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Concurrent Cisplatin, Etoposide, and Chest Radiotherapy in Pathologic Stage IIIB Non–Small-Cell Lung Cancer: A Southwest Oncology Group Phase II Study, SWOG 9019

From Loyola University Stritch School of Medicine, Maywood, IL; Southwest Oncology Group Statistical Center, Seattle, WA; Medical University of South Carolina, Charleston, SC; University of California at Davis, Sacramento, CA; Ohio State University Health Center, Columbus, OH; and University of Washington, Seattle, WA.

Address reprint requests to Southwest Oncology Group (SWOG-9019), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: There are no published survival data after chemoradiotherapy (chemoRT) in pathologically documented stage IIIB non–small-cell lung cancer. Studies of radiotherapy (RT) alone or chemotherapy followed by RT yield 5-year survivals less than 10%. The Southwest Oncology Group (SWOG) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy, safety, and long-term outcome of replacing postinduction surgery with additional chemoRT.

PATIENTS AND METHODS: Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1, T4N2, or N3 stage IIIB non–small-cell lung cancer. They had pulmonary function adequate to withstand combined-modality therapy, identical to the requirements of the previous trial with postchemoRT surgery. Induction therapy was two cycles of cisplatin plus etoposide (PE) concurrent with once-daily thoracic RT (45 Gy). In the absence of progressive disease, RT was completed to 61 Gy, with two additional cycles of cisplatin plus etoposide.

RESULTS: Fifty eligible patients were accrued with tumor-node (TN) substage confirmed on central review: 18, T4N0/1; 12, T4N2; and 20, N3. Grade 4 neutropenia was the most common toxicity (32%). Grade 3/4 esophagitis occurred in 12% and 8%. Median follow-up was 52 months, and overall median survival was 15 months (10 to 22, 95% confidence interval). Three- and 5-year survivals were 17% and 15% (5-year T4N0/1, 17%; T4N2, 13%; and N3, 15%).

CONCLUSION: Feasibility and long-term survival support the application of these results as a standard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared. These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PHASE III TRIALS conducted in stage III non–small-cell lung cancer (NSCLC) have demonstrated a survival benefit from chemotherapy plus radiotherapy (chemoRT) versus radiotherapy (RT) alone.^1-5 Each of these trials had a variable mix of clinically staged tumor (T) and node (N) subsets. Two studies with chemoRT reported no difference in outcome between patients with clinical stage IIIA and IIIB disease.^6,7 However, there are no published data on survival after chemoRT for patients with pathologic stage IIIB disease, nor are data available on outcome by pathologically staged T and N subsets of the IIIB designation.

The Southwest Oncology Group (SWOG) previously reported feasibility, morbidity and survival in 51 patients with bulky pathologic stage IIIB NSCLC who received induction chemoRT with concurrent cisplatin, etoposide (PE), and RT (45 Gy), followed by surgical resection (SWOG-8805).⁸ This pilot study (SWOG-8805) demonstrated encouraging survival compared with that observed in the RT-alone arms from the randomized trials cited above; similar survival as the subgroup with pathologic stage IIIA (N2) disease enrolled onto the same pilot trial (SWOG-8805); and in an exploratory subset analysis, superior survival for the T4N0/1 substage versus all other TN subsets.

These observations from SWOG-8805 called into question whether it was the inclusion of surgery, or instead the accrual of a fit cohort able to withstand trimodality therapy, that was responsible for the apparent improved outcome in bulky stage IIIB disease. Thus, the present study, SWOG-9019, was designed with the following objectives: (1) to evaluate the safety of and survival after concurrent PE-RT with definitive thoracic RT to 61 Gy in pathologic stage IIIB NSCLC; (2) to employ identical eligibility criteria as the predecessor trial SWOG-8805 so that the only difference was replacement of postinduction surgery with additional, uninterrupted chemoRT; and (3) to explore survival comparisons with the trimodality study SWOG-8805, both overall and for the T4N0/1 substage.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
These criteria duplicated those used in the trimodality study SWOG 8805.⁸ Histologic or cytologic proof of a newly diagnosed, single, primary-stage IIIB NSCLC was required. Pathologic confirmation from involved mediastinal or supraclavicular lymph nodes alone was allowed if a distinct primary lesion was evident on chest radiographs.

