Optimisation of chemotherapy and radiotherapy for Hodgkin lymphoma patients with respect to second cancers and survival
We aimed to compare various forms of treatment for newly diagnosed Hodgkin lymphoma involving chemotherapy with or without additional radiotherapy. We particularly looked at the risk of second cancers caused by these treatments, although survival and elimination of Hodgkin lymphoma were also investigated.
Since Hodgkin lymphoma often afflicts young people and highly effective treatments allow most patients to survive long after their diagnosis, curing the disease has to be weighed against the risk of causing long-term adverse effects. Second cancers are a particularly severe form of late toxicity after chemotherapy and radiotherapy. We performed a meta-analysis based on individual patient data from patients treated for newly diagnosed Hodgkin lymphoma in order to compare second cancer risk, survival and Hodgkin-free survival with various treatment options. These options included: (1) used of chemotherapy with or without additional radiotherapy; (2) use of a more extensive or more restricted radiation field; (3) use of a higher or lower radiation dose; (4) use of more or fewer courses of chemotherapy and (5) use of standard-dose or dose-intensified types of chemotherapy.
The evidence is current to July 2017, based on a total of 16 clinical trials which treated people between 1984 and 2007. Four eligible trials were excluded due to failure to obtain individual patient data, while one further eligible trial was identified only in 2015 and data were not sought. For each of the five study questions (see above), data from between three and six trials with between 1101 and 2996 participants were analysed. Each trial's data covered a follow-up period of between six and 11 years. All included trials employed modern, widely accepted forms of chemotherapy and radiotherapy. Patients were non-elderly adults of both sexes with early or advances stage disease, according to study question. All trials were funded by public bodies or charities without any direct industry funding.
In the comparison of chemotherapy alone versus same chemotherapy plus radiotherapy (all stages), the use of chemotherapy without additional radiotherapy was associated with a lower second cancer risk but possibly at the cost of more growth or regrowth of the disease.
In the comparison of chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages), neither second cancer risk, survival or Hodgkin-free survival was markedly different.
In the comparison of chemotherapy plus lower-dose radiation versus same chemotherapy plus higher-dose radiation (early stages), neither second cancer risk, survival or Hodgkin-free survival was markedly different.
In the comparison of fewer versus more courses of chemotherapy (early stages), neither second cancer risk, survival or Hodgkin-free survival was markedly different.
In the comparison of dose-intensified versus ABVD-like chemotherapy (advanced stages), dose-intensified chemotherapy improved Hodgkin-free survival, compared with ABVD-like regimens, at the cost of a greater risk of secondary leukaemia. Evidence suggesting improved survival with intensified chemotherapy was not conclusive, although escalated-dose BEACOPP appeared to lengthen survival.
Quality of the evidence
Evidence concerning survival and Hodgkin-free survival was of at least moderate quality, while evidence concerning second cancer risk was partly of low quality due to the small numbers of second cancers observed in the trials and too short follow-up. Thus, conclusions on second cancer risk remain tentative until more longer-term data are available. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.
The risk of secondary leukaemia is increased among patients treated with intensified chemotherapy protocols; on the other hand these regimens improve Hodgkin-free survival. Treatment decisions have to be tailored for the individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define a patient population that can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced dose radiotherapy did not appear to markedly affect Hodgkin-free survival or secondary malignancy risk.