- 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
- High-dose therapy with autologous stem-cell transplantation
- Suggested reading
Treatment of stage III/IV disease
Chemotherapy has become curative for many patients with advanced stages of HL. MOPP has been the primary effective combination chemotherapy regimen for advanced-stage disease since the 1960s. Over the past several years, ABVD has been shown to be more effective and less toxic than MOPP, particularly with respect to sterility and secondary leukemia.
Combination chemotherapy regimens
Doxorubicin-containing regimens A doxorubicin(Drug information on doxorubicin)-containing regimen, such as ABVD (Table 4), is the treatment of choice for patients presenting with stage III or IV disease, as demonstrated by a randomized phase III trial undertaken by the CALGB. This trial showed higher complete response rates with ABVD and ABVD/MOPP (82% and 83%, respectively) than with MOPP alone (65%).
One reason for the improved response rate in the groups treated with doxorubicin-containing regimens was the higher percentage of patients who were able to receive ≥ 85% of the expected chemotherapy dose, particularly in the ABVD group. In addition, rates of significant and life-threatening neutropenia were higher in patients treated with the MOPP-containing regimens than in those treated with other regimens.
Subsequent trials compared ABVD, alternating MOPP/ABVD, and a MOPP/ABV hybrid. Alternating MOPP/ABVD and the MOPP/ABV hybrid was found to be equally effective in treating advanced-stage HL. However, an intergroup study that compared ABVD with MOPP/ABV hybrid (without irradiation) was closed early because of concerns regarding treatment-related deaths and second malignancies (mostly acute myeloid leukemia and lung cancer) in the MOPP/ABV hybrid arm. ABVD and MOPP/ABV hybrid yielded similar 5-year failure-free and overall survival rates.
Shortened dose-intense regimens Shortened dose-intense regimens have shown promise. For example, the 12-week Stanford V regimen (see Table 4) combined with IFRT produced a 5-year overall survival rate of 96% and a freedom-from-disease-progression rate of 89%. The freedom-from-disease-progression rate was significantly superior among patients with a prognostic score of 0–2, compared with those with a score of 3 and higher (94% vs 75%; P = .0001). Of interest, in 142 patients from Stanford, no secondary leukemia was observed, and 42 pregnancies were reported.
An escalated dose version of BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide(Drug information on cyclophosphamide), Oncovin [vincristine], procarbazine(Drug information on procarbazine), and prednisone(Drug information on prednisone)) was found to have a statistically significant superior freedom from treatment failure at 5 years compared with standard-dose BEACOPP and alternating monthly COPP and ABVD for patients with advanced stages of HL. Short-term hematologic toxicity was greatest for escalated BEACOPP, and an increased risk for secondary acute leukemias was also seen as compared with standard-dose BEACOPP and COPP/ABVD.
In advanced-stage disease, PET scanning during or after chemotherapy is emerging as a powerful predictor of outcome. Patients with advanced-stage disease who have positive PET scans after 2 cycles of ABVD are at a higher risk of relapse following treatment than are patients who have negative PET scans. Risk-adapted clinical trials based on this finding currently are ongoing and opening in the United States and Europe. At present, a change in therapy due to PET scan results during treatment cannot be recommended outside of the setting of a clinical trial. The PET scan currently is standard for assessing response after the completion of therapy.
Although the role of consolidation radiotherapy after induction chemotherapy remains controversial, irradiation is routinely added in patients with advanced-stage disease who present with bulky disease or who remain in uncertain complete remission after chemotherapy. Retrospective studies have demonstrated that adding low-dose radiotherapy to all initial disease sites after chemotherapy-induced complete response decreases the relapse rate by ~25% and significantly improves overall survival.
Interpretation of the impact of irradiation in prospective studies has been controversial. However, a SWOG randomized study of 278 patients with stage III or IV HL suggested that the addition of low-dose irradiation to all sites of initial disease after a complete response to MOP-BAP (mechlorethamine, Oncovin [vincristine], prednisone, bleomycin(Drug information on bleomycin), Adriamycin [doxorubicin], and procarbazine) chemotherapy improves the duration of remission in patients with advanced-stage disease. An intention-to-treat analysis showed that the advantage of combined-modality therapy was limited to patients with nodular sclerosis. No survival differences were observed.
