Summary
Since July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p<0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p<0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600–900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.
Zusammenfassung
Seit Juli 1978 wurden 103 Patienten mit inoperablem kleinzelligem Bronchialkarzinom mit der Zytostatikakombination Adriamycin, Cyclophosphamid und Vincristin (ACO) behandelt. Im Stadium „limited disease“ (n=64) erfolgte während des zweiten Chemotherapiekurses eine prophylaktische Schädelbestrahlung, nach dem vierten eine konsolidierende thorakale Bestrahlung. Nach Erreichen einer kompletten Remission erhielten die Patienten prospektiv randomisiert Etoposid oder keine weitere spezifische Therapie. Ein objektives Ansprechen konnte bei 88/100 auswertbaren Patienten erzielt werden. Im Stadium „limited disease“ fanden sich 72%, im Stadium „extensive disease“ nur 33% komplette Remissionen. Im Stadium „limited disease“ betrug die hochgerechnete mediane Überlebenszeit 15,8, im Stadium „extensive disease“ 9,3 Monate (p<0.005). Es leben noch 29 Patienten, 4 rezidivfrei länger als 24 Monate. Patienten mit kompletter Remission hatten eine statistisch signifikant (p<0.001) längere Überlebenszeit als Patienten mit geringerem Ansprechen. Regelmäßig traten gastrointestinale und hämatologische Nebenwirkungen auf, drei Patienten starben während der Induktionsphase an Infektionen. Die kurzzeitige Induktionsbehandlung verbesserte jedoch den Krankheitsverlauf subjektiv und objektiv. Bisher ist kein positiver Effekt der zyklischen Etoposid-Gabe nach ACO festzustellen.
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Literatur
Abeloff MD, Ettinger DS, Order SE, Khouri N, Mellits ED, Dorschel NT, Baumgardner R (1981) Intensive induction chemotherapy in 54 patients with small cell carcinoma of the lung. Cancer Treat Rep 65:639–646
Aisner J, Wiernik PH (1980) Chemotherapy versus chemoimmunotherapy for small-cell undifferentiated carcinoma of the lung. Cancer 46:2543–2549
Alberto P, Brunner KW, Martz G, Obrecht JP, Sonntag RW (1976) Treatment of bronchogenic carcinoma with simultaneous or sequential combination chemotherapy, including methotrexate, cyclophosphamide, procarbazine and vincristine. Cancer 38:2208–2216
Alexander M, Glatstein EJ, Gordon DS, Daniels JR (1977) Combined modality treatment of oat cell carcinoma of the lung: a randomized trial. Cancer Treat Rep 61:1–6
American Cancer Society (1981) Cancer statistics, 1981. Ca 31:13–28
Aroney RS, Dalley DN, Chan WK, Bell DR, Levi JA (1981) Menigeal carcinomatosis in small cell carcinoma of the lung. Am J Med 71:26–32
Baglan RJ, Marks JE (1981) Comparison of symptomatic and prophylactic irradiation of brain metastases from oat cell carcinoma of the lung. Cancer 47:41–45
Bergsagel DE, Jenkin RDT, Pringle JF, White DM, Fetterly JCM, Klaassen DJ, McDermot RSR (1972) Lung cancer: Clinical trial of radiotherapy alone vs. radiotherapy plus cyclophosphamide. Cancer 30:621–627
Blum U, Ungeheuer E, Wacha H, Kiel G (1981) Ist die chirurgische Therapie beim kleinzelligen Bronchialkarzinom heute noch indiziert? Dtsch Med Wochenschr 106:1286–1288
Bradley WG, Lassmann LP, Pearce GW, Walton JN (1970) The neuromyopathy of vincristine in man. Clinical, electrophysiological and pathological studies. J Neurol Sci 10:107–131
Breslow N (1974) Covariance analysis of censored survival data. Biometrics 30:89–99
Byhardt RW, Libnoch JA, Cox JD, Holoye PY, Kun L, Komaki R, Clowry L (1981) Local control of intrathoracic disease with chemotherapy and role of prophylactic cranial irradiation in small-cell carcinoma of the lung. Cancer 47:2239–2246
Catane R, Schwade JG, Yarr I, Lichter AS, Tepper JE, Dunnick NR, Brody L, Brereton HD, Cohen M, Glatstein E (1981) Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy. Int J Radiat Oncol Biol Phys 7:105–109
Cohen MH, Ihde DC, Bunn PA jr, Fossieck BE jr, Matthews MJ, Shackney SE, Johnston-Early A, Makuch R, Minna JD (1979) Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 63:163–170
