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© 2000 American Society for Clinical Oncology Cisplatin, Ifosfamide, Oral Etoposide, and Concurrent Accelerated Hyperfractionated Thoracic Radiation for Patients With Limited Small-Cell Lung Carcinoma: Results of Radiation Therapy Oncology Group Trial 93-12From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Radiation Therapy Oncology Group and Fox Chase Cancer Center, Philadelphia, PA; and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Address reprint requests to Bonnie S. Glisson, MD, Box 80, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email bglisson{at}mdanderson.org
PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity. PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m2 and ifosfamide 1,200 mg/m2 on days 1 to 3 and etoposide 40 mg/m2 administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid x 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved. RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%). CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.
ALTHOUGH CHEMOTHERAPY remains the foundation of treatment for small-cell lung cancer (SCLC), several randomized trials demonstrate improved local control of disease and overall survival time with the addition of thoracic radiation to induction chemotherapy for patients with limited disease.1,2 Data from the trials extant also suggest that the survival benefit issuing from combined-modality therapy may require early incorporation of radiotherapy in a concomitant schedule rather than as consolidation treatment after chemotherapy3 or concurrent treatment after several cycles of chemotherapy.4,5 The feasibility of a concomitant approach was clearly facilitated by the use of etoposide-based (instead of doxorubicin-based) therapy, mainly because of reduced esophageal toxicity, and when etoposide was combined with cisplatin, myelosuppression was also reduced. The combination of etoposide and cisplatin (EP) concomitant with thoracic radiation has been extensively studied in recent trials4-8 and has been found to be well tolerated and effective. Five-year survival rates of 26% and 16% were observed in the experimental and control arms, respectively, of a large phase III Intergroup study that demonstrated the value of accelerated hyperfractionated thoracic radiation (AHTRT) given concurrently with EP.9 Although this represents a significant improvement over what was obtained with doxorubicin-based or cyclophosphamide-based therapy,1,2 clearly the majority of patients still die of recurrent disease, and more effective control, both locoregionally and systemically, is needed. Promising results were obtained in patients with extensive SCLC who were treated in a phase I-II trial with a modification of the EP regimen.10 This included the addition of ifosfamide and a change in etoposide scheduling to prolonged oral dosing (PIEo). An overall response rate of 93% and median survival duration of 54 weeks was achieved in 30 patients in this single-institution trial, an improvement relative to the 38-week median survival time in the historical experience at the same institution. On the basis of these results, a phase I trial of PIEo with concurrent AHTRT was performed in patients with limited SCLC. The regimen was found to be feasible and a maximum-tolerated dose (MTD) was defined.11 The current study, based on the data from the phase I trial, was performed to estimate response and survival rates with PIEo and concurrent AHTRT and gain broader experience with toxic effects in a cooperative group setting.
Patients Eligibility criteria included histologically or cytologically documented SCLC of limited extent as documented by chest x-ray; computed tomography (CT) of chest, brain, and abdomen; radionuclide bone scan; bone marrow aspiration and biopsy; and physical examination. Patients with N3 disease manifested by ipsilateral supraclavicular or contralateral mediastinal lymphadenopathy were eligible. Patients with contralateral hilar or contralateral supraclavicular lymphadenopathy or with pleural effusion visible on chest x-ray were excluded. Adequate organ function was required, including absolute granulocyte count  1,500/µL, platelets 150,000/µL, total bilirubin  1.5 mg/dL, and serum creatinine 1.5 mg/dL. A performance status of 70% (Karnofsky scale), no previous chemotherapy or radiotherapy, no recent history of other malignancy (excluding nonmelanoma skin cancer or carcinoma-in-situ of the uterine cervix), and ability to provide informed consent were also required. The treating radiation oncologist was required to certify that the tumor could be encompassed by limited radiation fields that would not significantly compromise pulmonary function. The protocol was approved by the institutional review boards of all 19 participating Radiation Therapy Oncology Group (RTOG)–affiliated institutions.