Stage IIIB disease was assigned by either N3 disease (contralateral mediastinal or supraclavicular nodes but not cervical nodes), or by T4 disease from invasion of mediastinal structures, heart, great vessels, trachea, carina, esophagus, or vertebral body. Confirmation of T4 or N3 status was determined by (1) T4 invasion found by the surgeon at thoracotomy or thoracoscopy; (2) involvement of the trachea or carina by bronchoscopy; (3) direct invasion of the heart, esophagus, aorta, or vertebral body by computed tomographic (CT) scan, magnetic resonance imaging (MRI) scan, or transesophageal ultrasound; or (4) biopsy by any method of supraclavicular or contralateral mediastinal N3 nodes. A substage designation of T4N0/1 required documentation of T4 status as above, with either a negative mediastinoscopy or no mediastinal nodes of any size on CT scan. Patients with a T4 substage from malignant pleural effusion were ineligible. A pleural effusion was allowed only if it developed after exploratory surgery or mediastinoscopy or if it was present only on the CT scan and deemed too small to tap under ultrasound or CT guidance. Patients with pericardial effusions were ineligible for inclusion.

Patient eligibility criteria consisted of a SWOG performance status of 0 or 1 and a prestudy evaluation that provided no evidence of distant metastatic disease, including the following: history and physical examination; serum chemistries, lactate dehydrogenase, alkaline phosphatase, AST or ALT, bilirubin, albumin and calcium; chest radiograph; CT of chest, liver, and adrenal glands; bone scan; and contrast CT or MRI scans of the brain. All patients had measurable or assessable disease and had received no prior therapy for the primary cancer. The presence of weight loss was not a requirement for eligibility, but weight loss data were collected on all patients as percent loss of the weight 6 months before registration on study.

Additional eligibility criteria were a WBC count of at least 4,000/mm³, platelets at or above the institutional lower limits of normal, hepatic function (AST or ALT and bilirubin) at or below 1.5 times the institutional upper limits of normal unless explained by a known benign disease, and a creatinine clearance 50 mL/min. Pulmonary function test results had to match criteria from the preceding trial (SWOG-8805) that incorporated surgical resection after chemoRT⁸—that is, forced expiratory volume in one second 2.0 L, or for the contralateral lung, 800 mL by quantitative V/Q scan.

Eligible patients had no other serious medical illnesses that would preclude PE-based chemoRT and no previous primary invasive cancer unless they had been free of disease for at least 5 years. They were cleared for participation in this trial after a joint evaluation by a medical and radiation oncologist. All patients were informed of the investigational nature of this study and signed a written informed consent in accordance with local institutional review board and federal guidelines.

Study Design
The induction chemoRT was identical to that given in the previous trial SWOG-8805: cisplatin, 50 mg/m²/d on days 1, 8, 29, and 36; etoposide, 50 mg/m²/d on days 1 to 5 and 29 to 33; and RT, 1.8 Gy per day, 5 days a week, starting within 24 hours of the first day of chemotherapy.⁸ A protocol-mandated hydration and polyantiemetic regimen was used for all patients. Weekly complete blood counts with a differential and a chemistry battery before each chemotherapy cycle were required. Dose modification criteria were identical to those employed in the predecessor trial,⁸ with toxicity reporting criteria according to National Cancer Institute guidelines.

Radiation treatment planning utilized two-dimensional planning techniques that were standard during the era this trial was conducted. The induction RT required delineation of the target volume: primary tumor plus a 1.5- to 2.0-cm margin, ipsilateral hilum, superior mediastinum, subcarinal nodes, and ipsilateral supraclavicular fossa. Treatment of the contralateral supraclavicular fossa was optional, unless those nodes were involved with disease. The contralateral hilum was excluded. The paraesophageal and inferior pulmonary ligament nodal regions were included if the lesion was in the lower lobe. Normal tissue tolerance criteria for the heart, spinal cord, involved and uninvolved lung were mandated as follows. For the spinal cord, the maximum dose was 50 Gy to any point, when reference points 1 cm from the top, at the middle, and the bottom of the cord were used. After the 50 Gy dose was reached, the spinal cord was shielded from direct radiation. The entire heart could not receive more than 35 Gy. The lung containing the primary tumor could receive up to 25 Gy, but the contralateral lung could not receive more than 5 Gy. Any lung receiving more than 15 Gy was limited to that lung tissue that was within the specified target volume. The induction RT dose of 45 Gy was delivered with 4 MeV photons by a linear accelerator in 5 weeks without interruption. However, a short break was allowed if either severe esophagitis requiring hospitalization, weight loss 10% of baseline, grade 4 neutropenic fever, or grade 4 thrombocytopenia occurred.

