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Phase III Randomized Intergroup Trial of Subtotal Lymphoid Irradiation Versus Doxorubicin, Vinblastine, and Subtotal Lymphoid Irradiation for Stage IA to IIA Hodgkin’s Disease

From the Fred Hutchinson Cancer Research Center; University of Washington; and Southwest Oncology Group Statistical Center, Seattle, WA; University of Michigan Medical Center, Ann Arbor, MI; University of Arizona Cancer Center, Tucson, AZ; Washington University Jewish Hospital, St Louis, MO; Loyola University, Stritch School of Medicine, Maywood, IL; and University of Minnesota, Minneapolis, MN.

Address reprint requests to Southwest Oncology Group 9133, Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.

	ABSTRACT

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PURPOSE: The management of early-stage Hodgkin’s disease in the United States is controversial. To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkin’s disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients, a phase III intergroup trial was performed.

PATIENTS AND METHODS: Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkin’s disease were randomized without staging laparotomy to treatment with either subtotal lymphoid irradiation (STLI) or combined-modality therapy (CMT) consisting of three cycles of doxorubicin and vinblastine followed by STLI.

RESULTS: The study was closed at the second, planned, interim analysis because of a markedly superior failure-free survival (FFS) rate for patients on the CMT arm (94%) compared with the STLI arm (81%). With a median follow-up of 3.3 years, 10 patients have experienced relapse or died on the chemoradiotherapy arm, compared with 34 on the radiotherapy arm (P < .001). Few deaths have occurred on either arm (three deaths on CMT and seven deaths on STLI). Treatment was well tolerated, with only one death on each arm attributed to treatment.

CONCLUSION: These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone. Extended follow-up is necessary to assess freedom from second relapse, overall survival, late toxicities, patterns of treatment failure, and quality of life.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HODGKIN’S DISEASE is the classic example of a malignancy that has been transformed from a uniformly fatal disease to a highly curable one by advances in modern radiotherapy and chemotherapy.¹ Despite this fact, there is currently no uniform standard in the United States for management of the most curable stages of the disease (stages IA and IIA).^2-4 Curiously, the current discord has only arisen in the past decade. Until the 1990s, a general consensus existed in North America that patients with clinical stage IA to IIA Hodgkin’s disease as defined by the Ann Arbor staging system^5,6 should undergo pathologic staging (including laparotomy with splenectomy) followed by STLI for patients found to be free of subdiaphragmatic disease. This approach afforded disease-free survivals of 69% to 82% and overall survivals of 85% to 93% 10 years after treatment.^7-11 Although these results were impressive, several forces led to a divergence of practice patterns in the 1990s. First, investigators became dissatisfied with the potential morbidity and mortality of staging laparotomy, a procedure introduced in the late 1960s to allow accurate evaluation of splenic involvement with Hodgkin’s disease and to permit pathologic confirmation of abnormalities detected by lymphangiography.¹² Approximately 20% to 30% of patients with clinical stage I to II supradiaphragmatic Hodgkin’s disease have occult infradiaphragmatic involvement detectable by staging laparotomy.¹³ Despite this relatively high incidence of surgical upstaging, the routine use of staging laparotomy became increasingly controversial because of the lack of evidence of a survival advantage afforded by the procedure and because of appreciable morbidity.^14-22 Furthermore, randomized European trials suggested no improvement in survival for patients staged pathologically compared with those staged clinically and treated with definitive radiotherapy.^8,23,24

A second factor that led to divergence from the conventional paradigm of staging laparotomy and STLI was the recognition that wide-field radiotherapy predisposed patients to the development of secondary solid malignancies, premature coronary artery disease, and other serious cardiopulmonary sequelae, which often appeared after prolonged latent periods.^3,14 Finally, oncologists began to question whether improvements in disease-free survival might be afforded by the addition of short-course chemotherapy to radiotherapy and whether such short-course systemic chemotherapy could obviate the need for pathologic staging and simultaneously permit reduction in the sizes of the radiation fields and/or the radiation doses.^25,26

In 1989, the Southwest Oncology Group (SWOG) began designing a protocol to investigate some of these issues but recognized that not all hypotheses could be tested in a single study. On the basis of the European experience, SWOG decided to rely on clinical staging without staging laparotomy and observe whether failure-free survival (FFS) and overall survival comparable to those reported abroad could be achieved. In addition, SWOG chose to rigorously test in a randomized controlled fashion whether a short course of limited chemotherapy followed by STLI (36 to 40 Gy) administered to patients with clinical stage IA to IIA Hodgkin’s disease would improve the FFS or overall survival compared with standard STLI and whether the patterns of treatment failure and freedom from second relapse would be impacted.

