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Pulmonary toxicity (PT) with combined modality therapy for limited stage small cell lung cancer (SCLC)
170
py for Small Cell Lung Cancer (SCLC). Thatcher, N., Anderson, H., Mohan, P., Barber, P.V., Carroll, K.B. Christie Hospital & Wythenshawe Hospital, Manchester, UK. 106 patients without clinical evidence of CNS metastases, Karnofsky score (KS) > 20 and < 70 years of age were consecutively entered into the study. Median age was 60 years (34-70) with 60 males, 38 females. 55 patients were limited stage LS, and 51 extensive stage ES. Metastatic sites were nodes (not ipsilateral, SCF) 20%, liver 21%, bone 12%, skin, soft tissues 46%, other sites 8%Ifosfamide 5 g/m 2 with Mesna was given over 24 ~ours on day 1 with etopgside 120 mg/m-i.v, day 1,2 & 240 mg/m- O. day 3. The courses were given at 3 week intervals for a total of 6. 3 weeks after the last course, 4 MeV thoracic XRT, 3250 cGy, 8F, i0 days was started. 62% of patients have so far completed the protocol (activated December 1983). A total of 517 CT courses have been given, 85% of patients who have responded did so by the 3rd course. 12% of courses have been delayed for 1-2 w k s b e c a u s e of toxicity, 5% required i.v. antibiotics and 7% of patients have died from non lung cancer causes. The response rate for LS patients is 86% (64% CR, the majority confirmed on repeat bronchoscopy) and 70% for ES paients (18% CR). The median survival for ES is 9 months and 13 months for LS patients, 51% of whom are alive with no tumour. After therapy 89% of LS patients had a KP ~ 80, compared with 20% initially, and 58% ES had a KP > 80 compared with 15% at presentation. The above regimen provides a hig~ response rate for SCLC with acceptable toxicity, and encouraging survival results. Maintenance Interferon (IFN) vs. Maintenance Chemotherapy (CT) Following Induction Chemotherapy and Consolidation Radiotherapy (RT) in Small Cell Lung Cancer (SCLC). A Multicenter Study, Participating Centers; Helsinki University Central Hospital, Tiuru, Kotka and Etel~-Saimaa Hospitals, National Institute of Public Health, Finland. Presented by Karin Mattson. Patients with previously untreated SCLC (all stages), responding (CR, PR) to induction CT and consolidation RT were randomly assigned to one three arms: maintenance-IFN, maintenance-CT or no maintenance treatment at all (0-arm). All patients initially received 4 cycles2of induction CT (cyclophosphamide21200 mg/m i.v. d i, vinc~istine 1.3 mg/m i.~. d 1+8, VPI6 150 mg/ m- i.v. d I, 200 mg/m- p.o. d 3), 3 of which were administered before RT and 1 during the 3-week rest interval of the
split-course regimen consisting of 55 Gy/20 F/ 7 wk to the primary tumor, mediastinum and supraclavicular areas. Maintenance treatment was given during 6 months: human leukocyte interferon (HuIFN-S) as a d~se of 3 x i0 IU i.m. daily (i mo) and 6 x I0 IU i.m. three times weekly (5 mo), CT as26 cycles of CAP (cyclopho~phamide 400 mg/m i.v., ad~iamycin 40 mg/m i.v., cis-platinum 40 mg/m i.v., d i, repeated at monthly intervals). All patients including those in the 0-arm were evaluated for response at monthly intervals during the study period. To date, 124 patients have been accepted, 63 are evaluable for response to CT+ RT and 63 have been randomized (IFN 23, CAP 22, 0-arm 18). Complete remission after 3 cycles of induction CT was obtained in 15% of patients, and 62% had PR. The overall objective response rate after CT+RT, before maintenance treatment, was 89%. Data on survival are inconclusive at present but there seems to be a trend of shorter survival in the 0-arm. Toxicity was acceptable in all treatment groups. The study is ongoing, and updated results will be presented. A Prospective Study of Combined Modality Therapy Including Surgery (SR) for Limited Small Cell Cancer (L-SCLC). Shepherd, F.A., Evans, W.K., Ginsberg, R., Pearson, F.G., Cooper, J., Patterson, A., Todd, T., Feld, R., Waters, P., Ilves, R., DeBoer, G. University of Toronto, Toronto, Ontario, Canada. Prior to starting treatment, 20 patients were identified prospectively as potential candidates for adjuvant SR following remission induction with chemotherapy. All patients received chemotherapy: cyclophosphamide, adriamycin and vincristine (CAV) (ii pts), CAV plus etoposide (8 pts) and CAV alternating with etoposide and cisplatin (i pt). Following maximal tumor response patients were staged, and if disease remained limited they underwent SR, followed by thoracic irradiation and prophylactic cranial irradiation. There were ii males and 9 females, median age 61 yrs (range 36-73 yrs). Ten patients achieved CR and i0 patients PR with chemotherapy. Fifteen patients had lobectomy, 4 patients pneumonectomy, and 1 patient was unresectable at SR. Surgery was considered curative with complete resection of tumor and negative resection margins in 17 patients. The pathological staging following surgery was TIN0, 3; TIN1, 6; T2N0, i; T2NI, 3; TIN2, 5; T2N2, 2. Pathology revealed residual SCLC (18 pts), fibrous tissue only (i pt) and poorly differentiated mixed adeno-squamous cancer (i pt). Seven patients have relapsed and died. The 3 patients with incomplete SR died with local progression and 4 patients developed distant metastases. Two patients are alive with recurrence. The median survival for the entire group is 128 weeks. No differences in survival
171
could be detected between patients with stage I or II disease or between patients who had achived a CR or a PR with chemotherapy. The survival of these 20 patients was also not significantly longer than that of 33 stage I patients treated only with CAV and radiotherapy. The true role of adjuvant SR in SCLC awaits prospective randomized trials.
Pulmonary Toxicity (PT) With Combined Modality Therapy for Limited Stage Small Cell Lung Cancer (SCLC). Ihde, D., Brooks, B., Seifter, E., Walsh, T., Zabell, A., Johnston-Early, A., Makuch, R., Edison, M., Bunn, P., Lichter, A., Cohen, M., Glatstein, E. NCI-Navy Med. and Rad. Oncol. Brs., Natl. Cancer Inst. and Naval Hosp., and VA Med. Cent., Bethesda, MD 20814 and Washington DC 20422, U.S.A. In a prospective randomized study in limited SCLC, 40 patients received combination chemotherapy (CT) alone and. 40 were given CT + radiation therapy (RT) (4000 rads/15 fractions/initial 3 weeks concurrent with CT). We noted 13 cases of lifethreatening PT, defined as bilateral pulmonary infiltrates extending beyond radiation ports and requiring hospital admission. PT occurred in ii patients (28%) on CT + RT and in 2 (5%) on CT alone (p<0.02). Seven patients died from PT with no clinical evidence of tumor in 6. PT initially presented at a median of 63 days (range 21150) after start of CT + RT and at a median of 217 days after CT alone. Biopsies obtained in l0 patients revealed interstitial fibrosis with no evidence of an infectious agent. Review of pretreatment parameters such as age, prior pulmonary disease, performance status, and radiation field size failed to reveal any significant differences between patients with or without PT. However, initial pulmonary function tests (PFTs) revealed significantly lower vital capacity (p=0.03) and forced expiratory volume/l.0 second (p=0.04) in patients with subsequent PT. PT was significantly more common with combined modality therapy than with CT alone and worse than expected with RT alone. Furthermore, PFTs prior to therapy may identify patients at risk for PT. Despite the increased incidence of PT in the CT + RT group, overall survival was not significantly different in the 2 groups, but a clear trend favored the combined modality arm. Enhanced local control and disease-free survival appeared to compensate for the initial increased pulmonary morbidity and mortality in the CT + RT group.
