Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel.

BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.     

Recombinant interferon alpha-2A combined with prednisone in metastatic renal-cell carcinoma: treatment results, serum interferon levels and the development of antibodies.

Five partial responses were seen in 23 patients with metastatic renal-cell carcinoma (MRCC) receiving interferon-alpha 2a (IFN)+prednisone (P). Four of 24 subsequent patients responded to IFN+P (combined response rate 19%). The median response duration was 8 months (3 to 30 months). The one-year survival for all eligible patients was 52%. Eight of 26 evaluable patients developed antibodies detected by an enzyme immunoassay. In 2 patients, high levels of neutralizing antibodies were also found, together with particularly low IFN levels. In one patient the development of neutralizing antibodies coincided with the loss of initial response. The treatment was well tolerated by most patients. Premature discontinuation of treatment was necessary in only 2 patients. In MRCC, combination treatment with IFN+P is as effective as IFN monotherapy (response rate 19%), with significantly reduced subjective toxicity. The clinical relevance of the development of antibodies against IFN requires further investigation.     

Interferon alpha-2a and 13-cis-retinoic acid in patients with metastatic renal cell cancer

Treatment of patients with metastatic renal cell cancer (RCC) with interferon-alpha-2a (IFN) and 13-cis-retinoic acid (CRA) was first reported to be tolerable on an outpatient basis and to yield a 30% objective response rate. We sought to confirm these preliminary results by conducting a phase II trial of therapy with IFN/CRA in patients with bidimensionally measurable RCC. Twenty-five patients were enrolled. The median age was 58 (range, 47-75 years) and the median Karnofsky performance status was 90 (range 60-100). Seventeen patients (60%) had undergone prior nephrectomy and none had received prior systemic therapy. Treatment consisted of oral CRA at 1 mg/kg/day and IFN self-administered by subcutaneous injection at 3 MU/day with weekly escalation to 6 and 9 MU/day. Treatment was well tolerated, with cheilitis, influenza-like symptoms, and fatigue the most common toxicities. Severe toxicity was reversible and consisted of grade 4 cheilitis in one patient and grade 3 malaise/fatigue in two patients. One complete and four partial responses were absented, for an objective response rate of 20% (95% confidence interval, 4-36%). We conclude that treatment with CRA/IFN for RCC is tolerable on an outpatient basis and induces objective responses in some patients. The contribution, if any, of CRA to the responses observed will be determined in ongoing randomized phase III trials.     

Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.     

Phase I/II study of thalidomide in combination with interleukin-2 in patients with metastatic renal cell carcinoma

BACKGROUND: The purpose of the study was to determine, in a Phase I/II study, the efficacy and safety profile of thalidomide with interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma (MRCC). METHODS: Fifteen patients (8 of whom were previously treated) enrolled in Phase I were treated with escalating doses of oral thalidomide (200-600 mg) and a fixed dose of IL-2 (7 mIU/m(2)) by subcutaneous injection. A course was 6 weeks, with the exception of Course 1, which was 7 weeks. Thirty-seven Phase II patients who had not received prior chemotherapy or immunotherapy for renal cell carcinoma (RCC) received an initial thalidomide dose of 200 mg at Week 0, which was escalated to 400 mg after 48 hours. Subcutaneous IL-2 was administered at the same fixed daily dose used in Phase I. RESULTS: Fifty-one of 52 Phase I/II patients were evaluable. Twenty-seven patients (52%) experienced disease control, including 4 (8%) complete responses, 15 (29%) partial responses, and 8 (15%) cases of stable disease. Disease progression was observed in 24 patients (47%). Survival in the 2 phases ranged from 4 weeks to 45.2+ months. At the time of last follow-up, 2 of 51 patients (4%) remained on maintenance thalidomide therapy and continue to be followed. Three of the 51 patients with CRs (6%) ceased thalidomide therapy at 23-25 months and have maintained their responses to date. One complete responder was lost to follow-up. As of January 2005, 14 of 51 patients (27%) remained alive. Toxicities were mild to moderate, including Grade 1 to 2 somnolence, constipation, neuropathy, rash, flu-like symptoms, fluid retention, hypotension, and hypothyroidism (according to version 2.0 of National Cancer Institute Common Toxicity Criteria). In addition, two patients experienced deep venous thrombosis. CONCLUSIONS: Thalidomide in combination with IL-2 is tolerable and can produce durable, active responses in patients with MRCC. To evaluate the merits of thalidomide as a valuable agent against MRCC and to more fully determine the efficacy of thalidomide/IL-2 combination therapy, the scrutiny of Phase III testing is required. Further development of thalidomide/IL-2 combination therapy will be the focus of this group.     

Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study

Fifty-eight patients with metastatic transitional cell carcinoma of the urinary tract received cisplatin, methotrexate, and vinblastine (CMV) combination chemotherapy. Complete responses (CRs) were noted in 14 of the 50 (28%) evaluable patients and partial responses (PRs) in 14 patients for an overall response rate of 56% (95% confidence limits of 42% to 70%). The median duration of the 14 CRs was 9 months. Six of the 14 CRs (43%) remain in unmaintained remission from 6 + to 35 + months from onset of treatment. The median survival of evaluable patients receiving CMV was 8 months. Median survival for CRs was 11 months v 7 months for PRs (P less than .05) and 6 months for nonresponders. Renal and hematologic toxicities with this regimen were moderate. CMV is an effective regimen for patients with metastatic transitional cell carcinoma of the bladder. Prolonged disease-free survival may result from a CR to this regimen.     

Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study

BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.     

Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575, generation V--a randomized comparison of four cisplatin-containing regimens

Between December 1979, and October 1981, the Eastern Cooperative Oncology Group (ECOG) compared four cisplatin-containing regimens in the treatment of patients with metastatic non-small-cell bronchogenic carcinoma (NSCBC). CBP (cyclophosphamide, bleomycin, and cisplatin) and AFP (doxorubicin, 5-fluorouracil, and cisplatin) had shown activity in generation II of this study (EST 2575). These were compared to MVP (mitomycin C, vinblastine, and cisplatin) and CAP (cyclophosphamide, doxorubicin, and cisplatin) which were reported efficacious in single institution studies. A total of 479 previously untreated patients with metastatic NSCBC (ECOG performance status 0, 1, or 2) were entered, and of these, 432 (90%) were evaluable. Although MVP resulted in a higher response rate (5 complete responses [CRs], 22 partial responses [PRs], 26% overall) than CBP (4 CRs, 18 PRs, 20% overall), AFP (0 CRs, 18 PRs, 17% overall), or CAP (1 CR, 23 PRs, 23% overall), the difference was not significant. Survival by treatment did not differ significantly. There were 45 life-threatening and six lethal complications of therapy. Although each of the above regimens offers a modest chance of inducing greater than 50% tumor shrinkage (17% to 26%, 21% overall) the effect that these responses have an overall median survival (21.6 to 23.7 weeks, 22.9 weeks overall) is unclear.     

A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas

BACKGROUND: The authors conducted a two-arm Phase II study of temozolomide to determine its efficacy and toxicity in patients with soft tissue sarcomas (STSs) who had received, had refused, or were not eligible for standard chemotherapy with doxorubicin and ifosfamide (Arm 1) and in patients with gastrointestinal stromal tumors (GISTs; Arm 2). Patients with GIST were eligible regardless of prior therapy before imatinib was available. METHODS: Sixty patients were enrolled in the current study, 19 of whom had GISTs and 41 of whom had other STSs. The patients received temozolomide at a dose of 85 mg/m2 orally for 21 days followed by 7 days without treatment. Standard radiographic imaging after every two cycles was used to assess the treatment response. RESULTS: Of the 39 patients in Arm 1, there was 1 complete response and 1 partial response of 39 evaluable patients, for a total response rate of 5% (95% confidence interval, 0-12%). The responses lasted 7 months and 8 months, respectively. In Arm 2, there was no response in 17 patients. The disease was stable in 22% of the patients with GISTs and 33% of the patients with other STSs. The median overall survival time was 26.4 months in patients with GISTs and 11 months in patients with other STSs. The median time to disease progression was 2.3 months in patients with GISTs and 3.3 months in patients with other STSs. Grade 3 and Grade 4 adverse effects (according to National Cancer Institute Common Toxicity Criteria) were rare and included fatigue (eight patients), anemia (six patients), constipation (four patients), neutropenia (four patients), and thrombocytopenia (four patients). CONCLUSIONS: The data from the current study suggest that temozolomide is well tolerated but has only minimal efficacy and a limited role in the treatment of patients with STSs.     

