Ten-Year Survival of Patients With Small-Cell Lung Cancer Treated With Combination Chemotherapy With or Without Irradiation By Bruce E. Johnson, Jane Grayson, Robert W. Makuch, R. Ilona Linnoila, Michael J. Anderson, Martin H. Cohen, Eli Glatstein, John D. Minna, and Daniel C. Ihde We evaluated the 10- to 15-year outcome of 252 patients with small-cell lung cancer entered into therapeutic clinical trials with or without chest and cranial irradiation. Thirty-two patients (13%) survived free of cancer for 2 or more years. Twelve patients (5%) survived at least 10 years free of cancer, and 10 patients are currently alive and free of cancer beyond 10 years. Six of these 10 patients currently function at a level comparable with that before diagnosis. The other 22 patients who were cancer-free at 2 years have died. Nine patients died from recurrent small-
INITIAL
STUDIES of patients with smallcell lung cancer treated with combination chemotherapy reported that 7% to 13% remain in a complete remission for 1.0 to 2.3 years.'-3 After patient cohorts were observed for additional periods of time, several investigators reported patients surviving cancer-free for more than 5 years, 4-9 including our report with 5- to 11-year follow-up.5 However, these studies also documented that patients with small-cell lung cancer continue to relapse up to and occasionally after 5
From the National CancerInstitute-Navy Medical Oncology Branch and the Radiation Oncology Branch, Clinical Oncology Program, National Cancer Institute and Naval Hospital; the Uniformed Services University of the Health Sciences and the Internal Medicine Department, Naval Hospital, Bethesda, MD; the Medical Service, Veterans Administration Medical Center, Washington, DC; and the Division of Biostatistics,Yale University, New Haven, CT. Sumbitted June 5, 1989; accepted October 3, 1989. The opinions or assertionscontained herein arethe private views of the authors andare not to be construedas official or as reflecting the views of the Department of the Navy or the Departmentof Defense. Partialsupport for Robert W. Makuch was provided by Grant no.16359from the National CancerInstitute, USA. Address reprint requests to Bruce E. Johnson, MD, National Cancer Institute-Navy Medical Oncology Branch, Building 8, Room 5101, Naval Hospital, Bethesda, MD 20814. This is a US government work. There are no restrictions on its use. 0732-183X/90/0803-0013$0.00/0
396
cell lung cancer 2 to 6.2 years after initiation of chemotherapy. Five died from non-small-cell lung cancer, three died of other malignancies, and five died of causes other than cancer. A small fraction of patients with small-cell lung cancer are cured of their original malignancy, but these patients remain at high risk for second cancers and death from other causes. J Clin Oncol 8:396-401. This is a US government work. There are no restrictions on its use.
years and appear to be at substantial risk for second lung cancers. 4 12 Additional time for follow-up has been needed to document cure of small-cell lung cancer patients treated with combination chemotherapy and to continue to evaluate the risk of non-small-cell lung cancers and other causes of death. An additional 5 years have passed since the time of our previous report on 252 patients treated with combination chemotherapy with or without irradiation from 1973 to 1978.5 To better understand the natural history of such patients, we present the 10- to 15-year follow-up data on these patients, providing information on late relapses, development of nonsmall-cell lung cancers, and their functional status. PATIENTS AND METHODS Patients Two hundred fifty-two newly diagnosed patients with histologically confirmed small-cell lung cancer received their initial treatment from March 1973 through December 1978 in a series of Institutional Review Board-approved intramural National Cancer Institute therapeutic trials. This cohort of patients has been previously described and the patient characteristics, staging, and treatment reported. 5 The patients included 198 (79%) men and 54 (21%) women. At the time of protocol entry, their median age was 56 years (range, 35 to 74); 103 had limited-stage, and 149 extensive-stage disease. Of the original 252 patients, 32 (13%) were alive and free of cancer at 2 years. The other 220 patients had relapsed or died. All 32 of the 2-year cancer-free survivors had a primary pulmonary tumor and all had assessable tumor lesions at the initiation of therapy. The diagnostic pathology specimens
Journalof ClinicalOncology, Vol 8, No 3 (March), 1990: pp 396-401
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
397
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC have been reviewed and found to confirm the diagnosis of small-cell lung cancer."n' To determine functional status, all small-cell lung cancer patients who were alive and free of cancer were requested to return for a history, physical examination, and chest radiograph. All patients returning for follow-up were seen by the same examiner (BEJ). The course and outcome of the other patients who survived for 2 years and later died were identified by reviewing the clinical records, operative reports, postmortem examinations, and histologic sections of surgical biopsies, and by discussions with the patients' families and attending physicians. All biopsies diagnostic of a second primary tumor were reviewed.
Table 1. The Outcome of 10 or More Years of 32 Small-Cell Lung Cancer Patients Surviving 2 Years Free of Cancer Outcome
No. (%)
Alive and free of cancer Died from small-cell lung cancer Died from non-small-cell lung cancer Died of other malignancies (gastric carcinoma, erythroleukemia,t and suspected malignancy) Other causes of death (sudden death in three, neurologic deterioration in one, and pneumonia in one)
10" (31) 9 (28) 5 (16)
3 (9)
5(16)
*Two additional patients survived 10 years from the initiation of treatment and died from non-small-cell lung cancer and sudden death.
