A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors

In order to evaluate the activity and toxicity of a three-drug combination of vindesine, ifosfamide and cisplatin (VIP) for inoperable non-small-cell lung cancer (NSCLC), we conducted a randomized trial comparing VIP with a two-drug combination of cisplatin and vindesine (VP). Between September 1987 and March 1992, a total of 132 patients with stage III or IV NSCLC were randomly allocated to either VIP or VP. The VIP regimen consisted of vindesine (VDS 3 mg/m(2) on days 1 and 8), ifosfamide (IFX 1300 mg/m(2) on days 1-5), and cisplatin (CDDP 20 mg/m(2) on days 1-5). The VP regimen consisted of VDS and CDDP with the same dose and schedule as the VIP regimen. Both regimens were repeated every 4 weeks. Objective response rates were 49.3% (95% confidence interval: 95%CI, 43.1-55.4%) in the VIP arm and 44.6% (95%CI, 38.4-50.2%) in the VP arm; the difference was not significant (P=0.5390). Median response duration, median survival time, and two-year survival rates were 26.5 weeks, 49.6 weeks, and 14.9% in the VIP arm and 28.7 weeks, 37.1 weeks, and 12.3% in the VP arm, respectively. There were also no significant differences between these two treatment arms. In comparison with the VP regimen, however, a survival advantage of the VIP regimen could be confirmed when the data were evaluated with Cox's multivariate analysis (P=0.0131). In both arms, the principal toxicity was myelosuppression, which was significantly more frequent in the VIP arm, although generally well tolerated. CONCLUSION: This study suggested the survival advantage of the VIP regimen over the VP regimen for treatment of patients with advanced NSCLC.     

A randomized trial of three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC): a study of the Umbrian Lung Cancer Group

Survival in patients with locally advanced (stage III Mo) and metastatic (Ml) non-small-cell lung cancer (NSCLC) is short. Phase II studies have reported objective responses ranging from 20% to 60% using cisplatin-based chemotherapeutic regimens, yet few have shown improvement in median survival. In our phase II pilot studies with cisplatin (CDDP) and etoposide (VP-16), we observed a 26% response rate; with CDDP, VP-16, and mitomycin-C, a 38% response rate was obtained in advanced NSCLC patients. A total of 156 consecutive patients with locally advanced and metastatic NSCLC were randomized to one of three treatment arms to determine whether the chemotherapy protocols had any effect on response rate and median survival in a large, randomized study. Arm 1 consisted of CDDP (120 mg/m2 x 3 weeks); arm 2, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 given i.v. on days 1-3), repeated every 3 weeks; and arm 3, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 on days 1-3) given every 3 weeks, plus mitomycin C (10 mg/m2 on days 1, 21, and 42, then every 6 weeks, for a maximal dose of 100 mg). After 71 patients had been enrolled in the study, we stopped accrual in the CDDP arm due to a lack of response [1 complete response (CR) in 24 patients; 4%] and continued enrollment in the two combination-chemotherapy arms. In the CDDP/VP-16 arm a 30% response rate [1 CR, 18 partial responses (PRs)] was obtained, and in the CDDP/VP-16 mitomycin C arm a 26% response rate (4 CRs, 11 PRs) was seen among a total of 150 evaluable patients. Responses were observed in 31% of patients with favorable performance status (PS) (ECOG 0-1) vs 14% in patients with a poor PS (ECOG 2-3). Of patients with locally advanced disease (III Mo), 17 (33%) obtained an objective response, compared with 20 patients (20%) with metastatic disease. Median survival was 18 weeks in the CDDP arm, 35 weeks in the CDDP/VP-16 arm, and 37 weeks in the CDDP/VP-16/mitomycin C arm. The median survival in the multimodal chemotherapy arms was significantly greater than that obtained with CDDP alone. Toxicity was predominantly myelosuppression in the mitomycin C-containing arm (27%, wtto grade 3-4). Our study shows that combination chemotherapy using CDDP/VP-16 is active and safe in the treatment of advanced NSCLC patients with a good performance status. The addition of mitomycin C did not improve the therapeutic response.     

