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© 1999 American Society for Clinical Oncology Dose-Intensive Therapy for Limited-Stage Small-Cell Lung Cancer: Long-Term OutcomeFrom the Department of Medicine, Division of Biostatistics, Dana-Farber Cancer Institute; and the Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Anthony Elias, MD, Harvard Medical School, Department of Medicine, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email anthony_elias{at}macmailgw.dfci.harvard.edu
PURPOSE: To determine progression-free survival (PFS) and overall long-term survival for limited-stage small-cell lung cancer (SCLC) patients aged 60 years or younger who respond to first-line chemotherapy followed by high-dose combination alkylating agents (cyclophosphamide 5,625 mg/m2, cisplatin 165 mg/m2, and carmustine 480 mg/m2) with hematologic stem-cell support and chest and prophylactic cranial radiotherapy. PATIENTS AND METHODS: Patients were selected on the basis of their continued response to first-line therapy, their relative lack of significant comorbidity, and their ability to obtain financial clearance. RESULTS: Of 36 patients with stage III SCLC, nine patients (25%) had achieved a complete response (CR), 20 had achieved a near-CR, and seven had achieved a partial response before undergoing high-dose therapy. Toxicity included three deaths (8%). For all patients, the median PFS was 21 months. The 2- and 5-year survival rates after dose intensification were 53% (95% confidence interval [CI], 39% to 72%), and 41% (95% CI, 28% to 61%). Of the 29 patients who were in or near CR before undergoing high-dose therapy, 14 remain continuously progression-free a median of 61 months (range, 40 to 139 months) after high-dose therapy. Actuarial 2- and 5-year PFS rates were 57% (95% CI, 41% to 79%) and 53% (95% CI, 38% to 76%). By multivariate analysis, short intensive induction chemotherapy was associated with favorable outcome (P < .05). CONCLUSION: Use of high-dose systemic therapy with intensive local-regional radiotherapy was associated with manageable treatment-related morbidity and mortality. Patients who were in or near CR before intensification are enjoying an unmaintained 5-year PFS rate of 53%. Late complications were infrequent, and most patients returned to full-time work and activity. A randomized comparison of this approach and conventional-dose therapy should define the use of dose intensification with hematopoietic support in patients with responding limited-stage SCLC.
LUNG CANCER IS THE LEADING cause of death from cancer in both men and women1 and is epidemic throughout the world due to increased tobacco consumption. Approximately 15% to 25% of all bronchogenic carcinomas are small-cell lung cancer (SCLC), including 30,000 new cases per year in the United States. Consensus treatment consists of four to six cycles of etoposide and platinum with concurrent chest radiation therapy for the one third of patients who have limited-stage disease, traditionally defined as disease confined to the chest within a single radiation-therapy port.2 Numerous other two- to three-drug combinations constructed from established agents (cisplatin or carboplatin, etoposide or teniposide, ifosfamide, cyclophosphamide, vincristine, doxorubicin, or paclitaxel) produce almost identical short- and long-term results. Expected median survival is 14 to 20 months from initiation of therapy. More recent trials that use more intensive chest radiotherapy together with etoposide and cisplatin produce survivals that cluster at the upper end of the reported median survival range. Two-year survivors comprise approximately 20% to 40% of this patient population, and of these, almost one half will relapse during the next year.3,4 Only 10% to 20% of limited-stage patients survive 5 years. The contribution of dose or dose-intensity of chemotherapy to response and survival remains controversial. Seven randomized trials have evaluated dose-intensity in SCLC, mostly in the extensive-stage setting.5-11 Dose-intensity of the high-dose arms varied from 1.2 to twofold that of the lower-dose arms. Of statistical significance, but of less impact clinically, response and modest survival benefits were observed for the higher-dose arms. In the only randomized trial in which exclusively limited-stage patients were treated, Arriagada et al11 treated patients with six cycles of conventional-dose chemotherapy. The first cycle was either standard dose or modestly intensified. Intensification resulted in a complete response (CR) and survival advantage. In the only randomized transplantation trial, Humblet et al12 treated 101 SCLC patients with chemotherapy for five cycles without thoracic radiotherapy. Forty-five patients were eligible for randomization to one additional cycle of either high-dose or conventional-dose therapy with cyclophosphamide, etoposide, and carmustine; clear dose response was demonstrated. Conversion from partial response (PR) to CR occurred in approximately 77% of patients after high-dose therapy; no patients converted from PR to CR after conventional-dose treatment. Disease-free survival was significantly enhanced, and a trend toward improved survival was observed. However, an 18% toxic death rate on the autologous bone marrow transplantation arm led the investigators to conclude that dose-intensive therapy should not be considered as standard therapy in SCLC. Moreover, because chest radiotherapy had not been given in this trial, almost all patients who relapsed experienced disease recurrence in the chest. Because SCLC is associated with heavy smoking in 98% of cases and presents at a median age of 60 to 65 years, the application of dose-intensive therapy may be complicated by underlying smoking-related comorbid disease and enhanced risk of secondary smoking-related malignancies. Nonetheless, the safety of high-dose therapy has improved markedly during the past 5 to 10 years, particularly with the advent of peripheral-blood progenitor cell (PBPC) support. Thus the strategies of intensifying induction therapy, dose-intensive chest radiotherapy, and dose-intensive combination therapies with stem-cell support represent feasible areas for clinical application. We present the long-term outcomes of 36 patients with limited-stage SCLC who experienced PR or CR to conventional-dose induction chemotherapy and chest radiotherapy who subsequently received dose-intensive combination alkylating agent therapy with hematopoietic stem-cell support followed by prophylactic cranial radiotherapy. The high-dose regimen (cyclophosphamide, cisplatin, and carmustine) has had widespread use in the treatment of breast cancer.13 Because of preexisting smoking-related pulmonary disease and planned thoracic radiation, the carmustine dose was reduced by 20% to 480 mg/m2 and was given by fractionated administration to limit hepatic and pulmonary toxicities of the phase II regimen. Preliminary results of the first 19 patients were presented previously.14 Median and minimum follow-up is now 5 years and more than 40 months since high-dose intensification, respectively.
Eligibility Patients younger than 60 years with limited-stage, histologically documented SCLC who were in continued response to first-line conventional-dose induction chemotherapy were eligible for this study. At the time of high-dose therapy, the following criteria were required for eligibility: a score on the Zubrod performance scale of 0 to 1, leukocytes  3,000/µL, platelets 100,000/µL, creatinine 1.5 times normal, creatinine clearance 60 mL/min, serum glutamic-oxaloacetic transaminase and bilirubin 1.5 times normal, forced vital capacity and carbon monoxide diffusing capacity of 60% of predicted (corrected for hemoglobin). All diagnostic pathology and cytology specimens were reviewed by the Brigham and Women's Hospital Department of Pathology. Written informed consent was obtained, and the study was conducted according to the guidelines of the Dana-Farber Cancer Institute and Beth Israel Hospital institutional review boards.
Treatment
Induction therapy. No standardized induction chemotherapy regimen was mandated. After maximal response from induction chemotherapy (generally ~four cycles) and/or on referral, restaging studies were carried out, including head, chest, and upper abdominal computed tomography (CT) scans, bone scan, bilateral marrow aspirates and biopsies, and eligibility laboratory tests. Surgical staging was used to clarify the disease status of accessible residual masses in selected patients to confirm pathologic CR. Hematopoietic stem-cell collection. With the patient under general anesthesia, marrow was harvested and cryopreserved as previously described.15 PBPCs were collected by leukapheresis and cryopreserved after mobilization with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor according to standard methods.15 Patients were eligible for participation on several sequential supportive care protocols. Thus hematopoietic support consisted of marrow alone in eight patients (one patient was syngeneic), marrow followed by recombinant erythropoietin in three patients, or marrow augmented by G-CSF– or granulocyte-macrophage colony-stimulating factor–mobilized PBPCs in 25 patients. High-dose therapy. High-dose intensification chemotherapy consisted of cyclophosphamide 1,875 mg/m2 as a 2-hour infusion daily for 3 days, cisplatin 55 mg/m2 per day by continuous infusion during a 72-hour period, and carmustine 60 mg/m2/dose given as a 1-hour infusion twice daily for 4 days. The total doses were 5,625, 165, and 480 mg/m2, respectively. Hematopoietic stem-cell reinfusion (day 0) occurred 48 to 72 hours after completion of chemotherapy. Radiotherapy. Consolidative chest (50 to 60 Gy for 5 to 6 weeks) and prophylactic cranial radiotherapy (30 Gy in 15 fractions) were administered after complete recovery from the acute side effects of intensification chemotherapy. Patients who had received chest radiotherapy before intensification were eligible for protocol if their pulmonary function remained adequate as defined by the eligibility criterion.
Statistical Methods
Patient Characteristics From December 1985 to October 1994, 36 patients were enrolled and completed high-dose intensification (Table 1). The patients were selected for lack of significant active comorbid disease, continued response to first-line therapy, and ability to obtain financial coverage; these patients represent approximately one third of patients younger than 60 years seen at our institutions during the same time period. The median age was 49 years (range, 25 to 59 years); 67% had a performance status of 0 at initiation of high-dose therapy, and 64% were male. Except for chronic bronchitis or emphysema, most patients had no active comorbid disease (one patient had sequelae from childhood polio; three had previously undergone vascular or coronary angioplasty). All patients had stage III disease. Of the 15 patients with stage IIIA disease, one patient had mixed SCLC and adenocarcinoma and two patients presented with paraneoplastic syndromes (syndromes of inappropriate antidiuretic hormone and ectopic adrenal corticotropin hormone). Of the 21 patients with stage IIIB, pericardial and pleural effusions were present in two and seven patients, respectively, and four patients had supraclavicular node involvement. Invasion of the trachea and sternum was present in two patients.
Treatment Thirty-two of 36 patients (89%) received chest radiotherapy to include the primary lesion, hilum, mediastinum, and bilateral supraclavicular areas (15 patients before and 17 patients after high-dose therapy). Congestive heart failure, interstitial pneumonitis, persistent thrombocytopenia, and early infectious death (in one patient each) precluded chest radiotherapy. The median doses to the extended and involved fields were 40.0 Gy (range, 28.8 to 50 Gy) and 50.2 Gy (range, 28.8 to 60 Gy), respectively. Doses were attenuated in two patients due to persistent thrombocytopenia after high-dose therapy. Of the 17 patients receiving chest radiotherapy after dose intensification, the median time to the start of radiotherapy from the start of high-dose chemotherapy was 91 days (range, 56 to 124 days). Prophylactic cranial irradiation (PCI) was given to 26 patients (median dose, 30 Gy; range, 25 to 36 Gy; in 2-Gy fractions). PCI was not given due to early death (three patients), residual toxicity (one patient), residual local-regional disease (two patients), known small-vessel disease (two patients), and brain relapse before planned PCI (two patients).
Toxicity to High-Dose Therapy
Hematologic toxicity.
Median time to granulocytes Infectious toxicity. Acutely, all but two patients required antibiotics for support of fever during neutropenia. Eleven patients had positive blood cultures, which were related to infection of central venous lines in nine patients (Staphylococcus epidermidis in seven patients and alpha streptococcus in two patients). Late infections occurred in the first year and included transient reactivations of CNS toxoplasmosis, intestinal strongyloides, and Pneumocystis carinii (each during steroid treatment), and hepatitis B. Seven patients who did not receive prophylactic acyclovir developed localized herpes zoster. Interstitial pneumonitis. Overall, of 29 evaluated patients, the median decline in percentage predicted of forced expiratory volume in one second and forced vital capacity was small (7%; range, 0% to 35%), but carbon monoxide diffusing capacity decreased by 18% (range, 0% to 67%). Eight patients developed dyspnea, nonproductive cough, intermittent fever, and a chest x-ray pattern compatible with interstitial pneumonitis within 3 months of high-dose chemotherapy. All patients responded promptly to 1 mg/kg of prednisone followed by a gradual taper over a 3- to 6-week period. Two patients had recurrent symptoms (one after an abbreviated course of chest radiotherapy) and required prolonged corticosteroid treatment with a slow taper over a 2- to 3-month period. More recently, patients on corticosteroids received prophylactic acyclovir and trimethoprim-sulfisoxazole. Other toxicity. Two patients developed grade 3 congestive heart failure consistent with cyclophosphamide cardiotoxicity on days +8 and +9; both cases resolved completely. Reversible elevations in creatinine were observed in nine patients, appearing immediately after completion of chemotherapy in two patients. The remainder of cases occurred after prolonged aminoglycoside or amphotericin B exposure. Late events in long-term survivors (n = 15) included those associated with chest radiotherapy (pericarditis 3 years later; subclavian artery stenosis with steal in a patient who continued to smoke 5 years later) and transient ischemic attacks in two patients. One former smoker developed an ipsilateral adenocarcinoma 6 years after transplantation.
Response to High-Dose Chemotherapy
Time to Failure and Relapse
Survival Sixteen patients were progression-free for more than 24 months after transplantation. Patient characteristics are listed in Table 4 and include stage IIIA and IIIB disease in three and 13 patients, respectively, CR in four patients, and greater than 90% PR in 12 patients. One patient relapsed with SCLC at 30 months, and one developed adenocarcinoma at 6 years.
The degree of response to induction chemotherapy (CR/near-CR v PR) was the most important prognostic factor for survival (P = .0005) and progression-free survival (PFS) (P = .002) after high-dose chemotherapy (Table 4). Fourteen of 29 patients in or near CR remain alive and disease-free, with a median follow-up period of 61 months (range, 40 to 139 months) after high-dose therapy. A Cox regression analysis showed that young age (< 50 years), fewer cycles of induction chemotherapy (
High-dose therapy clearly achieves higher response rates (including higher CR rates) than does conventional-dose therapy for a variety of hematologic and epithelial malignancies. In some malignancies, such as breast and ovarian cancer, a dose-survival advantage has been suggested by promising results in phase II trials. In others, such as multiple myeloma and certain subsets of lymphoma, a survival advantage for high-dose therapy with autologous hematopoietic support has been rigorously demonstrated in randomized trials. In SCLC, proof of principle was demonstrated in a small randomized trial comparing conventional therapy with high-dose intensification with marrow support, but with an 18% mortality rate.12 Other prior phase I/II trials evaluating dose intensification with hematopoietic stem-cell support (many using single agents or no thoracic radiotherapy) have also demonstrated enhanced CR rates without obvious survival benefits, particularly given the high morbidity and patient selection biases that are evident.16 We were able to deliver high-dose combined alkylating agent therapy together with chest radiotherapy with relatively low rates of morbidity and mortality. We report a 53% 5-year unmaintained relapse-free survival rate for a selected group of limited-disease patients in or near CR before dose intensification. This long-term outcome compares favorably with previous studies of both high-dose and conventional-dose therapies in SCLC. Selection factors that favored our patients included younger age, a relative lack of comorbid diseases, and the insistence that they cease smoking, which would reduce the frequency of second lung cancers or other non–cancer-related morbid events should they survive their SCLC. Secondly, these patients tolerated their induction therapy fairly well and were able to preserve or regain their performance status and achieve an excellent response to therapy before intensification. At least 70% of limited-stage patients would be expected to achieve this level of response with conventional therapy. In contrast, disease characteristics were generally unfavorable. Sixteen (44%) patients would have been ineligible for most cooperative group limited-stage studies because of pleural (seven patients) or pericardial effusions (two patients), supraclavicular lymph node involvement (four patients), paraneoplastic syndromes (two patients), or mixed small-cell/adenocarcinoma histology (one patient). Only 25% of patients achieved CR after induction therapy. Whether these results can be generalized to the general population of SCLC patients depends on the interactions between these selection biases and outcomes. A randomized comparison between high-dose and conventional-dose therapy for patients with limited-stage SCLC who achieved a near CR or better will be necessary to sort out these selection biases and to define the utility of dose intensification with hematopoietic support. During the past 5 years, the morbidity and mortality from high-dose chemotherapy has declined substantially with the development of peripheral-blood progenitor cells and hematopoietic cytokines. In this time frame, the upper age range of transplantation candidates has increased from 50 years to 65 years. Although smokers will always experience higher rates of complications than do nonsmokers (eg, SCLC v breast cancer patients), the applicability of high-dose therapy in patients with SCLC is much greater than it was a few years ago. Moreover, the use of combined chemoradiotherapy seems to increase CR rates and median survival times and may result in a greater proportion of patients being considered suitable for treatment with high-dose consolidation. In addition to the reduction in host toxicity, several other strategies may be used to try to improve on our results, including intensification of thoracic radiotherapy, earlier intensification of chemotherapy, support with purged/selected stem cells, and the development of non–cross-resistant immunologic therapy peri-intensification. With chemotherapy alone, the 3-year probability of relapse in the chest is 90%.17,18 Thoracic radiotherapy to 45 to 50 Gy increases local-regional control by about 25% to 30%, which is associated with a 5% increase in long-term PFS for limited-stage SCLC.19,20 If systemic control is improved by high-dose chemotherapy, initial failure in local-regional sites may become more likely.21,22 In our trial, local-regional relapse was detected in nine (47%) of the relapsing patients (all five partial responders and four patients (29%) in the CR/near CR group). The dose-intensity of chest radiotherapy has not been adequately studied. The Eastern Cooperative Oncology Group and Radiation Therapy Oncology Group recently reported a comparison of 45-Gy chest radiotherapy given either daily over a 5-week period or twice daily over a 3-week period concurrent with cisplatin and etoposide chemotherapy.23 Intensified chest radiotherapy reduced chest failure from 61% to 48% actuarial at 2 to 3 years (P < .05). Although no advantage in median survival (20 months) was observed, the long-term survival seems to be improved for the more dose-intensive radiotherapy arm.24 Choi et al25 escalated the dose of radiotherapy in cohorts of five to six patients with limited-stage SCLC; thoracic radiotherapy was given concurrently with cisplatin and etoposide either as daily 1.8-Gy fractions or twice daily 1.5-Gy fractions. The maximal-tolerated doses seem to be 45 Gy for twice daily administration and 66 to 70 Gy when given once daily. Thus marked intensification of radiotherapy dose is possible. A randomized trial is now planned to evaluate this concept. Systemic relapse is still the major challenge. Initial intensification of induction may improve overall disease-free and overall survival.11 Induction therapy reduces tumor burden and allows selection of patients possessing chemotherapy-sensitive tumors for subsequent intensification. Moreover, it can control rapidly progressive systemic and local symptoms from SCLC and improve performance status dramatically. However, chemotherapy-resistant tumor cells may develop and proliferate or may even be induced by induction therapy. This inference is supported by the Cox regression analysis in this study, which indicated that short intense inductions are preferable. The administration of long induction in our patients was generally not due to poor induction response but rather later referral or delays in obtaining financial clearance. Multicycle dose-intensive combination therapies supported by cytokines and peripheral-blood progenitor cells represent logical promising treatment concepts, although they do compromise early intense chest radiotherapy.26-33 New systemic modalities may have particular impact after high-dose therapy, because most patients will achieve a minimal residual tumor burden. The biologic characteristics of residual tumor cells, presumably enriched for in vivo resistance mechanisms, can be identified to delineate novel treatment strategies and modalities. Most biologic strategies such as replacement of the retinoblastoma gene and/or p53 function, interference with autocrine or paracrine growth loops, or immunologic therapy (interleukin 2, interleukin 12, immunotoxins, tumor vaccines) work best against minimal tumor burden. Stem-cell contamination with tumor cells surviving induction therapy may also be a source of relapse. Gene marking experiments indicate that residual tumor cells do contribute to relapse in certain hematologic malignancies and neuroblastomas34-36 (M.K. Brenner, personal communication, March 1993). The bone marrow is one of the most common homing sites for metastases from SCLC. Immunohistochemical techniques that have a sensitivity of detection of one in 104 cells demonstrate that 13% to 54% of limited-stage SCLCs and 44% to 77% of extensive-stage SCLCs with histologically negative marrows had subclinical SCLC involvement at diagnosis.37-41 This suggests that early intensification using stem cells derived from untreated or post–first cycle therapy may have a high rate of tumor contamination. In patients with metastatic SCLC or breast cancer, peripheral blood cells mobilized with G-CSF during the first cycle of vincristine, infusfamide, and cisplatin chemotherapy had demonstrable circulating tumor cells, although their viability was not established.42 Even after achieving a CR to chemotherapy, two small series suggest a high rate of residual contamination. Hay et al43 reported 83% positive screens, with no obvious decrement with therapy. Leonard et al44 found that eight of 12 limited-stage SCLC patients in response had residual tumor cells in the bone marrow detectable by a panel of monoclonal antibodies. Six of these eight patients subsequently relapsed. High rates of subclinical marrow involvement are also observed in our own experience45 (unpublished data). It is therefore somewhat surprising that more than 50% of our patients, supported with bone marrow harvesting, remain relapse-free long term, and this suggests that completely tumor-free autografts may not be absolutely required. It is not yet clear whether currently available purging methods are sufficiently effective, or indeed whether the presence of residual tumor in the autograft indicates that the patient is burdened by chemotherapy-resistant tumor cells that are ineradicable by high-dose therapy. We are currently exploring the use of partially purified CD34-selected peripheral-blood progenitor cells as autograft support.
Supported in part by Public Health Service grant no. CA13849 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
months), respectively 
4 v > 4), and use of an ifosfamide, carboplatin, and etoposide chemotherapy regimen during induction therapy (rather than platinum and etoposide alone or non–platinum-containing induction regimens) were statistically significant for the end points of progression-free and overall survival (P 
