Background
Hodgkin lymphoma (HL) is a malignancy of the lymphatic system. It occurs in children and adults, but it is more common in the third decade of life. It is one of the most curable forms of cancer. There are four stages of HL, stages I and II are considered as early stage HL and stages III and IV as advanced stage. Using risk factors such as presence or absence of bulky disease and presence or absence of B-symptoms, like night sweats or fever, early stage HL is further classified into early favourable and early unfavourable stages. Treatment options are chemotherapy, radiotherapy or both. Radiotherapy may have, more treatment- related side effects than chemotherapy, including second malignancies; this applies at least to the large treatment fields used in the past. However, with modern, very limited treatment fields, the risks of long-term side effects caused by radiotherapy have been reduced significantly.
Review question
This systematic review compares overall survival (OS) and progression free survival (PFS) in adults with early stage HL after receiving chemotherapy alone or chemotherapy plus radiotherapy.
Study characteristics
We searched important medical databases such as the Cochrane Central Register of Controlled Trials and MEDLINE. Two review authors independently screened, summarised and analysed the results. This led to the inclusion of seven randomised controlled trials involving with 2564 patients.
The evidence provided is current to December 2016.
Key results
For the comparison of chemotherapy alone and chemotherapy plus radiotherapy with the same number of chemotherapy cycles in both arms, this systematic review found no evidence for a difference regarding OS between the interventions, however, two included trials had potential other high risk of bias due to a high number of patients not receiving radiotherapy as planned beforehand. After excluding these trials in a further analysis, OS was superior in adults receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. PFS was also superior in adults receiving chemotherapy plus radiotherapy. Most trials reported adverse events (AEs), but in different ways. Because of insufficient comparable data we focused on adverse events considered of particular interest. For infection- related mortality, second cancer- related mortality and cardiac disease- related mortality, there was no evidence for a difference between treatment groups. For complete response rate (CRR) there was no evidence for a difference between treatment groups either.
For the comparison of chemotherapy alone and chemotherapy plus radiotherapy with different numbers of chemotherapy cycles in the arms, OS was reported in one trial only. The use of chemotherapy alone may improve OS compared to chemotherapy plus radiotherapy. There was no evidence for a difference between treatment groups regarding PFS. After excluding one trial with patients not receiving the planned therapy the results showed that chemotherapy plus radiotherapy improved PFS. For infection- related mortality, second cancer- related mortality and cardiac disease- related mortality, there is no evidence for a difference between treatment groups. CR was not reported.
Quality of evidence
For the same number of chemotherapy cycles in both arms, we judged the quality of evidence for OS and PFS as moderate, for AEs and CR as low.
For different numbers of chemotherapy cycles in the arms, we considered the quality of evidence for OS, PFS and AEs to be low.
Conclusion
This systematic review compared the effects of chemotherapy alone and chemotherapy plus radiotherapy in adults with early stage HL .
For the comparison with same numbers of chemotherapy cycles in both arms we found moderate- quality evidence that PFS is superior in patients receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. The addition of radiotherapy to chemotherapy has probably little or no difference on OS. A further analysis without the trials with potential other high risk of bias showed that chemotherapy plus radiotherapy improves OS (both analyses moderate- quality evidence).
For the comparison of chemotherapy alone and chemotherapy plus radiotherapy with different numbers of chemotherapy cycles between the arms there were no implications for OS and PFS possible, because of the low quality of evidence of the results.
This systematic review compared the effects of chemotherapy alone and chemotherapy plus radiotherapy in adults with early stage HL .
For the comparison with same numbers of chemotherapy cycles in both arms, we found moderate- quality evidence that PFS is superior in patients receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. The addition of radiotherapy to chemotherapy has probably little or no difference on OS . The sensitivity analysis without the trials with potential other high risk of bias showed that chemotherapy plus radiotherapy improves OS compared to chemotherapy alone.