A meta-analysis demonstrated that the addition of radiotherapy to chemotherapy reduced the rate of relapse but did not show a survival benefit for the combined-modality approach.
The EORTC conducted a randomized trial in patients with stages III and IV HL in which those achieving a complete remission with MOPP/ABV hybrid were randomized to receive either low-dose IFRT or no radiotherapy. Of the 739 patients enrolled, 421 achieved a complete remission. The median follow-up was 79 months. There was no statistically significant difference in 5-year event-free or overall survival. Partial responders received low-dose IFRT, and their event-free and overall survival rates were similar to those patients who achieved a complete remission.
More recently, an analysis of data collected prospectively within a randomized controlled trial of induction chemotherapy that included ABVD showed that patients who received consolidation radiotherapy had significantly better 5-year progression-free and overall survival compared with those who had not received radiation (see sidebar). The GHSG HD15 trial revealed that additional radiotherapy after 6 to 8 cycles of chemotherappy with escalated BEACOPP is only necessary in patients with PET-positive residual lymphoma larger than 2.5 cm. The negative prognosis value of PET defined as the proportion of PET-negative patients without progression, relapse, or radiotherapy within 12 months was 94.6%.
The CALGB trial and the intergroup trials mentioned previously (see section on "Combination chemotherapy regimens") noted differences in the long-term toxicities of various combination chemotherapeutic regimens.
Myelodysplasia and acute leukemia
MOPP therapy is known to be related to the development of myelodysplastic syndromes and acute leukemia. These secondary hematologic malignancies begin 2 years following therapy and decline by 10 years, with the maximum risk between 5 and 9 years. Patients with these malignancies have a poor prognosis.
The incidence of secondary leukemia appears to increase with cumulative doses of chemotherapy, age > 40 years when receiving chemotherapy for HL, and splenectomy. It is controversial whether combined-modality therapy increases the risk of leukemia compared with chemotherapy alone.
Cytogenetic studies of secondary leukemias reveal a loss of the long arm of chromosome 5 and/or 7. Less frequently, there is a loss of chromosome 18 or rearrangement of the short arm of chromosome 17. A balanced rearrangement of 11q23 and 2lq22 also has been described with etoposide(Drug information on etoposide) therapy.
Other types of cancer also are being observed with increasing frequency after chemotherapy (most regimens included alkylating agents), particularly lung cancer and other solid tumors. These malignancies have a longer latency period and usually are not observed until 15 years after therapy.
The inability to conceive a child after trying for 1 year is another long-term complication seen with combination chemotherapy. At least 80% of males have permanent azoospermia or oligospermia following more than 3 cycles of MOPP chemotherapy; < 10% of men will have recovery of spermatogenesis within 1–7 years following the end of chemotherapy. The risk of infertility with ABVD chemotherapy is significantly lower (~ 15%–25%) than that with MOPP. All men who desire childbearing potential following therapy should be counseled regarding sperm banking.
In females, there is a 50% rate of primary ovarian failure overall. The risk is 25% to 30% in patients treated at age 25 or younger but increases to 80% to 100% in women older than age 25. Many women who maintain ovarian function during chemotherapy will have premature menopause following therapy.
Female fertility appears to be well preserved following administration of ABVD, which does not contain alkylating agents of the nitrogen mustard type or procarbazine. Male fertility also probably is better preserved with such treatment, although this finding is not as well documented.
Lung problems have been reported with ABVD chemotherapy and are related to bleomycin-induced lung toxicity. In a MSKCC study of 60 patients with early-stage HL receiving ABVD chemotherapy with or without mediastinal irradiation, bleomycin was discontinued in 23% of patients. Following ABVD therapy, there was a significant decline in median forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide. Radiotherapy following ABVD chemotherapy resulted in a further decrease in FVC but did not significantly affect functional status. In a study from the Mayo Clinic, bleomycin pulmonary toxicity (BPT) was observed in 18% of patients. Increasing age and use of ABVD and granulocyte colony-stimulating factor were associated with development of BPT. Patients with BPT had a 5-year overall survival of only 63% as compared with 90% (P = .001) in patients without BPT. Mortality from BPT was 4.2%; mortality was 24% in those who developed BPT.