Therapy
Acute toxicity was scored using the National Cancer Institute Cooperative Group common toxicity criteria and, for in-field toxicity, the RTOG Acute Radiation Morbidity Scoring Criteria. Grade 4 neutropenia of more than 5 days’ duration or associated with fever or infection, grade 3/4 thrombocytopenia, or bleeding were defined as dose-limiting effects and required dose reduction of one level with the next cycle. All courses were held pending hematologic recovery to an absolute neutrophil count of 1,500/µL and a platelet count of 100,000/µL. Etoposide was discontinued early if the absolute neutrophil count was 1,000/µL or the platelet count was 50,000/µL during oral therapy. Use of granulocyte colony-stimulating factor was permitted during febrile neutropenia and in subsequent cycles in lieu of dose reduction in the event of prolonged grade 4 or febrile neutropenia. Granulocyte colony-stimulating factor use was not permitted during AHTRT. Grade 3 nonhematologic toxicity required dose reduction of one level and grade 4 resulted in treatment discontinuation. AHTRT was begun within 24 hours of day 1, cycle 1 of chemotherapy and consisted of 1.5 Gy fractions bid x 30 fractions, for a total dose of 45 Gy. Daily fractions were separated by no less than 6 hours and no more than 8 hours. The target volume included the primary tumor plus regional hilar, mediastinal, and in some cases, ipsilateral supraclavicular lymph nodes with 1- to 2-cm margins. Ipsilateral supraclavicular irradiation was performed for adenopathy in that region when necessary for primary tumor coverage (primary tumor in upper lobe with upper mediastinal node involvement) or in the case of bulky (> 5 cm) pre- or paratracheal adenopathy. The spinal cord was limited to a total dose of 36 Gy. Prophylactic cranial irradiation (PCI) was offered to all patients whose disease responded completely and to those patients with partial disease response who desired it. It was begun no sooner than 4 weeks after completion of cycle 4 of chemotherapy, at which time final response designation was made. The treatment consisted of 2.5 Gy in single daily fractions x 10 fractions, for a total dose of 25 Gy.
Study Design Survival time was measured from the first day of treatment until the date of death from any cause and calculated by the Kaplan-Meier method.13 Progression-free survival time was measured from the first day of treatment to the date on which disease progression was documented. Patients who died without documented disease progression were counted as having experienced disease progression at the time of death. The primary end point of this trial was estimation of progression-free and overall survival at 1 year. To estimate this rate with an 8% SE, it was required that 40 patients survive at least 1 year. Given experience with a previous RTOG trial in a similar patient population, it was estimated that 55 assessable patients would be needed. Assuming an inassessability rate of 10%, the final targeted sample size was 61 patients.
Patients A total of 67 patients were entered onto this study between March 17, 1994, and April 1, 1996. Patient characteristics are listed in Table 2. A majority (77%) of the patients accrued had a Karnofsky performance status of 90% to 100% and weight loss of less than 5% (79%) of total body weight. Five patients were ineligible because of pleural effusion observed on chest x-ray (one patient), extensive disease at registration (one patient), nonprotocol chemotherapy given (one patient), inability to radiate original volume of disease (one patient), and absence of on-study data (one patient).
Response The entire treatment regimen was completed in 41 patients (66%). Therapy was discontinued prematurely because of toxic effects in 12 patients (19%) and because of disease progression in three patients (5%). One patient died before completing treatment and two refused further therapy. One patient was taken off study before cycle 4 because a pleural effusion developed, which in retrospect was judged to be unrelated to disease progression. Of the patients deemed to be in complete remission and eligible for PCI, there was documentation of PCI administration in 23(56%) of 41 patients. No documentation of whether PCI was given could be found for 11 patients. Four patients developed brain metastases and two developed extracranial metastases before initiation of PCI. One patient refused PCI. One patient who died during therapy was unassessable for response. Of the 61 assessable patients, 48 (78%) had a major response, with 41 (67%) achieving complete response and seven (11%) achieving a partial response.
