Combination chemotherapy with carboplatin, etoposide, and vincristine as first-line treatment in small-cell lung cancer.

PURPOSE: The antineoplastic activity of carboplatin and etoposide may be improved by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in small-cell lung cancer (SCLC). A phase II study with CEV was carried out. PATIENTS AND METHODS: One hundred twenty-one untreated patients with SCLC (63 with limited disease [LD], 58 with extensive disease [ED]) were treated with a combination of 300 mg/m2 intravenous (IV) on day 1, etoposide 140 mg/m2 IV daily on days 1 to 3, and vincristine 1.4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. RESULTS: A 90% rate overall response rate including 56% complete responses (CRs) was achieved in LD and an 83% overall response rate including 35% CRs was observed in ED. Median survival time was 13 months in limited disease and 9.5 months in extensive disease. The 24 and 36 months survival rates were 29% in LD and 9% in ED. Myelosuppression was the main form of toxicity. CONCLUSION: The combination of CEV is a new active and well-tolerated regimen in the treatment of SCLC. Prospective randomized studies of CEV with conventional chemotherapy are warranted.

Etoposide/vincristine-based chemotherapy with or without carboplatin in extensive-stage small cell lung cancer: a prospective randomized phase III trial.

In the treatment of small cell lung cancer, carboplatin/etoposide/vincristine (CEV) is one of the most active regimens. In contrast, the etoposide/vincristine (EV) combination also has produced acceptable results in patients with extensive disease. To evaluate the efficacy and survival of patients treated with EV in comparison to those treated with more intensive CEV chemotherapy, a prospective, randomized, phase III trial was performed. The protocol for the treatment groups was as follows: treatment A (156 patients): carboplatin 300 mg/m2 day I, etoposide 140 mg/m2 days 1 through 3, and vincristine 1.4 mg/m2 days 1, 8, and 15; and treatment B (161 patients): etoposide 200 mg/m2 days 1 through 3 and vincristine 1.4 mg/m2 days 1 and 8. Chemotherapy cycles in each treatment arm were repeated every 4 weeks. Doses were reduced by 20% when hematologic or nonhematologic toxicity (grade 4) occurred. In all, 317 evaluable patients were treated. The overall response rate for patients treated with CEV was 79.8% compared with 59.8% for those treated with EV (P < .001). The median length of survival was 10 months for CEV-treated patients compared with 9 months for EV-treated patients (P = .19). Based on long-term survival rates, there was an advantage for the CEV-treated patients if they had good performance status, were younger than 60 years, had no distant metastases, and achieved a complete response to first-line therapy. We conclude that patients with poor prognostic factors (ie, poor performance status, multiple distant metastases, and less than partial response to the first cycle of chemotherapy) should appropriately be treated with the less aggressive two-drug combination chemotherapy. On the other hand, patients with good prognostic factors should be treated as aggressively as possible, and they will benefit from the more aggressive induction chemotherapy.

Phase II and III studies with carboplatin in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (11% complete response [CR], 59% CR plus partial response [PR]). Combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease (LD), with 52% CRs. The median survival time with this combination was 14 months in patients with LD and 9.5 months in those with extensive disease (ED). The 30-month survival rates are 30% in LD and 10% in ED, which represents a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in ED patients, CR and overall response rates to date are higher in the CEV arm (CR, 20% versus 15%; CR plus PR, 83% versus 65%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial are presented.

Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a phase II trial.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated significant antineoplastic activity against different tumor types, notably ovarian and breast carcinoma. Two phase II trials of 24-hour paclitaxel infusions in chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer (NSCLC) reported response rates of 21% and 24%. Leukopenia was dose limiting: as many as 62.5% of patients experienced grade 4 leukopenia. We investigated the efficacy and toxicity of a 3-hour paclitaxel infusion in a phase II trial in patients with inoperable stage IIIB or IV NSCLC. The 58 patients treated (41 men and 17 women) had a median age of 59 years (age range, 25 to 75) and a performance status of 0 through 2. Most patients (72.4%) had stage IV NSCLC. Paclitaxel 225 mg/m2 was infused over 3 hours every 3 weeks with standard prophylactic premedication. Of 50 patients evaluable for response, 12 (24%) had partial remission, 26 (52%) had no change, and 12 had disease progression (24%). Hematologic toxicities were mild: only one patient (2%) developed grade 3 or 4 neutropenia, while 29% had grade 1 or 2. Grade 1 or 2 polyneuropathy affected 56% of patients while only one (2%) experienced severe polyneuropathy. Similarly, grade 1 or 2 myalgia/arthralgia was observed in 63.2% of patients, but only 14.3% experienced grade 3 or 4. Nausea and vomiting were infrequent, with 14% of patients experiencing grade 1 or 2 and only 2% experiencing grade 3 or 4. Paclitaxel is thus an active single agent in this patient population, with a 3-hour infusion proving comparably effective to a 24-hour infusion and superior in terms of the incidence of hematologic and nonhematologic toxicity. Further phase II studies with paclitaxel combined with other drugs active against NSCLC are indicated, and phase III studies comparing paclitaxel with standard chemotherapy remain to be completed.

