Wednesday, June 29, 1994

Chemotherapy III - Small Cell Lung Cancer

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Dase Intensive Combined Modality Therapy for Small Cell Lung Cancer. Anthony D. Elias, M.D. Dana-Farber Cancer Institute, Boston, MA 02115

SCLC is a deceptively resistant solid tumor to chemoradiotherapy. Chemoradiotherapy at conventional doses has resulted in a high response rates: 80-100% (Xl-70% complete) for disease limited to the chest, and and 60-80% (20-40% complete) for metastatic disease. However, cure is elusive. Median survival of 14-18 months for limited disease and 8-12 months for extensive disease are achieved. About 20% of limited stage and 5% of extensive stage patients will survive two years. Survival beyond 5 years occurs in 3-8% of patients with SCLC (1). Chest radiotherapy improves actuarial local control rates from 10% to about 4060% and is associated with improved survival (2).

The inability to destroy the residual cells despite “chemosensitivity” suggests the existence of a tumor stem cell resistant to cytotoxic therapy. Maximizing dose and dose intensity to the limits of acceptable toxicity might overcome resistance. Hematopoietic stem cell support, using marrow or peripheral blood progenitor cells, provides the opportunity to evaluate dose-response to the limits of organ tolerance.

Currently available cytokines (eg, GM-CSF and G-CSF) are able to ameliorate chemotherapy- induced myelosuppression and reduce febrile neutropenia. While trials involving SCLC patients were instrumental in providing support for FDA approval for the clinical use of cytokines (3), there is no evidence that the consequent maintenance of dose intensity has had significant impact on disease-free or overall survival. To date, dose and dose intensity can be increased by only 1.5-2 fold with cytokine use; differences unlikely to produce survival advantages.

We have focussed on two strategies to intensify therapy to enhance cure: a) high dose combined modality therapy with stem cell support (“induction/ intensification”); and b) multicycle dose-intensive chemotherapy supported by cytokines alone or plus peripheral blood progenitor cells.

The first approach utilizes conventional dose CT as induction with the addition of chest radiotherapy to target overt and potentially chemotherapy-resistant disease, followed by intensification with high dose combined alkylating agents with stem cell support. The second approach is designed to enhance efficacy of induction therapy by intensifying multiple courses, and should be considered potentially complementary to the frost approach. Enhanced efficacy upfront will likely lead to greater numbers of better candidates for intensification.

Historically, high dose therapy with marrow support in solid tumors was developed for patients with responding SCLC based on its sensitivity to multiple chemotherapeutic agents at conventional doses. These high dose regimens have demonstrated enhanced complete response rates without an overall survival benefit. Similar to that observed with conventional dose therapy, relapse in sites of prior tumor involvement following dose intensive therapy remained the rule. Within the most favorable subset, patients with limited disease in complete response prior to high dose therapy, 24 of 71 (34%) patients remained disease-free with a median follow-up >3 years. Since physiologically robust patients were selected, but high treatment-related morbidity and mortality was encountered, investigators concluded that potential benefits did not justify the risks of the procedure. The one randomized trial compared conventional therapy to high dose intensification with marrow support in patients with responding SCLC, but without chest radiotherapy (4). Despite high local-regional relapse (8 l%), this study demonstrated greater responses and disease-free survival with a trend toward improved survival for the high dose arm.

Since 1985, we have conducted a phase II trial of high dose combination of alkylating agents (cyclophosphamide, carmustine and cisplatin) with marrow support followed by chest and prophylactic cranial radiotherapy in patients with limited SCLC responding to first line conventional dose chemotherapy. Patients under age 60 in good physiologic status with limited stage small cell lung cancer in response to first line conventional dose induction chemotherapy were eligible (5). 25

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patients (median age 49) with stage III SCLC have been enrolled. At presentation, 14 had stage IIIB SCLC, with pleural and pericardial effusions in 8. At the time of high dose therapy, 7 patients (28%) had achieved a complete response to induction chemotherapy, 12 had >90% reduction in tumor size, and 6 had 50-90% reduction in the size of their tumor, but with residual nodular disease radiographically. Twenty of 25 (80%) patients received chest radiotherapy (median of 5020 cGy); six before and 14 after high dose therapy. One toxic death from fungal infection occurred (4%). Steroid responsive and reversible interstitial pneumonitis occurred in 25% within 2-3 months of high dose therapy. After completion of high dose intensification, 21 of 25 were in complete response. The median event-free survival after high dose therapy for all patients was 21 months. The median survival after intensification was 27 months. Of the 10 patients who relapsed, eight recurred in the chest, leading to the incorporation of intensive chest radiotherapy concurrent with early induction. Of the 19 patients in or near complete response prior to high dose therapy, 14 (74%) remain disease-free with no further chemotherapy a median of 18 (4-82+) months after high dose therapy. Actuarial 2- year disease-free survival is 66% (32-99%; 95% confidence interval). Although this multimodality approach is dose-intensive, it is associated with low morbidity and an acceptable mortality of under 5%. With the exception of herpes zoster, late complications (> 3 months after high dose therapy) are rare and most patients were able to return to full-time work. (Gf 18 patients with metastatic disease or extrapulmonary small cell carcinoma in response, four (22%) have remained progression free at 15-27 months).

In an effort to improve local-regional control, current patients are receiving twice daily fractionated chest radiotherapy concurrent with induction chemotherapy. A phase II trial has been activated within the CALGB and SWOG (CALGB 9331) to evaluate the safety of high-dose CBP following twice daily chest radiotherapy given concurrently with chemotherapy in a multiinstitutional setting. An important goal is to perform a randomized comparison between high dose and conventional dose therapy to define the utility of dose intensification with hematopoietic support in these patients.

Immunological screening of bone marrow from SCLC patients has shown that approximately 50% of histologically normal marrow aspirates and biopsies from patients with limited disease have cells that specifically bind monoclonal antibodies directed against SCLC membrane antigens (6,7). The clinical significance of this finding has not been established. In CALGB 9331, we will evaluate the prognostic importance of initial screening (positive vs negative), the conversion from positive to negative screen after induction, correlation with clinical overall response (> 90% PR vs CR) and the possible effect of positive screening of the marrow harvest and peripheral blood progenitor cell collections on disease-free survival and relapse patterns in these patients who receive marrow and PBPC support. We are about to begin using G-CSF mobilized CD34-antigen selected peripheral blood progenitor cells as sole hematologic support. We will correlate the degree of tumor cell contamination of the PBPC with subsequent outcome in this cohort of patients as well.

References:

1: Seifter EJ, Ihde DC. Semin Oncol 1988;15(3):278-299. Waarde P, Payne D. J Clin Oncoll992; 10: 890-895.

:: Crawford J, et al. New Engl J Med 1991; 325: 164-170. Humblet Y, et al. J Clin Oncol 1987;5:1864-1873.

2 Elias AD, et al. J Natl Cancer Inst 1993; 85: 559-566.

7: Humblet Y, et al. Cancer Res 1989; 49: 5058-5061. Stahel RA, et al. Int J Cancer 1985; 35: 587-592.