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© 2002 American Society for Clinical Oncology Stanford V and Radiotherapy for Locally Extensive and Advanced Hodgkin’s Disease: Mature Results of a Prospective Clinical TrialByFrom the Department of Medicine, Division of Medical Oncology, and Departments of Radiation Oncology and Health Research and Policy, Stanford University Medical Center, Stanford, CA. Address reprint requests to Sandra J. Horning, MD, Division of Medical Oncology, Department of Medicine, 1000 Welch Rd, Suite 202, Palo Alto, CA 94304; email: sandra.horning{at}stanford.edu
PURPOSE: To provide more mature data on the efficacy and complications of a brief, dose-intense chemotherapy regimen plus radiation therapy (RT) to bulky disease sites for locally extensive and advanced-stage Hodgkin’s disease.
PATIENTS AND METHODS: One hundred forty-two patients with stage III or IV or locally extensive mediastinal stage I or II Hodgkin’s disease received Stanford V chemotherapy for 12 weeks followed by 36-Gy RT to initial sites of bulky ( RESULTS: With a median follow-up of 5.4 years, the 5-year FFP was 89% and the OS was 96%. No patient progressed during treatment, and there were no treatment-related deaths. FFP was significantly superior among patients with a prognostic score of 0 to 2 compared with those with a score of 3 and higher (94% v 75%, P < .0001). No secondary leukemia was observed. To date, there have been 42 pregnancies after treatment. Among 16 patients who relapsed, the FF2R was 69% at 5 years. CONCLUSION: These data confirm our preliminary report that Stanford V chemotherapy with RT to bulky disease sites is highly effective in locally extensive and advanced Hodgkin’s disease. It is most important to compare this approach with standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the ongoing intergroup trial (E2496) to determine whether Stanford V with or without RT represents a therapeutic advance.
DOXORUBICIN, BLEOMYCIN, vinblastine, and dacarbazine (ABVD) chemotherapy is presently considered the standard treatment for patients with advanced-stage Hodgkin’s disease on the basis of the results of a series of randomized clinical trials and a relatively favorable toxicity profile.1-5 In the most recent intergroup trial led by Cancer and Leukemia Group B (CALGB), the 5-year failure-free survival rates after ABVD and mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) –ABV hybrid chemotherapy were both 75%, but the hybrid arm produced more toxicity, particularly second malignancies.5 It is well-known that the incidence of sterility and leukemia are far less with ABVD compared with MOPP, whereas pulmonary fibrosis and potential cardiac effects are essentially restricted to ABVD.6 Clinically severe pulmonary toxicity occurred in 6% of patients treated with ABVD in the CALGB study, and fatal pneumonitis was reported in three of 115 patients.4 Although not established on the basis of randomized trials, combined-modality therapy is considered the standard of care for patients with locally extensive mediastinal Hodgkin’s disease on the basis of the high cure rate.7,8 The potential for lung toxicity may be enhanced by the combination of ABVD and mediastinal irradiation, because both can have deleterious effects on pulmonary function.9 The observation of progressive or recurrent disease in approximately 25% of patients who present with advanced-stage disease and concerns for pulmonary sequelae in the combined modality setting form the basis for the investigation of alternative chemotherapy approaches that are effective and well-tolerated both short and long term. The rationale for the use of radiation therapy (RT) as an adjuvant to chemotherapy in stage III and IV patients is based on the observations of relapse in previously involved sites, most often bulky lymph nodes, even in patients with stage IV disease.10 Given the reliability of radiation therapy to provide local control, many studies have incorporated combined-modality therapy. However, randomized, cooperative group trials have failed to show a substantial benefit for low-dose, consolidative RT to initial sites of disease, although small patient numbers and deviations from assigned treatment leave open the possibility of a type II error in some of these trials.11,12 Although well tolerated acutely, RT is associated with an increased risk of second cancers and ischemic heart disease on the basis of dose, volume, and other technical factors.13 In particular, women receiving RT to the mantle field before 30 years of age are known to be at increased risk for breast cancer.14 The addition of RT to alkylating agent–based chemotherapy resulted in inferior long-term survival in a meta-analysis of advanced-stage patients.15 These considerations recommend the judicious application of RT to bulky disease sites after chemotherapy in locally extensive and advanced Hodgkin’s disease.
The 12-week chemotherapy program, Stanford V (nomenclature refers to the fifth novel treatment regimen developed for lymphoma), alone or in combination with RT to bulky disease, was introduced in 1988 with the objectives of maintaining or improving the rate of cure and minimizing acute and long-term toxicities.16 Major features of the regimen include an abbreviated course of treatment, maintenance or increase in dose-intensity of individual drugs, reduction in the cumulative doses of bleomycin and doxorubicin compared with ABVD or hybrid programs, and marked reduction of nitrogen mustard with omission of procarbazine. It was anticipated that pulmonary and cardiac dysfunction, sterility, and leukemogenesis might be reduced or avoided with the Stanford V chemotherapy program. Consolidative irradiation, 36 Gy, was restricted to sites of bulky disease (
Since May 1989, patients between the ages of 15 and 60 years with untreated locally extensive or advanced, biopsy-proven Hodgkin’s disease confirmed in the Laboratory of Surgical Pathology at Stanford University were eligible for this study. Advanced disease was defined as Ann Arbor stage IIIA, IIIB, or IV disease, and locally extensive disease was defined as clinical stage I or II with a mediastinal mass greater than one third of the maximum intrathoracic diameter on a standing posteroanterior chest radiograph.20,21 Exclusion criteria included a positive human immunodeficiency viral test and a serum bilirubin greater than 5 mg/dL. Patients with a WBC count less than 4,000/µL or a platelet count less than 100,000/µL were also excluded unless associated with biopsy-proven bone marrow disease or hypersplenism. All participants gave written informed consent for the treatment protocol, which was reviewed and approved at least annually by the Committee for the Protection of Human Subjects at Stanford University during the course of this study from November 1988 to the present. Standardized diagnostic procedures were performed, and the results were presented at a weekly multidisciplinary conference to determine stage and protocol eligibility. History, physical examination, blood studies, chest radiograph, bone marrow biopsy, computerized tomography (chest, abdomen, and pelvis), and bipedal lymphogram were considered standard procedures. Many patients were evaluated with gallium scanning and positron emission tomography, some in the context of a prospective trial, the results of which will be reported separately. The Stanford V chemotherapy regimen has been previously reported.16,18 Chemotherapy was given weekly for 12 weeks as follows: vinblastine 6 mg/m2 and doxorubicin 25 mg/m2 on weeks 1, 3, 5, 7, 9, and 11; vincristine 1.4 mg/m2 (maximum dose, 2 mg) and bleomycin 5 units/m2 on weeks 2, 4, 6, 8, 10, and 12; mustard 6 mg/m2 on weeks 1, 5, and 9; and etoposide 60 mg/m2 daily times two on weeks 3, 7, and 11. Prednisone 40 mg/m2 was administered orally every other day on weeks 1 through 10 and tapered during weeks 11 and 12. Doses of doxorubicin, vinblastine, mustard, and etoposide were reduced to 65% if the absolute neutrophil count was less than 1,000/µL, and treatment was delayed if the absolute neutrophil count (ANC) was less than 500/µL. When it became commercially available in May 1991, granulocyte colony-stimulating factor (G-CSF) was incorporated after the initial dose reduction or delay. G-CSF was administered thereafter for 5 days on the odd weeks after myelosuppressive chemotherapy. Prophylactic ancillary medication included trimethoprim-sulfamethoxazole, ranitidine, and acyclovir, which were given throughout the treatment period.
Initially, 36 to 44 Gy RT was delivered 2 to 4 weeks after chemotherapy to initial bulky disease sites and to residual radiographic disease (patients 1 through 25). As previously described, the indications for RT were amended in August 1991, after which time 36 Gy RT was restricted to initial disease Response and follow-up evaluation included a complete blood cell count, chemistry panel, erythrocyte sedimentation rate, chest x-ray, and plain film of the abdomen every month during treatment, at the completion of RT, and every 2 months during year 1, every 3 months during year 2, every 4 months during year 3, and every 6 months during years 4 and 5. All computed tomography scans that were abnormal at diagnosis were repeated at the conclusion of chemotherapy and RT and scans of the chest, abdomen, and pelvis were done at the end of years 1, 2, and 5. Overall survival curves were calculated from the start of treatment to death from any cause or the last follow-up. FFP was calculated from the start of treatment until disease progression, relapse, or last follow-up. FFP and OS curves were estimated by the method of Kaplan and Meier.22 Tests of statistical significance in the comparison of survival curves were calculated using the Gehan test and the log-rank statistic.23,24
Patient Population From December 1988 through March 1999, 142 eligible patients with bulky and advanced Hodgkin’s disease were accrued to study. During that time period, 31 patients of similar stage were either not eligible or elected alternate treatment. The median age was 28 years (range, 16 to 58 years). Patient characteristics are detailed in Table 1. According to the Ann Arbor system, 32% presented in stage IV, 32% had limited-stage disease with locally extensive mediastinal adenopathy, and the remaining 36% had stage III disease. Fifty-eight patients (41%) had constitutional B symptoms, including more than two thirds of patients with stage IV disease. Involvement of the spleen was observed in 39 patients. Most patients (92%) had mediastinal disease, and this was scored as locally extensive in 66 cases (46%). One hundred twenty-one patients (85%) had nodal sites  5 cm, which defined one of the criteria for the inclusion of radiation therapy after chemotherapy. The anatomic extent of disease ranged broadly from one to 13 sites, with a median of five Ann Arbor sites.20
Eighty-two patients (58%) had extranodal extension of disease. Thoracic sites, including the lungs, pericardium, pleura, and chest wall, were most common. Lung involvement was considered disseminated (stage IV) if more than one lobe was involved and as an E (extranodal) site if the disease was confined to a single lobe. Radiographic evidence of pleural and pericardial disease was interpreted as contiguous involvement from lymph nodes. Hepatic disease was based on histologic confirmation or a constellation of clinical criteria, including macroscopic disease on a computed tomography scan or significant hepatic enlargement combined with abnormal liver function tests. The distribution of prognostic factors, expressed as the international prognostic score, according to the criteria established by an international consortium is listed in Table 2. Because of eligibility criteria and referral pattern, only nine patients were 45 years or older. The distribution for other prognostic factors were as follows: male, 79 patients; stage IV, 45 patients; hemoglobin lower than 10.5 g/dL, 16 patients; albumin less than 4 g/dL, 71 patients; lymphocytes less than 600/µL or less than 8%, 29 patients; and neutrophils higher than 15,000/µL, 24 patients. The distribution of prognostic score in the study group was as follows: zero (n = 19), one (n = 38), two (n = 44), three (n = 21), and four or higher (n = 20). One hundred one patients (71%) had none, one, or two adverse factors, whereas 41 patients (29%) had three or more adverse factors. For reference, the distribution of prognostic factors in the international analysis involving 1,618 patients is provided in Table 2.
Acute Toxicity All 142 patients completed the planned 12-week course of Stanford V chemotherapy. Consolidative radiotherapy was delivered to 129 patients, per protocol specifications, as outlined in Table 3. As previously noted, most patients received treatment to the mediastinum and low neck. There were no treatment-related deaths. Myelosuppression constituted the major acute toxicity. One hundred seventeen patients had an ANC less than 500/µL and 23 patients had an ANC less than 100/µL at some time during chemotherapy. As described above, after May 1991, G-CSF was routinely used after the initial dose reduction or delay. A total of 94 patients received G-CSF. Grade 3 anemia (hemoglobin < 8 g/dL) was observed in 44 patients, and five of these had grade IV anemia (hemoglobin < 6.5 g/dL). After significant anemia was appreciated in some patients with the Stanford V regimen, erythropoietin was incorporated at the investigators’ discretion. Thrombocytopenia was unusual, with a platelet count less than 100,000/µL recorded in seven patients, and one patient, who was later found to have an underlying hepatic disorder, had grade III thrombocytopenia (platelet count nadir, 38,000/µL).
Thirty-five patients were hospitalized at some time during or within 2 months of completing Stanford V chemotherapy. The major reasons for hospitalization were fever and neutropenia (n = 20) and severe constipation (n = 10). Two patients were hospitalized with deep vein thrombosis. Ten patients experienced grade III fatigue. In addition to severe constipation and obstipation requiring hospitalization, neurotoxicity included grade III constipation (n = 16), grade III neuromuscular toxicity (n = 5), grade III neurosensory toxicity (n = 9), and grade III pain (n = 10).
Late Toxicity Reproductive function was informally assessed during the routine follow-up of patients. Two women, ages 44 and 48 at diagnosis, are presently taking hormone replacement therapy. Among the 53 remaining women assessed, 43 had regular menses and 10 had irregular menses, including one who conceived after treatment. At this reporting, there have been 43 pregnancies after treatment, including 19 conceptions among 13 men and 24 conceptions among 19 women treated on this study. One woman conceived twice after Stanford V, irradiation, and high-dose chemotherapy with hematopoietic cell transplantation.
Disease Control and Survival
At 5 years, the FFP according to prognostic score was as follows: 100% for no risk factors (n = 19), 91% for one risk factor (n = 38), 95% for two risk factors (n = 44), 86% for three risk factors (n = 21), and 65% for four or more risk factors (n = 20). In Fig 2A, FFP is described according to the international prognostic score. For patients with zero to two adverse prognostic factors (n = 101), the 5-year FFP was 94% (95% CI, 89% to 99.2%) compared with 75% (95% CI, 61.8% to 87.6%) for patients with three or more adverse prognostic factors (n = 41) (P < .0001 [Gehan], P < .0001 [log rank]). The probability of OS was 99% (95% CI, 95.7% to 100%) among patients with a prognostic score of zero to two, significantly higher than the 89% (95% CI, 79.2% to 99.4%) OS estimated for patients with a prognostic score of three or greater (P = .006 [Gehan], P = .011 [log rank]). In fact, the one death among those with the lower prognostic score occurred in a patient in continuous remission.
Features and Management at Relapse Table 4 details selected features of the 16 patients who developed recurrent disease. Although none progressed during chemotherapy, half of the patients relapsed within 6 months of the completion of treatment. Nine of the 16 relapsing patients had four adverse prognostic factors according to the international score. A single patient with stage II disease experienced a relapse; in retrospect, the hilar recurrence represented a marginal miss of radiation therapy. Two patients with locally extensive mediastinal disease relapsed in the infraclavicular region at the margin of the radiation field. One patient with an unusual presentation and course relapsed with a composite T-cell lymphoma and Hodgkin’s disease.
Relapses were more common among patients who were treated with chemotherapy alone (six of 13) according to protocol specification. Five of these six relapsed in original sites of disease, but because of early relapse within 60 days of completing chemotherapy, it would not have been possible to incorporate all initial disease sites within radiotherapy ports before relapse. Furthermore, the sites of relapse, which were frequently extranodal, as described in Table 4, indicate the need for a more effective systemic treatment rather than more radiotherapy in these cases. In considering the risk of relapse after treatment with Stanford V alone, it must be appreciated that multiple sites of initial disease were not irradiated in patients who did receive radiotherapy limited to bulky ( 5 cm) sites. That is, control of unirradiated disease should be considered on a site-specific rather than a patient-specific basis. Eleven of 16 relapsing patients were managed with high-dose carmustine, etoposide, and cyclophosphamide and autologous hematopoietic cell transplantation. Consolidative irradiation was given after transplantation in two cases. Five patients were managed with combination chemotherapy and RT. Chemotherapy alone was given to another patient who was older and had several comorbid conditions; this was the patient who developed lung cancer. As indicated in Fig 3, the FF2R for the 16 patients who relapsed was estimated at 69% (95% CI, 46% to 92%) at 5 years. Four patients failed second-line therapy, three after transplantation and one after chemotherapy alone. One of the transplant failures had asymptomatic growth of abdominal and pelvic lymph nodes. A repeat biopsy was difficult to interpret but was read as a composite T-cell lymphoma and Hodgkin’s disease. The patient has been well without additional treatment. The remaining patients are alive and disease-free at 24, 24, 34, 35, 43, 46, 47, 62, 74, 83, 107, and 108 months.
In this study, we describe the results of a novel treatment strategy for bulky and advanced-stage Hodgkin’s disease. Despite a reduction in overall time on treatment, a reduction in cumulative doses of alkylating agents, doxorubicin and bleomycin, and a reduction in radiotherapy dose and volume, the treatment results compare favorably to those achieved previously at our institution and elsewhere. The excellent outcome with Stanford V with or without radiotherapy may be attributed to the relatively dose-intense chemotherapy program and the early application of radiotherapy to sites at greatest risk for drug failure. Improvements in the radiographic staging of Hodgkin’s disease and omission of staging laparotomy with its attendant delay in therapy may also have contributed to the overall success of our treatment plan compared with previous results. It is gratifying that the present high rates of cure have been achieved with chemotherapy that is just 12 weeks in duration and with modified radiotherapy volumes, particularly the omission of axillary treatment in the modified mantle field, which may lessen the risk of secondary breast cancer. The demonstrated ability of both men and women to conceive after Stanford V chemotherapy is especially gratifying. With a median follow-up of 5.4 years, the absence of myelodysplasia or leukemia supports the postulate that the Stanford V regimen is less leukemogenic than regimens containing greater cumulative doses of alkylating agents. The diagnosis of a single secondary solid tumor, arguably related to therapy, is encouraging, but it is far too early to determine the late consequences of modified dose and volume of radiotherapy in our study patients. Perhaps the most remarkable outcome in the present study is the projected overall survival of 96% at 10 years in bulky and advanced Hodgkin’s disease, a result that rivals even the best pediatric data from Stanford and other centers. These survival data represent both the efficacy of the Stanford V regimen and the ability to successfully treat patients who relapse, primarily with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation.25,26 The success of second-line therapy in more than 60% of our patients, some of whom relapsed less than 90 days after treatment and would be considered induction failures, contrasts with the recent study in which only 19% of Hodgkin’s disease induction failures were alive and disease-free at 5 years.27 In this series from Germany, the proportion of patients with primary induction failure who received high-dose therapy was 37%. It is possible that the disease among patients who relapsed after Stanford V represents an inadequate duration of treatment rather than absolute drug resistance. On the other hand, most of our patients were young (median age, 28 years), and greater success may have been seen with the early application of myeloablative therapy on relapse. The German Hodgkin’s Lymphoma Study Group developed the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen for intermediate or advanced Hodgkin’s disease on the basis of mathematical simulation that predicted a 10% improvement in tumor control at 5 years with a moderate dose escalation of 30%.28 BEACOPP was developed and tested in standard and escalated versions, the latter facilitated by G-CSF.29 Subsequently, the standard and later escalated BEACOPP regimens were compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD in a large, multicenter phase III trial. In an interim analysis with 505 assessable patients, the pooled BEACOPP arms resulted in significantly superior freedom from treatment failure compared with COPP/ABVD at 24 months (84% v 75%, respectively; P = .034).30 Approximately two thirds of patients on both arms of the study received 36-Gy RT to initial bulky or residual sites of disease. In a recent update of this study with 1,180 assessable patients, the failure-free survival rates were 70%, 79%, and 89% for COPP/ABVD, BEACOPP, and escalated BEACOPP, respectively.31 The differences in these results were statistically significant. Survival rates for the BEACOPP arms (91% and 92%) were higher than the 86% observed for COPP/ABVD. However, with 40 months of median follow-up, 10 cases of acute myelogenous leukemia were reported, eight after escalated BEACOPP and two after standard BEACOPP. As anticipated, on the basis of cumulative doses of cyclophosphamide and procarbazine, all three regimens sterilized patients. The benefit of dose-intense therapy was limited to patients younger than 60 years of age. Because no differences in outcome were noted according to the number of prognostic factors in the BEACOPP series, the risk to benefit ratio may favor the use of this program in the subset (approximately 19%) of patients with four or more risk factors.
In contrast, the international prognostic score was found to be predictive in our analysis of the Stanford V plus RT data. Patients with zero to two factors had a 94% FFP at 5 years compared with 75% for patients with three or more factors (P < .0001). OS also significantly favored lower-risk patients, 99% versus 89% (P = .011). These results, which compare favorably with the 74% FFP predicted by the international prognostic score, and the favorable toxicity profile recommend a comparison of Stanford V with or without RT with ABVD in bulky and advanced Hodgkin’s disease in the present E2496 intergroup trial. Patients in this study are randomized to receive ABVD with RT for locally extensive mediastinal disease or Stanford V with RT for sites We believe the present data with Stanford V and RT are highly encouraging and deserving of additional study in the present E2496 intergroup trial comparing this approach to ABVD. Additional follow-up is needed to determine the full extent of complications associated with the Stanford V and radiotherapy program, because secondary solid tumors may have a long latency. Because cure is possible for all patients with Hodgkin’s disease, it is increasingly important to define optimal treatment in the context of cure rate and early and late toxicity.
Supported by grant no. 2R01 CA56060 from the National Institutes of Health, Bethesda, MD.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
