Late toxicities from radiation therapy are frequent in patients with Hodgkin lymphoma and can hamper survival. These late toxicities should decrease with modern radiation therapy, but results are not mature and so the importance of this decrease is still unknown. Hence, all studies in Hodgkin lymphoma must report longer-term outcome.
by Bertand Coiffier and Olivier Casasnovas
In a recent publication, Meyer et al. presented a 12-year follow-up of patients with localised non-bulky Hodgkin lymphoma included in a study that compared chemotherapy to a radiation-based treatment.1 Inclusion criteria in this study – previously published with a short follow-up period2 – were not-too-low risk patients (stage IA with one involved node and erythrocyte sedimentation rate [ESR] <50 mm were excluded) but not-too-high risk (patients with tumour diameter >9 cm, a tumour larger than one-third of the chest wall diameter or with intra-abdominal disease were excluded). The study design was quite complicated and divided the patients into a chemotherapy arm and a radiation arm. After randomisation, patients in the chemotherapy arm received doxo-rubicin, bleomycin, vinblastine and dacarbazine (ABVD); patients with a complete remission or unconfirmed complete remission after two cycles received four cycles in total, and the remaining patients received six cycles in total. Patients assigned to the radiation arm with at least one unfavourable risk factor (>39 years old, ESR >49 mm, more than three disease sites, or mixed cellularity or lymphocyte-depleted histology) received two cycles of ABVD before radiotherapy, whereas those patients with no risk factor received only radiotherapy (subtotal nodal radiation therapy). The study was opened to enrolment in January 1994 and terminated in April 2002, but only 405 of the 450 patients had completed enrolment. The decision to terminate enrolment was taken by the Data and Safety Monitoring Board because by that time the radiation protocol was outdated. This trial was a complicated study with too many possible biases and difficult-to-interpret results that would likely have had little effect on the existing pool of Hodgkin lymphoma trial data. The first results with a 4.2-year median follow-up period showed a significantly better progression-free survival (PFS; or freedom-from-disease progression as it was called in the study) for patients randomised to the radiation arm, with a similar overall survival in both arms but a slight increase of death from causes other than Hodgkin lymphoma in the radiation arm. 
This study was saved by the late analysis, even though 14% of the patients were lost to follow up;1 late results (median follow-up period 11.3 years) showed a lower 12-year PFS (87% vs 92%; hazard ratio [HR] 1.91; P=0.05) but an improved 12-year overall survival rate (94% vs 87%; HR 0.50; P=0.04) for the patients in the chemotherapy arm compared with the radiotherapy arm. This longer overall survival was related to a lower number of patients dying from causes other than Hodgkin lymphoma (12 deaths in the ABVD arm versus 24 in the radiation arm). These numbers will likely continue to increase because the number of secondary cancers is much higher in the radiation-based arm than the chemotherapy arm (23 vs 10). These results raise several questions: first, what is a good balance between chemotherapy and radiotherapy in patients with localised Hodgkin lymphoma? Second, is it possible to reduce the intensity of therapy in some patients? Third, when can results from a randomised study be considered definitive in patients with Hodgkin lymphoma? Finally, what is the best endpoint for future studies in patients with Hodgkin lymphoma?
The current treatment for localised Hodgkin lymphoma – a short course of chemotherapy plus low-dose involved-field radiotherapy – cures over 90% of patients.[3,4] To increase this cure rate, deaths after relapse or from other causes need to be decreased or avoided. The treatment of relapsed patients has improved recently with the use of high-dose therapy with stem-cell transplants and new drugs. The ABVD regimen was associated with few severe late complications; secondary myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) are rare and the dose of doxorubicin is usually too low to induce cardiac failure. By contrast, MDS and AML are more frequent with combined therapy, and secondary solid tumours increase over time after radiotherapy. The 30-year incidence of secondary cancers with mantle radiation therapy is around 30% but decreases by 60% to 12% with involved-field radiation therapy. The long term follow-up of another trial – EORTC/GELA H10 – will give insights on the risk of a secondary cancer after involved-node radiation therapy. Cardiovascular complications are also more frequent after radiotherapy, even though they are less common now with the standard use of involved-field radiation therapy.
Is it possible to reduce the use of radiotherapy or to reserve it for a subgroup of patients with localised Hodgkin lymphoma? To date, two studies comparing results of chemotherapy alone versus the combined modality have been reported with a short follow-up period; these studies demonstrated either no PFS benefit8 or a marginally better PFS9 for the combined modality and the same overall survival for both treatment modalities.8,9 To a certain extent, the Meyer et al.1,2 study also compared both modalities, as 73% of the patients included in the radiation arm received a combination of chemotherapy plus radiation. However, long-term outcome favours the chemo-therapy arm, the extended radiation arm being hampered by an excess of death due to late toxic effects.
