Randomized Comparison of Low-Dose Involved-Field Radiotherapy and No Radiotherapy for Children with Hodgkin's Disease Who Achieve a Complete Response to Chemotherapy

Authors: Nachman JB, Sposto R, Herzog P, Gilchrist GS, Wolden SL, Thomson J, Kadin ME, Pattengale P, Davis PC, Hutchinson RJ, White K; Children's Cancer Group.
Source:J Clin Oncol. 2002 Sep 15;20(18):3765-71

Background

Standard therapy for pediatric Hodgkin's disease is combined modality treatment, typically COPP/ABVD chemotherapy with 25 Gy of involved-field radiation therapy (IF-RT). Long-term survival results with this therapy are 95% in early stage and 85% in advanced stage disease. Given this excellent outcome, the focus has become how to reduce treatment-related toxicity, specifically late effects of chemotherapy and radiation. This study was started in 1995 by the Children's Cancer Group to investigate whether the superior event-free and overall survival data produced with combined modality regimens could still be achieved with chemotherapy alone in patients who showed complete response to chemotherapy.

Methods

• Pts < 21 years old with newly diagnosed Hodgkin's disease were enrolled between 1/95 and 12/98.
• Clinical staging only
• Classified by presence or absence of "B" symptoms (weight loss, fever, night sweats) and "adverse risk factors" as defined by investigators (hilar adenopathy, nodal aggregate with diameter greater than 10 cm, etc)
• Three different treatment groups defined based on above classification criteria
• Group 1 received COPP/ABV hybrid chemotherapy x 4 cycles every 28 days
• Group 2 received COPP/ABV hybrid chemotherapy x 6 cycles every 28 days
• Group 3 received intensive multidrug chemotherapy (COPP/ABV, cytarabine, etoposide) x 2 cycles every 63 days
• Patients with complete response to chemotherapy (including incomplete radiologic responses but at least 70% reduction in volume) randomized to low dose IF-RT vs. no RT
• Low-dose IF-RT given 3 weeks after completing chemotherapy, 21 Gy = 12 fractions of 1.75 Gy each
• If Stage IV disease with pulmonary disease, additional 10.5 Gy given to lungs
• Primary endpoint of event-free survival (EFS)
• Secondary endpoint of overall survival (OS) and post-relapse survival
• Accrual goal = 650 pts for 83% power to detect ~6% reduction in EFS at minimum 1 year of follow-up
• Primary analysis was intent-to-treat, but data also presented for treatment-received
• Randomization stopped prematurely secondary to increased number of relapses on no-RT arm

Results

• 834 enrolled, 5 ineligible
• 501 randomized: 251 got RT and 250 no RT

Entire cohort

• 83% complete response
• 3-yr EFS = 87%
• 3-yr OS = 95%

Randomized Group

• 3-yr EFS = 92% in RT arm vs. 87% in no RT arm (p=.057)
• 3-yr OS = 98% in RT arm vs. 99% in no RT arm (p=0.90)

• * No significant difference between intent-to-treat and as-treated analyses
• *Of note, 30 of the 501 randomized pts switched arms
• • 23 moved from RT to no RT arm, and 5 of these 23 relapsed
  • 7 moved from no RT to RT arm, and none of these relapsed
• Median time to relapse in no RT arm = 6 mos, with most relapses occurring in sites of previously known disease
• Median time to relapse in RT arm = 14 mos
• Acute toxicity generally chemo-related, with higher rates of infectious and GI complications in group 3 pts (more intense chemo) vs. groups 1 and 2

Author's Conclusions

• Better EFS with chemotherapy + low-dose involved-field RT compared to chemotherapy alone in pediatric Hodgkins' disease
• No OS difference seen yet between RT vs. no RT arms, as authors admit follow-up is not long enough
• Although OS is often considered the ultimate goal, the value of EFS should not be neglected. Salvage therapy for relapsed disease is not benign and has a significant effect on quality of life as well as risk of late effects. Preventing a relapse in the first place, ie: improving event-free survival is thus a very significant endpoint.
• Modern radiation techniques with low-dose involved fields have decreased treatment-related toxicity compared to standard dose RT.
• While late effects and toxicity of chemotherapy are certainly of concern, the use of hybrid regimens has allowed reduction in total exposure to any one single agent, thereby reducing associated single-agent toxicity, all while sustaining efficacy.
• Although results of this trial clearly demonstrate a role for radiation in the management of these patients, the authors still suggest the possible existence of a subset of these patients whose likelihood of microscopic residual disease following chemotherapy is low enough to justify exclusion of radiation therapy, ie: risks outweigh any potential benefit.
• For now, however, combined modality therapy remains the standard of care.