Improved tolerability and quality of life with maintained efficacy using twice-daily low-dose interferon-alpha-2b: results of a randomized phase II trial of low-dose versus intermediate-dose interferon-alpha-2b in patients with metastatic renal cell carcinoma

BACKGROUND: In vivo data have shown a more potent antiangiogenic effect and a higher antitumor activity of low-dose interferon (IFN) given twice daily. In a randomized Phase II trial, the authors tested the hypothesis that twice-daily low-dose IFN is more effective than daily intermediate-dose IFN in patients with metastatic renal cell cancer (MRCC). METHODS: A total of 118 patients (59 per arm) were randomly assigned to receive IFN at a dose of 0.5 million units (MU) given subcutaneously twice daily (IFN1) or IFN at a dose of 5 MU given subcutaneously daily (IFN5). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR), overall survival (OS), toxicity, and quality of life (QOL). RESULTS: There were no significant differences in either PFS or OS between IFN1 and IFN5 (median of 3.7 months and median of 3.4 months PFS, respectively; median of 25.5 months and median of 17.5 months OS, respectively). The RRs were identical in the 2 arms (6.7%; 95% confidence interval [95% CI], 1.8-16.5%). Two patients, 1 in each arm, remained in complete remission at the time of last follow-up, at 45+ and 38+ months from treatment. Thirty-two patients receiving IFN5 and 19 patients receiving IFN1 experienced Grade 3 or higher adverse events (graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]) (P = .025). Eighteen patients receiving IFN5 and 4 patients receiving IFN1 had dose reductions (P = .002). There was a significant deterioration in QOL and an increase in depression associated with IFN5 but no change was noted with IFN1. CONCLUSIONS: Compared with IFN5, IFN1 is neither more nor less effective but is less toxic, with a better reported QOL. These results may have implications for the design of combination regimens incorporating IFN with targeted agents.     

Capecitabine in the treatment of metastatic renal cell carcinoma

To evaluate the therapeutic effects and systemic toxicities of a capecitabine-based home therapy regimen in patients with metastatic renal cell carcinoma, 30 patients were enrolled in a phase II clinical trial. Treatment consisted of oral capecitabine combined with subcutaneous recombinant human interferon-alpha 2a, recombinant human interleukin-2 and oral 13-cis-retinoic acid. There were two (7%) complete responses (CRs) and eight (27%) partial remissions (PRs), for an overall objective response rate of 34% (95% CI 17-53%). Except one, all responses are ongoing, with a median duration of 9+ and 8+ months for CRs and PRs, respectively. Additionally, 12 patients (40%) reached stable disease. Eight patients (27%) showed continued disease progression despite treatment. Therapy was well tolerated and was given in the outpatient setting. Capecitabine-related World Health Organization (WHO) grade 2 and 3 toxicities were observed in five and two patients respectively, and were limited to fatigue, nausea/vomiting, diarrhoea, stomatitis, dermatitis and hand-and-foot syndrome. The substitution of capecitabine for 5-FU in the pre-existing biochemotherapy regimen did not result in a reduced therapeutic efficacy and showed significant anti-tumour activity in patients with advanced renal cell carcinoma.     

Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients with melanoma in-transit metastases

For melanoma, in-transit metastases (ITMs) are a harbinger of systemic disease in over 70% of patients and thus warrant a systemic approach to management. In this study, previously untreated patients with ITMs (n=15) received a systemic regimen of 'CVD' in 21 day cycles (median, three cycles) as follows: dacarbazine 800 mg/m2 intravenously (i.v.) on day 1, vinblastine 1.6 mg/m2 i.v. on days 1-5, and cisplatin (CDDP) 100 mg/m2 by 24 h intra-arterial (i.a.) infusion in 1l of heparinized saline via the iliac or subclavian artery on day 3. There were three clinical complete responses (CRs) in patients with a modest burden of ITMs (< 3 cm in size) and seven partial responses (PRs), yielding a 67% response rate (95% confidence interval, 38-88%). One of the clinical CRs had microscopic residual disease at surgery (a pathological PR). The times to progression (TTP) for the CRs were 5, 21 and 38+ months; the median TTP for the PRs was 4.5 months (range, 2-10 months). Overall median survival was 31 months. Systemic toxicities were similar to those induced by i.v. CVD. However, patients noted more pronounced paraesthesia in the infused extremity. Also, two patients experienced severe CDDP-induced burns, one patient developed brachial plexopathy, and one patient had a haemorrhage in an occult brain metastasis. The high clinical activity of this regimen will have to be confirmed in more patients before a first-pass i.a. advantage can be claimed. Furthermore, the dose, schedule and technique of i.a. CDDP delivery must be further refined before it can be routinely incorporated in regimens as an alternative to isolated regional hyperthermic perfusion, which is technically more difficult and is not readily available in community-based hospitals.     