Within the 7 days before completion of the 45-Gy induction RT (approximately at the time of the second chemotherapy cycle), a reevaluation was required that included the same tests as in the previous trimodality trial⁸: history and physical, full laboratory screen as was preformed prestudy, repeat pulmonary function tests with diffusion capacity, chest radiograph, and CT scan. A bone scan and a CT or MRI scan of the brain were required only if new symptoms developed. If these tests provided evidence of distant metastases, local progression of disease, or worsening of pulmonary function, the patient was removed from study. All other patients without interruption completed the RT to a total dose of 61 Gy and received two additional cycles of PE at the same doses and schedule. The RT was completed with 2-Gy fractions via a postinduction target defined by the reevaluation CT scan plus a 1.0- to 1.5-cm normal tissue margin. The maximal spinal cord dose was 50 Gy.

Follow-up studies included a posttreatment, baseline CT scan at 4 to 6 weeks from completion of all chemotherapy. Subsequently, follow-up examinations were performed every 2 months for 1 year, then every 3 months for 3 years, then every 6 months. Patients were removed from protocol treatment for disease progression, unacceptable toxicity, development of intercurrent, noncancer-related illnesses that prevented continuation of treatment, or at the patient’s request.

Study Evaluation and Statistical Methods
Institutional designation of the T and N substage was accepted for registration, followed by standard SWOG procedures for review of eligibility criteria and notification to institutions of deviations, with opportunity for response. A rapid radiation quality control review was conducted within 48 hours of initiation of treatment. This was performed by the radiation oncology study coordinator by using the actual CT scans, simulator films with drawn target volume, port films, treatment prescription, dosimetry calculation sheet, and the initial daily dose record. Its purpose was to document and report to the Statistical Center any gross staging errors and to correct the institution’s radiation treatment plan according to the protocol guidelines, if necessary.

In addition, as the trial was approaching completion, a comprehensive central review of the CT scan report in conjunction with pathology and operative reports was conducted by the study coordinators and statistician. This was necessary in order to accomplish the main objective of accrual of at least 50 stage-eligible patients with pathologic documentation of T4 or N3 disease. The central review was performed with the same rigor as in the previous trimodality trial (SWOG-8805) to ensure final designation of the correct substages. As part of this process, a second medical oncologist was involved who assessed all substage assignments and other eligibility criteria independent of the principal investigator. This second oncologist was blinded to the individual patient’s demographic, weight loss, and outcome data. Accrual was continued until the planned sample size was reached with stage-eligible cases. Those data from cases that did not meet the stage IIIB eligibility criteria on central review were not included in the main analysis and the institution was notified and provided an opportunity to rebut the decision with additional supporting data, if available. If treatment was still ongoing, they were permitted to complete it, but most patients were already in the follow-up phase at the time of the central review.

All toxicities were graded according to standard SWOG toxicity criteria (version 1990). Response assessments (complete or partial response or stable disease) were not required for this study because the study end point was overall survival. Instead, documentation of nonprogression (as noted above) was performed at the 45-Gy point. All patients (eligible and ineligible) were observed until death. Site or sites of first relapse and cause of death data were ascertained. Subsequent relapse sites were not coded.

A sample size of 50 eligible patients with stage IIIB disease confirmed on the central review was required to allow for estimation of survival rates given complete follow-up to within, at worst, ± 14% (95% confidence interval [CI]). Overall survival was determined on the basis of the method of Kaplan and Meier.⁹ Exploratory survival analyses were intended for the IIIB substages of T4N0/1, T4N2, and N3, but as a result of small numbers, formal comparison with P values was not appropriate. The primary analysis was planned only for the 50 fully eligible patients with pathologic stage IIIB disease because the main objective was to report the results in this population only and to allow the best possible comparison with the identically staged IIIB cohort from the predecessor trimodality trial SWOG-8805. However, an intent-to-treat secondary analysis was also conducted, adding those patients with stage IIIB disease who were ineligible for other reasons.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
The study was activated on April 15, 1992, and closed December 1, 1995, after 50 consecutive, fully eligible patients were accrued who were also confirmed on central review to have pathologically documented stage IIIB disease. The initial number registered was 68, 11 of whom on central review were found to not have evidence of stage IIIB disease and instead clearly had either a less advanced stage or had metastatic disease at distant organ sites. Seven of the 57 patients with confirmed stage IIIB disease did not meet other eligibility criteria and were excluded from the primary analysis.

