High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma

Hodgkin lymphoma (HL) is a malignancy of single lymph nodes, the lymphatic system, and might affect other additional organs. It is a relatively rare disease, accounting for two or three people per 100,000 every year in Western countries, but it is one of the most common cancers in young adults between 20 and 30 years of age. The second peak of the disease is after the age of 60 years. Treatment options for HL have improved since the 1980s, so that even patients in advanced stages may be cured with adequate therapy. Treatment approaches include chemotherapy, radiotherapy or chemotherapy combined with radiotherapy (combined-modality treatment), of which the combined-modality treatment is standard for most patients nowadays. Nevertheless, 15% to 20% of patients do not reach complete remission and have refractory disease or relapse. For these patients high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) has become the optimal treatment option. However, the impact of this regimen on overall survival is still unclear. Therefore, we conducted a Cochrane Review on efficacy and safety of HDCT followed by ASCT in patients with primary refractory or relapsed HL. We searched several important medical databases (the Cochrane Central Register of Controlled Trials and MEDLINE) and summarised and analysed evidence from randomised controlled trials (RCTs). We identified three RCTs corresponding to our pre-defined inclusion criteria treating 398 patients. We included two trials that compared HDCT followed by ASCT versus conventional chemotherapy alone, and one trial evaluating additional sequential HDCT (SHDCT) followed by ASCT against HDCT followed by ASCT.

Both trials assessing HDCT followed by ASCT versus conventional chemotherapy showed no significant improvement in overall survival, however progression-free survival was significantly improved with HDCT followed by ASCT. Only one trial reported adverse events and showed no difference between the treatment arms. The other trial was prematurely closed as patients refused randomisation and requested ASCT.

Only one trial evaluated the effect of SHDCT before HDCT plus ASCT, compared to HDCT plus ASCT. Overall survival and progression-free survival were similar in both arms. However, after three years, there was a negative trend for the SHDCT arm regarding mortality as well as significantly increased adverse events.

In summary, the currently available evidence suggests a benefit for patients with relapsed HL treated with HDCT followed by ASCT compared to conventional chemotherapy.

Authors' conclusions: 

The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect.

Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.

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Background: 

Hodgkin lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients, even in advanced stage. After first-line therapy, 15% to 20% do not respond to treatment and relapse. For those patients, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a frequently used therapy option.

Objectives: 

To find the best available treatment with HDCT followed by ASCT for patients with relapsed or refractory HL after first-line treatment.

Search strategy: 

We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, and relevant conference proceedings up to January 2013 for randomised controlled trials (RCTs). We also contacted experts for unpublished data.

Selection criteria: 

We included RCTs comparing HDCT followed by ASCT versus conventional chemotherapy without ASCT, or versus additional sequential HDCT (SHDCT) followed by ASCT. We also included RCTs with different HDCT regimens before ASCT in patients with relapsed or primary refractory HL after any first-line therapy.

Data collection and analysis: 

Two review authors (MR, NS) independently selected relevant studies, extracted data and assessed trial quality. We used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and we calculated risk ratios (RR) for the other outcomes. We presented all measures with 95% confidence intervals (CI).

We assessed the quality of evidence using GRADE methods.

Main results: 

Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses.

Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence).

For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients).

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