To our knowledge, this is the first trial in which a select group of children with favorable risk Hodgkin lymphoma experienced a high rate of 2- and 5-year event-free survival without exposure to radiotherapy, alkylating agent, epipodophyllotoxin, or bleomycin chemotherapy and a relatively low cumulative dose of anthracyclines. The desire to avoid late treatment complications—particularly those resulting from high doses of irradiation—has motivated most treatment modifications for pediatric Hodgkin lymphoma. Early trials established the effectiveness of combined-modality therapy featuring multi-agent chemotherapy and lower cumulative doses of radiation to involved sites of disease.18–20
To avoid radiation complications altogether, chemotherapy-only trials were developed prescribing multiple courses of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) or derivatives.21–23
These regimens proved to be effective in achieving long term remissions.24–26
However, most trials featured high cumulative doses of alkylating agents, anthracyclines, or bleomycin leading to increased morbidity from myelosuppression, cardiopulmonary and gonadal toxicity, and secondary leukemia. As a result, contemporary combined-modality trials focus on balancing efficacy and toxicity of therapy. Investigators have also sought to identify patients with favorable features who would be candidates for therapy reductions. These efforts led to the evaluation of a response-based radiation approach, which was first undertaken in Stanford pediatric protocols prescribing lower doses of radiation to patients with good response to MOPP.27
This experience has shaped our consortium trials since.6;28;29
The Children’s Cancer Group study CCG594230
and the GPOH-HD954
study (confirmed in the GPOH-HD20025
study) pursued response-based trials in the mid 1990’s aimed to omit radiation. The GPOH trials had comparable outcomes for non-irradiated favorable risk patients who achieved complete response after 2 cycles of vincristine, procarbazine, prednisone, and doxorubicin (OPPA; for girls) or vincristine, etoposide, prednisone, and doxorubicin (OEPA; for boys), compared to those who achieved less than complete response and received radiotherapy. A marked event-free survival advantage with combined-modality therapy was only appreciated in intermediate and high risk groups, while overall survival remained comparable.4
In the CCG study, patients who achieved a complete response after all chemotherapy were randomized to 21 Gy IFRT or no additional treatment (eTable1
). There was a 3-year event-free survival advantage for the irradiated group (100% vs. 89%); however, survival in the two groups was identical (3-year overall survival 100%), raising the concern of the number of children needed irradiated to prevent one relapse. This is particularly pertinent in our study where patients developing relapse after chemotherapy-only were successfully retrieved with standard multi-agent chemotherapy and IFRT without high-dose chemotherapy or stem-cell transplant. As a result, more than 50% of patients on our study could be spared radiotherapy, and the majority could be cured without exposure to leukemogenic agents.
We previously reported the results using VAMP chemotherapy and low-dose IFRT.6;11
The 5-year event-free and overall survival for the entire cohort were 93% and 99%, respectively. Results of the current study are similar with a 5-year event-free and overall survival of 89% and 100%, respectively. In the present study, the 5-year event-free survival for patients with classical Hodgkin lymphoma was 89%, with no difference in outcome between those treated with and without radiotherapy (p=0.61).
Historically, patients with nodular lymphocyte predominant Hodgkin lymphoma have a favorable outcome and have been treated on regimens suitable for classical Hodgkin lymphoma; however, there are several reports in the adult and pediatric literature suggesting that such patients can be cured with less therapy. In adults, radiotherapy-only approaches are favored;31;32
however, the required doses of 30 to 36 Gy would result in significant musculoskeletal toxicity in children. Most children with nodular lymphocyte predominant Hodgkin lymphoma do well regardless of therapy chosen; toxicity remains the main concern for more involved treatment approaches.33–35
Remarkably, a substantial proportion of children with limited-stage, completely-resected nodular lymphocyte predominant Hodgkin lymphoma achieve long-term remission with surgical resection alone without additional therapy.37
In view of these results, the outcome for patients with nodular lymphocyte predominant Hodgkin lymphoma on our study who were treated without irradiation was disappointing. Twenty-six of 32 patients were early responders and thus treated without irradiation. Four of them (15%) relapsed, compared with no treatment failures in our prior experience with a combined-modality approach wherein all such patients were irradiated.6
In the current study, none of the ten patients with nodular lymphocyte predominant Hodgkin lymphoma who had undergone complete resection relapsed; thus, it is possible that many of them could have been spared chemotherapy altogether. In contrast, patients with stage II (and unresected) nodular lymphocyte predominant Hodgkin lymphoma who did not receive radiotherapy are at increased risk of relapse. Whether or not the omission of alkylating agents from the VAMP regimen can account for the less favorable result is speculative. However, it appears that even low dose irradiation may be beneficial for children with nodular lymphocyte predominant Hodgkin lymphoma who are treated with chemotherapy regimens that omit alkylating agents.
A limitation of this study is the relatively small sample size limiting the power to assess differences between study sites and limiting subgroup analyses. Thus, it would be important to confirm the results in a larger cohort. Our results suggest that a risk-adapted response-based approach may be very effective and well tolerated for a selected group of patients with favorable risk Hodgkin lymphoma. Such patients can achieve high 2-year event-free survival without alkylating agent, bleomycin, or epipodophyllotoxin chemotherapy, and more than half without radiotherapy. Future studies should consider further tailoring of radiotherapy reserving irradiation for patients who remain PET positive at early response evaluation.