Characteristics of the 50 fully eligible patients are listed in Table 1. The median age was 58 years, with a range of 36 to 78 years. Eighteen percent were female, and 10% were black. All patients were fully ambulatory, and 18% had a lactate dehydrogenase level above the institutional normal range. Squamous histology was found in 48% of tumors. Significant weight loss occurred in 22 patients (43%), as listed in Table 1. The substage breakdown based on the central review was 18 (36%), T4N0/1; 12 (24%), T4N2; and 20 (40%), N3. Only one of the 20 patients with N3 disease had ipsilateral supraclavicular nodal involvement without N2 or contralateral mediastinal N3 nodes; 10 patients had contralateral mediastinal involvement, and nine had supraclavicular nodes plus bulky N2 disease.

The maximal toxicity observed per patient was grade 2 in 12 (24%); grade 3 in 17 (34%); grade 4 in 20 (40%); and grade 5 in one (2%). The frequency of each major toxicity is summarized in Table 2. Grade 4 neutropenia, most often transient without fever, was the most common toxicity and was observed in 16 patients (32%). Grade 3 esophagitis occurred in six patients (12%), and grade 4 esophagitis was reported in four patients (8%). Grade 3 to 4 anemia and grade 3 dehydration were observed in six (12%) and two (4%) patients, respectively. Grade 3 respiratory infections occurred in three patients, and one other patient experienced a grade 4 pulmonary infection. There were no serious or life-threatening events of radiation pneumonitis, nor was the adult respiratory distress syndrome observed.

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall long-term survival for the 50 fully eligible patients with pathologic stage IIIB NSCLC enrolled onto the phase II study SWOG-9019.

First sites of treatment failure in 40 patients are listed in Table 4. The primary tumor (and/or regional nodes) was the first site of disease progression in 23%, distant metastases occurred in 65%, and no specific site of failure was provided for 12%. The brain was the most common distant site of first failure (n = 10, 20%). Only one patient experienced recurrence of disease simultaneously in the primary tumor site and a distant area (brain). Cause of death was due to the primary lung cancer in all but four patients (one, respiratory failure; one, treatment-related; and two, unknown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The present phase II study cannot establish the relative worth of concurrent chemoRT induction versus the sequential approach of induction chemotherapy followed by RT. However, its results are superior to the 5-year survivals of 8% and 9% from the sequential arms of the Radiation Therapy Oncology Group (RTOG) and Japanese phase III trials, respectively.^10,11 In fact, a survival benefit for concurrent chemoRT over the sequential approach in stage III NSCLC was established in two updated phase III trials.^11,12 Another potential explanation for the favorable results of the present study is that full-dose chemotherapy was not only provided concurrent with the RT, but additional cycles were prescribed after the induction chemoRT was completed. It is of note that the newer agents now applied with some success as second-line treatment for the most part were not utilized at the time this study was conducted.

The findings from SWOG-9019 also seem promising against these historical comparisons because only those patients with pathologically confirmed, bulky, locally advanced, unresectable disease were enrolled. In contrast, prior phase III trials accrued patients with all stage III subsets and variable disease bulk and did not require pathologic staging that would confirm unresectable tumors. Thus, the current study cohort was "weighted" with poor prognostic substages. In addition, among the 20 patients with N3 disease, only one had the potentially more favorable substage of isolated supraclavicular nodal involvement without N2 or contralateral mediastinal N3 disease. Furthermore, significant weight loss was present in a number of patients. To address a potential source of bias, a secondary intent-to-treat analysis revealed an identical outcome when the stage IIIB patients who were ineligible for other reasons were added to the main cohort. Nevertheless, historical comparisons of the outcome of this chemoRT trial with other studies must be made with caution. Even though the current trial selected an advanced stage cohort and required pathologic documentation of stage IIIB disease, on the other hand, it required accrual of "fit" patients who could theoretically withstand postinduction surgery on the basis of pulmonary function and performance status criteria. These strict selection criteria were deliberate to allow an exploratory comparison of outcome with the predecessor trial SWOG-8805⁸ that used surgical resection after the same induction chemoRT in identically eligible patients with stage IIIB disease.