Evaluation of chemotherapy of unresectable non-small cell lung cancer]

For this evaluation, a comparison was made of survival of 34 patients with non-small cell lung cancer who had undergone chemotherapy (Group B) with that of 38 patients without this chemotherapy (Group A). Group B had received neither radiotherapy for primary lesions nor bronchial artery infusion of anticancer drugs, and the chemotherapeutic regimen was CDDP + VDS or CDDP + VDS + MMC chemotherapy. MST of this group was significantly longer than that of Group A (4.5 months vs 7.3 months. P less than 0.01), but the PS features of the two groups differed significantly. A comparison was thus made of survival for PS 1-2 cases in both groups (Group A: 17 cases, Group B: 27 cases). MST of group A and B were 6.8 and 9.8 months, respectively (P less than 0.05). The efficacy of the treatment for prolonging survival in terms of age, sex, PS, histology, T factor, N factor and M factor was evaluated by multivariate analysis using the proportional hazard model of Cox. The results obtained indicated the chemotherapy significantly prolonged survival.     

An early phase II trial combining cisplatin, carboplatin and vindesine in patients with inoperable non-small cell lung cancer

We conducted an early phase II trial of advanced non-small cell lung cancer (NSCLC) to evaluate the response efficacy of a combination of cisplatin (CDDP), carboplatin (CBDCA) and vindesine (VDS). The twenty-four patients in the study had had no previous treatment. CDDP (15 mg/m2), CBDCA (200 mg/m2) and VDS (3 mg/m2) were administered on Day 1, CDDP (15 mg/m2) was administered on Days 2-5, and VDS (3 mg/m2) was administered on Day 8. We observed 9 partial responses (PR), with a total response rate of 39%. The overall median survival was 72 weeks, and the 1-year survival rate was 57%. Major toxicities were hematologic; leukopenia of grades 3 and 4 occurred in 25% patients, and thrombocytopenia occurred in 21%. Therefore, the combination of CBDCA with CDDP and VDS chemotherapy was effective against inoperable NSCLC with tolerable toxicities and a favorable median survival time.     

Phase II studies of a single agent and a cis-platinum-based two-drug combination in patients with non-small cell lung cancer

Phase II studies of single agent and CDDP-based two drug combination were performed in 189 patients with inoperable non-small cell lung cancer. Six drug regimens were performed: CDDP alone, VDS alone, Epi-ADM alone, CDDP + VDS, CDDP + CPA, CDDP + ADM. The response rates were 15.4% (6/39) with CDDP alone, 8.0% (2/25) with VDS alone, 6.1% (2/33) with Epi-ADM alone, 26.7% (8/30) with CDDP + VDS, 14.3% (4/28) with CDDP + CPA, 17.6% (6/34) with CDDP + ADM and one CR was performed with CDDP + ADM. In patients with no prior chemotherapy, the response rates were 20.0% (6/30), 11.8% (2/17), 12.5% (2/16), 26.7% (8/30), 16.0% (4/25) and 25.0% (3/12), respectively. The median survival times were 25, 27, 23, 33, 25, and 45 weeks, respectively. The efficacy of CDDP in non-small cell lung cancer patients was re-confirmed, and that of CDDP + VDS, CDDP + ADM was suggested. No death due to toxicity occurred and toxicity was generally tolerable.     

Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix.

PURPOSE: To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS: A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS: A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION: This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.     

Beneficial effect of cisplatin based combination chemotherapy on adenocarcinoma of the lung

Cisplatin (CDDP) based combination chemotherapy has improved the response rate of non-small cell lung cancer (NSCLC). However, the survival benefit of CDDP-based chemotherapy in patients with NSCLC is still controversial. In order to determine whether CDDP had a meaningful impact on the course of NSCLC, the survival of patients treated by combination chemotherapy containing CDDP (CDDP arm: PVB; CDDP + vindesine + bleomycin, VIP; vindesine + ifosfamide + CDDP) was compared with that treated by chemotherapy without CDDP (no CDDP arm: COMP; cyclophosphamide + vincristine + methotrexate + procarbazine, MVB; mitomycin C + vindesine + bleomycin), retrospectively. Survival in CDDP arm (median survival time [MST]; 10.2 months) was significantly longer than in the no-CDDP arm (MST; 6.9 months) (p less than 0.01). These results indicate that CDDP-based combination chemotherapy can not only improve response rate but also prolong survival of NSCLC.     