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.     

EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group.

In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN-alpha 2c monotherapy. A possible detrimental effect cannot be excluded.     

Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale

BACKGROUND: A prospective, randomized Phase III trial was performed to determine whether, compared with gemcitabine (GEM) alone, the addition of cisplatin (CDDP) to GEM was able to improve the time to disease progression and the clinical benefit rate in patients with advanced pancreatic adenocarcinoma. The objective response rate, overall survival rate, and toxicity patterns of patients in the two treatment arms were evaluated as secondary end points. METHODS: Patients with measurable, locally advanced and/or metastatic pancreatic adenocarcinoma were randomized to receive GEM (Arm A) or a combination of GEM and CDDP (Arm B). In Arm A, a dose of 1000 mg/m(2) GEM per week was administered for 7 consecutive weeks, and, after a 2-week rest, treatment was resumed on Days 1, 8, and 15 of a 28-day cycle for 2 cycles. In Arm B, CDDP was given at a dose of 25 mg/m(2) per week 1 hour before GEM at the same dose that was used in Arm A. On Day 22, only GEM was administered. Patients were restaged after the first 7 weeks of therapy and then again after the other 2 cycles. RESULTS: A total of 107 patients entered the trial: Fifty-four patients were randomized to Arm A, and 53 patients were randomized to Arm B. The median time to disease progression was 8 weeks in Arm A and 20 weeks in Arm B; this difference was statistically significant (P = 0.048). In Arm A, one complete response and four partial responses were recorded on the basis of an intent-to-treat analysis, with an overall response rate of 9.2% (95% confidence interval [95%CI], 3-20%). In Arm B, there were no complete responses, whereas 14 partial responses were achieved, with an overall response rate of 26.4% (95%CI, 15-40%). This difference in the overall response rates was statistically significant (P = 0.02). The tumor growth control rate (i.e., total number of patients who achieved complete responses, partial responses, and stable disease) was 42.6% (95%CI, 29-57%) in Arm A and 56.6% (95%CI, 42-70%) in Arm B. A clinical benefit was observed in 21 of 43 patients (49%) in Arm A and in 20 of 38 patients (52.6%) in Arm B without any significant difference. The median overall survival was 20 weeks for patients in Arm A and 30 weeks for patients in Arm B (P = 0.43). Toxicity was mild in both treatment arms, with no significant differences between the two groups except for the statistically higher incidence of Grade 1-2 asthenia in Arm B (P = 0.046). CONCLUSIONS: The addition of CDDP to GEM significantly improved the median time to disease progression and the overall response rate compared with GEM alone. The clinical benefit rate was similar in both arms, whereas the median overall survival rate was more favorable for Arm B, although the difference did not attain statistical significance. The authors conclude that the combination of CDDP and GEM currently may be considered as an optimal treatment for patients with locally advanced and/or metastatic adenocarcinoma of the pancreas.     

Phase II study of cytarabine and etoposide in children with refractory or relapsed non-Hodgkin's lymphoma: a study of the French Society of Pediatric Oncology

Twenty-five children or adolescents with relapsed or refractory non-Hodgkin's lymphoma (NHL) were included in this phase II study of the combination of cytarabine (ARA-C) 50 mg/m2/d by 12 hours continuous infusion day 1 to day 5, ARA-C 3 g/m2/d in 3 hours day 1 to day 4, and etoposide (VP 16) 200 mg/m2 daily from day 1 to day 4. Twelve patients had B-cell, 12 T-cell, and one non-T, non-B-cell lymphoma; according to Murphy's staging system, 15 had stage III and nine stage IV disease with bone marrow involvement at diagnosis. All had previously received ARA-C by push or continuous infusion. Two patients had received epipodophyllotoxins. At the time of the study, three children had initial refractory disease, 18 were in first relapse (14 on therapy), two in first refractory relapse, and two in second relapse (on therapy). The overall response rate (RR) was 60%: eight complete responses (CRs), seven partial responses (PRs) (two became CRs after a second course). The RR was 66% (four CRs plus four PRs) in B-cell and 54% (four CRs, three PRs) in non-B-cell NHL. It was 20% (one PR per five patients) in initial or relapsed refractory disease. In four patients with measurable CNS disease, there were three CRs. Duration of response was nonassessable since all the responding patients received high-dose polychemotherapy followed by autologous bone marrow transplantation (ABMT) (five are alive with long follow-up [FU]). Toxicity was marked mostly by pancytopenia for 2 weeks, and half the patients encountered a grade-3 infection. One severe diarrhea was observed. In conclusion, high-dose ARA-C (HD-ARA-C) and VP 16 are an effective regimen in relapsed NHL, especially with CNS disease, and its toxicity is acceptable with regards to the prognosis of the disease.     