The choice of chemotherapy for such a combined-modality approach was controversial. At the time the study was designed, a few small trials had been performed that suggested the efficacy of limited chemotherapy (either single-agent vinblastine^8,27 or vinblastine, bleomycin, and methotrexate [VBM]²⁵) in conjunction with radiotherapy for improving the FFS of stage I to II Hodgkin’s disease. However, these regimens were not standard for Hodgkin’s disease and were considered to have only modest potency. Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were the two accepted regimens for Hodgkin’s disease used in 1989, but MOPP had been found to be excessively toxic in several trials for adjuvant therapy of early-stage disease and was not shown to improve overall survival.^28,29 ABVD was deemed more attractive than MOPP because of its superior efficacy and lesser toxicity (ie, preservation of fertility and lower risk of secondary malignancies³⁰). However, the substantial pulmonary toxicity reported in several studies that used adjuvant ABVD or other regimens containing bleomycin (eg, VBM^31,32) was deemed undesirable for stage I to II patients. In addition, the phlebitis and nausea associated with dacarbazine were felt to be problematic for adjuvant therapy. Accordingly, SWOG chose to study three cycles of doxorubicin and vinblastine, the most active agents in the ABVD regimen, in conjunction with radiotherapy. Potential augmentation of radiation-induced cardiac toxicity by doxorubicin was minimized by limiting the chemotherapy to three cycles and by inserting a 4- to 6-week interval between the third cycle of chemotherapy and the initiation of radiotherapy. In accordance with established principles that govern the conduct of randomized trials, only a single variable differed between the two groups of patients treated, namely the presence or absence of adjuvant chemotherapy. Consequently, all patients entered onto the trial were clinically staged without a staging laparotomy, and all received the same radiation doses and fields (36 to 40 Gy STLI). The Cancer and Leukemia Group B joined this study in 1993. The current report describes the findings of this prospective, randomized, phase III intergroup trial.

	PATIENTS AND METHODS

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Eligibility
Patients over the age of 16 with biopsy-proven, clinically staged IA, I_EA, IIA, and II_EA Hodgkin’s disease according to the modified Ann Arbor classification system⁶ were eligible for entry onto this trial if they had a SWOG performance status of 0 to 2, pretreatment granulocyte counts 2,000/µL, platelets more than or equal to the institutional lower limit of normal, and bilirubin and serum creatinine levels less than or equal to the institutional upper limit of normal. Excisional lymph node biopsies were required to establish the diagnosis of Hodgkin’s disease on this trial, and needle biopsies of lymph nodes and bone marrow biopsies were considered inadequate for study entry. The original diagnostic specimens underwent central pathologic review to confirm the diagnosis of Hodgkin’s disease. Patients who were able to read and understand English were required to register simultaneously for a companion quality-of-life protocol (SWOG-9208, Cancer and Leukemia Group B–9497).

Patients were excluded if they had infradiaphragmatic presentations, pericardial E lesions, mediastinal masses greater than one third the maximum thoracic diameter, B symptoms, concomitant serious diseases including AIDS, or prior malignancies (except for adequately treated basal cell or squamous cell skin cancer, cervical carcinoma-in-situ, or disease-free status for 5 years or longer). Patients who had previously received chemotherapy or radiation for any reason, had undergone a staging laparotomy, or were pregnant or lactating were not eligible.

Staging Studies
Studies performed before therapy included physical examination; complete blood counts; platelet counts; creatinine; liver function tests; lactate dehydrogenase; thyroid function tests; a chest x-ray; computed tomography scans of the chest, abdomen, and pelvis; bone marrow biopsies; pulmonary function testing; ECG; and cardiac gated blood pool scans or echocardiograms. Lymphangiograms, gallium scans, and positron emission tomography were strongly recommended but not required. All patients were informed of the investigational nature of this study and were required to sign a written informed consent approved in accordance with institutional and federal guidelines.

Chemotherapy
Patients randomized to the combined-modality therapy (CMT) arm were initially treated with doxorubicin (25 mg/m² intravenously) and vinblastine (6 mg/m² intravenously) on days 1 and 15 of each 28-day course for three cycles. Modifications in doxorubicin and vinblastine doses were made for myelosuppression on the day of treatment and for serious nonhematologic toxicities, as previously described.³³ At the completion of the third cycle of chemotherapy, staging studies were repeated, and a period of 6 weeks after the last doses of doxorubicin and vinblastine was allowed to elapse before the initiation of STLI (36 to 40 Gy).

Radiotherapy
Patients on both arms of the protocol were treated with STLI that consisted of sequential mantle and periaortic/spleen fields to a dose of 36 to 40 Gy for 4 weeks each (1.8 or 2 Gy administered in 20 fractions) using megavoltage radiotherapy in the 4- to 10-MeV range, as described by Hoppe.¹¹ Radiotherapy records were submitted within 48 hours of initiation of treatment for central radiation therapy review to verify that fields, doses, and techniques were correct.