A randomized study comparing cisplatin alone or combined in the palliative treatment of carcinoma of the head and neck. Analysis of a series of 209 patients

Two hundred and nine patients, with locoregional or metastatic recurrences of head and neck epidermoid carcinoma, were randomized to receive a palliative chemotherapy. The chemotherapy regimens were delivered every 3 weeks, and consisted in (1) cisplatin, 80 mg/m2 given alone (CDDP regimen), or (2) in combination with vincristine, 1 mg, methotrexate 10 mg/m2 d 1, 2, 3, and bleomycin 10 mg/m2, d 1, 2 and 3 (1040 regimen). Short-term results were better for patients treated by the 1040 regimen, with a 30% response rate (including 4 complete responses) vs 15% with the CDDP regimen (P = 0.01). A superiority of combination chemotherapy was found for all tumoral sites, but was particularly significant for pulmonary and cutaneous metastases, in previously un irradiated areas (P = 0.001). Tolerance was significantly better with the CDDP regimen (P = 0.001); severe side effects, affecting mainly general status, digestive tract and bone marrow were encountered in 5% of the patients in the CDDP group, vs 21% in the 1040 group, with one death related to pancytopenia. The median duration of remissions was not statistically different in the 2 groups, as well as the 2 years overall survival. Among responders, the survival was slightly better in those treated with CDDP alone; moreover, the quality of long term results was found highly correlated with a good initial general status, and with low levels of side effects. Those results confirm recent data of the literature, and lead to the following conclusions: (1) combination chemotherapy with CDDP give a better response rate than CDDP alone, (2) response rate doesn't influence overall duration of survival, (3) tolerance to treatment is crucial to preserve quality of life, and thus, (4) palliative chemotherapy in head and neck cancer should be efficient but also as short of intensity as possible.     

Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS: Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.     

Cisplatin and vinorelbine followed by ifosfamide plus epirubicin vs the opposite sequence in advanced unresectable stage III and metastatic stage IV non-small-cell lung cancer: a prospective randomized study of the Southern Italy Oncology Group (GOIM).

A multicentric, prospective phase III study was carried out with the aim of testing the so-called ''worst drug rule'' hypothesis, which suggests the use of an effective but ''less active'' regimen that first eradicates tumoral cells resistant to a second effective and ''more active'' regimen. With respect to this hypothesis, we considered the cisplatin plus vinorelbine regimen (CCDP/VNR) as the more active regimen compared with the non-cisplatin-containing regimen of ifosfamide plus high-dose epirubicin (IFO/EPI). Thus, a randomized study was carried out to compare the sequencial strategy of three cycles of CDDP/VNR followed by three cycles of IFO/EPI with the opposite sequence in advanced non-small-cell lung cancer. A total of 100 consecutive previously untreated patients with stage III-IV non-small-cell lung cancer were centrally randomized in two arms according to stage of disease and the performance status. Patients allocated to arm A received CDDP (100 mg m-2 on day 1) plus VNR (25 mg m-2 i.v. on days 1 and 8) every 21 days for three cycles (step 1) followed, after restaging, by three cycles of IFO (2.5 g m-2 with mesna on day 1) plus high-dose EPI (100 mg m-2 on day 1) every 21 days (step 2). Patients in arm B received the opposite sequence. Type and rates of objective response were evaluated after step 1 and step 2 in agreement with WHO criteria and an intent-to-treat analysis. Patients were also analysed for toxicity patterns, time to progression and survival. After the first three cycles (step 1), overall response rate (ORR), calculated according to an intent-to-treat analysis, was 47% and 21% for arm A and arm B respectively (P = 0.0112). ORR for stage III patients was 55% and 14% for arm A and B respectively (P = 0.0097). In stage IV patients ORR was higher in arm A than in arm B (42% vs 28%) but not statistically significant (P = 0.4). Clinical responses to the shift of chemotherapy (step 2) showed that no patient pretreated with CDDP/VNR and subsequently treated with IFO/EPI showed further response, whereas in the inverse sequence arm CDDP/VNR was able to induce 26% partial response (PR) rate in patients pretreated with IFO/EPI. This difference was statistically significant (P = 0.037). The overall median time to progression (TTP) of arm A and arm B did not significantly differ (6 vs 4 months; P = 0.665). However, median TTP of stage III patients was, respectively, 7 months for arm A and only 3 months for arm B. This difference was statistically significant (P = 0.049). Median overall survival (OS) was 9 and 7 months respectively for arm A and arm B. Despite this trend the difference was not significant (P = 0.328). Median OS of stage III patients showed a statistically significant advantage for arm A over arm B (13 vs 7 months, P = 0.03). In addition, no statistically significant difference in OS was recorded for stage IV patients (both arms 7 months, P = 0.526). Our data do not confirm Day''s ''worst drug rule'' hypothesis, at least in patients with advanced non-small-cell lung cancer treated with the above-mentioned regimens. The combination of CDDP and VNR seems more active, at least in terms of response rate, than the IFO/EPI, which performed poorly.     