i0, OTHER TREATMENT MODALITIES "Wait & See" in Asymptomatic Non-Operable Non-Small Cell Lung Cancer (NSCLC), an Im-
portant Question? van Zandwijk, N., Dalesio, O., Kirkpatrick, A., McVie, J.G. for the EORTC Lung Cancer Cooperative Group. We studied the reasons behind the lack of accrual of patients (pts) in a multicenter trial comparing immediate versus delayed radiotherapy in asymptomatic non-operable NSCLC patients sponsored by the EORTC Lung Cancer Cooperative Group. Although estimation on the basis of a literature survey, clinical experience and a pretrial enquiry indicated that the Group would accrue enough patients within two years to answer the question whether immediate treatment is superior to "wait and see" in terms of survival or quality of life, in the first year of the study only 7 pts were randomized. A questionnaire followed by prospective registration of all NSCLC pts seen in i0 institutions during 9 months, revealed that only 25 out of 504 pts met the eligibility criteria. This is far fewer than predicted and is explained by a significant proportion of patients presenting with i. extensive disease (39%), 2. and/ or major symptoms (27%). Of the small group of patients who met the eligibility criteria the majority of patients refused to be randomized. 70% of the doctors reported that the procedure of "informed consent" prior to randomization made the trial impossible. Thought should be given in future trials to "post randomization informed consent".
Long Term Results of Injection of Autologous Tumour Cells and Percutaneous BCG into Patients Undergoing Resection of Lung Cancer. Stack, B.H.R., Hole, D.J., Spilg. W.G.S. West of Scotland Lung Cancer Group. In an attempt to stimulate postooperative cell-mediated immunity to residual tumour cells, autologous tumour cells and adjuvant percutaneous BCG were injected into patients undergoing resection of lung cancer. Eighty-three patients were given one single percutaneous multiple puncture treatment with BCG Glaxo one week before operation. At the time of operation, patients were randomly allocated to the autograft (39) or control (44) groups. The autograft group patients received serial injections of irradiated autologous tumour cells and percutaneous BCG during 3 weeks after operation. All patients were reviwed at regular intervals for 5 years and on one further occasion in 1984. Five years after operation the percentage of patients surviving were 36% (autograft) and 32% (control), difference not significant (NS). The median survival times for each group were 27 (autograft) and 14 (control) months, (NS). The 5 year survival percentage for DNCB positive patients were 69% (autograft, n = 17) and 25% (control, n = 17) and their median survival times were > 60 months and 12 months
(p = o.o4). Postoperative injection of autologous tumour
py for Small Cell Lung Cancer (SCLC). Thatcher, N., Anderson, H., Mohan, P., Barber, P.V., Carroll, K.B. Christie Hospital & Wythenshawe Hospital, Manchester, UK. 106 patients without clinical evidence of CNS metastases, Karnofsky score (KS) > 20 and < 70 years of age were consecutively entered into the study. Median age was 60 years (34-70) with 60 males, 38 females. 55 patients were limited stage LS, and 51 extensive stage ES. Metastatic sites were nodes (not ipsilateral, SCF) 20%, liver 21%, bone 12%, skin, soft tissues 46%, other sites 8%Ifosfamide 5 g/m 2 with Mesna was given over 24 ~ours on day 1 with etopgside 120 mg/m-i.v, day 1,2 & 240 mg/m- O. day 3. The courses were given at 3 week intervals for a total of 6. 3 weeks after the last course, 4 MeV thoracic XRT, 3250 cGy, 8F, i0 days was started. 62% of patients have so far completed the protocol (activated December 1983). A total of 517 CT courses have been given, 85% of patients who have responded did so by the 3rd course. 