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138 WEEKLY CHEMOTHERAPY FOR SMALL CELL LUNG CANCER Nevin Murray M.D. British Columbia Cancer Agency, Vancouver, Canada, V5Z 4E6 Pilot studies of weekly chemotherapy regimens have been reported for a variety of cancers including small cell lung cancer (SCLC). Although some phase II studies have been promising, phase III studies reported to date for SCLC’*’ show no advantage for weekly treatment compared to standard treatment given at intervals of three weeks. An adequate defence of weekly chemotherapy must provide a rationale for this strategy, explain existing negative controlled studies, and describe a weekly regimen potentially capable of improving SCLC results in randomized trials. Possible mechanisms of enhanced therapeutic effects from weekly chemotherapy include: 1) pharmacokinetic effects, 2) synchrony of cell kinetics, 3) resistance modification, 4) inhibition of accelerated repopulation, 5) increased dose-response or intensity-response, and 6) more drug diversity. Claims for the first four mechanisms are not substantiated by existing evidence. Benefits of increased treatment intensity and increased drug diversity (more agents) are supported by data from experimental models and some SCLC clinical trial data. Randomized trials in extensive stage SCLC have not shown improved outcome when “standard” dose regimens are compared to programs with higher than standard doses. However, when standard dose regimens are compared to low dose regimens, an inferior outcome is usually easily demonstrated. This body of information suggests that standard SCLC regimens are near the plateau of the intensity- response curve. Rather than increasing the intensity of a regimen by escalating the dose above standard levels it may be more rational to intensify a regimen by adding more agents at full dose intensity thereby increasing the drug diversity of the combination, Greater drug diversity provides a broader range of coverage of resistant cell lines in a heterogenous tumor population and prevents or slows the development of new resistant lines. Multi- agent chemotherapy provides maximal cell kill within the range of toxicity tolerated by the host for each drug. The advantage of drug diversity will be limited to the extent that the drugs within the regimen have overlapping toxicity for the host and cross-resistance for the tumor. Weekly chemotherapy regimens are unlikely to be successful unless they obey the fundamental rules of combination chemotherapy.5 These rules include: 1) Select only active drugs, 2) Use drugs of different classes. 3) Select drugs with non-overlapping toxicity. 4) Use drugs in their optimal dose and schedule. 5) Treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive target tissue (usually the bone marrow). Table 1 DOSE INTENSITY OF WEEKLY REGIMENS mgfm2/week Standard CODE’ Miles2 Sculie? Taylor4 Cisplatin Vincristine Doxorubicin Etoposide Cyclophosphamide Ifosfamide Methotmxate Vindesine 20 - 30 25 25 20 15 0.4 - 0.5 0.55 0.4 0.7 15 - 20 20 12.5 8.3 10 80 - 120 100 75 40 56 250 - 350 167 100 2500 - 3000 - 1000 ? 33 50 3 1

Weekly chemotherapy for small cell lung cancer

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WEEKLY CHEMOTHERAPY FOR SMALL CELL LUNG CANCER Nevin Murray M.D. British Columbia Cancer Agency, Vancouver, Canada, V5Z 4E6

Pilot studies of weekly chemotherapy regimens have been reported for a variety of cancers including small cell lung cancer (SCLC). Although some phase II studies have been promising, phase III studies reported to date for SCLC’*’ show no advantage for weekly treatment compared to standard treatment given at intervals of three weeks. An adequate defence of weekly chemotherapy must provide a rationale for this strategy, explain existing negative controlled studies, and describe a weekly regimen potentially capable of improving SCLC results in randomized trials.

Possible mechanisms of enhanced therapeutic effects from weekly chemotherapy include: 1) pharmacokinetic effects, 2) synchrony of cell kinetics, 3) resistance modification, 4) inhibition of accelerated repopulation, 5) increased dose-response or intensity-response, and 6) more drug diversity. Claims for the first four mechanisms are not substantiated by existing evidence. Benefits of increased treatment intensity and increased drug diversity (more agents) are supported by data from experimental models and some SCLC clinical trial data.