Carboplatin in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (14% complete response [CR] and 61% CR + partial response [PR]). The combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 30-month survival rates are 30% in limited disease and 10% in extensive disease with a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in SCLC patients with extensive disease, CR and overall response rates to date are higher in the CEV arm (CR 30% v 10%, CR + PR 90% v 75%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.

Phase II studies with carboplatin in non-small cell lung cancer.

Since 1987, we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer (NSCLC) who had not received prior chemotherapy. Single-agent carboplatin produced a 20% response rate in 51 patients treated with 390 mg/m2 intravenously every 4 weeks. A 3-day schedule of etoposide 140 mg/m2 on days 2, 3, and 4, and carboplatin 150 mg/m2 on days 1 and 5 also resulted in a 26.7% response rate in 46 patients. Myelosuppressive toxicity associated with carboplatin/etoposide was substantially greater than that seen with carboplatin alone. Carboplatin as a single agent is active in previously untreated patients with advanced NSCLC. The two-drug combination of carboplatin and etoposide also shows activity in NSCLC similar to other combination chemotherapeutic regimens based on comparable prognostic factors in untreated patients. Further evaluation of carboplatin as part of combination chemotherapy in NSCLC is warranted.

Single-agent paclitaxel as a 3-hour infusion.

This ongoing phase II trial of patients with inoperable stage IIIB-IV non-small cell lung cancer is seeking to determine the efficacy and toxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered as a 3-hour infusion. The 58 patients now evaluable met standard eligibility requirements, including no prior chemotherapy. Paclitaxel 225 mg/m2 was delivered every 3 weeks for up to 10 courses, depending on patient response. All patients were evaluable for toxicity and 50 were evaluable for response. There were no complete responses, 12 patients had partial responses, 12 had progressive disease, and 26 had no change. The median time to response was 8.7 weeks; the median survival was 10 months. Leukopenia, when observed, was grade 1 or 2 in all but one case. Likewise, all nonhematologic effects were mild, with the exception of one case of grade 3 gastrointestinal toxicity. The 3-hour infusion schedule is more convenient, and the authors feel that the safety of the schedule is confirmed by these results. However, the efficacy of the shortened schedule, compared with a 24-hour infusion, remains to be proven.

Phase III trial with and without lonidamine in non-small cell lung cancer.

One hundred eighty four patients with advanced inoperable non-small cell lung cancer were treated with either lonidamine (A), mitomycin-C/vindesine (B), or mitomycin-C/vindesine plus lonidamine (C) in a prospective randomized trial. The response rates for each treatment arm were 3.4% (A), 22.4% (B) and 25.9% (C), respectively. This difference is statistically significant (P less than 0.01). The median survival time for patients treated with mitomycin-C/vindesine and mitomycin-C/vindesine plus lonidamine was 194 days and 221 days, respectively. In comparison with 145 days for lonidamine alone there is a statistically significant difference in survival between the chemotherapy groups (P less than 0.01). When combined with mitomycin-C/vindesine, lonidamine induces an increase in the response rate and there is a higher proportion of patients living after 12 months of treatment (32% v 20%) in comparison to mitomycin-C/vindesine alone. The subjective tolerance of all treatment groups was very good, toxicity was only mild without major differences between the treatment arms. Combination chemotherapy with mitomycin-C/vindesine plus or minus lonidamine could prolong survival in advanced inoperable nonsmall cell lung cancer significantly without severe toxicity.

Phase II study with paclitaxel for the treatment of advanced inoperable non-small cell lung cancer.

Paclitaxel is a plant product isolated from the bark of the Western yew (Taxus brevifolia) that promotes the formation and stabilization of microtubules. This leads to growth arrest in the G2/M phase of the cell cycle. Paclitaxel has demonstrated significant antineoplastic activity in different tumor types, most notably in ovarian and breast carcinoma. In two Phase II trials (Eastern Cooperative Oncology Group [ECOG]/M.D. Anderson) in patients with previously untreated Stage IIIB-IV non-small cell lung cancer (NSCLC), response rates of 21% and 24% were reported. We are performing a Phase II trial investigating the efficacy of paclitaxel in patients with inoperable Stage IIIB-IV NSCLC. Forty-three patients were treated, 31 males and 12 females, with a median age of 59 years (range, 29-75), ECOG performance status 0-2, Stage IIIB 30%, Stage IV 70%. Patients were treated every 3 weeks with 225 mg/m2 as a 3-h infusion with standard premedication. Preliminary efficacy results from 37 patients include partial remissions in eight (21.6%) patients, no change in 22 (59.5%) and disease progression in seven (19%) patients. Eight patients are still receiving therapy. The hematologic toxicities (n = 43) were mild, and no World Health Organization (WHO) Grade 4 neutropenia was observed. Nonhematologic toxicities were Grade 1/2 polyneuropathy in 97.6%, Grade 1-3 myalgia/arthralgia in 76%, and Grade 1-3 nausea/vomiting in 18.6% of the patients. In conclusion, paclitaxel is an active single agent in this patient population. Mild hematologic toxicities were observed in the 3-h infusion setting (compared with 24-h infusion) and therapy was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized trial with mitomycin-C/ifosfamide versus mitomycin-C/vindesine versus cisplatin/etoposide in advanced non-small-cell lung cancer.

