatment was repeated every 3 weeks for a maximum of six cycles. The response was assessed after two cycles and toxicity at every cycle, according to World Health Organization (WHO) and National Cancer Institute (NCI) criteria, respectively. At a median follow-up of 8 months, only four patients (14%) were still alive. The overall response rate was 33%, with three (11%) complete responses lasting for 17, 14 and >24 months. There were six (22%) partial responses and three stable disease. Amongst the responders, three patients progressed at the level of the central nervous system. The median time to progression and overall survival were 3.5 and 9 months, respectively. The most common grade 3-4 toxicity was neutropenia, reported in 25 of the 28 patients (92%). Only two patients (7%) experienced neutropenic fever. Thrombocytopenia grade 3-4 occurred in seven of the 28 patients (25%), with only one patient needing transfusional support. One toxic death due to neutropenic fever occurred. It can be concluded that the chemoimmunotherapy schedule evaluated is active and may be considered for patients with metastatic melanoma who have a good performance status and a limited disease burden.     

Docetaxel and cisplatin as first-line treatment for patients with metastatic esophageal cancer: a pilot study

BACKGROUND: We investigated the combination of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic esophageal cancer. PATIENTS AND METHODS: 16 chemotherapy-na?ve patients with distant metastases were included in the study (15 male, 1 female; median age: 58.5 years (range 37-69); median ECOG performance status: 1). 11 patients (69%) had esophageal cancer, and 5 patients (31%) had cancer of the gastroesophageal junction. Patients received docetaxel 75 mg/m2 and cisplatin 80 mg/m2 on day 1 every 3 weeks. A total of 55 chemotherapy cycles was administered. The median number of cycles was 3 (range 1-6). RESULTS: The overall response rate was 31.3%. 4 out of 10 patients (40%) with squamous cell carcinoma and 1 out of 5 patients (20%) with adenocarcinoma responded to chemotherapy. The median overall survival was 29.6 weeks, and the median progression-free survival was 18.6 weeks. Hematological and non-hematological toxicities were moderate (neutropenia WHO grade III/IV: 42.9%, alopecia grade II/III: 64.3%, nausea/vomiting grade II/III: 57.2%, neurotoxicity grade II: 14.3%). CONCLUSION: The combination of docetaxel and cisplatin is an active regimen with moderate toxicity in the treatment of patients with metastatic esophageal cancer. This pilot study demonstrates the feasibility of a combination treatment containing a taxane and cisplatin in metastatic esophageal cancer.     

A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer.

From April 1985 to September 1988, 128 patients with advanced non-small-cell lung cancer (NSCLC) were enrolled in a prospective randomized trial evaluating chemotherapy (arm A) versus best supportive care (arm B). Chemotherapy consisted of cyclophosphamide 500 mg/m2 intravenously (IV) day 1, epirubicin 50 mg/m2 IV day 1, and cisplatin 80 mg/m2 IV day 1 (CE'P regimen) alternating every 4 weeks with methotrexate 30 mg/m2 IV day 1, etoposide 200 mg/m2 IV day 1, and lomustine (CCNU) 70 mg/m2 orally day 1 (MEC' regimen) until progression. Of the 123 patients (62 treated and 61 controls) eligible for survival, 115 were fully evaluable for response (58 treated and 57 controls). Response rates were 21% partial response, 53% stable disease, and 26% progressive disease in arm A, and 47% stable disease and 53% progressive disease in arm B. Median survival was 34.3 weeks (range, 4.3 to 218.6+ weeks) in arm A versus 21.1 weeks (range, 4.3 to 188.6 weeks) in arm B; the difference was not significant at P = .153 (Mantel-Cox). Subgroups of patients retrospectively analyzed by age, performance status, stage M0/M1, and weight loss or not showed no significant difference in survival. Poor-risk patients (at least two of the following: poor performance status, stage M1, weight loss) of arm A survived significantly longer than poor-risk patients of arm B (23.6 weeks v 12.4 weeks, Mantel-Cox P = .008); a significant difference in survival was also observed between nonsquamous cell patients of arm A and those of arm B (median survival, 38.6 weeks v 16.7 weeks; Mantel-Cox P = .041). Toxicity on the chemotherapy arm was hematologic (World Health Organization [WHO] grade greater than 3) in 12% of CE'P and in 13% of MEC' courses and gastroenteric (WHO grade greater than 3) in 24% of CE'P courses and in 8% of MEC' courses. Our alternating treatment was not significantly superior to supportive care. It is likely that certain subgroups of the NSCLC category may have an advantage with chemotherapy.     

Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. Belgian Study Group for Ovarian Carcinoma

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50-100 mg/m2 per course) plus carboplatin (CBDCA: 300-400 mg/m2 per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine greater than 1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/m2 per course and CDDP at 100 mg/m2 per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy.     

Phase I study of vinorelbine by 96-hour infusion in advanced metastatic breast cancer

The purpose of this study was to evaluate the maximum tolerated dose and the toxicity profile of vinorelbine administered by continuous infusion for 96 hours to patients who had received prior chemotherapy for metastatic breast cancer. Forty-three patients with metastatic breast cancer were treated with vinorelbine 8 mg intravenously for 10 minutes (day 1) followed by continuous infusion of vinorelbine for 96 hours. Treatments were repeated every 3 weeks. Eighty-eight percent of the patients had had two or more prior chemotherapeutic regimens: 91% had prior doxorubicin therapy and 77% had prior paclitaxel therapy. All 43 patients were evaluable for toxicity. The median age was 49 years. All patients had a performance status less than or equal to 2 and a life expectancy more than 12 weeks. Eight dose levels were evaluated, and a total of 182 cycles were given. National Cancer Institute grade III or IV granulocytopenia was observed in 64 (35%) cycles, neutropenic fever in 27 (15%) cycles, fatigue (National Cancer Institute grade III or IV) in 18 (10%) cycles, and hand-foot syndrome in 8 (4%) cycles. In 17 (9%) cycles, patients were hospitalized. The maximum tolerated dose of this regimen was determined to be vinorelbine 8 mg intravenously for 10 minutes (day 1) followed by continuous vinorelbine infusion 11 mg/m2 for 96 hours. The dose-limiting toxicity was neutropenic fever and stomatitis.     

Phase II study of the modified regimen of etoposide, leucovorin and 5-fluorouracil for patients with advanced gastric cancer

BACKGROUND: The efficacy of the treatment of advanced gastric cancer is not very good. The response rate to the original etoposide--leucovorin--5-fluorouracil (ELF) treatment is 53% with tolerable side effects. Whether increasing the dose intensity by prolonging the duration of infusion with 5-fluorouracil (5-FU) and leucovorin (LV) from 3 to 5 days for advanced or metastatic gastric cancer patients would enhance the efficacy but not increase side effects is still unknown. METHODS: Thirty-six advanced or metastatic gastric cancer and chemotherapy-naive patients with measurable or evaluable diseases were scheduled to receive intravenous etoposide 100 mg/m2/day on days 2-4, LV 300 mg/m2/day intravenously and 5-FU 500 mg/m2/day intravenously on days 1-5, every 4 weeks. All patients who received at least two courses of chemotherapy were evaluated for tumor response, survival and response duration and toxicity according to the WHO criteria. RESULTS: Thirteen patients showed a response, including five with complete response (CR). The overall response rate was 36% (95% confidence interval, CI, 20-52%) in the whole group and 46% (95% CI 28-66%) in the 28 patients with measurable disease. The median progression-free interval and overall median survival time were 5 and 7 months, respectively. The most frequent toxicity was alopecia (grade I/II 56.3%). The incidence of grade III or greater myelosuppression was 5.9%. No treatment-related death occurred. CONCLUSIONS: The efficacy of the modified ELF by increasing the dosages of 5-FU and LV is not superior to the results of the original regimen, yet it is a relatively safe and tolerable combination regimen for advanced gastric cancer.      

Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease.

BACKGROUND: An important variable affecting outcome in relapsed and refractory Hodgkin's disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 3-4 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkin's lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD. PATIENTS AND METHODS: Patients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 1-4, cisplatin 100 mg/m(2) i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m(2) i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 micro g/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT. RESULTS: The median age of the 102 patients included was 34 years (range 21-64 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 0-6) and 48% (mean duration 1.4 days, range 0-11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 x 10(6)/kg CD34(+) cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients. CONCLUSIONS: A brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.     

Phase II study of irinotecan and ifosfamide in patients with advanced non-small cell lung cancer

OBJECTIVES: This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable or evaluable disease. CPT-11 (80 mg/m(2)) was administered intravenously on days 1, 8, and 15, while ifosfamide (1.5 g/m(2)) was given on days 1 through 3 every 4 weeks. RESULTS: Forty-four patients (31 men) with a median age of 65 years (range 43-75) and a median ECOG performance status of 1 (range 0-2) were enrolled. The response rate was 29.5% [95% CI: 16.7-45.2%], with 13 partial responses. The median survival was 12.5 months, the median time to progression was 5.3 months, and the 1 and 2-year survival rates were 52.3 and 11.3%, respectively. Toxicity was generally mild; WHO grade 3-4 neutropenia was recorded in 38.6% of the patients, grade 3 diarrhea in 6.8%, and grade 3-4 nausea/vomiting in 0%. CONCLUSIONS: CPT-11 combined with ifosfamide demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of cisplatin-based chemotherapy but with a more favorable toxicity profile.     

Gemcitabine, vinorelbine and cisplatin combination chemotherapy in advanced non-small cell lung cancer: a phase II trial

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m(2) gemcitabine and 25 mg/m(2) vinorelbine on days 1 and 8 and 75 mg/m(2) cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40-72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27-64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5-12.8+ months), median time to progression was 5.1 months (95% CI: 3.5-7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7-76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.     

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.     

拓扑替康联合顺铂治疗晚期卵巢癌的近期疗效观察

目的:观察拓扑替康(TPT)联合顺铂(PDD)治疗晚期卵巢癌的疗效、毒副反应。方法:对45例临床确诊的晚期卵巢癌病人进行化疗,TPT0.75mg/m2,PDD20mg/m2,连用5天为1个疗程,21天为1周期,2个周期结束后评价疗效。结果:45例病人化疗后,总有效率44.44%(20/45),其中初治病人有效率68.75%(11/16),复治病人有效率31.03%(9/29)。化疗后毒副作用主要表现为骨髓抑制,白细胞下降75.56%(34/45),Ⅲ度以上46.67%(21/45);血小板下降44.44%(20/45),Ⅲ度以上24.44%(11/45)。结论:TPT联合PDD治疗晚期卵巢癌,疗效肯定;尤其是对复发病人仍有效,可做为复发卵巢癌的二线或三线化疗。     

Phase II study of irinotecan plus cisplatin induction followed by concurrent twice-daily thoracic irradiation with etoposide plus cisplatin chemotherapy for limited-disease small-cell lung cancer.