For the comparison with different numbers of chemotherapy cycles between the arms there are no implications for OS and PFS possible, because of the low quality of evidence of the results.
Combined modality treatment consisting of chemotherapy followed by localised radiotherapy is the standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long- term adverse effects such as secondary malignancies the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication.
To assess the effects of chemotherapy alone compared to chemotherapy plus radiotherapy in adults with early stage HL .
For the or i ginal version of this review, we searched MEDLINE, Embase and CENTRAL as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology and International Symposium of Hodgkin Lymphoma) from January 1980 to November 2010 for randomised controlled trials (RCTs) comparing chemotherapy alone versus chemotherapy regimens plus radiotherapy. For the updated review we searched MEDLINE, CENTRAL and conference proceedings to December 2016.
We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in patients with early stage HL. We excluded trials with more than 20% of patients in advanced stage. As the value of radiotherapy in addition to chemotherapy is still not clear, we also compared to more cycles of chemotherapy in the control arm. In this updated review, we also included a second comparison evaluating trials with varying numbers of cycles of chemotherapy between intervention and control arms, same chemotherapy regimen in both arms assumed. We excluded trials evaluating children only, therefore only trials involving adults are included in this updated review.
Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. As effect measures we used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RR) for response rates. Since not all trials reported PFS according to our definitions, we evaluated all similar outcomes (e.g. event-free survival) as PFS/tumour control.
Our search led to 5518 potentially relevant references. From these, we included seven RCTs in the analyses involving 2564 patients. In contrast to the first version of this review including five trials, we excluded trials randomising children. As a result, we excluded one trial from the former analyses and we identified three new trials.
Five trials with 1388 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with the same number of chemotherapy cycles in both arms. The addition of radiotherapy to chemotherapy has probably little or no difference on OS (HR 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, moderate- quality evidence), however two included trials had potential other high risk of bias due to a high number of patients not receiving planned radiotherapy. After excluding these trials in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved OS compared to chemotherapy alone (HR 0.31; 95% CI 0.19 to 0.52; P <0.00001, moderate- quality evidence). In contrast to chemotherapy alone the use of chemotherapy and radiotherapy improved PFS (HR 0.42; 95% CI 0.25 to 0.72; P = 0.001; moderate- quality evidence). Regarding infection- related mortality (RR 0.33; 95% CI 0.01 to 8.06; P = 0.5; low- quality evidence), second cancer- related mortality (RR 0.53; 95% CI 0.07 to 4.29; P = 0.55; low- quality evidence) and cardiac disease- related mortality (RR 2.94; 95% CI 0.31 to 27.55; P = 0.35; low- quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. For complete response rate (CRR) (RR 1.08; 95% CI 0.93 to 1.25; P = 0.33; low- quality evidence), there is also no evidence for a difference between treatment groups.
Two trials with 1176 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with different numbers of chemotherapy cycles in both arms. OS is reported in one trial only, the use of chemotherapy alone (more chemotherapy cycles) may improve OS compared to chemotherapy plus radiotherapy (HR 2.12; 95% CI 1.03 to 4.37; P = 0.04; low- quality evidence). This trial also had a potential other high risk of bias due to a high number of patients not receiving planned therapy. There is no evidence for a difference between chemotherapy alone and chemotherapy plus radiotherapy regarding PFS (HR 0.42; 95% CI 0.14 to 1.24; P = 0.12; low- quality evidence). After excluding the trial with patients not receiving the planned therapy in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved PFS compared to chemotherapy alone (HR 0.24; 95% CI 0.070 to 0.88; P = 0.03, based on one trial). For infection- related mortality (RR 6.90; 95% CI 0.36 to 132.34; P = 0.2; low- quality evidence), second cancer- related mortality (RR 2.22; 95% CI 0.7 to 7.03; P = 0.18; low- quality evidence) and cardiac disease-related mortality (RR 0.99; 95% CI 0.14 to 6.90; P = 0.99; low-quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. CRR rate was not reported.