Follow-Up Studies
Patients were formally assessed on an annual basis to determine remission status, performance status, and presence of any residual toxicities. Any test results that were abnormal on the previous evaluation (eg, computed tomography scans, multiple-gated acquisition scans) were repeated annually until they normalized. Patients were removed from protocol treatment if they experienced progressive disease (PD), unacceptable toxicity, or voluntarily withdrew. All patients enrolled onto the study will be followed up until death, and quality-of-life forms will be submitted annually.

Response Assessments
Patients with measurable disease at the time of study entry were categorized as having a complete response (CR), unconfirmed complete response (CRu), partial response, stable disease, or PD as defined by the Cotswold convention.⁶ Two objective assessments of CR at least 4 weeks apart were required for a best response of CR.

Statistical Considerations
Patients were stratified according to sex, age ( 35; > 35), number of involved sites (one v two to three v four) histology (nodular sclerosing or lymphocyte predominant v other), presence or absence of a high neck presentation (at or above the mandibular angle), and whether or not a lymphangiogram had been performed. Patients were randomized to STLI or doxorubicin and vinblastine (administered for three cycles) and STLI according to a dynamic allocation scheme. The initial end point of the study was to compare the FFS between patients treated with STLI alone or STLI plus three cycles of doxorubicin and vinblastine. Time to treatment failure was calculated from the date of randomization to the date of disease progression or death. The total sample size was projected to be 420 eligible patients to provide adequate statistical power of 0.795 to detect a hazards ratio of 1.7 for FFS (one-sided critical alpha, 0.05). The comparison of FFS between treatment arms was adjusted for design-specified stratification factors using partial likelihood score tests and Cox regression.³⁴ Two formal interim analyses were planned during the accrual period, which occurred after 50% and 80% of the patients had been entered. The significance levels of the first and second analyses for early closure on the basis of FFS were .005 and .01, respectively. With 210 patients projected per arm, the probability of a particular toxicity could be estimated to within a 95% confidence interval of ± 0.068. Any toxicity that occurred with at least a 1% probability had an 88% chance to be seen at least once.

	RESULTS

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Patient Characteristics
This trial was closed at the recommendation of the Data Safety Monitoring Committee on April 15, 2000, after 348 patients (80% of the planned accrual) had been entered and randomized. The second planned interim analysis demonstrated a markedly superior FFS for patients treated with combined chemoradiotherapy compared with those treated with STLI alone. Twenty-two registered patients were ineligible (12 on the STLI arm and 10 on the CMT arm) because seven had the incorrect stage, seven did not have Hodgkin’s disease, four had mediastinal masses greater than one third the thoracic diameter, two had B symptoms, one had laboratory values outside the required ranges, and one patient did not simultaneously register for the required companion quality-of-life study. These patients were coded as having major protocol violations. The patient characteristics of the 161 eligible patients randomized to STLI and the 165 eligible patients randomized to CMT were well matched, as demonstrated in Table 1. Three eligible patients refused radiation therapy after they received chemotherapy; they are included in the toxicity analysis. Two eligible patients refused treatment after randomization, and two patients did not receive treatment on the basis of physician preference. These four patients were coded as major protocol deviations and were not assessable for toxicity.

FFS and Overall Survival
At the time of the intent-to-treat analysis on September 20, 2000, 10 (6%) of 165 patients on the CMT arm and 34 (21%) of 161 patients on the STLI arm had experienced disease progression or death. The 3-year estimates of FFS rates were 94% on the CMT arm and 81% on the STLI arm (P < .001). The hazards ratio for PFS for STLI versus CMT was 3.9 (95% confidence interval, 1.9 to 7.8). At the time of analysis, seven patients (4.3%) had died on the STLI arm, and three (1.8%) had died on the CMT arm. The total number of deaths is small, so it is too early to make definite statements regarding survival differences (Figs 1 and 2).

View larger version (16K): [in this window] [in a new window]   Fig 1. FFS of 326 eligible patients with stage I to IIA Hodgkin’s disease treated with either STLI or three cycles of doxorubicin plus vinblastine followed by STLI.