Survival
Patterns of Recurrence The patterns of first failure of treatment are described in Table 3 for the 33 patients who had documented disease progression before death. The dominant mode of first recurrence was with distant metastases, accounting for nearly two thirds of the recurrences. Isolated locoregional recurrence was much less common, accounting for 26% (nine of 33) of the documented recurrences. This amounts to a 14% isolated locoregional recurrence rate (nine of 62) for the entire study population. Overall locoregional recurrence (with or without sites of metastasis outside the chest) was observed in 12 patients (20%) of the entire study population at any time. Isolated brain metastases occurred in two (9%) of 23 patients who had received PCI and in six (13%) of 45 who did not.
Toxicity Table 4 lists myelosuppressive toxic effects. Despite grade 4 granulocytopenia in 34 patients (55%), significant infectious complications were infrequent. One patient experienced life-threatening infection and one patient died of neutropenic sepsis and multiorgan failure.
Acute nonmyelosuppressive toxic effects are listed in Table 5. Acute chemoradiation esophagitis was dominant, with grade 3 toxicity in 23 patients (37%) and grade 4 in four patients (6%). Grade 3/4 mucositis and nausea/vomiting were also fairly frequent, both occurring in 30% of patients. One patient experienced coma related to ifosfamide being given despite the patient’s ongoing renal insufficiency.
Nonmyelosuppressive toxic effects occurring more than 90 days after initiation of chemoradiation were classified as late and are listed in Table 6. Late grade 4 toxicity was limited to one patient who developed a tracheoesophageal fistula approximately 2 years after initial treatment.
The regimen that we evaluated in this phase II trial was based on our previous promising results with PIEo in patients with extensive SCLC in whom a median survival time of 54 weeks was observed. A formal phase I trial for patients with limited disease in which PIEo was combined with AHTRT allowed determination of the regimen’s MTD without exposing large numbers of patients to excessive risk.11 This is in contrast with other trials of similar regimens in the settings of both limited- and extensive-stage disease in which myelosuppressive toxic effects and treatment-related death rates have been rather high when MTDs were not defined before phase II evaluation.14,15 In this phase II RTOG trial, PIEo and AHTRT produced a 68% complete remission rate, an 80% locoregional control rate, and a median survival duration and 3-year survival rate of 23.7 months and 39%, respectively. The median survival duration seen in this trial is very similar to that of the AHTRT arm of Intergroup study 0096 (23 months) in which RTOG participated and in which patients received a short course (daily x 3 days) of intravenous (IV) EP only.9 There is, however, suggestion of improved locoregional control with PIEo relative to the AHTRT arm of the intergroup study (overall locoregional relapse 20% v 36%), although, admittedly, the follow-up period was longer (median 8 years) for the Intergroup 0096 study. It is notable that AHTRT arm of Intergroup study 0096 was proven superior to the control arm, in which conventionally fractionated radiation was given, after only 5 years of follow-up. Further, improved survival in the AHTRT arm was attributed to decreased locoregional recurrence. Given the excellent locoregional control we have observed at this point, it is conceivable that longer follow-up of the patients in this trial will yield better survival rates than those observed in the AHTRT arm of Intergroup study 0096. This suggested improvement in locoregional control is offset by a 10% increase in the rate of grade 3 esophageal toxicity compared with that seen in the AHTRT arm of Intergroup 0096 (37% v 27%), although acute grade 4 esophagitis (6% v 5%) and treatment-related death rates (2% v 3%) were quite low and similar in both trials. It is notable that both modifications of the base EP regimen in PIEo have been studied in randomized trials of patients with extensive-stage SCLC. The Hoosier Oncology Group studied the addition of ifosfamide in a phase III trial of etoposide 75 mg/m2, ifosfamide 1.2 g/m2, and cisplatin 20 mg/m2 (VIP), on days 1 through 4 versus VP (the same doses of etoposide and cisplatin only).16 Patients receiving VIP experienced improved median (9.0 v 7.3 months) and 2-year survival rates (13% v 5%). Although the prolongation of median survival time is quite modest, the increased long-term survival suggested the potential favorable impact of ifosfamide on the outcome of treatment for patients with limited-stage disease. Modification of the etoposide schedule to prolonged oral dosing was primarily based on preclinical data indicating increased efficacy with prolonged exposure to low levels of the drug17 