12% of courses have been delayed for 1-2 w k s b e c a u s e of toxicity, 5% required i.v. antibiotics and 7% of patients have died from non lung cancer causes. The response rate for LS patients is 86% (64% CR, the majority confirmed on repeat bronchoscopy) and 70% for ES paients (18% CR). The median survival for ES is 9 months and 13 months for LS patients, 51% of whom are alive with no tumour. After therapy 89% of LS patients had a KP ~ 80, compared with 20% initially, and 58% ES had a KP > 80 compared with 15% at presentation. The above regimen provides a hig~ response rate for SCLC with acceptable toxicity, and encouraging survival results. Maintenance Interferon (IFN) vs. Maintenance Chemotherapy (CT) Following Induction Chemotherapy and Consolidation Radiotherapy (RT) in Small Cell Lung Cancer (SCLC). A Multicenter Study, Participating Centers; Helsinki University Central Hospital, Tiuru, Kotka and Etel~-Saimaa Hospitals, National Institute of Public Health, Finland. Presented by Karin Mattson. Patients with previously untreated SCLC (all stages), responding (CR, PR) to induction CT and consolidation RT were randomly assigned to one three arms: maintenance-IFN, maintenance-CT or no maintenance treatment at all (0-arm). All patients initially received 4 cycles2of induction CT (cyclophosphamide21200 mg/m i.v. d i, vinc~istine 1.3 mg/m i.~. d 1+8, VPI6 150 mg/ m- i.v. d I, 200 mg/m- p.o. d 3), 3 of which were administered before RT and 1 during the 3-week rest interval of the
split-course regimen consisting of 55 Gy/20 F/ 7 wk to the primary tumor, mediastinum and supraclavicular areas. Maintenance treatment was given during 6 months: human leukocyte interferon (HuIFN-S) as a d~se of 3 x i0 IU i.m. daily (i mo) and 6 x I0 IU i.m. three times weekly (5 mo), CT as26 cycles of CAP (cyclopho~phamide 400 mg/m i.v., ad~iamycin 40 mg/m i.v., cis-platinum 40 mg/m i.v., d i, repeated at monthly intervals). All patients including those in the 0-arm were evaluated for response at monthly intervals during the study period. To date, 124 patients have been accepted, 63 are evaluable for response to CT+ RT and 63 have been randomized (IFN 23, CAP 22, 0-arm 18). Complete remission after 3 cycles of induction CT was obtained in 15% of patients, and 62% had PR. The overall objective response rate after CT+RT, before maintenance treatment, was 89%. Data on survival are inconclusive at present but there seems to be a trend of shorter survival in the 0-arm. Toxicity was acceptable in all treatment groups. The study is ongoing, and updated results will be presented. A Prospective Study of Combined Modality Therapy Including Surgery (SR) for Limited Small Cell Cancer (L-SCLC). Shepherd, F.A., Evans, W.K., Ginsberg, R., Pearson, F.G., Cooper, J., Patterson, A., Todd, T., Feld, R., Waters, P., Ilves, R., DeBoer, G. University of Toronto, Toronto, Ontario, Canada. Prior to starting treatment, 20 patients were identified prospectively as potential candidates for adjuvant SR following remission induction with chemotherapy. All patients received chemotherapy: cyclophosphamide, adriamycin and vincristine (CAV) (ii pts), CAV plus etoposide (8 pts) and CAV alternating with etoposide and cisplatin (i pt). Following maximal tumor response patients were staged, and if disease remained limited they underwent SR, followed by thoracic irradiation and prophylactic cranial irradiation. There were ii males and 9 females, median age 61 yrs (range 36-73 yrs). Ten patients achieved CR and i0 patients PR with chemotherapy. Fifteen patients had lobectomy, 4 patients pneumonectomy, and 1 patient was unresectable at SR. Surgery was considered curative with complete resection of tumor and negative resection margins in 17 patients. The pathological staging following surgery was TIN0, 3; TIN1, 6; T2N0, i; T2NI, 3; TIN2, 5; T2N2, 2. Pathology revealed residual SCLC (18 pts), fibrous tissue only (i pt) and poorly differentiated mixed adeno-squamous cancer (i pt). Seven patients have relapsed and died. The 3 patients with incomplete SR died with local progression and 4 patients developed distant metastases. Two patients are alive with recurrence. The median survival for the entire group is 128 weeks. No differences in survival
171
could be detected between patients with stage I or II disease or between patients who had achived a CR or a PR with chemotherapy. The survival of these 20 patients was also not significantly longer than that of 33 stage I patients treated only with CAV and radiotherapy. The true role of adjuvant SR in SCLC awaits prospective randomized trials.
Pulmonary Toxicity (PT) With Combined Modality Therapy for Limited Stage Small Cell Lung Cancer (SCLC). Ihde, D., Brooks, B., Seifter, E., Walsh, T., Zabell, A., Johnston-Early, A., Makuch, R., Edison, M., Bunn, P., Lichter, A., Cohen, M., Glatstein, E. NCI-Navy Med. and Rad. Oncol. Brs., Natl. Cancer Inst. and Naval Hosp., and VA Med. Cent., Bethesda, MD 20814 and Washington DC 20422, U.S.A. In a prospective randomized study in limited SCLC, 40 patients received combination chemotherapy (CT) alone and. 40 were given CT + radiation therapy (RT) (4000 rads/15 fractions/initial 3 weeks concurrent with CT). We noted 13 cases of lifethreatening PT, defined as bilateral pulmonary infiltrates extending beyond radiation ports and requiring hospital admission. PT occurred in ii patients (28%) on CT + RT and in 2 (5%) on CT alone (p<0.02). Seven patients died from PT with no clinical evidence of tumor in 6. PT initially presented at a median of 63 days (range 21150) after start of CT + RT and at a median of 217 days after CT alone. Biopsies obtained in l0 patients revealed interstitial fibrosis with no evidence of an infectious agent. Review of pretreatment parameters such as age, prior pulmonary disease, performance status, and radiation field size failed to reveal any significant differences between patients with or without PT. However, initial pulmonary function tests (PFTs) revealed significantly lower vital capacity (p=0.03) and forced expiratory volume/l.0 second (p=0.04) in patients with subsequent PT. PT was significantly more common with combined modality therapy than with CT alone and worse than expected with RT alone. Furthermore, PFTs prior to therapy may identify patients at risk for PT. Despite the increased incidence of PT in the CT + RT group, overall survival was not significantly different in the 2 groups, but a clear trend favored the combined modality arm. Enhanced local control and disease-free survival appeared to compensate for the initial increased pulmonary morbidity and mortality in the CT + RT group.
i0, OTHER TREATMENT MODALITIES "Wait & See" in Asymptomatic Non-Operable Non-Small Cell Lung Cancer (NSCLC), an Im-
portant Question? van Zandwijk, N., Dalesio, O., Kirkpatrick, A., McVie, J.G. for the EORTC Lung Cancer Cooperative Group. We studied the reasons behind the lack of accrual of patients (pts) in a multicenter trial comparing immediate versus delayed radiotherapy in asymptomatic non-operable NSCLC patients sponsored by the EORTC Lung Cancer Cooperative Group. Although estimation on the basis of a literature survey, clinical experience and a pretrial enquiry indicated that the Group would accrue enough patients within two years to answer the question whether immediate treatment is superior to "wait and see" in terms of survival or quality of life, in the first year of the study only 7 pts were randomized. A questionnaire followed by prospective registration of all NSCLC pts seen in i0 institutions during 9 months, revealed that only 25 out of 504 pts met the eligibility criteria. This is far fewer than predicted and is explained by a significant proportion of patients presenting with i. extensive disease (39%), 2. and/ or major symptoms (27%). Of the small group of patients who met the eligibility criteria the majority of patients refused to be randomized. 70% of the doctors reported that the procedure of "informed consent" prior to randomization made the trial impossible. Thought should be given in future trials to "post randomization informed consent".
Long Term Results of Injection of Autologous Tumour Cells and Percutaneous BCG into Patients Undergoing Resection of Lung Cancer. Stack, B.H.R., Hole, D.J., Spilg. W.G.S. West of Scotland Lung Cancer Group. In an attempt to stimulate postooperative cell-mediated immunity to residual tumour cells, autologous tumour cells and adjuvant percutaneous BCG were injected into patients undergoing resection of lung cancer. Eighty-three patients were given one single percutaneous multiple puncture treatment with BCG Glaxo one week before operation. At the time of operation, patients were randomly allocated to the autograft (39) or control (44) groups. The autograft group patients received serial injections of irradiated autologous tumour cells and percutaneous BCG during 3 weeks after operation. All patients were reviwed at regular intervals for 5 years and on one further occasion in 1984. Five years after operation the percentage of patients surviving were 36% (autograft) and 32% (control), difference not significant (NS). The median survival times for each group were 27 (autograft) and 14 (control) months, (NS). The 5 year survival percentage for DNCB positive patients were 69% (autograft, n = 17) and 25% (control, n = 17) and their median survival times were > 60 months and 12 months
(p = o.o4). Postoperative injection of autologous tumour