Cohen MH, Lichter AS, Bunn PA, Glatstein EJ, Ihde DC, Fossieck BE, Matthews MJ, Minna JD (1980) Chemotherapyradiation therapy (CT-RT) versus chemotherapy (CT) in limited small cell lung cancer (SCLC). In: Hansen HH, Dombernowsky P (eds) II. World conference on lung cancer, Abstracts. Excerpta Medica, Amsterdam Oxford Princeton, p 146
Corbett TH, Griswold DP, Mayo JG, Laster WR, Schabel FM jr (1975) Cyclophosphamide-adriamycin combination chemotherapy of transplantable murine tumors. Cancer Res 35:1568–1573
Cox JD, Yesner R, Mietlowski W, Petrovich Z (1979) Influence of cell type on failure pattern after irradiation for locally advanced carcinoma of the lung. Cancer 44:94–98
Cutler SJ, Ederer F (1958) Maximum utilization of the life table method in analyzing survival. J Chron Dis 8:699–712
DeVita VT, Young RC, Canellos GP (1975) Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer. Cancer 35:98–110
DeWys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO jr, Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG, Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey DC (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 69:491–497
Eagan RT, Frytak S, Nichols WC, Ingle JN, Creagan ET, Kvols LK (1981) Cyclophosphamide and VP-16-213 with or without cis-platin in squamous cell and small cell lung cancers. Cancer Treat Rep 65:453–458
Fox RM, Woods RL, Brodie GN, Tattersall MHN (1980) A randomized study: Small cell anaplastic lung cancer treated by combination chemotherapy and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 6:1083–1085
Freise G, Gabler A, Liebig S (1978) Bronchial carcinoma and long-term survival. Retrospective study of 433 patients who underwent resection. Thorax 33:228–234
Garfinkel L (1981) Time trends in lung cancer mortality among nonsmokers and a note on passive smoking. J Natl Cancer Inst 66:1061–1066
Ginsberg SJ, Comis RL, Gottlieb AJ, King GB, Goldberg J, Zamkoff K, Elbadawi A, Meyer JA (1979) Long-term survivorship in small-cell anaplastic lung carcinoma. Cancer Treat Rep 63:1347–1349
Greco FA, Richardson RL, Snell JD, Stroup SL, Oldham RK (1979) Small cell lung cancer. Complete remission and improved survival. Am J Med 66:625–630
Gropp C, Havemann K, Scheuer A (1980) Ectopic hormones in lung cancer patients at diagnosis and during therapy. Cancer 46:347–354
Hansen HH, Dombernowsky P, Hirsch FR (1978) Staging procedures and prognostic features in small cell anaplastic bronchogenic carcinoma. Semin Oncol 5:280–287
Hansen HH, Dombernowsky P, Hirsch FR, Hansen M, Rygård J (1980) Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic brain irradiation in patients receiving combination chemotherapy. Cancer 46:279–284
Higgins GA, Shields TW, Keehn RJ (1975) The solitary pulmonary nodule. Ten-year follow-up of Veterans Administration-Armed Forces cooperative study. Arch Surg 110:570–575
Hoffmann PC, Golomb HM, Bitran JD, DeMeester TR, Cohen L, Griem ML, Cooksey JA, Mintz U, Gordon LI, Desser RK, Kinnealey AE, Sovik CA (1980) Small-cell carcinoma of the lung: a five-year experience with combined modality therapy. Cancer 46:2550–2556
Holoye PY, Samuels ML, Lanzotti VJ, Smith T, Barkley HT jr (1977) Combination chemotherapy and radiation therapy for small cell carcinoma. JAMA 237:1221–1224
Høst H (1973) Cyclophosphamide (NSC-26271) as adjuvant to radiotherapy in the treatment of unresectable bronchogenic carcinoma. Cancer Chemother Rep 4(3):161–164
Hyde L, Yee J, Wilson R, Patno ME (1965) Cell type and the natural history of lung cancer. JAMA 193:140–142
Ihde DC, Cohen MH, Bernath AM, Matthews MJ, Bunn PA, Minna JD (1978) Serial fiberoptic bronchoscopy during chemotherapy for small cell carcinoma of the lung. Chest 74:531–536
Jackson DV, Richards II F, Cooper R, Ferree C, Muss HB, White DR, Spurr CL (1977) Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study. JAMA 237:2730–2733
Jamshidi K, Swaim WR (1971) Bone marrow biopsy with unaltered architecture: a new bipsy device. J Lab Clin Med 77:335–342
Johnson RE, Brereton HD, Kent CH (1976) Small-cell carcinoma of the lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289–291
Joss R, Kapanci Y, Widmann JJ, Brunner KW, Alberto P (1981) Langfristig tumorfrei überlebende Patienten mit anaplastischem kleinzelligen Bronchialkarzinom. Schweiz Med Wochenschr 111:1282–1286