Effects of combined therapy with irradiation, cisplatin and vindesine in lymph node recurrence of esophageal cancer

The effects of combined therapy with irradiation, cisplatin and vindesine for lymph node recurrence of esophageal cancer was studied. The subjects were 95 patients with lymph node recurrence, who were divided into the following four treatment groups: Group I: Radiotherapy alone (R) (n = 31); Group II: cisplatin (CDDP) alone (n = 18); Group III: R + CDDP(n = 9); Group IV: R + CDDP + VDS (n = 10). The response rate (CR + PR) of Groups III and IV was 66.7% and 100%, respectively, which was significantly more favorable than 11.1% of Group II. The survival duration after recurrence was prolonged in the order of Group IV, Group III, Group II and Group I. In conclusion, combination therapy using R, CDDP and VDS will be effective for lymph node recurrence of esophageal cancer.     

Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer. A prospective randomized study

One hundred-forty-five postmenopausal women with metastatic breast cancer entered a prospective randomized trial comparing treatment A (cyclophosphamide, methotrexate, and 5-fluorouracil; CMF) with treatment B (the same chemotherapy plus tamoxifen; CMF plus T). Patients on treatment A had T added to CMF at the time of progression or relapse (second-line CMF plus T). One hundred thirty-three cases were evaluable. Considering response rate to first-line treatment, CMF plus T appeared to be significantly superior to CMF alone (74 versus 51%, respectively; P less than 0.01). Median time to failure to first-line treatments, considering all patients, was longer in CMF plus T than in CMF arm (48 and 24 weeks, respectively; P = 0.06). Considering patients showing objective remission, median duration of response to CMF was similar to that of CMF plus T (47 and 51 weeks, respectively). Twelve of 39 evaluable women treated with second-line CMF plus T showed objective responses (31%). Median time to failure to treatment procedures scheduled in arm A (CMF leads to CMF + T) was longer than that to treatment in arm B (CMF plus T) (56 and 48 weeks, respectively; P = 0.08). Median survival was longer in patients randomized to treatment A (111 weeks) than in patients randomized to treatment B (78 weeks), but this difference was not statistically significant (P = 0.25). It can be concluded from this study that a combination of endocrine therapy and chemotherapy is significantly more active than chemotherapy alone in inducing an objective remission. This strategy of treatment is advisable in situations urgently requiring a clinical response. However, as a sequence of chemical and endocrine therapy induced a longer time to development of progressive disease and a better survival, sequential therapy is advisable for common clinical use.     

Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer.

PURPOSE: To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). PATIENTS AND METHODS: Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1000 [corrected] mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). RESULTS: A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). CONCLUSION: Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment.     