The TN substage mix and the median and 3-year survivals are nearly identical for the stage IIIB subset of SWOG-8805 (induction chemoRT followed by surgery) and the patients enrolled onto the present trial.⁸ Longer follow-up of SWOG-8805 demonstrated a 6-year survival of 20% in the stage IIIB cohort.¹³ Whether this favorable long-term survival is significantly better than the 5-year survival of 15% in the present report of SWOG-9019—thus endorsing a role for postchemoRT surgery—is uncertain and would require a randomized comparison. Therefore, these studies underscore the importance of ongoing randomized trials in the United States and Europe that address the worth of surgery along with chemotherapy and RT in stage III disease.^14-16 A German phase III trial will specifically enroll patients with pathologic stage IIIB disease, whereas the other ongoing studies focus on stage IIIA (N2) with bulky disease.^16,17

The T4N0/1 substage is of interest in the current and previous SWOG studies. In the exploratory subset analysis of SWOG-9019, the 5-year survival was 17% (0% to 34%, 95% CI; Table 3) for 18 patients with this stage designation. These results are not dissimilar to the 5-year outcomes of the T4N2 and N3 subsets in this trial. (Table 3) The same exploratory substage analysis was updated for SWOG-8805.¹³ For 17 patients with T4N0/1 disease, 6-year survival was 49% (23% to 71%, 95% CI). Although there are small numbers of patients with this substage in each trial, if validated in a prospective trial, these results may support a role for surgery after chemoRT in this uncommon T4N0/1 subset.

The toxicity profile in this multi-institutional study was reasonable, with only one treatment-related death. The rates of severe esophagitis and radiation pneumonitis were much lower than predicted, and improved polyantiemetic therapy regimens resulted in better tolerance of the cisplatin-based program. These safety data, together with the favorable long-term outcome, validate use of this approach as the control arm in the National Cancer Institute High Priority Intergroup Trial 0139 (RTOG 93-09) for bulky IIIA (N2) NSCLC.¹⁴ In this trial, the regimen reported herein is compared with the same induction chemoRT (to 45 Gy), but followed by surgical resection instead of completion of definitive RT. Given the local first failure rate of 23% in SWOG-9019 (this report) compared with 11% in the predecessor trimodality trial (SWOG-8805, Albain et al⁸), the role of postinduction surgery in local and subsequent distant disease control remains an unanswered question in unresectable stage III NSCLC.

The recurring themes of dominance of distant sites of failure (as in this study) and not insignificant rates of local progression support trials that test the added worth of newer chemotherapeutic and biologic agents as either consolidation or part of the induction chemoRT, as well as novel radiotherapeutic approaches. Many such trials have been initiated and reported in early follow-up since the present study was conducted (in the era before the advent of the newer agents).^18-25 Several of these trials report promising 2- to 3-year intermediate survival, whereas others do not. Their long-term results will be strongly influenced by the TN subset mix within both stage IIIA and IIIB, so pathologic documentation of stage is needed for cross-trial comparisons. To date, it seems that more favorable outcomes may require greater than two cycles of full dose systemic therapy, as well as chemotherapy concurrent with the RT. Conversely, regimens that use lower doses of newer agents with RT but do not prescribe additional full dose chemotherapy may yield inferior long-term survival. Toxicity profiles are also unique to each of the newer agent chemoRT programs, so additional safety and feasibility data are awaited.

Long-term survival and safety data from these trials with newer agents, novel radiotherapeutic approaches, or a combination of these two modalities are not yet known. Until then, the improved 5-year survival from use of the SWOG-9019 approach, coupled with its safety profile, justify its role as a control arm in ongoing trials that test the worth of surgery after chemoRT or that study novel radiotherapeutic designs. This study also sets a long-term outcome standard against which mature results from current combined modality trials with new chemotherapeutic and biologic agents may be compared.

	ACKNOWLEDGMENTS

 
Supported in part by the following Public Health Service Cooperative Agreement grant numbers awarded by the National Cancer Institute, Department of Health and Human Services, Bethesda, MD: CA32102, CA38926, CA46441, CA04920, CA46282, CA27057, CA22433, CA20319, CA37981, CA12644, CA58882, CA52654, CA42028, CA45450, CA45807, CA58348, CA46113, CA42777, CA45377, CA35261, CA32734, CA58686, CA58861, CA13612, CA45807, CA58416, CA46136, CA52772, CA58658, CA12213, and CA35192.

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Submitted March 13, 2001; accepted May 13, 2002.

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