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Statist Ass 53:457–481
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH (1948) The use of the nitrogen mustards in the palliative treatment of carcinoma. With particular reference to bronchogenic carcinoma. Cancer 1:634–656
Kimura I, Nakata Y, Hiraki S (1980) Chemotherapy of small cell lung carcinoma. In: Hansen HH, Dombernowsky P (eds) II. World conference on lung cancer, Abstracts. Excerpta Medica, Amsterdam Oxford Princeton, p 156
Komaki R, Cox JD, Whitson W (1981) Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 65:811–814
Kreyberg L, Liebow AA, Uehlinger EA (1967) Histological typing of lung tumours. World Health Organization, Geneva
Lanzotti VJ, Thomas DR, Boyle LE, Smith TL, Gehan EA, Samuels ML (1977) Survival with inoperable lung cancer. An integration of prognostic variables based on simple clinical criteria. Cancer 39:303–313
Livingston RB, Moore TN, Heilbrun L, Bottomley R, Lehane D, Rivkin SE, Thigpen T (1978) Small-cell carcinoma of the lung: combined chemotherapy and radiation. A Southwest Oncology Group study. Ann Int Med 88:194–199
Lowenbraun S, Bartolucci A, Smalley RV, Lynn M, Krauss S, Durant JD and the southeastern cancer study group (1979) The superiority of combination chemotherapy over single agent chemotherapy in small cell lung carcinoma. Cancer 44:406–413
Mantel N (1967) Ranking procedures for arbitrarily restricted observation. Biometrics 33:65–78
Matthews MJ (1973) Morphologic classification of bronchogenic carcinoma. Cancer Chemother Rep 4(3):299–302
Mattson K, Holsti LR (1980) Prognostic value of doubling time in lung cancer. Strahlentherapie 156:632–636
Maurer LH, Tulloh M, Weiss RB, Blom J, Leone L, Glidewell O, Pajak TF (1980) A randomized combined modality trial in small cell carcinoma of the lung. Comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer 45:30–39
Maurer LH, Pajak TF (1981) Prognostic factors in small cell carcinoma of the lung: a Cancer and Leukemia Group B study. Cancer Treat Rep 65:767–774
McMahon LJ, Herman TS, Manning MR, Dean JC (1979) Patterns of relapse in patients with small cell carcinoma of the lung treated with adriamycin-cyclophosphamide chemotherapy and radiation therapy. Cancer Treat Rep 63:359–362
Medical Research Council (1979) Radiotherapy alone or with chemotherapy in the treatment of small-cell carcinoma of the lung. Br J Cancer 40:1–10
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Mountain CF (1978) Clinical biology of small cell carcinoma: relationship to surgical therapy. Semin Oncol 5:272–279
Muggia FM, Krezoski SK, Hansen HH (1974) Cell kinetic studies in patients with small cell carcinoma of the lung. Cancer 34:1683–1690
Niederle N, Schmidt CG, Seeber S (1980) Nichtoperative Therapie des Bronchialkarzinoms. Int Welt 3:359–368
Niederle N, Nakhosteen JA, Maassen W, Seeber S (1981a) Advanced bronchogenic carcinoma — control of therapy by bronchoscopy. In: Nakhosteen JA, Maassen W (eds) Bronchology: Research, diagnostic and therapeutic aspects. Martinus Nijhoff Publ, The Hague Boston London, pp 367–370
Nicderle N, Krischke W, Schmidt CG, Seeber S (1981b) Vindesine plus cisplatin chemotherapy in recurrent and primarily resistant small cell bronchogenic carcinoma. In Brade W, Nagel GA, Seeber S (eds) Proceedings of the international vinca alkaloid symposium-vindesine. S. Karger, Basel München Paris London New York Sydney, pp 314–319
Nugent JL, Bunn PA jr, Matthews MJ, Ihde DC, Cohen MH, Gazdar A, Minna JD (1979) CNS metastases in small cell bronchogenic carcinoma. Increasing frequency and changing pattern with lengthening survival. Cancer 44:1885–1893
Pettengill OS, Sorenson GD, Wurster-Hill DH, Curphey TJ, Noll WW, Cate CC, Maurer LH (1980) Isolation and growth characteristics of continuous cell lines from small-cell carcinoma of the lung. Cancer 45:906–918
Pickren JW, Vincent RG (1979) Effect of therapy in lung cancer: an autopsy study. In: Muggia F, Rozencweig M (eds) Lung Cancer: Progress in therapeutic research. Raven Press, New York, pp 151–154