192 evaluable patients with advanced inoperable non-small-cell lung cancer were treated with either mitomycin-C/ifosfamide (A), mitomycin-C/vindesine (B), or cisplatin/etoposide (C) in a prospective randomized trial. The response rates for each treatment arm were 30.0% (A), 22.7% (B), and 25% (C), respectively. There was no statistically significant difference (p = 0.4) between treatment arms. The median survival time was 27 weeks (A), 23 weeks (B), and 25 weeks (C), respectively. With regard to toxicity the combination mitomycin-C/vindesine was superior to treatment arms A and C. Nausea and vomiting (WHO 3 + 4) occurred only in 6.1% of the patients versus 43.3% of those treated with mitomycin-C/ifosfamide and 36.7% of those treated with cisplatin/etoposide. This difference is statistically highly significant (p = 0.0001). Because of its very low toxicity, especially for gastrointestinal symptoms, the combination mitomycin-C/vindesine was judged superior to the other combinations. None of these regimens, however, had a major impact on survival in advanced non-small-cell lung cancer.

[Chemotherapy of advanced non-small cell bronchial cancer with mitomycin C/ifosfamide versus mitomycin C/vindesine versus cisplatin/etoposide--a prospective randomized study]. / Chemotherapie des fortgeschrittenen nicht-kleinzelligen Bronchialkarzinoms mit Mitomycin-C/Ifosfamid versus Mitomycin-C/Vindesin versus Cisplatin/Etoposid--Eine prospektiv randomisierte Studie.

In a prospective randomised study involving patients with inoperable non-small-cell lung cancer, no differences were to be seen in the remission rates (30.3%, 22.7% and 25%, respectively; p = 0.4) achieved by the combinations mitomycin/ifosfamide, mitomycin/vindesine and cisplatin/etoposide. Nor were any statistically significant differences to be found in terms of the duration of survival. The median survival durations were 6.5, 5.5 and 6 months, respectively (p = 0.7). With respect to toxicity, the combination mitomycin/vindesine proved to be superior, in particular since virtually no gastrointestinal toxicity was observed with this combination. On the basis of these results and the-state of our knowledge to date, the conclusion may be drawn that cisplatin-containing combinations should no longer be employed in the chemotherapeutic treatment of non-small-cell cancers.

Carboplatin/etoposide/vincristine therapy in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC; 14% complete response, CR; and 61% CR + partial response, PR). The combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 4-year survival rates are 26% in limited disease and 8% in extensive disease, with a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in SCLC patients with extensive disease, CR and overall response rates are higher in the CEV arm (CR 32 vs. 17%, CR + PR 80 vs. 60%), with statistically significant difference. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.

Intrapleural palliative treatment of malignant pleural effusions with mitoxantrone versus placebo (pleural tube alone).

From 11/87 until 7/90 103 patients entered a prospective randomized trial on the treatment of malignant pleural effusions (MPE) with intrapleural mitoxantrone versus placebo (pleural tube alone with instillation of isotonic NaCl). Our data suggest no statistically significant difference between the two arms with respect to response and response duration. There is no influence on survival time. The toxicity is moderate, with only fever occurring more often in the mitoxantrone arm. We recommend performance of pleurodesis in patients with MPE first by sufficient drainage with a tube of 16-20 char. Only in instances of failure it is necessary to add sclerosing agents such as tetracycline, etc.

[Chemotherapy of small cell bronchial cancer with a combination of carboplatin, vincristine and etoposide]. / Die Chemotherapie des kleinzelligen Bronchialkarzinoms mit einer Kombination aus Carboplatin, Vincristin und Etoposid.

In a phase II study, the combination of the new platinum derivative carboplatin with vincristine and etoposide is associated with a remission rate of 81.8 per cent (LD 84.4%, ED 79.1%). The median survival rates for patients with limited disease have not yet been reached, and, at 11.5 months in the case of patients with extensive disease, are unexpectedly high. In comparison with combinations containing cisplatin, the present combination would appear to be superior, and its toxicity is also lower. For a definitive assessment of its usefulness, it must be compared with other standard treatment regimens in prospective, randomized studies.