Übersichtsarbeiten/Review Articles Onkologie 1990:13:157-164
Alternating Chemotherapy in Small Cell Lung Cancer M. Wolf, K. Havemann Department of Internal Medicine. Division of Hcmatology/Oncology. Philipps University Hospitals, Marburg, FRG
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Based on the hypothesis of Goldie and Coldman, rapid cyclic alternat ing chemotherapy has been supposed to be a favorable treatment modality in small cell lung cancer. This approach has been tested in a large series of trials since the late 70's. A few trials performed randomization between alternating and continuous treatment after a period of initial common continuous therapy. The results of these studies are controversial and their interpretation is complicated by the effects of the continuous pretreatment. Recently, most trials were designed as 2-arm approaches with a comparison of continuous stand ard therapy based on the CAV- or CMC-protocol with an alternating schedule often consisting of the CAV- or CMC-derived combinations and a second regimen including cisplatinum and/or etoposide. In these trials the addition of the second regimen in the alternating treatment arms has improved the treatment results. However, these trials could not clarify whether this advantage was due to the concept of alternat ing treatment or to the high activity of new drugs given early in the course of therapy in the alternating treatment arms. To ameliorate this weakness, 3 studies were designed as 3-arms approaches using both alternating protocols as continuous control arms. Whereas one investi gation noticed an advantage of the alternating schedule, the two others observed no difference. These studies did not report their criteria for shifting non-responding patients from continuous treat ment to second line therapy. The longer these patients stayed on the continuous protocol the more the study design favoured the alternat ing therapy. We considered this point of criticism in a German multicenter study comparing a fixed cyclic alternating treatment with IE and CAV to a response orientated protocol with IE therapy up to the maximum response and subsequently a immediate switch to CAV. The study showed no advantage of the alternating treatment arm indicating that cyclic alternating therapy is not superior to an optimal performed continuous therapy in small cell lung cancer.
Aufgrund des mathematischen Modells von Goldie und Coldman zur Resistenzentwicklung bei malignen Tumoren wurde die zyklisch alter nierende Therapie als eine der am besten geeigneten Behandlungsfor men des kleinzelligen Bronchialkarzinoms angesehen. Dieses Thera piekonzept ist seit Ende der 70er Jahre in einer großen Zahl von klinischen Studien getestet worden. Einige Studien haben die Randomisation zwischen zyklisch alternierender und kontinuierlicher Behandlung nach einer gemeinsamen Initialphase mit kontinuierlicher Therapie durchgeführt. Die Ergebnisse waren widersprüchlich und ihre Interpretation wird durch die vorausgegangene kontinuierliche Vorbehandlung erschwert. In neueren Untersuchungen wurde zumeist ein zweiarmiges Design angewendet, wobei eine kontinuierliche Stan dardbehandlung basierend auf dem CAV- oder CMC-Protokoll gegen eine zyklisch alternierende Behandlung mit einem dieser Standardpro tokolle und einem zweiten Schema unter Einschluß von Cisplatin und/ oder Etoposid geprüft wurde. In diesen Studien hat die Addition des zweiten Behandlungsprotokolles im alternierenden Therapiearm die Ergebnisse verbessert. Diese Studien erlauben jedoch keine Aussage darüber, ob der Vorteil der alternierenden Behandlung durch das Therapiekonzept oder durch die höhere Aktivität der zusätzlich im alternierenden Arm eingesetzten Medikamente bedingt war. In drei Studien wurden daher beide :m alternierenden Arm eingesetzten Protokolle gleichzeitig als kontinuierliche Kontrolltherapien einge setzt. Eine dieser Untersuchungen zeigt einen Vorteil für das alternie rende Programm, die beiden anderen wiesen keine Unterschiede nach. Diese Studien geben keine Auskunft über ihre Kriterien zum Wechsel des Therapieprotokolles bei nichtansprechenden Patienten unter kontinuierlicher Behandlung. Je länger diese Patienten mit dem initialen Protokoll weiterbehandelt wurden, desto mehr begünstigte das Studiendesign die alternierende Therapie. Wir haben diesen Punkt in einer deutschen multizentrischen Studie berücksichtigt und eine zyklisch alternierende Therapie mit IE und CAV gegen eine am Ansprechen orientierte Behandlung mit IE-Gabe bis zu maximalem Response und einem sofortigen Wechsel auf CAV bei keinem weite ren Ansprechen verglichen. Die Studie zeigte keine Unterschiede zwischen beiden Behandlungsmodalitäten. Diese Ergebnisse weisen darauf hin. daß die zyklisch alternierende Therapie einer optimal durchgeführten kontinuierlichen Behandlung nicht überlegen ist.