and the activity of extended oral etoposide as a salvage regimen in patients with recurrent SCLC.18,19 Prolonged oral dosing with etoposide either as a single agent or in combination with cisplatin or carboplatin and ifosfamide also proved promising in phase II trials for patients with untreated extensive-stage disease.14,20,21 Miller et al22 reported the results of a randomized trial of 21-day oral versus 3-day IV etoposide in combination with cisplatin in patients with extensive-stage SCLC. Although the study was designed to deliver the same dose-intensity of both cisplatin and etoposide over 24 weeks to clearly test the schedule dependency of etoposide, it is probable that dose-intensity was higher in the oral arm given the increased myelosuppressive toxic effects in that group. This was likely due to underestimation of the bioavailability of oral etoposide. Despite this increased exposure to etoposide on the oral arm, response rates and median failure-free time and overall survival time did not differ between the two treatment arms. Our study had actually been accruing patients for 2 years when these results were reported, which seem to refute the superiority of prolonged oral etoposide compared with short-course IV etoposide in systemic control of disease. However, for locoregional disease control, there is additional rationale for the study of oral etoposide as a radiosensitizer in chemoradiation regimens for limited SCLC. Lee et al23 have reported the results of RTOG 91-06, in which patients with locally advanced unresectable non–small-cell lung cancer were treated with hyperfractionated thoracic radiation (1.2 Gy bid to a total 69.6 Gy) and two cycles of concurrent oral etoposide (50 mg bid on days 1 through 14) and cisplatin (50 mg/m2 on days 1 and 8). Although this regimen was associated with a 53% incidence of acute grade 3/4 esophageal toxicity, the median duration of survival (19 months) and 2-year survival rate (35%) were promising. In a subsequent phase II study, a decrease in the duration of etoposide exposure to 10 days/cycle led to improved esophageal tolerance (grade 3/4 at 37%); however, a reduced median survival time of 14.4 months, as opposed to the 19-month median in RTOG 91-06, suggests that efficacy may have been compromised with the lower etoposide exposure.24 The efficacy of this modified regimen has been further tested in RTOG 94-10, a three-arm phase III trial for patients with locally advanced non–small-cell lung cancer. Accrual is complete and the study is under evaluation. Although PIEo and AHTRT were associated with excellent locoregional control and a promising 3-year survival rate of 39%, 19% of patients did not complete all planned therapy because of toxicity. The relatively high incidence of acute grade 3/4 chemoradiation esophagitis (43% of patients) and its sequelae (ie, weight loss, debility, and pain) clearly contributed to early termination of therapy. Better therapeutic results may be achieved if the regimen can be made more tolerable without reducing the intensity of either the radiation or the chemotherapy. The mucosal protectant amifostine has been shown to protect salivary gland tissue and reduce xerostomia after radiation to the head and neck, without reducing locoregional control of the cancer.25 Its ability to protect the esophagus during chemoradiation in patients with non–small-cell lung cancer is currently being studied in randomized trials (eg, RTOG 98-01). Improvement of therapeutic index with this approach would certainly facilitate the use of aggressive chemoradiation regimens such as the one we describe herein, possibly by preventing premature termination of therapy. Although protocol guidelines recommended the administration of PCI in patients who achieved complete remission of disease, documentation of PCI was found for only 23 (56%) of the 41 potentially eligible patients in this trial. In 11 (27%) of the 41 complete responders, no documentation could be identified as to whether they received PCI. In those 23 individuals who definitely received PCI, isolated brain relapse occurred in only two patients (9%), compared with relapse in six (13%) of the 45 patients who did not receive PCI. Admittedly, because of lack of randomization, these data are only speculative; however, they are in keeping with the data extant from randomized trials that show fewer instances of brain recurrence and isolated brain recurrence in patients who receive PCI. Further, a recent meta-analysis indicates that patients with complete remission after treatment of SCLC obtain a small (5%) but statistically significant long-term survival benefit from PCI.26 We predict that as the impact of aggressive combined-modality therapy continues to improve the long-term outlook for patients with limited SCLC, the importance of disease control in the CNS and thus the impact from PCI will increase in parallel.