PURPOSE: Irinotecan plus cisplatin (IP) chemotherapy demonstrated a promising outcome with a high complete response (CR) rate in chemotherapy-na?ve patients with extensive small-cell lung cancer (SCLC). We evaluated the efficacy of induction IP chemotherapy followed by concurrent etoposide plus cisplatin (EP) chemotherapy with twice-daily thoracic radiotherapy (TDTRT) in limited-disease SCLC (LD-SCLC). PATIENTS AND METHODS: Between November 2001 and May 2003, 35 chemotherapy-na?ve patients with LD-SCLC were enrolled. Thirty-three patients (94%) were male, and 29 (83%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median age was 63 years. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m2 and irinotecan 80 mg/m2 intravenously (i.v.) on days 1 and 8 followed by two 21-day cycles of cisplatin 60 mg/m2 i.v. on days 43 and 64, and etoposide 100 mg/m2 i.v. on days 43 to 45 and 64 to 66, with concurrent TDTRT of total 45 Gy beginning on day 43. RESULTS: All 35 patients were assessable for response. The objective response rate was 97% (CR, 3; partial response [PR], 31) after induction chemotherapy and 100% (CR, 15; PR, 20) after concurrent chemoradiotherapy (CCRT). After a median follow-up of 26.5 months, the median survival was 25.0 months (95% CI, 19.0 to 30.9) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Median progression-free survival (PFS) was 12.9 months with a 1- and 2-year PFS of 58.5% and 36.1%, respectively. The most common toxicities were grade 3 or 4 neutropenia in 68% of patients during induction chemotherapy and 100% during CCRT. Febrile neutropenia occurred in 20% of patients during induction chemotherapy and 60% during CCRT. CONCLUSION: IP induction chemotherapy followed by concurrent TDTRT with EP chemotherapy showed a promising activity with favorable 1- and 2-year survival rates. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.     

Treatment of advanced seminoma with cyclophosphamide, vincristine and carboplatin on an outpatient basis.

This study describes the efficacy and toxicity of a combination regimen consisting of cyclophosphamide, vincristine (oncovin) and carboplatin (COC) for advanced seminoma on an outpatient basis. Twenty-seven patients (mean age 43 years, range 28-63 years) were classified as stage IIC (n = 5), stage IID (n = 12), stage III (n = 9) or stage IV (n = 1). Six had been treated with prior radiotherapy; elevated beta-HCG and elevated LDH serum levels were observed in 15 and 25 patients respectively. Patients were treated with four cycles of 750 mg m-2 cyclophosphamide intravenously (i.v.), 1.4 mg m-2 vincristine i.v. (maximum 2 mg) and carboplatin adjusted to creatinine clearance. Cycles were given at 3 week intervals. The median dose of carboplatin administered was 400 mg m-2 (range 300-450 mg m-2). Six patients [22%; 95% confidence interval (CI), 6-38%] achieved a complete response (CR), 19 (70%; 95% CI, 51-88%) a partial response and two (8%; 95% CI, 0 18%) showed only a response in tumour markers but not a reduction of retroperitoneal mass (NR). Post-chemotherapeutic masses were not removed surgically or irradiated. After a median follow-up of 26 months (range 5-69 months), two patients have died, one from cardiac arrest 2 years after achieving CR, the other with relapsed seminoma 5 months after therapy. None of the other patients relapsed. Main toxicity was haematological, with 22 patients (81%) experiencing thrombocytopenia WHO grade III/IV and 27 (100%) leucocytopenia WHO grade III/IV, requiring dose reduction in five patients. Seven patients experienced granulocytopenic fever. Non-haematological toxicity was rare. Peripheral neuropathy grade I was observed in four patients and grade III in one. Haemorrhagic cystitis occurred once. In conclusion, despite considerable haematological toxicity, COC is feasible on an outpatient basis, even after prior radiotherapy, and is an effective regimen for advanced seminoma with only 1/27 treatment failures after a median follow-up of 26 months.     

Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.     

A phase II trial of 6-hydroxymethylacylfulvene (MGI-114, irofulven) in patients with relapsed or refractory non-small cell lung cancer

PURPOSE: To assess the efficacy and toxicity of 6-hydroxymethylacylfulvene (HMAF; MGI-114, irofulven) as therapy for relapsed or refractory non-small cell lung cancer. METHODS: A two-stage phase II design was employed separately for refractory and relapsed patients to differentiate between ineffective treatment (response rate < or =10%) and active treatment (response rate > or =30%). Eligible patients received HMAF 11 mg/m2 per day intravenously over 5 min on days 1-5, with cycles repeated every 28 days. RESULTS: Thirty-six patients (15 relapsed; 21 refractory) were treated, and no responses were seen. TOXICITY: Grade 3 neutropenia and grade 3 thrombocytopenia each occurred in 11% of the patients. Grade 3 nausea occurred in 47%; grade 3-4 vomiting in 42%. Twenty-two percent developed grade 3 fatigue. Eleven percent developed grade 3 hallucinations. CONCLUSIONS: HMAF, administered at this dose and schedule, is not active as salvage therapy for relapsed or refractory non-small cell lung cancer.     