Small cell lung cancer - Alternating chemotherapy
Review article
Kleinzelliges Bronchialkarzinom - Alternierende Chemotherapie Übersichtsarbeit
Small cell lung cancer (SCLC) accounts for approximately 25% of all lung malignancies. In contrast to the heterogenous group of non-small cell carcinomas, it is characterized by a high cell proliferation fraction and short cell cycle times [1]. The biological properties are responsible for both the rapid tumor growth and dissemination, and the sensitivity to chemoand radiotherapy. The introduction of polychemotherapy pro
tocols in the treatment of SCLC has prolonged survival about 4-fold and median survival has now reached 1 year for large patients populations. However, despite initially high response rates, more than 90% of all patients ultimately die of their disease due to the development of a chemotherapy resistance. It remains unclear whether the development of drug resistance is due to clones of resistant cells existing before the start of
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Introduction
treatment or arising during chemotherapy by means of spon taneous mutations. However, despite controversial results in preclinical investigations [2-4], the clinical experience of rapid tumor response and the high complete remission rate indicate that drug resistance may arise during the course of treatment. About 10 years ago, Goldie and Coldman [5] provided the theoretical basis for the latter suggestion. They described the development of drug-resistant clones by spontaneous muta tions during tumor growth. According to their concept, the probability of developing drug-reistant clones is directly related to the frequency of cell divisions, meaning that the larger the tumor burden and the longer the delay of treatment, the higher the probability of developing drug-resistant clones. As a clinical consequence of this hypothesis, as may active cytotoxic drugs as possible with different ways of action should be applied as soon as possible to eradicate the various sub populations of tumor cells. Therefore, rapidly cyclic alternat ing chemotherapy with two or more equally effective and potentially non-cross resistant drug combinations was consid ered to be the preferrable treatment approach for SCLC. Since 1980, we have tested the concept of alternating chemo therapy in two consecutive German multicenter trials. Similar treatment approaches have been made by a large number of other study groups around the world, so that up to now more than 15 large randomized trials,each including more than 100 patients, have been conducted. The designs and results of these trials will be summarized and discussed in this article. Results
Since the late 1970s, substantial efforts have been performed to test the concept of alternating chemotherapy. To facilitate a comparison of the various trials and their results, investi gations with similar methological approaches were taken together and are discussed in one of the 4 following sections. Trials with “Late Randomization" In several trials the randomization between alternating and continuous treatment was performed after several cycles of continuous treatment had been given previously. These studies are summarized in table 1. In the trial conducted by Sikic et al. [6] 135 patients were randomized to receive either sequential POCC treatment (procarbacinc, vincristine, cyclophosphamide, CCNU) or 3 initial cycles of VAM (VP16, adriamycin, methotrexate) fol lowed by alternation of POCC and VAM. The results showed a statistically significant superiority of the alternating regimen in 89 patients with extensive stage disease (median survival 300 days versus 209 days, p
Alternating Chemotherapy in Small Cell Lung Cancer M. Wolf, K. Havemann Department of Internal Medicine. Division of Hcmatology/Oncology. Philipps University Hospitals, Marburg, FRG
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Based on the hypothesis of Goldie and Coldman, rapid cyclic alternat ing chemotherapy has been supposed to be a favorable treatment modality in small cell lung cancer. This approach has been tested in a large series of trials since the late 70's. A few trials performed randomization between alternating and continuous treatment after a period of initial common continuous therapy. The results of these studies are controversial and their interpretation is complicated by the effects of the continuous pretreatment. Recently, most trials were designed as 2-arm approaches with a comparison of continuous stand ard therapy based on the CAV- or CMC-protocol with an alternating schedule often consisting of the CAV- or CMC-derived combinations and a second regimen including cisplatinum and/or etoposide. In these trials the addition of the second regimen in the alternating treatment arms has improved the treatment results. However, these trials could not clarify whether this advantage was due to the concept of alternat ing treatment or to the high activity of new drugs given early in the course of therapy in the alternating treatment arms. To ameliorate this weakness, 3 studies were designed as 3-arms approaches using both alternating protocols as continuous control arms. Whereas one investi gation noticed an advantage of the alternating schedule, the two others observed no difference. These studies did not report their criteria for shifting non-responding patients from continuous treat ment to second line therapy. The longer these patients stayed on the continuous protocol the more the study design favoured the alternat ing therapy. We considered this point of criticism in a German multicenter study comparing a fixed cyclic alternating treatment with IE and CAV to a response orientated protocol with IE therapy up to the maximum response and subsequently a immediate switch to CAV. The study showed no advantage of the alternating treatment arm indicating that cyclic alternating therapy is not superior to an optimal performed continuous therapy in small cell lung cancer.