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival of 326 eligible patients with stage I to IIA Hodgkin’s disease treated with either STLI or three cycles of doxorubicin plus vinblastine followed by STLI.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This phase III, randomized, intergroup trial is the first large North American trial to demonstrate that excellent overall survival and FFS can be achieved in a nationwide setting using clinical staging without laparotomy and splenectomy, as suggested by several smaller European and single-institution United States trials.^8,9,23,24 In addition, this study conclusively demonstrates that three cycles of doxorubicin and vinblastine followed by STLI is a well-tolerated regimen that produces an FFS rate superior to that of STLI alone for patients with clinical stage IA to IIA Hodgkin’s disease. This study has several strengths as well as some limitations. To our knowledge, it is the largest randomized trial of early-stage Hodgkin’s disease conducted in the United States in the past two decades. The arms were well balanced, the conclusions were clear-cut, the toxicities were minimal, pathology was centrally confirmed, radiotherapy fields were centrally reviewed, and quality-of-life concerns were prospectively assessed (and will be reported separately after longer follow-up). Several previous studies have also demonstrated that CMT improves PFS compared with STLI alone; however, most of these used variants of the MOPP regimen, which produces unacceptable hematologic toxicity, frequently induces secondary malignancies, and renders most recipients infertile (reviewed in Specht et al²⁹). VBM has been used successfully by the Stanford group in conjunction with limited radiation for clinical stages I to IIA,^25,26 although subsequent studies by groups in England and Italy have found excessive pulmonary toxicity associated with this regimen.^31,32 Doxorubicin and vinblastine afford a beneficial improvement in FFS equal or superior to these other regimens without the deleterious toxicities reported with them. The conclusions of our study are also supported by preliminary reports from the German HD7 trial.³⁵ This study randomized patients with stage I to IIA Hodgkin’s disease to either STLI or two cycles of ABVD followed by STLI. With a median follow-up of 22 months, fewer relapses were recorded in the CMT arm, but overall survival was not significantly different.³⁵

Despite the decisive conclusions of this study, several caveats must be acknowledged in the interpretation of our results. First, there is as yet no conclusive evidence that CMT improves overall survival compared with STLI alone, either in this trial or in several previous ones that compared chemoradiotherapy with STLI for stage I to II Hodgkin’s disease (as reviewed in Specht et al²⁹). This observation reflects the success of second-line salvage therapies for patients who experience relapse after primary therapy for early-stage Hodgkin’s disease. Further follow-up will be needed to determine if the failure patterns between the two arms will vary, and furthermore, whether the freedom from second relapse after salvaging the STLI relapses with salvage chemotherapy will differ. Our current analysis suggests that relapses are diminished both within and outside the irradiated field.

A second potential criticism is that treatment on this trial was not risk-adapted on the basis of a detailed analysis of prognostic features, as has been performed on several European trials^36-38 and as suggested by recent decision analyses.³⁹ However, there was no uniformly accepted model for risk adaptation at the initiation of this study. Furthermore, the current approach affords excellent results in 94% of patients using a simple scheme that has been proven to work effectively in community hospitals across the United States. A third potential limitation of the current study is that further follow-up is required to fully assess late toxicities, overall survival, and effects on quality of life (secondary malignancies, employment, fertility, and so on). Fortunately, the importance of these parameters was recognized at the initiation of the trial, and annual follow-up will be conducted on all patients until death to allow future assessments of these variables.

Finally, concepts regarding the management of early-stage Hodgkin’s disease have evolved during the time that this trial was being conducted. In the 1990s, many Hodgkin’s disease authorities hypothesized that widefield radiotherapy should be replaced by smaller fields and limited doses for stage IA to IIA Hodgkin’s disease to decrease the rates of long-term toxicities, such as secondary malignancies and cardiopulmonary toxicities.⁴ Several small, single-institution trials have been conducted that support the tolerability and short-term efficacy of such approaches using limited, minimally toxic chemotherapy together with limited radiotherapy. Although this strategy is logical and promising, long-term follow-up and randomized comparisons are not yet available to validate the hypothesized benefits of such an approach on secondary malignancies and cardiopulmonary events. Nevertheless, the combined modality approach has been widely embraced in the United States, and STLI as a single modality is now uncommonly used. An alternative approach that uses chemotherapy alone has been proposed for early-stage Hodgkin’s disease.⁴⁰ Ongoing randomized trials in Germany and North America will, hopefully, provide definitive answers to these important questions. At this time, our study demonstrates in a national setting that clinically staged patients with early Hodgkin’s disease can be effectively treated with CMT using doxorubicin, vinblastine, and STLI.

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service Cooperative Agreement grant nos. CA38926, CA32102, CA20319, CA27057, CA13612, CA04920, CA46282, CA35261, CA22433, CA12644, CA45377, CA45807, CA46368, CA46113, CA58415, CA58861, CA58723, CA35176, CA52654, CA35192, CA04919, CA42777, CA58416, CA35128, CA14028, CA76447, CA96429, CA35090, CA63844, CA63845, CA16385, CA52386, CA12213, CA35281, CA58686, CA76132, CA35431, CA76448, CA35262, CA58348, CA32291, CA77440, and CA16450 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.

We thank Scott Kurruk, Tamra Oner, Dana Sparks, Diana Lowry, and the Operations and Statistical Offices of SWOG for administrative assistance with the conduct of this trial and the preparation of the manuscript and Mark Derleth for analyzing patterns of treatment failure.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 6, 2001; accepted June 27, 2001.

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