StatisticalMethods The time to failure curves were calculated using the Kaplan-Meier method." Observed times were considered to be uncensored when the particular failure type was obtained; the observed times were censored otherwise. For example, when the curve for time to lung cancer was calculated, only the times of patients who developed any type of lung cancer were considered uncensored observations. Times of patients alive without lung cancer, or dead without evidence of lung cancer, were considered censored observations. Censored observations are denoted by a vertical line on the KaplanMeier curve. This graphic technique illustrates the number of people at any point on the curve still at risk of failing at some later time. Hazard function analyses were performed as previously described."4 RESULTS Of the 252 patients, 12 (5%) survived for 10 years free of cancer. These include 10 of 103 (10%) limited-stage patients and two of 149 (1.5%) extensive-stage patients. Four were treated with combination chemotherapy and eight received combination chemotherapy plus chest irradiation. Eight were given prophylactic cranial irradiation. Two of these 12 patients have died after 10 years of cancer-free survival from causes other than small-cell lung cancer. Ten patients (4%) continue to survive for 10 to 13 years from the initiation of therapy with no evidence of cancer (Table 1). Eight of the 10 patients returned for evaluation in our clinics while the other two patients and their families were contacted by phone to determine their functional status. None of the 10 patients are currently institutionalized and all are ambulatory. Two are Zubrod performance status 0, six are performance status 1, and two are performance status 2. Six patients have returned to a lifestyle comparable with that before treatment for small-cell lung cancer. Two patients currently work full time, two are homemakers, and
tone patient who died from erythroleukemia also had an incidental non-small-cell lung cancer discovered at the postmortem examination.
two who are 77 and 80 years old are retired but active. Of the other four patients, three patients are somewhat impaired but able to care for themselves. Two patients retired after diagnosis of small-cell lung cancer and have not returned to their jobs, one because of persistent fatigue and one because of intellectual impairment. An additional patient requires dilatation of a persistent esophageal stricture. The fourth patient is disabled from intellectual impairment and cannot care for himself. Both patients who have intellectual impairment were treated with prophylactic cranial irradiation. A more detailed description of the neurologic and neuropsychologic abnormalities of these patients is presented elsewhere.I5 Twenty-two of the 32 patients who were cancerfree survivors at 2 years have died. Nine died of small-cell lung cancer. The anatomic sites of initial presentation and relapse of this cohort of patients have been previously described.12 The last relapse occurred at 6.2 years and with 5 years of additional follow-up we have not observed other patients recurring with small-cell lung cancer (Fig 1). Six patients have developed non-small-cell lung cancer and five died of this malignancy. A previous report has established on clinical grounds that most of these tumors are likely to be second lung cancers rather than recurrence of the original small-cell lung cancer.12 In addition to the five non-small-cell lung cancers that have been previously described," a woman presented with small-cell lung cancer in the right lower and middle lobe documented by chest radiograph, fiberoptic bronchoscopy, and
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
398
JOHNSON ET AL
1.0 C G CANCER
0.8
TOTAL 32 32 32
Z o 0.6 a-
O
0.4
Fig 1. Actuarial analyses of the 32 patients with small-cell lung cancer who were cancerfree 2 years from the initiation of treatment show freedom from
0.2
n
· mnll-crll in·
2
3
4
5
6
7
8
9 YEARS
10
surgical biopsy. She survived cancer-free for 11 years, and then developed a new mass lesion superior to the right hilum in the right upper lobe documented by chest radiograph, computed tomography of the chest, fiberoptic bronchoscopy, and surgical biopsy. There was no evidence of cancer in her right lower or right middle lobe. Histologic examination of the surgical biopsy specimen showed undifferentiated large-cell carcinoma of the lung. She was treated with 4320 cGy of irradiation and survived 6 months from the diagnosis of her second cancer. No postmortem examination was performed. Patients have continued to die from other causes including malignancies other than lung cancer. One patient currently alive and free of cancer developed a T1 N 0 laryngeal squamous cell carcinoma 9 years from the initiation of treatment for small-cell lung cancer. He had continued smoking after the diagnosis and treatment of his small-cell lung cancer. The patient was treated with 6,000 cGy of external beam irradiation and remains free of cancer 2 years later, 11 years from the initiation of chemotherapy for smallcell lung cancer. Another patient developed a suspected second lung cancer, but we were unable to establish a pathologically documented diagnosis. He presented with small-cell lung cancer involving his left mainstem bronchus and hilum, documented by chest radiograph, chest
11
12
13
14
15
an..nr.
fqr,•lm
from all lung cancers, and survival. SCLC, small-cell lung cancer.
tomography, and multiple fiberoptic bronchoscopic examinations.' 6 He survived 11.5 years cancer-free and presented to an outside hospital with a new mass in the left upper lobe documented by chest radiograph and chest computed tomography. A barium enema disclosed no evidence of colon carcinoma. Because of his advanced age (76 years old), poor medical condition, and wishes of his family, the lesion in his left upper lobe was not biopsied. He received supportive care and died six months later. In this report, we report his survival time as uncensored but censor him in the analysis of recurrent small-cell lung cancer and all lung cancers because of the lack of histologic confirmation (Figs 1 and 2). One patient died of gastric cancer and one of erythroleukemia. The patient who died of erythroleukemia also had an incidental non-smallcell lung cancer discovered at postmortem examination.2 Five patients have died from causes other than cancer. Three men in their 50s and 60s who had been free of cancer at their last clinic visit died suddenly. One woman died of sudden neurologoic deterioration. 5 Another patient who had been clinically free of cancer at his last clinic visit died of pneumonia 2 years from the initiation of chemotherapy. Thus, the survival of small-cell lung cancer patients who are cancer-free for 2 years continues to be compromised by the development of
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC
399
. A
1.0
tively short for most patients. An additional 5 years of follow-up has now failed to show any additional relapses. Other investigators reporting long-term follow-up of small-cell lung cancer patients have identified their last relapse at 3.3,8 5,4.6 and 8.17 years from the initiation of treatment. The patient who had been reported to recur at 8.1 years redeveloped small-cell lung cancer in the mediastinum, the site of cancer involvement at the time of initial presentation, and therefore appears to represent a true recurrence. 7 In all these series, including our own, relatively few patients remain at risk beyond the last documented recurrence. However, relapse after 5 to 6 years appears to be a rare event. In addition to late relapses, Livingston et
.90 .80 .70 .60 .50 .40 .30 .20 .10 0.0
al reported a patient who develonned a second 2
3
4
5
6
7
8
9
10
YEARS Fig 2. Cumulative hazard function for relapse of smallcell lung cancer, and development of non -small-cell lung cancer. SCLC, small-cell lung cancer; NSCL , non-small-cell lung cancer.
second malignancies, particularly non-small-cell lung cancer and other causes of death (Fig 1). The proportion free of small-cell lung cancer remains constant after 6.2 years, thhe time of the last death from small-cell lung cancer. The hazard function analysis (Fig 2) shoiws the cumulative hazard for development of non-small-cell lung cancer continues to increase luring the 10 years analyzed, while the risk for dedevelopment of small-cell lung cancer reaches a pl ateau after 6 years. After 10 years the cumul ative risk of developing non-small-cell lung ca ncer exceeds the risk of recurrent small-cell lung cancer (Fig 2). DISCUSSION
This 10- to 15-year follow-up data of 252 small-cell lung cancer patients tr eated at our institution demonstrates that small- cell lung cancer can be cured with combination c hemotherapy with or without chest irradiation. Ten patients remain alive and free of cancer 1 0 to 13 years from the initiation of chemotherapy , with the last relapse occurring at 6.2 years. Our previous report showed that freedom from simall-cell lung cancer recurrence reached a plat eau after 6.2 years, but follow-up beyond that pcoint was rela-
primary small-cell lung cancer at 4.3 years 6 and we have recently reported a patient not included in this cohort of patients who developed a new primary small-cell lung cancer 8 years after his initial treatment."
We believe it is important
that investigators document the anatomic sites of involvement at presentation and redevelopment of lung cancer in long-term survivors of smallcell lung cancer, so it can be determined if these late events represent relapses or second primary small-cell or non-small-cell lung cancers. A few patients with small-cell lung cancer treated with local modalities (chest radiotherapy or surgery) have been previously reported to survive for 10 or more years. Fox and Scadding reported that three of 73 patients (4%) with small-cell lung cancer with potentially operable limited-stage disease treated with chest radiotherapy survived 10 years. 17 These were highly selected patients with sufficiently localized cancer to consider attempting surgical resection. In addition, Matthews et al established a patient registry of long-term survivors and reported 15 patients from multiple institutions who lived 10 years from diagnosis, including six treated with surgical resection alone.s8 This current report of a series of consecutive patients with small-cell lung cancer treated with combination chemotherapy with or without chest irradiation documents the 10-year outcome of patients with both limited and extensive stages of disease. Compared to the 4% 10-year survival of highly selected limitedstage small-cell lung cancer patients treated with
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
400
JOHNSON ET AL
thoracic radiotherapy,17 the 10% 10-year survival for our limited-stage patients appears to be a modest improvement when combination chemotherapy is used with or without chest radiotherapy. When observed for 10 years from the initiation of treatment, other adult malignancies demonstrated to be curable with combination chemotherapy in a larger fraction of cases than smallcell lung cancer nonetheless have temporal patterns of relapse similar to the small-cell lung cancer patients described here. Patients with Hodgkin's disease and testicular cancer treated with combination chemotherapy survive for more than 10 years.'9-21 Although most relapses have occurred before 5 years, rare patients treated for Hodgkin's disease as well as testicular cancer will relapse after 5 or more years.'1921 The patients with small-cell lung cancer remain at risk for the development of other lung cancers. The fraction free of lung cancer has not reached a plateau and the hazard of patients developing non-small-cell lung cancer remains fairly constant during the entire 10 years. This is certainly related to the fact that patients who were heavy cigarette smokers have a respiratory epithelium that remains at high risk for the development of other malignancies.4"10'12 The development of a second malignancy in the lung is probably less likely to be related to chemotherapy administration because a similar risk for occurrence of second lung cancers is seen in surgically resected patients with non-small-cell lung cancer to whom no chemotherapy was administered. 2223 ' The pathologic confirmation of second lung cancers in patients treated for smallcell lung cancer is important because these cancers may not represent treatment failures but instead may be new potentially surgically resectable non-small-cell lung cancers. The risk of death from other causes in patients cured of small-cell lung cancer is much greater 1 9 20 than in patients cured of Hodgkin's disease ' and testicular cancer.21 In contrast to Hodgkin's disease and testicular cancer patients who are typically diagnosed in their 20s and 30s, the patients with small-cell lung cancer are typically diagnosed in their 50s and 60s and have long histories of exposure to tobacco smoke. Their survival remains much less than what would be expected in an age-matched population because
the smoking that led to their initial small-cell lung cancer also contributes to higher risk for other causes of death. The patients surviving cancer-free beyond 2 years have a 10.5-fold excess mortality at 7 years after initiation of treatment compared with the expected mortality of an age-matched unselected population. The expected mortality was calculated using ageadjusted standard mortality tables for the United States population. Continued observation of patients treated for small-cell lung cancer who have survived for more than 10 years has allowed us to document a number of functional deficits. Four of the 10 patients in this study described impaired function, one because of fatigue, one because of an esophageal stricture, and two because of intellectual impairment. Although prolonging survival of patients with small-cell lung cancer remains the overriding concern in designing new clinical trials, the long-term impairments seen in 10- or more year survivors are of concern. When designing future treatment regimens, modifications that may potentially avoid these complications, such as reduced doses per fraction of cranial irradiation, should be considered. In summary, this report of 10- to 15-year follow-up of patients with small-cell lung cancer helps establish its curability with appropriate combination chemotherapy. Five years of additional follow-up time have strengthened the conclusion that no relapses have occurred after 6.2 years from the initiation of therapy. The majority of the 10-year survivors function at a level comparable with that prior to diagnosis. These patients remain at high risk for the redevelopment of second malignancies, particularly nonsmall-cell lung cancer, and need to be followed closely. From the data presented here we believe patients with small-cell lung cancer beginning treatment with currently available combination chemotherapy with or without irradiation can be assured that the proposed therapy offers not only substantial prolongation of survival compared with supportive care alone but also a small chance of cure. ACKNOWLEDGMENT We would like to thank Anita Anderson, RN, Margaret Edison, RN, and Jan Rowland, RN, for their help in evaluating these patients.
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
401
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC REFERENCES 1. Hansen M, Hansen HH, Dombernowsky P: Long-term survival in small-cell carcinoma of the lung. JAMA 244:247250, 1980 2. Cohen MH, Ihde DC, Bunn PA Jr, et al: Cyclic alternating combination chemotherapy for small-cell bronchogenic carcinoma. Cancer Treat Rep 63:163-170, 1979 3. Livingston RB, Moore TN, Heilbrun L, et al: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Intern Med 88:194-199, 1978 4. Osterlind K, Hansen HH, Hansen M, et al: Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small-cell lung cancer. J Clin Oncol 4:1044-1052, 1986 5. Johnson BE, Ihde DC, Bunn PA, et al: Patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation: Data on potential cures, chronic toxicities, and late relapses after a five to eleven year follow-up. Ann Intern Med 103:430-438, 1985 6. Livingston RB, Stephens RL, Bonnet JD, et al: Longterm survival and toxicity in small-cell lung cancer: Southwest Oncology Group study. Am J Med 77:415-417, 1984 7. Vogelsang GB, Abeloff MD, Ettinger DS, et al: Longterm survivors of small-cell carcinoma of the lung. Am J Med 79:49-56, 1985 8. Jacobs RH, Greenburg A, Bitran JD, et al: A 10-year experience with combined modality therapy for stage III small-cell lung carcinoma. Cancer 58:2177-2184, 1986 9. Smith IE, Sappino AP, Bondy PK, et al: Long-term survival five years or more after combination chemotherapy and radiotherapy for small-cell lung carcinoma. Eur J Cancer Clin Oncol 17:1249-1253, 1981 10. Craig J, Powell B, Muss HB, et al: Second primary bronchogenic carcinomas after small-cell carcinoma: Report of two cases and review of the literature. Am J Med 76:1013-1020, 1984 11. Howard JR Jr, Veach SR, DeVaney K, et al: The development of small-cell lung cancer in the contralateral lung of a patient surviving 8 years after the original diagnosis of small-cell lung cancer. Cancer 62:436-439, 1988
12. Johnson BE, Ihde DC, Matthews MJ, et al: Non-smallcell lung cancer: Major cause of late mortality in patients with small-cell lung cancer. Am J Med 80:1103-1110, 1986 13. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 14. Simes RJ, Zelen M: Exploratory data analysis and the use of the hazard function for interpreting survival data: An investigator's primer. J Clin Oncol 3:1418-1431, 1985 15. Johnson BE, Patronas N, Hayes W, et al: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: Further follow-up of 6-13 year survivors. J Clin Oncol 8:48-56, 1990 16. Cohen MH: Small-cell bronchogenic carcinoma: A prolonged remission following chemotherapy. JAMA 237: 2528, 1977 17. Fox W, Scadding JG: Medical research council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus:Tenyear follow-up. Lancet 2:63-65, 1973 18. Matthews MJ, Rozencweig M, Staquet MJ, et al: Long-term survivors with small-cell carcinoma of the lung. Europ J Cancer 16:527-531, 1980 19. Rosenberg SA, Kaplan HS: The evolution and summary results of the Stanford clinical trials of the management of Hodgkin's Disease: 1962-1984. Int J Rad Oncol Biol Phys 11:5-22, 1985 20. Longo DL, Young RC, Wesley M, et al: Twenty years of MOPP therapy for Hodgkin's Disease. J Clin Oncol 4:1295-1306, 1986 21. Roth BJ, Greist A, Kubilis PS, et al: Cisplatin-based combination chemotherapy for disseminated germ cell tumors: Long-term follow-up. J Clin Oncol 6:1239-1247, 1988 22. Shields TW, Humphrey EW, Higgins FA, Jr, et al: Long-term survivors after resection of lung carcinoma. J Thorac Cardiovasc Surg 76:439-445, 1978 23. Cortese D, Pairolero PC, Bergstralh E, et al: Roentgenographically occult lung cancer. A ten-year experience. J Thorac Cardiovasc Surg 86:373-380, 1983
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
INITIAL
STUDIES of patients with smallcell lung cancer treated with combination chemotherapy reported that 7% to 13% remain in a complete remission for 1.0 to 2.3 years.'-3 After patient cohorts were observed for additional periods of time, several investigators reported patients surviving cancer-free for more than 5 years, 4-9 including our report with 5- to 11-year follow-up.5 However, these studies also documented that patients with small-cell lung cancer continue to relapse up to and occasionally after 5
From the National CancerInstitute-Navy Medical Oncology Branch and the Radiation Oncology Branch, Clinical Oncology Program, National Cancer Institute and Naval Hospital; the Uniformed Services University of the Health Sciences and the Internal Medicine Department, Naval Hospital, Bethesda, MD; the Medical Service, Veterans Administration Medical Center, Washington, DC; and the Division of Biostatistics,Yale University, New Haven, CT. Sumbitted June 5, 1989; accepted October 3, 1989. The opinions or assertionscontained herein arethe private views of the authors andare not to be construedas official or as reflecting the views of the Department of the Navy or the Departmentof Defense. Partialsupport for Robert W. Makuch was provided by Grant no.16359from the National CancerInstitute, USA. Address reprint requests to Bruce E. Johnson, MD, National Cancer Institute-Navy Medical Oncology Branch, Building 8, Room 5101, Naval Hospital, Bethesda, MD 20814. This is a US government work. There are no restrictions on its use. 0732-183X/90/0803-0013$0.00/0
396
cell lung cancer 2 to 6.2 years after initiation of chemotherapy. Five died from non-small-cell lung cancer, three died of other malignancies, and five died of causes other than cancer. A small fraction of patients with small-cell lung cancer are cured of their original malignancy, but these patients remain at high risk for second cancers and death from other causes. J Clin Oncol 8:396-401. This is a US government work. There are no restrictions on its use.
years and appear to be at substantial risk for second lung cancers. 4 12 Additional time for follow-up has been needed to document cure of small-cell lung cancer patients treated with combination chemotherapy and to continue to evaluate the risk of non-small-cell lung cancers and other causes of death. An additional 5 years have passed since the time of our previous report on 252 patients treated with combination chemotherapy with or without irradiation from 1973 to 1978.5 To better understand the natural history of such patients, we present the 10- to 15-year follow-up data on these patients, providing information on late relapses, development of nonsmall-cell lung cancers, and their functional status. PATIENTS AND METHODS Patients Two hundred fifty-two newly diagnosed patients with histologically confirmed small-cell lung cancer received their initial treatment from March 1973 through December 1978 in a series of Institutional Review Board-approved intramural National Cancer Institute therapeutic trials. This cohort of patients has been previously described and the patient characteristics, staging, and treatment reported. 5 The patients included 198 (79%) men and 54 (21%) women. At the time of protocol entry, their median age was 56 years (range, 35 to 74); 103 had limited-stage, and 149 extensive-stage disease. Of the original 252 patients, 32 (13%) were alive and free of cancer at 2 years. The other 220 patients had relapsed or died. All 32 of the 2-year cancer-free survivors had a primary pulmonary tumor and all had assessable tumor lesions at the initiation of therapy. The diagnostic pathology specimens
Journalof ClinicalOncology, Vol 8, No 3 (March), 1990: pp 396-401
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
397
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC have been reviewed and found to confirm the diagnosis of small-cell lung cancer."n' To determine functional status, all small-cell lung cancer patients who were alive and free of cancer were requested to return for a history, physical examination, and chest radiograph. All patients returning for follow-up were seen by the same examiner (BEJ). The course and outcome of the other patients who survived for 2 years and later died were identified by reviewing the clinical records, operative reports, postmortem examinations, and histologic sections of surgical biopsies, and by discussions with the patients' families and attending physicians. All biopsies diagnostic of a second primary tumor were reviewed.
Table 1. The Outcome of 10 or More Years of 32 Small-Cell Lung Cancer Patients Surviving 2 Years Free of Cancer Outcome
No. (%)
Alive and free of cancer Died from small-cell lung cancer Died from non-small-cell lung cancer Died of other malignancies (gastric carcinoma, erythroleukemia,t and suspected malignancy) Other causes of death (sudden death in three, neurologic deterioration in one, and pneumonia in one)
10" (31) 9 (28) 5 (16)
3 (9)
5(16)
*Two additional patients survived 10 years from the initiation of treatment and died from non-small-cell lung cancer and sudden death.
StatisticalMethods The time to failure curves were calculated using the Kaplan-Meier method." Observed times were considered to be uncensored when the particular failure type was obtained; the observed times were censored otherwise. For example, when the curve for time to lung cancer was calculated, only the times of patients who developed any type of lung cancer were considered uncensored observations. Times of patients alive without lung cancer, or dead without evidence of lung cancer, were considered censored observations. Censored observations are denoted by a vertical line on the KaplanMeier curve. This graphic technique illustrates the number of people at any point on the curve still at risk of failing at some later time. Hazard function analyses were performed as previously described."4 RESULTS Of the 252 patients, 12 (5%) survived for 10 years free of cancer. These include 10 of 103 (10%) limited-stage patients and two of 149 (1.5%) extensive-stage patients. Four were treated with combination chemotherapy and eight received combination chemotherapy plus chest irradiation. Eight were given prophylactic cranial irradiation. Two of these 12 patients have died after 10 years of cancer-free survival from causes other than small-cell lung cancer. Ten patients (4%) continue to survive for 10 to 13 years from the initiation of therapy with no evidence of cancer (Table 1). Eight of the 10 patients returned for evaluation in our clinics while the other two patients and their families were contacted by phone to determine their functional status. None of the 10 patients are currently institutionalized and all are ambulatory. Two are Zubrod performance status 0, six are performance status 1, and two are performance status 2. Six patients have returned to a lifestyle comparable with that before treatment for small-cell lung cancer. Two patients currently work full time, two are homemakers, and
tone patient who died from erythroleukemia also had an incidental non-small-cell lung cancer discovered at the postmortem examination.
two who are 77 and 80 years old are retired but active. Of the other four patients, three patients are somewhat impaired but able to care for themselves. Two patients retired after diagnosis of small-cell lung cancer and have not returned to their jobs, one because of persistent fatigue and one because of intellectual impairment. An additional patient requires dilatation of a persistent esophageal stricture. The fourth patient is disabled from intellectual impairment and cannot care for himself. Both patients who have intellectual impairment were treated with prophylactic cranial irradiation. A more detailed description of the neurologic and neuropsychologic abnormalities of these patients is presented elsewhere.I5 Twenty-two of the 32 patients who were cancerfree survivors at 2 years have died. Nine died of small-cell lung cancer. The anatomic sites of initial presentation and relapse of this cohort of patients have been previously described.12 The last relapse occurred at 6.2 years and with 5 years of additional follow-up we have not observed other patients recurring with small-cell lung cancer (Fig 1). Six patients have developed non-small-cell lung cancer and five died of this malignancy. A previous report has established on clinical grounds that most of these tumors are likely to be second lung cancers rather than recurrence of the original small-cell lung cancer.12 In addition to the five non-small-cell lung cancers that have been previously described," a woman presented with small-cell lung cancer in the right lower and middle lobe documented by chest radiograph, fiberoptic bronchoscopy, and
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
398
JOHNSON ET AL
1.0 C G CANCER
0.8
TOTAL 32 32 32
Z o 0.6 a-
O
0.4
Fig 1. Actuarial analyses of the 32 patients with small-cell lung cancer who were cancerfree 2 years from the initiation of treatment show freedom from
0.2
n
· mnll-crll in·
2
3
4
5
6
7
8
9 YEARS
10
surgical biopsy. She survived cancer-free for 11 years, and then developed a new mass lesion superior to the right hilum in the right upper lobe documented by chest radiograph, computed tomography of the chest, fiberoptic bronchoscopy, and surgical biopsy. There was no evidence of cancer in her right lower or right middle lobe. Histologic examination of the surgical biopsy specimen showed undifferentiated large-cell carcinoma of the lung. She was treated with 4320 cGy of irradiation and survived 6 months from the diagnosis of her second cancer. No postmortem examination was performed. Patients have continued to die from other causes including malignancies other than lung cancer. One patient currently alive and free of cancer developed a T1 N 0 laryngeal squamous cell carcinoma 9 years from the initiation of treatment for small-cell lung cancer. He had continued smoking after the diagnosis and treatment of his small-cell lung cancer. The patient was treated with 6,000 cGy of external beam irradiation and remains free of cancer 2 years later, 11 years from the initiation of chemotherapy for smallcell lung cancer. Another patient developed a suspected second lung cancer, but we were unable to establish a pathologically documented diagnosis. He presented with small-cell lung cancer involving his left mainstem bronchus and hilum, documented by chest radiograph, chest
11
12
13
14
15
an..nr.
fqr,•lm
from all lung cancers, and survival. SCLC, small-cell lung cancer.
tomography, and multiple fiberoptic bronchoscopic examinations.' 6 He survived 11.5 years cancer-free and presented to an outside hospital with a new mass in the left upper lobe documented by chest radiograph and chest computed tomography. A barium enema disclosed no evidence of colon carcinoma. Because of his advanced age (76 years old), poor medical condition, and wishes of his family, the lesion in his left upper lobe was not biopsied. He received supportive care and died six months later. In this report, we report his survival time as uncensored but censor him in the analysis of recurrent small-cell lung cancer and all lung cancers because of the lack of histologic confirmation (Figs 1 and 2). One patient died of gastric cancer and one of erythroleukemia. The patient who died of erythroleukemia also had an incidental non-smallcell lung cancer discovered at postmortem examination.2 Five patients have died from causes other than cancer. Three men in their 50s and 60s who had been free of cancer at their last clinic visit died suddenly. One woman died of sudden neurologoic deterioration. 5 Another patient who had been clinically free of cancer at his last clinic visit died of pneumonia 2 years from the initiation of chemotherapy. Thus, the survival of small-cell lung cancer patients who are cancer-free for 2 years continues to be compromised by the development of
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC
399
. A
1.0
tively short for most patients. An additional 5 years of follow-up has now failed to show any additional relapses. Other investigators reporting long-term follow-up of small-cell lung cancer patients have identified their last relapse at 3.3,8 5,4.6 and 8.17 years from the initiation of treatment. The patient who had been reported to recur at 8.1 years redeveloped small-cell lung cancer in the mediastinum, the site of cancer involvement at the time of initial presentation, and therefore appears to represent a true recurrence. 7 In all these series, including our own, relatively few patients remain at risk beyond the last documented recurrence. However, relapse after 5 to 6 years appears to be a rare event. In addition to late relapses, Livingston et
.90 .80 .70 .60 .50 .40 .30 .20 .10 0.0
al reported a patient who develonned a second 2
3
4
5
6
7
8
9
10
YEARS Fig 2. Cumulative hazard function for relapse of smallcell lung cancer, and development of non -small-cell lung cancer. SCLC, small-cell lung cancer; NSCL , non-small-cell lung cancer.
second malignancies, particularly non-small-cell lung cancer and other causes of death (Fig 1). The proportion free of small-cell lung cancer remains constant after 6.2 years, thhe time of the last death from small-cell lung cancer. The hazard function analysis (Fig 2) shoiws the cumulative hazard for development of non-small-cell lung cancer continues to increase luring the 10 years analyzed, while the risk for dedevelopment of small-cell lung cancer reaches a pl ateau after 6 years. After 10 years the cumul ative risk of developing non-small-cell lung ca ncer exceeds the risk of recurrent small-cell lung cancer (Fig 2). DISCUSSION
This 10- to 15-year follow-up data of 252 small-cell lung cancer patients tr eated at our institution demonstrates that small- cell lung cancer can be cured with combination c hemotherapy with or without chest irradiation. Ten patients remain alive and free of cancer 1 0 to 13 years from the initiation of chemotherapy , with the last relapse occurring at 6.2 years. Our previous report showed that freedom from simall-cell lung cancer recurrence reached a plat eau after 6.2 years, but follow-up beyond that pcoint was rela-
primary small-cell lung cancer at 4.3 years 6 and we have recently reported a patient not included in this cohort of patients who developed a new primary small-cell lung cancer 8 years after his initial treatment."
We believe it is important
that investigators document the anatomic sites of involvement at presentation and redevelopment of lung cancer in long-term survivors of smallcell lung cancer, so it can be determined if these late events represent relapses or second primary small-cell or non-small-cell lung cancers. A few patients with small-cell lung cancer treated with local modalities (chest radiotherapy or surgery) have been previously reported to survive for 10 or more years. Fox and Scadding reported that three of 73 patients (4%) with small-cell lung cancer with potentially operable limited-stage disease treated with chest radiotherapy survived 10 years. 17 These were highly selected patients with sufficiently localized cancer to consider attempting surgical resection. In addition, Matthews et al established a patient registry of long-term survivors and reported 15 patients from multiple institutions who lived 10 years from diagnosis, including six treated with surgical resection alone.s8 This current report of a series of consecutive patients with small-cell lung cancer treated with combination chemotherapy with or without chest irradiation documents the 10-year outcome of patients with both limited and extensive stages of disease. Compared to the 4% 10-year survival of highly selected limitedstage small-cell lung cancer patients treated with
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
400
JOHNSON ET AL
thoracic radiotherapy,17 the 10% 10-year survival for our limited-stage patients appears to be a modest improvement when combination chemotherapy is used with or without chest radiotherapy. When observed for 10 years from the initiation of treatment, other adult malignancies demonstrated to be curable with combination chemotherapy in a larger fraction of cases than smallcell lung cancer nonetheless have temporal patterns of relapse similar to the small-cell lung cancer patients described here. Patients with Hodgkin's disease and testicular cancer treated with combination chemotherapy survive for more than 10 years.'9-21 Although most relapses have occurred before 5 years, rare patients treated for Hodgkin's disease as well as testicular cancer will relapse after 5 or more years.'1921 The patients with small-cell lung cancer remain at risk for the development of other lung cancers. The fraction free of lung cancer has not reached a plateau and the hazard of patients developing non-small-cell lung cancer remains fairly constant during the entire 10 years. This is certainly related to the fact that patients who were heavy cigarette smokers have a respiratory epithelium that remains at high risk for the development of other malignancies.4"10'12 The development of a second malignancy in the lung is probably less likely to be related to chemotherapy administration because a similar risk for occurrence of second lung cancers is seen in surgically resected patients with non-small-cell lung cancer to whom no chemotherapy was administered. 2223 ' The pathologic confirmation of second lung cancers in patients treated for smallcell lung cancer is important because these cancers may not represent treatment failures but instead may be new potentially surgically resectable non-small-cell lung cancers. The risk of death from other causes in patients cured of small-cell lung cancer is much greater 1 9 20 than in patients cured of Hodgkin's disease ' and testicular cancer.21 In contrast to Hodgkin's disease and testicular cancer patients who are typically diagnosed in their 20s and 30s, the patients with small-cell lung cancer are typically diagnosed in their 50s and 60s and have long histories of exposure to tobacco smoke. Their survival remains much less than what would be expected in an age-matched population because
the smoking that led to their initial small-cell lung cancer also contributes to higher risk for other causes of death. The patients surviving cancer-free beyond 2 years have a 10.5-fold excess mortality at 7 years after initiation of treatment compared with the expected mortality of an age-matched unselected population. The expected mortality was calculated using ageadjusted standard mortality tables for the United States population. Continued observation of patients treated for small-cell lung cancer who have survived for more than 10 years has allowed us to document a number of functional deficits. Four of the 10 patients in this study described impaired function, one because of fatigue, one because of an esophageal stricture, and two because of intellectual impairment. Although prolonging survival of patients with small-cell lung cancer remains the overriding concern in designing new clinical trials, the long-term impairments seen in 10- or more year survivors are of concern. When designing future treatment regimens, modifications that may potentially avoid these complications, such as reduced doses per fraction of cranial irradiation, should be considered. In summary, this report of 10- to 15-year follow-up of patients with small-cell lung cancer helps establish its curability with appropriate combination chemotherapy. Five years of additional follow-up time have strengthened the conclusion that no relapses have occurred after 6.2 years from the initiation of therapy. The majority of the 10-year survivors function at a level comparable with that prior to diagnosis. These patients remain at high risk for the redevelopment of second malignancies, particularly nonsmall-cell lung cancer, and need to be followed closely. From the data presented here we believe patients with small-cell lung cancer beginning treatment with currently available combination chemotherapy with or without irradiation can be assured that the proposed therapy offers not only substantial prolongation of survival compared with supportive care alone but also a small chance of cure. ACKNOWLEDGMENT We would like to thank Anita Anderson, RN, Margaret Edison, RN, and Jan Rowland, RN, for their help in evaluating these patients.
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
401
TEN-YEAR SURVIVAL OF PATIENTS WITH SCLC REFERENCES 1. Hansen M, Hansen HH, Dombernowsky P: Long-term survival in small-cell carcinoma of the lung. JAMA 244:247250, 1980 2. Cohen MH, Ihde DC, Bunn PA Jr, et al: Cyclic alternating combination chemotherapy for small-cell bronchogenic carcinoma. Cancer Treat Rep 63:163-170, 1979 3. Livingston RB, Moore TN, Heilbrun L, et al: Small-cell carcinoma of the lung: Combined chemotherapy and radiation. Ann Intern Med 88:194-199, 1978 4. Osterlind K, Hansen HH, Hansen M, et al: Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small-cell lung cancer. J Clin Oncol 4:1044-1052, 1986 5. Johnson BE, Ihde DC, Bunn PA, et al: Patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation: Data on potential cures, chronic toxicities, and late relapses after a five to eleven year follow-up. Ann Intern Med 103:430-438, 1985 6. Livingston RB, Stephens RL, Bonnet JD, et al: Longterm survival and toxicity in small-cell lung cancer: Southwest Oncology Group study. Am J Med 77:415-417, 1984 7. Vogelsang GB, Abeloff MD, Ettinger DS, et al: Longterm survivors of small-cell carcinoma of the lung. Am J Med 79:49-56, 1985 8. Jacobs RH, Greenburg A, Bitran JD, et al: A 10-year experience with combined modality therapy for stage III small-cell lung carcinoma. Cancer 58:2177-2184, 1986 9. Smith IE, Sappino AP, Bondy PK, et al: Long-term survival five years or more after combination chemotherapy and radiotherapy for small-cell lung carcinoma. Eur J Cancer Clin Oncol 17:1249-1253, 1981 10. Craig J, Powell B, Muss HB, et al: Second primary bronchogenic carcinomas after small-cell carcinoma: Report of two cases and review of the literature. Am J Med 76:1013-1020, 1984 11. Howard JR Jr, Veach SR, DeVaney K, et al: The development of small-cell lung cancer in the contralateral lung of a patient surviving 8 years after the original diagnosis of small-cell lung cancer. Cancer 62:436-439, 1988
12. Johnson BE, Ihde DC, Matthews MJ, et al: Non-smallcell lung cancer: Major cause of late mortality in patients with small-cell lung cancer. Am J Med 80:1103-1110, 1986 13. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 14. Simes RJ, Zelen M: Exploratory data analysis and the use of the hazard function for interpreting survival data: An investigator's primer. J Clin Oncol 3:1418-1431, 1985 15. Johnson BE, Patronas N, Hayes W, et al: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: Further follow-up of 6-13 year survivors. J Clin Oncol 8:48-56, 1990 16. Cohen MH: Small-cell bronchogenic carcinoma: A prolonged remission following chemotherapy. JAMA 237: 2528, 1977 17. Fox W, Scadding JG: Medical research council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus:Tenyear follow-up. Lancet 2:63-65, 1973 18. Matthews MJ, Rozencweig M, Staquet MJ, et al: Long-term survivors with small-cell carcinoma of the lung. Europ J Cancer 16:527-531, 1980 19. Rosenberg SA, Kaplan HS: The evolution and summary results of the Stanford clinical trials of the management of Hodgkin's Disease: 1962-1984. Int J Rad Oncol Biol Phys 11:5-22, 1985 20. Longo DL, Young RC, Wesley M, et al: Twenty years of MOPP therapy for Hodgkin's Disease. J Clin Oncol 4:1295-1306, 1986 21. Roth BJ, Greist A, Kubilis PS, et al: Cisplatin-based combination chemotherapy for disseminated germ cell tumors: Long-term follow-up. J Clin Oncol 6:1239-1247, 1988 22. Shields TW, Humphrey EW, Higgins FA, Jr, et al: Long-term survivors after resection of lung carcinoma. J Thorac Cardiovasc Surg 76:439-445, 1978 23. Cortese D, Pairolero PC, Bergstralh E, et al: Roentgenographically occult lung cancer. A ten-year experience. J Thorac Cardiovasc Surg 86:373-380, 1983
Downloaded from ascopubs.org by DFG Deutsche Forschungsgemeinschaft on August 31, 2019 from 129.187.254.047 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
