Review question
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.
Background
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.
Study characteristics
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.
Key results
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.
The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients 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 efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.
Efficacy and the risk of severe late effects have to be well-balanced in treatment of Hodgkin lymphoma (HL). Late adverse effects include secondary malignancies which often have a poor prognosis. To synthesise evidence on the risk of secondary malignancies after current treatment approaches comprising chemotherapy and/or radiotherapy, we performed a meta-analysis based on individual patient data (IPD) from patients treated for newly diagnosed HL.
We investigated several questions concerning possible changes in the risk of secondary malignancies when modifying chemotherapy or radiotherapy (omission of radiotherapy, reduction of the radiation field, reduction of the radiation dose, use of fewer chemotherapy cycles, intensification of chemotherapy). We also analysed whether these modifications affect progression-free survival (PFS) and overall survival (OS).
We searched MEDLINE and Cochrane CENTRAL trials databases comprehensively in June 2010 for all randomised trials in HL since 1984. Key international trials registries were also searched. The search was updated in March 2015 without collecting further IPD (one further eligible study found) and again in July 2017 (no further eligible studies).
We included randomised controlled trials (RCTs) for untreated HL patients which enrolled at least 50 patients per arm, completed recruitment by 2007 and performed a treatment comparison relevant to our objectives.
Study groups submitted IPD, including age, sex, stage and the outcomes secondary malignant neoplasm (SMN), OS and PFS as time-to-event data. We meta-analysed these data using Petos method (SMN) and Cox regression with inverse-variance pooling (OS, PFS) for each of the five study questions, and performed subgroup and sensitivity analyses to assess the applicability and robustness of the results.
We identified 21 eligible trials and obtained IPD for 16. For four studies no data were supplied despite repeated efforts, while one study was only identified in 2015 and IPD were not sought. For each study question, between three and six trials with between 1101 and 2996 participants in total and median follow-up between 6.7 and 10.8 years were analysed. All participants were adults and mainly under 60 years. Risk of bias was assessed as low for the majority of studies and outcomes.
Chemotherapy alone versus same chemotherapy plus radiotherapy. Omitting additional radiotherapy probably reduces secondary malignancy incidence (Peto odds ratio (OR) 0.43, 95% confidence interval (CI) 0.23 to 0.82, low quality of evidence), corresponding to an estimated reduction of eight-year SMN risk from 8% to 4%. This decrease was particularly true for secondary acute leukemias. However, we had insufficient evidence to determine whether OS rates differ between patients treated with chemotherapy alone versus combined-modality (hazard ratio (HR) 0.71, 95% CI 0.46 to 1.11, moderate quality of evidence). There was a slightly higher rate of PFS with combined modality, but our confidence in the results was limited by high levels of statistical heterogeneity between studies (HR 1.31, 95% CI 0.99 to 1.73, moderate quality of evidence).
Chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages) . There is insufficient evidence to determine whether smaller radiation field reduces SMN risk (Peto OR 0.86, 95% CI 0.64 to 1.16, low quality of evidence), OS (HR 0.89, 95% C: 0.70 to 1.12, high quality of evidence) or PFS (HR 0.99, 95% CI 0.81 to 1.21, high quality of evidence).
Chemotherapy plus lower-dose radiation versus same chemotherapy plus higher-dose radiation (early stages). There is insufficient evidence to determine the effect of lower-radiation dose on SMN risk (Peto OR 1.03, 95% CI 0.71 to 1.50, low quality of evidence), OS (HR 0.91, 95% CI 0.65 to 1.28, high quality of evidence) or PFS (HR 1.20, 95% CI 0.97 to 1.48, high quality of evidence).
Fewer versus more courses of chemotherapy (each with or without radiotherapy; early stages). Fewer chemotherapy courses probably has little or no effect on SMN risk (Peto OR 1.10, 95% CI 0.74 to 1.62), OS (HR 0.99, 95% CI 0.73 to1.34) or PFS (HR 1.15, 95% CI 0.91 to 1.45).Outcomes had a moderate (SMN) or high (OS, PFS) quality of evidence.
Dose-intensified versus ABVD-like chemotherapy (with or without radiotherapy in each case). In the mainly advanced-stage patients who were treated with intensified chemotherapy, the rate of secondary malignancies was low. There was insufficient evidence to determine the effect of chemotherapy intensification (Peto OR 1.37, CI 0.89 to 2.10, low quality of evidence). The rate of secondary acute leukemias (and for younger patients, all secondary malignancies) was probably higher than among those who had treatment with standard-dose ABVD-like protocols. In contrast, the intensified chemotherapy protocols probably improved PFS (eight-year PFS 75% versus 69% for ABVD-like treatment, HR 0.82, 95% CI 0.7 to 0.95, moderate quality of evidence). Evidence suggesting improved survival with intensified chemotherapy was not conclusive (HR: 0.85, CI 0.70 to 1.04), although escalated-dose BEACOPP appeared to lengthen survival compared to ABVD-like chemotherapy (HR 0.58, 95% CI 0.43 to 0.79, moderate quality of evidence).
Generally, we could draw valid conclusions only in terms of secondary haematological malignancies, which usually occur less than 10 years after initial treatment, while follow-up within the present analysis was too short to record all solid tumours.