Discussion
metabolic tumor, tumor, NLPHL, HL, toxicities, Cancer (EORTC)/The Lymphoma, PET-2-guided, CMT, nodular lymphocyte-predominant HL, Cancer
DISEASE, TUMOR, RECURRENCES, CANCER
This follow-up analysis of the GHSG HD16 trial confirms that RT cannot be omitted from the treatment of early-stage favorable HL after a negative PET-2 without a clinically relevant and statistically significant loss of efficacy. We could not observe any disadvantage of standard CMT over PET-2-guided treatment in terms of acute or late toxicities. OS remains on a high level and was - with the available follow-up - not impaired by the omission of RT, likely due to effective second-line therapies. We also could confirm PET-2-positivity as risk factor regarding PFS in patients receiving CMT, indicating the need for further improvement and innovative approaches in this group of patients.In the primary HD16 analysis [The fact that in the CMT group of the ITT population only two relapses more have been observed compared with the per-protocol population, and both patients dropped out of the per-protocol population because they refused RT, supports this result as well. Moreover, the majority of relapses after ABVD alone were within a theoretical IF-RT field, highlighting an important role of RT in local tumor control and preventing in-field relapses.Here, the question arises, how to improve the negative predictive value of PET-2 in order to allow for the omission of RT in selected patients. Novel tools such as circulating tumor DNA and metabolic tumor volume are currently under evaluation and might improve risk prediction in the future [Our results are in line with results from other randomized phase III trials such as the European Organisation for Research and Treatment of Cancer (EORTC)/The Lymphoma Study Association (LYSA)/Fondazione Italiana Linfomi (FIL) H10 and the UK National Cancer Research Institute (NCRI) RAPID studies [Even though PFS is significantly better in the standard CMT group compared to ABVD alone, OS continues to be very high in both groups – regardless of the higher rate of relapses for patients who did not receive RT. This can be attributed to the very effective second-line treatment options in HL. Most patients with relapse received HDCT and ASCT, which proves to be an effective treatment for relapse of HL, especially after initial early-stage disease [Of note, the findings from the present analysis comprising the whole study population of the HD16 trial and from the H10 and RAPID studies that only included individuals with classical HL also appear to hold true for patients with early-stage favorable nodular lymphocyte-predominant HL (NLPHL). A recent subgroup analysis of the patients with NLPHL treated within the HD16 study indicated that individuals presenting with this rare HL subtype also require consolidation RT irrespective of the PET-2 results to achieve the optimal disease control [Importantly, there are not more SPM in the CMT group and therefore, late toxicities caused by RT seem to play a much smaller role than initially predicted – limited by the fact that the follow-up still is rather short and that SPM might occur 20 to 30 years after CMT. This is of great importance since late toxicities caused by RT have contributed to the decline in OS of HL patients in the past [With prolonged follow-up, PFS rates continue to be significantly higher for PET-2-negative patients. Even years after end of CMT, there are still more recurrences in patients with a positive PET-2, which are mostly located outside of the radiation field. Thus, improving response rates and importantly PFS in these patients could be achieved by intensifying chemotherapy instead of intensifying or modifying RT. This approach has been investigated in the EORTC H10 trial and showed promising results when intensifying chemotherapy to two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in case of PET-positivity after two cycles of ABVD [Some of the inherent limitations of HD16 have been addressed already in the initial publication [In conclusion, this follow-up analysis of the GHSG HD16 trial confirms that RT cannot be omitted from treatment of early-stage favorable HL in case of a negative PET-2 without a significant and clinically relevant loss in efficacy. Accordingly, CMT remains standard treatment for early-stage HL patients. Since PET-2 positivity (≥DS 4) has a relevant negative impact on PFS, innovative treatment strategies are needed to improve outcomes after first-line treatment in these patients.