Supported by grant nos. CA-32115 and CA-21661 from the National Cancer Institute.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618–1624, 1992[Abstract] 2. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10:890–895, 1992[Abstract] 3. Goto K, Nishiwaki Y, Takada M, et al: Final results of a phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small cell lung cancer: The Japan Clinical Oncology Group Study. Proc Am Soc Clin Oncol 18:468a, 1999 (abstr 1805)
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Turrisi AT, Kyungmann K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265–271, 1999 10. Glisson BS, Lee JS, Palmer J, et al: Cisplatin, ifosfamide, and prolonged oral etoposide in the treatment of patients with extensive small cell lung carcinoma. Cancer 82:301–308, 1998[Medline] 11. Glisson BS, Komaki R, Lee JS, et al: Integration of filgrastim into chemoradiation for limited small cell lung cancer: A phase I study. Int J Radiat Oncol Biol Phys 40:331–336, 1998[Medline] 12. Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 47:207–214, 1981[Medline] 13. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958
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Wolff AC, Ettinger DS, Neuberg D, et al: Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: An Eastern Cooperative Oncology Group pilot study. J Clin Oncol 13:1615–1622, 1995 15. Loehrer PJ, Rynard S, Ansari R, et al: Etoposide, ifosfamide and cisplatin in extensive small cell lung cancer. Cancer 69:669–673, 1992[Medline] 16. Loehrer PJ, Ansari R, Gonin R, et al: Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: A Hoosier Oncology Group study. J Clin Oncol 13:2594–2599, 1995[Abstract] 17. Dombernowsky P, Nissen NI: Schedule dependence of the antileukaemic activity of the podophyllotoxin-derivative VP 16-213 (NSC 141540) in L1210 leukaemia. Acta Path Microbiol Immunol Scan 81:715–724, 1973 18. Johnson DH, Greco AF, Strupp J, et al: Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: A phase II trial. J Clin Oncol 8:1613–1617, 1990[Abstract] 19. Einhorn LH, Pennington K, McClean J: Phase II trial of daily oral VP-16 in refractory small cell lung cancer: A Hoosier Oncology Group study. Semin Oncol 7:32–35, 1990 20. Clark PI, Joel SP, Thompson PI, et al: Prolonged administration of single-agent oral etoposide in patients with untreated small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 9:226, 1990 (abstr 874) 21. Murphy PB, Hainsworth JD, Greco FA, et al: A phase II trial of cisplatin and prolonged administration of oral etoposide in extensive-stage small cell lung cancer. Cancer 69:370–375, 1992[Medline]
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Lee JS, Scott C, Komaki R, et al: Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancer: Radiation Therapy Oncology Group protocol 91-06. J Clin Oncol 14:1055–1064, 1996 24. Komaki R, Scott C, Ettinger D, et al: Randomized study of chemotherapy radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04. Int J Radiat Oncol Biol Phys 38:149–155, 1997[Medline] 25. Sauer R, Wannenmarcher M, Wasserman T, et al: Randomized phase III trial of radiation ± amifostine in patients with head and neck cancer. Proc Am Soc Clin Oncol 18:392a, 1999 (abstr 1516)
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Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N Engl J Med 341:476–484, 1999 Submitted December 2, 1999; accepted April 27, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