Elderly patients with advanced colorectal cancer: tolerability and activity of chemotherapy

AIMS AND BACKGROUND: Colorectal cancer is the most common gastrointestinal tumor in Western countries and is increasing in elderly patients. In recent years, new treatments based on the use of 5-fluorouracil associated with oxaliplatin or CPT-11 have shown promising activity. The aim of the present study was to analyze the tolerability and activity of chemotherapy with 5-fluorouracil plus oxaliplatin or CPT-11 in elderly patients with advanced colorectal cancer. METHODS: Patients aged 70 years or older with advanced colorectal cancer were treated with 5-fluorouracil (400 mg/m2 in bolus and 600 mg/m2 in a 22-hr continuous infusion on days 1-2) plus folinic acid (100 mg/m2) associated to oxaliplatin (85 mg/m2 on day 1, FOLFOX regimen) or CPT-11 (180 mg/m2 on day 1, FOLFIRI regimen), every 14 days. RESULTS: Twenty-nine patients with a median age of 76 years (range, 70-82) were treated with FOLFOX or FOLFIRI as first-line chemotherapy for metastatic disease. We observed a partial response in 8/29 (27.6%), stable disease in 11/29 (37.9%) and progressive disease in 10/29 (34.5%). Median survival was 21 months; 1-year survival probability was 89.8%. Grade III leukopenia was observed in 2/29 (7%) patients and grade III diarrhea in 1/29 patients. No other grade III-IV toxicity was observed. CONCLUSIONS: FOLFOX and FOLFIRI appear to be active and well tolerated regimens for elderly patients with advanced colorectal cancer.     

Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial.

PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m(2) as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m(2) as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m(2) preceded 5-FU administration of 400 mg/m(2)/d initial IV bolus dose followed by 600 mg/m(2)/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks. RESULTS: All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred. CONCLUSION: The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.     

Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: optimal compliance and promising 4-year results

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.     

4′-O-Tetrahydropyranyl-doxorubicin in advanced breast cancer: a phase II study

Summary In a phase II study, 35 patients with advanced breast cancer were treated with 4′-O-tetrahydropyranyldoxorubicin (THP-DXR) (70 mg/m² i.v. on day 1); treatment was repeated every 3 weeks. Eight patients had failed prior chemotherapy for advanced disease. A total of 34 patients were evaluable for response. After a median of 10 treatment courses (range, 3–15), objective tumor response was seen in 59% (20 of 34 patients) (95% confidence limits, 42%–75%). In all, 17 partial remissions and 3 complete remissions were observed; stable disease occurred in 13 patients. The median duration of response was 42+ weeks (range, 21–77+ weeks). The dose-limiting side effects were leukopenia (26 patients, WHO grade III–IV) and thrombocytopenia (9 patients, WHO grade II–IV). Nausea/vomiting was experienced by 34 patients; in 18, it reached WHO grade II–III. Other treatment-related side effects included alopecia (WHO grade II–III) in 26 patients and stomatitis and diarrhea (WHO grade I–III) in 9 patients. At cumulative doses of THP-DXR of at least 700 mg/m² (range, 700–1,050 mg/m²), no signs of congestive heart failure were observed. We conclude that THP-DXR is effective for first- and second-line chemotherapy in advanced breast cancer and that side effects are manageable.     

Final results of a prospective trial of a PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) regimen followed by radiotherapy after curative surgery for pancreatic adenocarcinoma

BACKGROUND: Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial. METHODS: The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18-70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) > or =70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (alpha 0.05; beta 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery. RESULTS: Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3-4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 +/- 7%. Two-year overall survival was 53 +/- 7%. CONCLUSION: Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome.