- TABLE OF CONTENTS
- Etiology and risk factors
- Signs and symptoms
- Staging and prognosis
- Treatment of stage I/II disease
- Technical aspects of radiation therapy
- Side effects and complications of radiotherapy
- Treatment of stage III/IV disease
- Long-term toxicities of combination chemotherapy
- Management of relapsed disease
- Suggested reading
HL is sensitive to radiation and many chemotherapeutic drugs, and, in most stages, there is more than one effective treatment option. Disease stage is the most important determinant of treatment options and outcome. All patients, regardless of stage, can and should be treated with curative intent.
A common treatment choice for favorable and unfavorable early-stage HL is brief chemotherapy followed by involved-field radiotherapy (IFRT). Most of the experience that yielded excellent treatment results with low toxicity was with ABVD (Adriamycin [doxorubicin], bleomycin(Drug information on bleomycin), vinblastine(Drug information on vinblastine), and dacarbazine(Drug information on dacarbazine)) for 4 cycles and IFRT of 30 to 36 Gy. Table 3 summarizes data from randomized studies that reported on the combination of short chemotherapy (4 or even only 2 cycles) followed by IFRT. The three top randomized studies have also indicated that adding extended-field radiotherapy (EFRT) to chemotherapy is not necessary and the small involved field is adequate.
The most recent (and, as yet, not fully mature) excellent results are with shortening the duration of chemotherapy to only 2 cycles of ABVD in favorable patients and reducing the IFRT dose to 20 Gy (Table 3). The addition of consolidative IFRT to chemotherapy for patients with bulky disease, which usually appears in the mediastinum, remains standard treatment. However, the definitive role of PET scans in assessing response during or after chemotherapy and the possibility of omitting radiotherapy in patients with negative PET scans are both controversial and the subject of ongoing clinical trials.
Subtotal lymphoid irradiation
This therapeutic modality (ie, treatment of the mantle and para-aortic fields only) remains an alternative treatment of favorable (nonbulky and without B symptoms) early-stage HL (stage I/II). Yet, this option is no longer the treatment of choice due to the risk of second tumors and (to a lesser degree) coronary artery disease in long-term survivors of extensive radiotherapy alone as practiced in the past. In classic (non–lymphocyte-predominant) HL, subtotal lymphoid irradiation is adequate for patients who are not candidates for a chemotherapy-containing strategy.
In patients who underwent pathologic staging (laparotomy) and were treated with primary irradiation alone, several large series reported a 15- to 20-year survival rate of nearly 90% and a relapse-free survival rate of 75% to 80%. Most relapses (75%) occurred within 3 years after the completion of therapy; late relapses were uncommon. More than half of the patients who relapsed after radiotherapy alone were still curable with standard chemotherapy.
Two recently published, large, randomized trials, the EORTC H7-F trial and the GHSG HD7 trial, further established significant decreases in relapse rates at 7 and 10 years, respectively, for combined-modality chemotherapy and IFRT as compared with EFRT alone. However, neither study showed a difference in survival between the two arms.
Canadian and European studies have reported excellent overall survival results in patients selected for radiotherapy on the basis of clinical prognostic factors alone. Thus, irradiation alone can be safely offered to patients with favorable prognostic factors who are not candidates for combined-modality treatment.
Early results of two prospective randomized trials found extended-field radiation therapy to be as effective as or superior to MOPP (mechlorethamine, [Mustargen], vincristine [Oncovin], procarbazine(Drug information on procarbazine) and prednisone(Drug information on prednisone)) chemotherapy in improving the survival of patients with early-stage Hodgkin lymphoma. However long-term follow-up of one of the studies demonstrated significantly higher disease-free and overall survival rates at 25 years for MOPP as compared with extended-field radiation therapy.
More recently, five prospective randomized studies compared chemotherapy alone with chemotherapy followed by IFRT or regional radiotherapy in patients with early-stage HL. The Children's Cancer Group tested the role of radiation therapy in young patients (< 21 years old) who attained a complete response with risk-adapted chemotherapy (mostly COPP [cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone)/ABV [Adriamycin (doxorubicin), bleomycin, and vinblastine], 4 to 6 cycles). They enrolled 829 patients into the study (68% had early-stage disease); 501 patients who achieved a complete response were then randomized to receive either low-dose (21 Gy) IFRT or no further treatment. The accrual was stopped earlier than planned because of a significantly higher number of relapses on the no-radiotherapy arm. The 3-year event-free survival rate with an intent-to-treat analysis was 92% for patients randomized to receive radiotherapy and 87% for those randomized to receive no further treatment (P = .057).
The EORTC/Groupe d'Etude des Lymphomes de l'Adulte (GELA) conducted a large randomized trial in patients with favorable early-stage classic HL. All patients received 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, and prednisone). Only patients who achieved a complete response were randomized to receive either IFRT of 36 Gy, IFRT of 20 Gy, or no irradiation. After an interim analysis, the EORTC/GELA groups closed the entry to the no-radiotherapy arm because of the excessive number of relapses. It should be noted that in previous EORTC studies, EBVP with IFRT was found to be inferior to MOPP/ABV with IFRT hybrid in patients with unfavorable disease but provided excellent results when compared with radiotherapy alone in patients with favorable disease.
The NCIC and ECOG included 405 patients with nonbulky stage I/II disease. They were randomized to receive either "standard therapy," namely, subtotal nodal irradiation (STNI) for favorable patients, and ABVD (2 cycles) followed by STNI for unfavorable (B symptoms, elevated ESR, ≥ 3 sites, age ≥ 40, mixed cellularity histology) patients or experimental therapy consisting of 6 cycles or 4 cycles (if complete response was attained after 2 cycles) of ABVD and no radiotherapy. At a median follow-up of 4.2 years, progression-free survival with ABVD alone was significantly inferior (P = .006; hazard ratio [HR] = 2.6; 5-year estimates of disease progression-free survival, 87% vs 93%). At 5 years, no event-free or overall survival difference has been detected. The study was planned for 12 years' analysis of survival.
The MSKCC trial included 152 patients with nonbulky, early-stage HL. Patients were randomized up front to receive either ABVD for 6 cycles alone or ABVD for 6 cycles followed by radiotherapy. At 60 months, the duration of complete response and freedom from disease progression for ABVD and radiotherapy vs ABVD alone were 91% vs 87% (P = .61) and 86% vs 81% (P = .61), respectively. Overall survival was 97% with ABVD and radiotherapy vs 90% with ABVD alone (P = .08). Although the differences between the outcome of the two treatment groups were not statistically significant, the study was not powered to detect differences between the treatment strategies that were smaller than 20%, due to the small number of patients and events.
In a prospective, randomized study reported from India, patients with HL who achieved a complete response after ABVD were randomized to receive either IFRT or no further therapy. The 8-year event-free and overall survival rates were significantly better for the patients who received consolidation with IFRT than for those who received ABVD alone. Subset analysis indicated that the benefit from added IFRT was more prominent in advanced-stage than in early-stage disease.
The NCCN guidelines recommend combined-modality therapy or ABVD or Stanford V alone as treatment options for favorable or unfavorable classic HL. For patients with bulky mediastinal involvement, combined-modality therapy remains the standard of care. The standard treatment by NCCN category 1 is ABVD plus radiotherapy and by category 2B is chemotherapy alone.
However, because of concern about the late morbidity and mortality related to radiotherapy, including second malignancies and cardiovascular complications, some medical oncologists favor the use of chemotherapy only for patients with nonbulky stages I and II HL. The treatment regimen employed is usually 6 cycles of ABVD or 4–6 cycles of ABVD (complete response + 2 additional cycles).