Cisplatin dose intensity in metastatic non-small cell cell lung cancer: Results of a phase III comparative study

The regimen of cisplatin, vincristine, doxorubicin, and etoposide (CODE) was designed to double the dose intensity of these drugs in comparison with a standard regimen (alternating cyclophosphamide, doxorubicin, and vincristine [CAV] and etoposide-cisplatin [EP]) for extensive-stage small-cell lung cancer (SCLC). The dose intensity was increased by more frequent treatments rather than by increasing the dose size. The structure of this outpatient protocol includes weekly administration of chemotherapy, alternation of myelosuppressive and nonmyelosuppressive treatments, supportive corticosteroids, gastroprotective agents, and prophylactic antibiotics. Although the duration of chemotherapy was brief (9 to 12 weeks), the total cumulative doses of drugs delivered were similar to the standard regimen. Patients with no residual disease outside the chest after chemotherapy received thoracic irradiation, and patients with complete responses (CRs) received prophylactic cranial irradiation. Eligible extensive-stage SCLC patients were ambulatory, younger than 66 years of age, and free of brain metastasis. Forty-eight extensive-stage SCLC patients were treated. Forty-five (94%) responded to chemotherapy, with 19 (40%) attaining CR. After consolidative thoracic irradiation, the CR rate was 56%. The median time to progression was 43 weeks, and the median survival was 61 weeks. The 2-year survival rate was 30%. The most common site of first relapse was brain (38%). Although two patients (4%) died of toxicity, overall toxicity was acceptable for an outpatient regimen. We conclude that the CODE regimen reliably produces palliative remissions for selected extensive-stage SCLC patients, and it may be associated with durable remissions for some patients. The results of this pilot study are sufficiently promising to justify a phase III trial of CODE versus standard (alternating CAV and EP) chemotherapy.

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New Radiotherapy and Chemoradiotherapy Approaches for Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2012.44.5064 ◽

2013 ◽

Vol 31 (8) ◽

pp. 1029-1038 ◽

Cited By ~ 48

Author(s):

Joseph K. Salama ◽

Everett E. Vokes

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Locally Advanced ◽

Dose Intensity ◽

Small Cell ◽

Phase Iii ◽

Poor Performance Status ◽

Small Cell Lung

Recent advances in systemic cytotoxic and molecularly targeted therapies coupled with technologic strides in radiotherapy have the potential to improve outcomes for patients with non–small-cell lung cancer (NSCLC). Investigations are ongoing to identify optimal cytotoxin-based chemoradiotherapy platforms. The influence of specific histologic and molecular mutation status on the combination of targeted therapies and radiotherapy is also being actively studied. Although there are no convincing randomized phase III data to date supporting a survival advantage for combining molecularly targeted agents with radiation or chemoradiotherapy in the setting of locally advanced NSCLC, phase II and III studies targeted to elderly patients and those with poor performance status are elucidating preferred chemoradiotherapy strategies. Radiotherapy dose escalation did not improve chemoradiotherapy outcomes, although increasing radiation dose-intensity with modern techniques is being actively studied. As modern radiotherapy techniques have been shown to improve outcomes of some patients with limited metastatic disease, investigations are ongoing regarding how to optimally integrate them with standard chemotherapy platforms.

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Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.5.873 ◽

1993 ◽

Vol 11 (5) ◽

pp. 873-878 ◽

Cited By ~ 104

Author(s):

D R Gandara ◽

J Crowley ◽

R B Livingston ◽

E A Perez ◽

C W Taylor ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Dose Intensity ◽

Small Cell ◽

Phase Iii ◽

High Dose ◽

Oncology Group ◽

Small Cell Lung ◽

Southwest Oncology Group

PURPOSE To test the concept that cisplatin dose-intensity is important in the treatment of non-small-cell lung cancer (NSCLC), the Southwest Oncology Group (SWOG) performed a randomized trial comparing standard-dose cisplatin (SDCP) 50 mg/m2 days 1 and 8 on a 28-day cycle for eight cycles, high-dose cisplatin (HDCP) 100 mg/m2 days 1 and 8 for four cycles, and high-dose cisplatin plus mitomycin (HDCP-M) 8 mg/m2 day 1. To isolate the effects of dose-intensity versus total dose, the planned cumulative cisplatin dose was 800 mg/m2 in each arm. PATIENTS AND METHODS Between July 1988 and April 1990, 356 patients were enrolled and 323 were eligible and assessable. All patients had metastatic, measurable disease, were chemotherapy-naive, and had a performance status (PS) of 0 to 2. RESULTS Confirmed complete plus partial response rates were SDCP, 12%; HDCP, 14%; and HDCP-M, 27% (P < .05). Complete responses were uncommon (HDCP, 3%; HDCP-M, 4%) and were observed only in the high-dose arms. Progressive disease occurred more frequently in the SDCP arm (57%) compared with HDCP (38%) or HDCP-M (34%) (P < .05). However, there were no significant differences in median survival times (SDCP, 6.9 months; HDCP, 5.3 months; HDCP-M, 7.2 months; P = .53). The mean delivered dose-intensity for cisplatin was significantly greater in the high-dose arms: HDCP 41 mg/m2/wk and HDCP-M 39 mg/m2/wk, versus SDCP 23 mg/m2/wk (P = .05). The high-dose arms resulted in an increased incidence of ototoxicity, emesis, and myelosuppression, but similar degrees of renal toxicity and neuropathy compared with SDCP. CONCLUSION This study does not confirm evidence of a steep clinical dose-response curve for cisplatin in NSCLC at the cisplatin dose-intensities achieved. The addition of mitomycin increases the response rate, but does not improve survival. Continued evaluation of new agents in this disease is warranted.

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