On the basis of these three studies,[1,2,8,9] there is no clear evidence that we can safely omit a modern radiotherapy treatment in all patients with localised non-bulky Hodgkin lymphoma because PFS results are controversial and data on long-term overall survival with current combined treatments are unavailable.
Recently, response-adapted therapy has emerged as a new concept that is supported by the development of functional imaging. In this therapy design, patients achieving complete remission as determined by 18FDG PET assessment after two chemotherapy cycles will not receive radiotherapy, but those without a complete remission will. To generalise this idea, randomised studies must show that these patients with early complete remission will not have a shorter survival than those receiving radiotherapy. Preliminary results of PET relevance to identify patients eligible for radiotherapy are in favour of this hypothesis, at least in advanced-stage Hodgkin lymphoma.10 However, the majority of these studies are ongoing and definitive results have not yet been published. Involved-field radiation therapy remains the standard treatment for these patients until such results demonstrate that radiotherapy is not necessary in early responders. Furthermore, an additional issue to address is establishing suitable rules for interpreting interim PET scan results.
The trial published by Meyer et al.[1,2] is also remarkable because results were modified from the early2 to the later1 report. Although PFS results did not change, overall survival changed from the same in both arms to being better in the chemotherapy arm, because of late toxic events in the radiotherapy arm. Clearly, for diseases in which overall survival is very good, such as localised Hodgkin lymphoma, results must not be reported early on and a minimum of 10 years is necessary to allow the analysis of the late effects and deaths caused by late toxic effects.
It is too frequently the case that study reports from trials in patients with Hodgkin lymphoma or non-Hodgkin lymphomas are published with less than five years of follow up. These early results are important, particularly if there is a difference in overall survival, or if a potential change for clinical practice is reported, but they must be called ‘preliminary’ and followed by the publication of mature results.
This recommendation for the publication of mature results leads to the evaluation of endpoints of studies that assess the first-line treatment of treatment-naive patients. Assessment of PFS allows the evaluation of the efficacy of the tested therapy, but not late toxicity. When there is a large difference between the two arms (larger than 20%), the early results are usually confirmed by late results; however, when the difference is small (less than 10%) results must be called preliminary and need to be confirmed by other studies and/or by mature results.
In summary, our first goal is to cure patients with cancer, but when long-term survival is over 90%, we need to look at the possible toxic effects of treatment on survival. All randomised studies showing a benefit in the experimental arm must be reported with a median follow-up longer than 10 years to allow this assessment to be completed.
1. RM Meyer et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. NEJM http://dx.doi.org/10.1056/NEJMoa1111961
2. RM Meyer et al. (2005) Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. JCO 23, 4634–42
3. A Engert et al. (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. NEJM 363:640–652
4. JO Armitage. (2010) Early-stage Hodgkin’s lymphoma. NEJM 363:653–662
5. D Hodgson. (2011) Late effects in the era of modern therapy for Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2011:323–329
6. AJ Swerdlow et al. (2011) Second cancer risk after chemotherapy for Hodgkin’s lymphoma: a collaborative British cohort study. JCO 29:4096–4104
7. BM Aleman et al. (2003) Long-term cause-specific mortality of patients treated for Hodgkin’s disease. JCO 21:3431–39
8. DJ Straus et al. (2004) Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104:3483–89
9. H Eghbali et al. (2005) Comparison of three radiation dose levels after EBVP regimen in favorable supradiaphragmatic clinical stages I-II Hodgkin’s lymphoma: preliminary results of the EORTC-GELA H9-F trial [abstract]. Blood 106:a240
10. A Engert et al. (2011) Reduced intensity of chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin lymphoma: The GHSG HD15 final results [abstract]. Ann Meeting Am Soc Hematol a589
Bertrand Coiffier, Department of Haematology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France; Olivier Casasnovas, Department of Haematology, Hôpital le Bocage, Dijon, France
- Radiotherapy is associated with late toxic effects
- Long-term follow up (>10 years) should be mandatory in Hodgkin lymphoma trials
- Chemotherapy alone might be sufficient treatment for selected patients
This article was first published in Nature Reviews Clinical Oncology vol. 9 no.3, and is published with permission. © 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2012.
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