Razek A, Vietti T, Valeriote F (1974) Optimum time sequence for the administration of vincristine and cyclophosphamide in vivo. Cancer Res 34:1857–1861
Saugier B, Brunat M, Cordier JF, Gerard JP, Dorsit G, Marchandise JF, Bastidon R, Perol M, Brune J, Galy P (1978) Cancer pulmonaire à “petites cellules”. Résultats de l'association adriamycine-vincristine-cyclophosphamide chez 38 patients. Nouv Presse Méd 7:1357–1361
Schneiderman MA, Levin DL (1972) Trends in lung cancer. Mortality, incidence, diagnosis, treatment, smoking, and urbanization. Cancer 30:1320–1325
Seeber S, Schmidt CG, Holfeld H, Scherer E (1977) Integrale Behandlung (Chemo- und Radiotherapie) des inoperablen Bronchialkarzinoms. Vorläufige Ergebnisse bei 50 Patienten. Dtsch Med Wochenschr 102:147–152
Seeber S, Niederle N, Schilcher RB, Schmidt CG (1980) Adriamycin, Cyclophosphamid und Vincristin (“ACO”) beim kleinzelligen Bronchialkarzinom. Verlaufsanalyse und Langzeitergebnisse. Onkologie 3:5–11
Seeber S, Higi M, Niederle N, Schmidt CG (1981) Individualisierte Intervallverkürzung bei der chemotherapeutischen Induktionsbehandlung solider Tumoren. Dtsch Med Wochenschr 106:1741–1744
Shank B, Natale RB, Hilaris BS, Wittes RE (1981) Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy. Int J Radiat Oncol Biol Phys 7:469–475
Sierocki JS, Hilaris BS, Hopfan S, Martini N, Barton D, Golbey RB, Wittes RE (1979) cis-dichlorodiammineplatinum(II) and VP-16-213: an active induction regimen for small cell carcinoma of the lung. Cancer Treat Rep 63:1593–1597
Sobin LH (1979) The WHO histological classification of lung tumors. In: Muggia F, Rozencweig M (eds) Lung cancer: progress in therapeutic research. Raven Press, New York, pp 83–90
Straus MJ (1974) The growth characteristics of lung cancer and its application to treatment design. Semin Oncol 1:167–174
Valaitis J, Warren S, Gamble D (1981) Increasing incidence of adenocarcinoma of the lung. Cancer 47:1042–1046
Valdivieso M, Tenczynski TF, Rodriguez V, Burgess MA, Mountain CF, Barkley HT, Hersh EM, Bodey GP (1981) Chemoimmunotherapy of small cell bronchogenic carcinoma with VP-16-213, ifosfamide, vincristine, adriamycin, and corynebacterium parvum. Cancer 48:238–244
Van Houtte P, Tancini G, De Jager R, Lustman-Maréchal J, Milani F, Bonadonna G, Kenis Y (1979) Small cell carcinoma of the lung: a combined modality treatment. Eur J Cancer 15:1159–1165
Vincent RG, Pickren JW, Lane WW, Bross I, Takita H, Houten L, Gutierrez AC, Rzepka T (1977) The changing histopathology of lung cancer. A review of 1682 cases. Cancer 39:1647–1655
Vincent RG, Wilson HE, Lane WW, Chen TY, Raza S, Gutierrez AC, Caracandas JE (1981) Progress in the chemotherapy of small cell carcinoma of the lung. Cancer 47:229–235
Weiss W, Boucot KR, Cooper DA (1970) The histopathology of bronchogenic carcinoma and its relation to growth rate, metastasis, and prognosis. Cancer 26:965–970
Wellens W, Mussgnug G, Habets L, Schäfer E, Westerhausen M (1980) Die Kombination Ifosfamid/VP 16-213 bei der Therapie des kleinzelligen Bronchialkarzinoms und anderer Malignome. In: Burkert H, Nagel GA (Hrsg) Neue Erfahrungen mit Oxazaphosphorinen unter besonderer Berücksichtigung des Uroprotektors Uromitexan. S. Karger, Basel München Paris London New York Sydney, S 84–90
Young JA, Dillman RO, Taetle R, Seagren SL, Royston I, Lehar TJ (1981) Induction chemotherapy, consolidation radiotherapy, and cross-over chemotherapy for small cell carcinoma of the lung (SCCL). Proc Am Assoc Cancer Res & Am Soc Clin Oncol 22:494
Zelen M (1973) Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 4(3):31–42
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Vorliegende Untersuchungen wurden gefördert im Rahmen des Forschungsprogramms „Arzneimittelentwicklung und -testung für die Krebstherapie“ des BMFT
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Niederle, N., Krischke, W., Schulz, U. et al. Untersuchungen zur kurzzeitigen Induktions- und zyklischen Erhaltungstherapie beim inoperablen kleinzelligen Bronchialkarzinom. Klin Wochenschr 60, 829–838 (1982). https://doi.org/10.1007/BF01728349
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DOI: https://doi.org/10.1007/BF01728349