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Originally published as JCO Early Release 10.1200/JCO.2004.10.910 on December 2 2003 © 2004 American Society of Clinical Oncology.
Chemotherapy or Combined Modality Treatment: The Optimal Treatment for Hodgkin's DiseaseUniversity of Köln, Köln, Germany The high cure rates for patients with Hodgkin's Disease (HD) in all prognostic groups during the last three decades have been paralleled in adult oncology only by the treatment success in testicular tumors in young men. From the 1950s to the 1970s, radiation therapy was the sole modality for treating HD, but during the 1980s polychemotherapy became an increasingly important tool in curative treatment with the advent of the mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine (ABV) plus dacarbazine (ABVD) regimens. The shift of balance from radiation to chemotherapy was accelerated by the realization of the late, often fatal, complications due to radiation, including secondary solid tumors and cardiopulmonary toxicities in long-term survivors of HD [1,2]. Initially, chemotherapy as an adjunct to curative intent radiation was used only in patients with advanced stages or in prognostically adverse early stage cases (B-symptoms, or bulky or extralymphatic disease). Today, even in favorable early stages, chemotherapy is more commonly combined with radiotherapy and has started to replace radiation in treatment plans. Thus far, however, well-designed prospective clinical trials with sufficient follow-up, that elucidate whether polychemotherapy alone yields the same results as the combination of both modalities, are lacking. Instead, a rather emotional discourse has erupted among hitherto cooperating colleagues of the two disciplines involved in the treatment of HD on the question of the most effective and least toxic tool to eradicate a maximum of tumor cells at the lowest cost and least long-term harm to the patient [3-5]. There are two generally accepted denominators that are crucial for the long-term survival of HD patients: first, the success of primary treatment, with a low number of deaths due to acute toxicity or progression of HD; second, a low rate of fatal therapy-induced complications (both acute and delayed), such as neutropenic sepsis, second neoplasms, and cardiopulmonary toxicities. In advanced stages of HD, the MOPP regimen, in combination with extended-field radiation therapy (EFRT), fulfilled the first criterion but failed the second. At present, the commonly used ABVD regimen, again often combined with consolidative radiation, results in 5-year event-free survival (EFS) rates of 70% to 75%, overall survival (OS) rates of 85% to 90%, and a reduced second tumor rate, but with a considerable potential risk of cardiotoxicity and second solid tumors when the mediastinum is treated by mantle field irradiation [6,7]. Unfortunately, at 15 years of follow-up, the tumor-free survival rate after treatment with ABVD plummeted to 45%, and the OS rate dropped to 60% [8]. These rather sobering results led to the initiation of a number of pivotal trials seeking higher initial tumor eradication and a longer-lasting, robust complete remission rate using dose- and time-intensified multidrug regimens. The goal was that through more effective chemotherapy, radiation could possibly be completely avoided or substantially reduced. These trials have recently been published at a median follow-up of more than 5 years, reporting initial tumor control in more than 90% of advanced stage patients, with acceptable acute toxicity and OS of more than 85% [9-11]. These studies, however, as an adjunct to chemotherapy, still used involved-field radiation therapy (IFRT) or even EFRT with 30 to 40 Gy in 65% to 85% of patients. Therefore, longer follow-up must confirm the validity of the long-term tumor control and adverse sequelae data. Several ongoing studies intend to prove that these intensified induction regimens, without consolidative radiation, are potent enough to exert the same tumor-cell kill as the combination of a less effective drug regimen and consolidative radiation [12]. Another approach is to significantly reduce radiation doses by applying only 20 to 30 Gy IFRT to patients with partial remission who have a positron emission tomography-positive residual tumor (> 2.5 cm), thus reducing additional radiation to less than 20% for the total study cohort [13]. In advanced HD, a number of trials have investigated whether radiation following conventional polychemotherapy (MOPP, ABVD, or derivatives) is superior to chemotherapy alone [14-16]. Most of these trials have not shown any overall survival benefit for combined modality treatment when patients had already achieved a complete response (CR) after a minimally necessary amount of chemotherapy such as eight courses of MOPP/ABV, ABVD or derivatives [10]. In some trials, however, a small advantage was seen for progression-free survival or for certain subgroups with bulky disease, B-symptoms, nodular sclerosis histology, or younger age groups [15,16]. The first large, prospective randomized trial reporting a survival advantage with consolidation radiation for patients in CR after six cycles of ABVD chemotherapy is reported by Laskar et al [17] in this issue of the Journal of Clinical Oncology. Patients who had stages I-IV, histologically proven HD, age 4 to 70 years, no prior history of malignancy and no prior therapy, and were HIV-negative, were included in this trial. Only patients in CR following six cycles of ABVD were randomly assigned to the experimental arm to receive either 21 Gy IFRT or 25 Gy EFRT, with a boost of 10 Gy to bulky sites. Eleven percent of patients received 21 Gy total nodal radiation because of extensive initial infradiaphragmatic disease. Of the 251 patients who started therapy, 179 achieved a CR, giving a CR rate of 71% with chemotherapy alone. Unfortunately, in this article, nothing is mentioned about subsequent treatment or the outcome of the important subgroup of 72 patients who did not achieve a CR, which accounted for 29% of the total. For the urgently needed answer to the complex question of when, where, and how much radiation one should or should not add to which induction chemotherapy regimen, the outcome of the non-CR patients might be of even more importance than the information on the patients who achieved CR, given that we need alternative strategies for the initially failing patients. It also was not reported whether partial response patients fared as well after additive radiation therapy (RT) as the primary CR patients, as was seen in the European Organization for Research and Treatment of Cancer (EORTC) study [10]. The 8-year EFS and OS for the entire randomly assigned group in the Laskar trial was 82% and 95%, respectively. The 8-year EFS for the combined modality treatment (CMT) arm was 88%, which was significantly better than 76% for the chemotherapy (CT)-alone arm. A multivariate subgroup analysis showed superiority for the CMT arm for patients younger than 15 years, B-symptoms, bulky disease, and advanced stages. The 8-year EFS rates for patients in stages III-IV was 59% and 78% for the CT and the CMT arm, respectively (P = .03). Surprisingly, radiation added more benefit in 8-year EFS for patients without involvement of the mediastinum: 75% in the CT arm and 89% in the CMT arm (P = .03). For OS, the CMT arm was significantly superior to the CT-only arm; this was again more pronounced in the subgroups of patients with B symptoms, stage III-IV disease, and patients younger than 15 years, but not for patients with bulky disease. For OS, RT added significantly more to patients without bulk or mediastinal involvement. This peculiar phenomenon might be explained by the preponderance (> 80%) of mixed cellularity and lymphocyte predominance (LP) histology in this young, Asian Indian population. Additionally, the chemotherapy regimen and dosage of RT possibly did not eliminate residual tumor cells in patients with bulky lesions of nodular sclerosis (NS) histology. In the report from the Children's Cancer Group by Nachmann [18], histology seemed to be an important risk factor: patients with NS histology fared much worse than the LP and MC patients, for both CT only and for CMT. It is noteworthy that this finding is in contrast to the Southwest Oncology Group trial, in which adult patients in CR were randomly assigned to receive IFRT or no further treatment. Patients with bulky, nodular sclerosing Hodgkin's disease had a significantly higher relapse free survival rate after IFRT following six courses of MOPP in combination with bleomycin, doxorubicin, and prednisone when compared to the group that did not get RT. The OS comparison did not show any difference [16]. Although this study by Laskar et al adds some valid information to the controversy about consolidative radiation, there are a few critical aspects that have to be discussed before one generalizes the conclusions from this study. First, half of the study population consisted of patients younger than 15 years of age, a study cohort that differs in outcome from adult HD patients [19]. A similar age group would be treated in pediatric oncology trials in Western countries, thus making it difficult to translate the results to adults. In addition, more than 50% of the randomly assigned patients were stage I or II, a cohort that typically would be treated as early stage disease, receiving four to six cycles of ABVD ± 20-30 Gy IFRT in most cooperative trial groups, with an expected 5-year EFS and OS of more than 90%. Eighty-eight percent of patients had nonbulky disease (< 7 cm), and only 20% to 35% had mediastinal involvement, the majority with the mixed cellularity subtype, which makes up less than 25% in Western studies. It is speculative whether the different histologies explain some of the interesting but—compared to Western studies—divergent features reported in this study. The EORTC recently published a trial [10] in which there was no benefit from additive radiation in CR patients after six cycles of MOPP/ABV for early responders (CR after four cycles) and eight cycles of MOPP/ABV for late responders (CR after six cycles), which differs from the results reported by Laskar et al. The EORTC trial used a response-adapted dynamic strategy of CR plus two cycles, thus allowing a robust CR and replacing radiation by two more courses of consolidative chemotherapy. Similar results have already been shown in earlier trials [20]. In the Laskar et al trial [21], radiation was added to a predetermined amount of chemotherapy (six cycles of ABVD) according to the model in the meta-analysis of a database of 1,740 patients. In this analysis, additional radiation after the same chemotherapy (CT1 v CT1 + RT: "additional design") showed an 11% overall improvement in tumor control rate after 10 years but no improvement for OS. In contrast, when combined modality treatment was compared with CT alone in the "parallel"-design trials (CT1 + CT2 v CT1 + RT or CT1 v CT2 + RT), no difference could be detected in tumor control rates, but OS was