Aufgrund des mathematischen Modells von Goldie und Coldman zur Resistenzentwicklung bei malignen Tumoren wurde die zyklisch alter nierende Therapie als eine der am besten geeigneten Behandlungsfor men des kleinzelligen Bronchialkarzinoms angesehen. Dieses Thera piekonzept ist seit Ende der 70er Jahre in einer großen Zahl von klinischen Studien getestet worden. Einige Studien haben die Randomisation zwischen zyklisch alternierender und kontinuierlicher Behandlung nach einer gemeinsamen Initialphase mit kontinuierlicher Therapie durchgeführt. Die Ergebnisse waren widersprüchlich und ihre Interpretation wird durch die vorausgegangene kontinuierliche Vorbehandlung erschwert. In neueren Untersuchungen wurde zumeist ein zweiarmiges Design angewendet, wobei eine kontinuierliche Stan dardbehandlung basierend auf dem CAV- oder CMC-Protokoll gegen eine zyklisch alternierende Behandlung mit einem dieser Standardpro tokolle und einem zweiten Schema unter Einschluß von Cisplatin und/ oder Etoposid geprüft wurde. In diesen Studien hat die Addition des zweiten Behandlungsprotokolles im alternierenden Therapiearm die Ergebnisse verbessert. Diese Studien erlauben jedoch keine Aussage darüber, ob der Vorteil der alternierenden Behandlung durch das Therapiekonzept oder durch die höhere Aktivität der zusätzlich im alternierenden Arm eingesetzten Medikamente bedingt war. In drei Studien wurden daher beide :m alternierenden Arm eingesetzten Protokolle gleichzeitig als kontinuierliche Kontrolltherapien einge setzt. Eine dieser Untersuchungen zeigt einen Vorteil für das alternie rende Programm, die beiden anderen wiesen keine Unterschiede nach. Diese Studien geben keine Auskunft über ihre Kriterien zum Wechsel des Therapieprotokolles bei nichtansprechenden Patienten unter kontinuierlicher Behandlung. Je länger diese Patienten mit dem initialen Protokoll weiterbehandelt wurden, desto mehr begünstigte das Studiendesign die alternierende Therapie. Wir haben diesen Punkt in einer deutschen multizentrischen Studie berücksichtigt und eine zyklisch alternierende Therapie mit IE und CAV gegen eine am Ansprechen orientierte Behandlung mit IE-Gabe bis zu maximalem Response und einem sofortigen Wechsel auf CAV bei keinem weite ren Ansprechen verglichen. Die Studie zeigte keine Unterschiede zwischen beiden Behandlungsmodalitäten. Diese Ergebnisse weisen darauf hin. daß die zyklisch alternierende Therapie einer optimal durchgeführten kontinuierlichen Behandlung nicht überlegen ist.
Small cell lung cancer - Alternating chemotherapy
Review article
Kleinzelliges Bronchialkarzinom - Alternierende Chemotherapie Übersichtsarbeit
Small cell lung cancer (SCLC) accounts for approximately 25% of all lung malignancies. In contrast to the heterogenous group of non-small cell carcinomas, it is characterized by a high cell proliferation fraction and short cell cycle times [1]. The biological properties are responsible for both the rapid tumor growth and dissemination, and the sensitivity to chemoand radiotherapy. The introduction of polychemotherapy pro
tocols in the treatment of SCLC has prolonged survival about 4-fold and median survival has now reached 1 year for large patients populations. However, despite initially high response rates, more than 90% of all patients ultimately die of their disease due to the development of a chemotherapy resistance. It remains unclear whether the development of drug resistance is due to clones of resistant cells existing before the start of
-
Downloaded by: King's College London 137.73.144.138 - 1/18/2019 9:31:45 AM
Introduction
treatment or arising during chemotherapy by means of spon taneous mutations. However, despite controversial results in preclinical investigations [2-4], the clinical experience of rapid tumor response and the high complete remission rate indicate that drug resistance may arise during the course of treatment. About 10 years ago, Goldie and Coldman [5] provided the theoretical basis for the latter suggestion. They described the development of drug-resistant clones by spontaneous muta tions during tumor growth. According to their concept, the probability of developing drug-reistant clones is directly related to the frequency of cell divisions, meaning that the larger the tumor burden and the longer the delay of treatment, the higher the probability of developing drug-resistant clones. As a clinical consequence of this hypothesis, as may active cytotoxic drugs as possible with different ways of action should be applied as soon as possible to eradicate the various sub populations of tumor cells. Therefore, rapidly cyclic alternat ing chemotherapy with two or more equally effective and potentially non-cross resistant drug combinations was consid ered to be the preferrable treatment approach for SCLC. Since 1980, we have tested the concept of alternating chemo therapy in two consecutive German multicenter trials. Similar treatment approaches have been made by a large number of other study groups around the world, so that up to now more than 15 large randomized trials,each including more than 100 patients, have been conducted. The designs and results of these trials will be summarized and discussed in this article. Results
Since the late 1970s, substantial efforts have been performed to test the concept of alternating chemotherapy. To facilitate a comparison of the various trials and their results, investi gations with similar methological approaches were taken together and are discussed in one of the 4 following sections. Trials with “Late Randomization" In several trials the randomization between alternating and continuous treatment was performed after several cycles of continuous treatment had been given previously. These studies are summarized in table 1. In the trial conducted by Sikic et al. [6] 135 patients were randomized to receive either sequential POCC treatment (procarbacinc, vincristine, cyclophosphamide, CCNU) or 3 initial cycles of VAM (VP16, adriamycin, methotrexate) fol lowed by alternation of POCC and VAM. The results showed a statistically significant superiority of the alternating regimen in 89 patients with extensive stage disease (median survival 300 days versus 209 days, p