Randomized trials in extensive stage SCLC have not shown improved outcome when “standard” dose regimens are compared to programs with higher than standard doses. However, when standard dose regimens are compared to low dose regimens, an inferior outcome is usually easily demonstrated. This body of information suggests that standard SCLC regimens are near the plateau of the intensity- response curve. Rather than increasing the intensity of a regimen by escalating the dose above standard levels it may be more rational to intensify a regimen by adding more agents at full dose intensity thereby increasing the drug diversity of the combination,

Greater drug diversity provides a broader range of coverage of resistant cell lines in a heterogenous tumor population and prevents or slows the development of new resistant lines. Multi- agent chemotherapy provides maximal cell kill within the range of toxicity tolerated by the host for each drug. The advantage of drug diversity will be limited to the extent that the drugs within the regimen have overlapping toxicity for the host and cross-resistance for the tumor.

Weekly chemotherapy regimens are unlikely to be successful unless they obey the fundamental rules of combination chemotherapy.5 These rules include: 1) Select only active drugs, 2) Use drugs of different classes. 3) Select drugs with non-overlapping toxicity. 4) Use drugs in their optimal dose and schedule. 5) Treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive target tissue (usually the bone marrow).

Table 1 DOSE INTENSITY OF WEEKLY REGIMENS mgfm2/week

Standard CODE’ Miles2 Sculie? Taylor4

Cisplatin Vincristine Doxorubicin Etoposide Cyclophosphamide Ifosfamide Methotmxate Vindesine

20 - 30 25 25 20 15 0.4 - 0.5 0.55 0.4 0.7 15 - 20 20 12.5 8.3 10 80 - 120 100 75 40 56

250 - 350 167 100 2500 - 3000 - 1000

? 33 50 3 1

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Table 1 shows the dose intensity (mg/m’/week) for several published chemotherapy regimens for SCLC. The regimens of Miles2 and Sculie? were not superior to standard (three week interval) chemotherapy in randomized comparisons. A possible explanation for this outcome is that the dose intensity achieved for a number of constituent drugs is below standard (violation of rule #4). The approximate aggregate dose intensity (using a relative dose intensity calculation of the Hryniuk method6) for the entire regimens of Miles 2, Sculie? and Taylor4 is not clearly greater than standard regimens. The relative dose intensity of CODE’ is about double that of standard alternating CAV/EP and the total dose of agents in CODE given over nine weeks is similar to CAV/EP given over 18 weeks. Table 2

TOTAL CUMULATIVE DOSES IN STANDARD AND CODE CHEMOTHERAPY

Standard -intended over 18 weeks

Cisnlatin 16 VP- DOX vex m’ 225 900 150 3.6 3000

CODE -intended over 9 wks

225 1080’ 200 5.0

All doses expressed as mg/m’

1- Oral dose assumed to be 85% IV dose + Cyclophosphamide not given in CODE

The standard interval between chemotherapy cycles is three weeks because of the recovery time from myelosuppression. Treatment intensity can be increased by decreasing intervals between cycles rather than increasing dose size. However, weekly delivery of myelosuppressive chemotherapy does not allow recovery of granulocytes2.3 (violation of rules #3 and #5). The CODE regimen increases treatment intensity by alternation of myelosuppressive and non-myelosuppressive weeks of therapy and use of supportive drugs (steroids and prophylactic antibiotics’ or G-CSF’).

An update of the Vancouver pilot study of extensive SCLC shows a median survival of greater than one year (55 weeks) and 5-year survival of 9%. The CODE regimen is currently being compared to standard chemotherapy (alternating CAV/EP) in North America by the National Cancer Institute of Canada and the Southwest Oncology Group. The Japanese Lung Cancer Chemotherapy Group is comparing CODE plus G-CSF with alternating CAV/EP. The value of this approach will soon be confirmed or refuted.

References 1. Murray N, et al. J Clin Oncol 1991;9:1632-1638. 2. Miles D, et al. J Clin Oncol 1991;9:280-285. 3. Sculier JP, et al. J Clin Oncol 1993;11:1858-1865. 4. Taylor CW, et al. J Clin Oncol 1990;8:1811-1817. 5. DeVita VT. Cancer: Principles and Practice of Oncology 1993. 6. Hryniuk WM, et al. J Clin Oncol 1984;2:1281-1288. 7. Masuda N, et al. Oncology 1992;49:19-24.