significantly better after 10 years in the group that did not receive RT. There were significantly fewer fatal events among patients in continuous CR if no RT was given. The simple conclusions from the existing literature about the role of radiation added to chemotherapy—at least in intermediate stage and advanced HD—is that it is beneficial when the preceding drug regimen is inadequate for effective tumor control [22,23], the total dose of drugs is not sufficient for maximal tumor-cell kill (eg, six instead of eight cycles of CT) and the amount of both CT and radiation is intentionally reduced to minimize toxicity and adverse sequelae, but the strengths and the specific impact of the two single modalities are well balanced to maximize synergy between both components (Stanford V). Therefore, in future trials, one should think of "consolidative" radiation only if one intentionally uses an inadequate or reduced intensity of chemotherapy that is not potent enough to eradicate all tumor cells. This might be the case, for example, in certain risk groups with nodular sclerosing histology, bulky disease where cytotoxic drugs might not effectively reach the last Hodgkin's-Reed Sternberg cell in the fibrotic tissue. There is evidence, however, that some of the conventional regimens (eg, MOPP/ABV) [10] and the new generation of dose- and time-intensified drug combinations with greater than a 90% initial CR induction render additional radiation superfluous, as was shown in advanced HD in the German Hodgkin’s Lymphoma Study Group HD12 trial [13]. In this trial, advanced stage HD patients were randomly assigned to either eight courses of intensified bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or four courses of intensified and four courses of standard BEACOPP, with a second randomization to 30 Gy IFRT or no radiation to bulk or residual disease. The third interim analysis in April 2003 showed that, after a median follow-up of 24 months, CR was achieved in 93%, the freedom from treatment failure (FFTF) rate for the total group was 89%, and OS was 95%. There was no difference for FFTF or OS in an intent-to-treat analysis between the RT or no-RT arm. Sixty-five percent of patients ultimately received radiation in the RT arm and 13% did so in the no-RT arm, in response to a review panel that made recommendations for each patient on the basis of pre- and posttreatment computed tomography. Whether to integrate radiation in the treatment strategy for patients with HD in early favorable (I-II A/B, without risk factors) and early unfavorable (intermediate) stages (I-IIA with risk factors: bulk [> 10 cm], large mediastinal mass, B-symptoms, high erythrocyte sedimentation rate, and > three lymph node areas) is not yet answered. Most trial groups, at least in North America and Europe, have abandoned RT alone for early stages and generally use a combined modality approach with two to four cycles of CT (typically ABVD) + 20 to 36 Gy of IFRT in early favorable stages and four to six cycles of ABVD + 20 to 36 Gy IFRT in early unfavorable stages. With these strategies, tumor control is extremely favorable, reaching 94% FFTF and 96% OS [24] in early favorable stages and 90% FFTF rate and 96% OS rate in early unfavorable (intermediate) stages [25]. In the German Hodgkin’s Lymphoma Study Group HD10 trial (early favorable group) after a median follow-up of 28 months in 847 patients, there was no difference for FFTF or OS, either for the comparison between two cycles of ABVD and four cycles of ABVD or for the comparison of 20 Gy IFRT versus 40 Gy IFRT. In August 2003, at the second interim analysis of the HD11 trial of 1,047 intermediate group patients, there was again no difference for the comparison between four courses of ABVD and four courses of standard BEACOPP, or for the comparison of 20 Gy IFRT with 30 Gy IFRT, with a 90% FFTF rate and 97% OS rate. The question remains, however, as to whether single modality ABVD would yield the same amount of initial tumor control and, in addition, would reduce the incidence of late adverse sequelae and therefore improve long-term survival in early stage HD. This question might be answered by the pivotal HD-6 trial of the National Cancer Institute of Canada Clinical Trials Group (JHD06). In this study, patients with early stage Hodgkin's disease (stages I and IIA) were stratified into low- (LP, NS, age < 40 years, erythrocyte sedimentation rate < 50, involvement of three or fewer disease-site regions) and high-risk (all others) categories. Patients were randomly assigned to standard therapy (subtotal nodal irradiation) alone for low-risk patients or two cycles of ABVD subtotal nodal irradiation for high-risk patients. Patients in the experimental arm received 4 cycles of ABVD; patients not achieving a CR (restaging after two cycles of ABVD) received six cycles of ABVD. The results of this important study are eagerly awaited and will be presented at the American Society of Hematology meeting 2003. There is great hope for the near future that new functional imaging techniques such as positron emission tomography, and the results of the novel techniques of gene expression profiling studies on HD tumor material will help to more sensitively discriminate between early responders, late responders, and nonresponders with induction chemotherapy and thus enable more dynamically tailored therapy based on when, where, and how much consolidative radiation is needed. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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