In the CALGB trial, there were 3 fatal pulmonary complications in 238 patients; all 3 patients were older than age 40.
Pulmonary fibrosis has also been described after combined-modality therapy. Pulmonary function testing usually reveals a decreased diffusion capacity and restrictive changes prior to the onset of symptoms.
Deteriorated myocardial function is a recognized complication of doxorubicin therapy but is not commonly seen in patients receiving ABVD chemotherapy. Patients who are treated with 6 cycles of ABVD chemotherapy receive a total doxorubicin dose of 300 mg/m²; cardiac toxicity is rarely seen in patients who receive a total dose ≤ 400 mg/m².
Relapse after radiation therapy
Patients with early-stage HL who relapse after initial therapy with irradiation alone have excellent complete remission rates and 50% to 80% long-term survival rates when treated with ABVD. The dose used for salvage therapy is the same as outlined in Table 4.
Relapse after combination chemotherapy
Among patients with advanced-stage HL, 70% to 90% will have a complete response to treatment; however, up to one-third of patients with stage III or IV disease will relapse, usually within the first 3 years after therapy.
Various studies have identified the following poor prognostic factors for response to first-line chemotherapy: B symptoms, age > 45 years, bulky mediastinal disease, extranodal involvement, low hematocrit, high ESR, high levels of CD30, and high levels of serum interleukin-10 (IL-10) and soluble IL-2 receptor.
An International Prognostic Index (IPI) has been devised for advanced HL based on a retrospective analysis of 1,618 patients from 25 centers. In the final model, seven factors were used: albumin < 4 g/dL, hemoglobin < 10.5 g/dL, male gender, stage IV disease, age ≥ 45 years, WBC ≥ 15,000/μL, and lymphocytes < 600/μL (or 8% of the WBC count). The worst prognostic group (7%) had a 5-year overall survival rate of 56% and a failure-free survival rate of 42%.
In a comparison of seven well-known prognostic models for HL applied retrospectively to a population of patients with advanced-stage disease, three were found to be the most predictive of outcome. One was the IPI, and the other two were the MSKCC model (employing age, LDH, hematocrit, inguinal nodal involvement, and mediastinal mass bulk) and the Database on Hodgkin Lymphoma model (employing stage, age, B symptoms, albumin level, and gender). Integration of the three models in a linear model improved their predictive power.
The preferred salvage method for patients who relapsed after combined-modality therapy or chemotherapy alone or remained refractory to those programs is high-dose therapy with autologous stem-cell transplantation (ASCT).
Two randomized studies (from Great Britain and Germany) demonstrated an event-free survival advantage with the high-dose therapy approach. Although a significant survival advantage was not observed due to the crossover design of the studies, most patients with refractory disease or postchemotherapy relapse are currently managed with high-dose chemotherapy and ASCT.
Analysis of prognostic factors in patients receiving high-dose salvage therapy indicated that B symptoms at relapse, extranodal disease, and short (< 1 year) remission or no remission are associated with a poor outcome.
A study from MSKCC reported the results of high-dose chemotherapy with ASCT in 65 patients with relapsed or refractory HL. At a median follow-up of 43 months, overall survival was estimated to be 73%, and event-free survival was estimated to be 58% by intent-to-treat analysis. In a multivariate logistic regression model, there were three adverse prognostic factors: extranodal sites of relapse or refractory disease, complete remission duration of < 1 year or refractory disease, and B symptoms. Patients with no or one adverse factor had an overall survival of 90% and an event-free survival of 83%, those with two adverse factors had an overall survival of 57% and an event-free survival of 27%, and those with three adverse factors had an overall survival of 25% and an event-free survival of 10%. A follow-up study of a risk-adapted approach based on the study previously described suggested that patients with adverse prognostic factors may benefit from further augmentation of high-dose programs, including a "double-transplant" for selected patients.