Combination chemotherapy of ifosfamide, cisplatin and vindesine for non-small cell lung cancer

Twenty patients with advanced non-small cell lung cancer were treated with a combination chemotherapy consisting of ifosfamide (IFX), cisplatin (CDDP) and vindesine (VDS). The treatment schedule was IFX 1.3 g/m2 i.v., on days 1-5, CDDP 20 mg/m2 i.v., on days 1-5, and VDS 3 mg/m2 i.v., on days 1 & 8, and, in principle, the regimen was repeated every 4 weeks. Of 19 evaluable patients, there were 1 CR, 7 PR, 10 NC and 1 PD, with an overall response rate of 42.1%. The median duration of responses was 7.45 months, and the median survival time of all patients was 13.2 months. The major toxicities occurring were hematologic toxicity, alopecia, gastrointestinal toxicity and peripheral neuropathy. Hematologic toxicity was severe and was judged to be dose limiting, but clinically manageable. These results indicate that this combination chemotherapy is active against non-small cell lung cancer and deserves further studies.     

Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group.

PURPOSE: Few randomized trials have demonstrated survival benefit of combination chemotherapy involving new agents plus cisplatin compared with classic combination chemotherapy in advanced non-small-cell lung cancer (NSCLC). The primary aim of this study was to test whether docetaxel plus cisplatin (DC) improves survival compared with vindesine plus cisplatin (VdsC) in patients with previously untreated stage IV NSCLC. PATIENTS AND METHODS: Eligible, stage IV, chemotherapy-naive patients (n = 311) were randomly assigned to receive docetaxel 60 mg/m(2) intravenously on day 1 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 3- or 4-week cycle, or vindesine 3 mg/m(2) intravenously on days 1, 8, and 15 plus cisplatin 80 mg/m(2) intravenously on day 1 of a 4-week cycle. Cross-over administration of docetaxel and vindesine was prohibited for both treatment groups. RESULTS: Overall, 302 patients were eligible for evaluation. The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% v 21%, respectively; P <.01) and median survival times (11.3 v 9.6 months, respectively; P =.014). Two-year survival rates were 24% for the DC arm compared with 12% for the VdsC arm. The physical domain of the Quality of Life for Cancer Patients Treated with Anticancer Drugs measure was significantly better in the DC arm than in the VdsC arm (P =.020). Toxicity was predominantly hematologic and was more severe in the VdsC arm. CONCLUSION: As first-line treatment for stage IV NSCLC, DC resulted in greater clinical benefit in terms of response rate (with marked improvements in overall and 2-year survival rates) and quality of life than did treatment with VdsC.     

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-na?ve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.     

Randomized controlled trial of neoadjuvant chemotherapy with cisplatin and vinorelbine in patients with stage IIIA non-small cell lung cancer in China

Aim:   The aim of this study was to evaluate the efficacy of cisplatin plus vinorelbine as a regimen of neoadjuvant chemotherapy on the improvement of surgical resectability and survival in Chinese patients with stage IIIA non-small cell lung cancer (NSCLC).
Methods:   Fifty-six patients with stage IIIA NSCLC were randomly assigned to undergo either surgery preceded by two cycles of chemotherapy with cisplatin plus vinorelbine (the neoadjuvant chemotherapy arm) or immediate surgery (the primary surgery arm). The patients who had a complete resection received two to four cycles of chemotherapy, and those with incomplete resection received radiotherapy followed by two cycles of chemotherapy after surgery.
Results:   The overall response rate to neoadjuvant chemotherapy was 53.6%, with a complete response of 7.1%. A pathological complete response was seen in two patients (8%). The complete resection rates were 78.6% in the neoadjuvant chemotherapy arm and 60.7% in the primary surgery arm. The median overall survival and median disease-free survival was 30 months and 24 months, respectively, in the neoadjuvant chemotherapy arm as compared to 16 months and 11 months in the primary surgery arm ( P  = 0.04 and P  = 0.048). The 3-year and 5-year survival rate was 49.7% and 31.9%, respectively, for the neoadjuvant chemotherapy arm and 29.2% and 3.6% for the primary surgery arm.
Conclusion:   Neoadjuvant chemotherapy with cisplatin plus vinorelbine regimen is effective and tolerable and can improve the overall survival and disease-free survival time in Chinese patients with stage IIIA NSCLC.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101).

BACKGROUND: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. PATIENTS AND METHODS: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. RESULTS: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. CONCLUSIONS: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.