Patterns of Relapse From a Phase III Study of Response-based Therapy for Intermediate-risk Hodgkin Lymphoma (AHOD0031): A Report from the Children’s Oncology Group
Reporter: Annemarie Fernandes, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 28, 2012
Presenter: KV.V. Dharmarajan Presenter's Affiliation: Memorial Sloan Kettering Cancer Center
Hodgkin’s lymphoma constitutes about 6% of childhood cancers and is most common in children > 10 years.
With event-free survival rates of 85% and overall survival rates of 93%, efforts are underway to reduce the intensity of treatment for children with Hodgkin’s lymphoma.
AHOD0031 was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. Initial results presented at the American Society of Hematology 2010 indicated that patients with an early response to chemotherapy may not benefit from consolidative radiation therapy
The purpose of this study was to examine the patterns of first relapse for patients treated on the AHOD0031 protocol.
Materials and Methods
1712 patients were enrolled from 2002-2010, making this study one of the largest is COG history.
Inclusion criteria: Age <22 years, Stage I-IIA with bulk, Stage I-IIAE, I-IIB and IIIA-IVA with or without bulk
Patients were categorized as rapid early responders (RER) or slow early responders (SER) after 2 cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide) chemotherapy based on CT imaging.
SER patients were randomized to either 2 additional cycles of ABVE-PC or augmented chemotherapy (dexamethasone, etoposide, cisplatin and cytarabine (DECA) x 2 cycles followed by 2 cycles of ABVE-PC). All SER patients received 21 Gy involved-field radiation therapy (IFRT).
RER patients underwent 2 additional cycles of ABVE-PC. Patients who achieved complete response (CR) were then randomized to IFRT with 21 Gy vs. no further treatment. Patients without CR were non-randomly assigned to IFRT with 21 Gy
The median follow-up was 4 years
242 patients relapsed and 194 patients were analyzed in this review
31 patients progressed during treatment and were excluded from the analysis
17 patients did not have imaging of the relapse and were excluded from the analysis
Of the 194 patients with relapsed disease analyzed, 30% had RER without CR, 27% had SER, 26% had RER with CR and no further treatment, and 15% had RER with CR and IFRT
The most common sites of relapse were the mediastinum (63%), supraclavicular fossa (39%), and neck (32%). Below the diaphragm, para-aortic failures were the most common site of relapse. Lung was most common non-nodal site of relapse.
Relapses rarely occurred at new sites (6%) and usually occurred at initially involved sites:
74% of patients who relapsed had relapses in initially bulky sites
76% of patients who relapsed had relapses in nonbulky sites
Among the patients with RER with CR who did not receive IFRT and experienced relapse, 88% failed in non-bulky sites of disease and 81% failed in bulky sites of disease.
Among the patients with RER with CR who received IFRT and experienced relapse, 62% failed in non-bulky sites and 76% failed in bulky sites of disease.
Among the patients with RER without CR (all patient received IFRT) who experienced relapse, 76% failed in non-bulky sites and 59% failed in bulky sites of disease.
In patients who underwent radiation therapy, exclusively out-of-field relapses were relatively rare (11%).
The majority of relapses occurred at sites that were initially involved: either bulky or non-bulky. Failures at new sites and failures out-of-radiation field were rare, regardless of treatment.
Given the low number of out-of-field failures, the authors conclude that expanding the radiation field is unlikely to benefit patients.
Because patients failed in bulky and non-bulky sites of disease, radiation therapy should be targeted to all areas of disease, not just bulky disease
The authors present interesting pattern of failure data in patients with intermediate-risk Hodgkin Lymphoma receiving response-based treatment. The initial results of AHOD0031 presented at the American Society of Hematology 2010 indicated that patients with an early response to chemotherapy might not benefit from consolidative radiation therapy. This was based on data showing that IFRT following 4 cycles of ABVE-PC did not appreciably improve outcome for RER/CR patients: 3-year EFS was 87.9% (95% CI 83.3-91.4%) for patients randomized to receive IFRT vs. 85.4% (95% CI 80.8-89.0%) for those randomized to no IFRT (p = 0.07). Though the p-value of the 3-year EFS was not statistically significant, there was a trend to improvement with IFRT.
The patterns of failure data presented today indicate that the patients with RER who did not receive IFRT had higher rates of relapses (of the patients who experienced a relapse, 26% were RER with CR, no IFRT vs. 15% were RER with CR, treated with IMRT). Although this patterns of failure analysis was not powered to detect a statistically significant difference, in this population of patients, absolute failure rates in non-bulky and bulky sites were higher in patients who did not receive IFRT.
Failures were predominantly at sites of initial disease, and local control remains very important in this disease. Attempts to eliminate IFRT in this intermediate-risk population should be undertaken with caution.
With patterns of failure revealing predominantly local failure, dose escalation for select patients may be necessary to better control local disease. In the adult population, higher doses of radiation therapy are more commonly used. Doses of 20 Gy are only reserved for patients with early-stage, very favorable disease.
Having said this, late effects associated with radiation for Hodgkin’s disease are well-recognized, particularly for children. Reducing over-treatment remains important, and risk-adapted therapy should continue to be explored both with modification of radiation dose and volume.
The study demonstrated comparable rates of failures at non-bulky and bulky sites of disease. Bulky disease has been thought to be associated with a higher risk of failure, so it is interesting that patients seem to fail in non-bulky and bulky sites of disease with similar frequencies.
Longer follow-up data is necessary to determine the risk of eliminating IFRT in patients with CR to chemotherapy.
Exploration of newer treatment modalities, using technologies such as proton therapy and 4D CT imaging, may allow improved normal tissue sparing in the future, allowing radiation dose delivery with reduced side-effect profile.
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