Phase II study ofcis-diammine(glycolato)platinum, 254-S,in patients with advanced germ-cell testicular cancer,prostatic cancer,and transitional-cell carcinoma of the urinary tract

Summary A multicenter cooperative study was conducted to evaluate the clinical efficacy and safety ofcis-diammine(glycolato)platinum (254-S), a second-generation anticancer platinum complex, in the treatment of genitourinary cancers. 254-S was given i. v. at 100 mg/m² at 4-week intervals. As a result, 2 complete responses (CRs) and 8 partial responses (PRs) were obtained in 35 patients with transitional-cell carcinoma (TCC) of the urinary bladder or pyeloureter, 3 PRs were obtained in 16 subjects with prostatic cancer, and 6 CRs and 6 PRs were obtained in 15 patients with testicular cancer, generating objective response rates of 28.6% [95% confidence interval (CI), 14.6%–46.3%], 18.8% (95% CI, 4.0%–45.6%), and 80.0% (95% CI, 51.9%–95.7%), respectively. Bone marrow suppression was the dose-limiting toxicity, although it was reversible. Although no hydration was performed in approx. 40% of the patients, the incidence of nephrotoxic effects was low and most of those encountered were mild, the exception being one patient who showed severe renal insufficiency after the first treatment. Nausea and vomiting occurred in approx. 70% of the patients, but most gastrointestinal toxicities were controlled without antiemetic treatment. In addition, liver-function impairment was rarely observed. We conclude that 254-S is a promising cisplatin analogue for the treatment of genitourinary cancers and is worthy of further investigation in large-scale, randomized comparative studies with other platinum derivatives in both single-agent and combination regimens.     

A randomized Phase II trial in patients with carcinoma of an unknown primary site

BACKGROUND: Current therapy for patients with carcinoma of an unknown primary site (CUP) is inadequate. To develop less toxic and more effective therapies for patients with CUP, a multicenter, randomized, Phase II study was conducted. Patients with CUP received either carboplatin and etoposide (CE) or a combination of paclitaxel, 5-fluorouracil, and leucovorin (TFL). METHODS: Patients randomized to Arm A received paclitaxel, 175 mg/m(2), intravenously over 3 hours on Day 1 followed by leucovorin, 300 mg, over 30-60 minutes and 5-fluorouracil, 350 mg/m(2), both intravenously on Days 1-3. Patients randomized to Arm B received etoposide, 100 mg/m(2), intravenously on Days 1-3 and carboplatin at an area under the curve of 6 on Day 1 only. The cycles in both treatment arms were repeated every 28 days. Patients were followed for tumor response, survival, and toxicity. RESULTS: Thirty-four patients were enrolled, 32 of whom were evaluable for response. An identical overall response rate of 19% (95% confidence interval, 4-45%) was noted in each treatment arm. The median survival for the entire study population was 194 days. The median survivals observed in Arm A and Arm B were 251 days and 194 days, respectively (P = 0.91 [difference not significant]). Hematologic toxicity on Arm B was considerable with 29% of the patients developing neutropenia and fever. Toxicity on Arm A was modest. CONCLUSIONS: In this randomized Phase II trial, CE and TFL appeared to have modest activity in CUP patients, with response rates similar to those reported with previously described chemotherapy regimens. Toxicity with CE was more severe than expected, although TFL was found to be well tolerated.     

Phase II trial of piritrexim in metastatic melanoma using intermittent, low-dose administration

A phase II trial of piritrexim (2,4-diamino-6[2,5-dimethoxybenzyl]-5-methyl pyrido-[2,3d] pyrimidine, 301U74; PTX) was conducted for patients with metastatic malignant melanoma using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Thirty-one patients were entered onto the study. Among 31 patients assessable for response, there were two complete responses (CRs) and five partial responses (PRs) for a response rate (CR plus PR) of 23% (95% confidence limit, 10% to 42%). Five responses occurred in soft tissue lesions, and two responses occurred in lung lesions. The initial dose schedule was well tolerated. The dose-limiting toxicity was myelosuppression. PTX administered in this schedule appears to be active against malignant melanoma. Further clinical trials to confirm these results are underway.