Evidence Based Questions Flashcards
What are the two important studies that have proven a benefit for IFRT for favorable pediatric Hodgkin’s disease?
The CCG trial 5942 randomized children to receive low-dose, involved-field radiotherapy or no radiotherapy after they had obtained a complete response to initial risk-adapted chemotherapy. The 3-year EFS was 93% for those who received radiotherapy compared to 85% for those that did not, which was a statistically significant difference. The German GPOH-HD 95 trial was a prospective study of response-adapted radiotherapy. The children who had a complete response to chemotherapy did not receive radiotherapy and those who obtained a partial response underwent 20 to 35 Gy IFRT. The 3-year EFS was equivalent for the favorable patients that obtained a CR and PR. However, both the intermediate-risk and high-risk patients who had a CR and no IFRT had a worse EFS compared to the patients who achieved a PR and received IFRT.
Nachman, JB, Sposto, R, Herzog, P, et al. Children’s Cancer Group. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol. 2002;20:3765-3771.
Ruhl, U, Albrecht, M, Dieckmann, K, et al. Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys. 2001;51:1209-1218.
Which early studies evaluated CHT deintensification in low-risk pediatric Hodgkin’s disease?
ABVD and MOPP led to excellent cure rates (>90%); however, have significant associated toxicity. Initial trials focused on testing whether less-intensive CHT would lead to equivalent outcomes with improved toxicity. German HD-90 trial and French MDH-90 trial demonstrated excellent outcomes with CHT deintensification + ISRT.
Is it possible to omit RT in patients who have a complete response (CR) to CHT?
This question was evaluated in HD-95, POG 8625, and CCG 5942. HD-95 suggested that in pts who achieve CR after two cycles, RT can be omitted. However, POG 8625 showed that to omit RT, two additional cycles of CHT are required. When CHT is further de-escalated from MOPP/ABVD, CCG 5942 showed that RT cannot be omitted (trial closed early). Therefore, omitting RT in the setting of de-escalated CHT is not recommended.
Can RT be omitted in pts who have a rapid early response?
This question is being evaluated in the AHOD0431 trial, which has been completed but not yet published. Early results demonstrate that rapid response (defined as CR after three cycles of AV-PC) does not adequately predict for those pts in which RT can be safely omitted (however, negative PET/CT after cycle 1 was prognostic). Of note, AV-PC is also de-escalated CHT. The next step in low-risk trials will evaluate whether CHT intensification can help eliminate the need for RT.
Can RT be avoided in patients with CR after CHT?
Several trials have evaluated whether RT can be eliminated for pts who have a CR to induction CHT. HD-95 and CCG 5942 studies showed that IFRT improved EFS, but no difference in OS. TATA Memorial from India suggested that there was an OS benefit to IFRT after CR (caveat was that ~50% were AYA or adult HD). However, POG 8725 trial (STNI) and CCG 521 (EFRT), both of which utilized large RT volumes, did not show an EFS or OS benefit to RT. These trials together suggested that there may be pts in whom RT could be avoided without impacting oncologic outcome; however, it was unclear who those pts are.
Since it is not clear which patients require titration of CHT and/or RT, is it possible to utilize response-based criteria to determine which intermediate-risk patients require escalation versus de-escalation of treatment?
Early response has been shown in previous studies to be predictive of long-term outcome. Therefore, the AHOD0031 trial was initiated and demonstrated that rapid early responders (defined as CR after two cycles of ABVE-PC) who achieve a CR have no benefit from IFRT. However, all others on the trial received IFRT.
What is the current high-risk pediatric Hodgkin’s disease trial?
AHOD0831 (closed, results pending). A Non-Randomized Phase III Study of Response Adapted Therapy for the Treatment of Children With Newly Diagnosed High Risk Hodgkin Lymphoma. The goal of this trial is to maintain comparable OS (as defined by 4-year “second-event”-free survival) between pts with high-risk HL who have a rapid or slow response to the initial two courses of ABVE-PC CHT. Pts who have a rapid response will receive two additional cycles of ABVE-PC with risk-adapted IFRT (i.e., only site of initial bulk will be radiation). Pts with slow response will receive intensified CHT (ABVE-PC x2c + ifosfamide/vinorelbine x2c) followed by risk-adapted IFRT (PET+ sites and sites ≥2.5 cm will be radiated). IFRT is to 21 Gy/14 fx.
How are patients with relapsed or refractory disease managed?
Refractory disease is marked by failure to achieve CR or good PR with initial chemo (~6% overall). Salvage therapy in this setting may include high dose CHT +/− RT with response rates of 50% to 70%, followed by autologous SCT. However, 5-yr DFS is only ~20%. Relapsed disease is usually treated with high dose CHT (HDC) and ASCT. The most common HDC is CBV or BEAM. In general, autologous is preferred over allogeneic SCT due to toxicity and overall lack of graft versus lymphoma effect. An RR of 1,200 pts with HD who underwent transplant showed that treatment-related mortality was 65% for allogeneic transplant versus 12% for autologous transplant and the 4-yr OS was 25% versus 37%, respectively (p = .005).17 IFRT as part of salvage therapy has been shown to improve EFS and trend toward OS (especially in RT naïve pts) in several studies.
Whole Lung Irradiation: If treating lungs with RT, do RT after the transplant. Other than in the lung, consider RT prior to transplant (especially in the pelvis RT prior to transplant prevents additional bone marrow toxicity to the new graft). Stem cells for transplant should be harvested prior to RT. Transplant has similar outcomes with or without TBI. If RT has been utilized prior to BMT, salvage RT may also be utilized to doses of 15 to 25 Gy.
What is the risk for second malignancies in patients treated for Hodgkin’s lymphoma?
The recently published observational study out of Netherlands shows that the risk for second malignancies continues to increase even up to 40 years after treatment for Hodgkin’s lymphoma. The cumulative incidence of second cancers at 40 years was 48.5%. Compared to the general population, pts treated for Hodgkin’s lymphoma had a standardized incident ratio (SIR) of 4.6 for the development of second cancers (equivalent to 121.8 excess cancer diagnoses per 10,000 person years). The risk for secondary hematological malignancies was lower in the more recent treatment years due to reduction in utilization of alkylating agents. However, reduction in solid tumors was not lower in more recent years (supradiaphragmatic RT was associated with lower second malignancies compared to mantle field RT). One study by O’Brien showed that all pts who developed secondary leukemias (usually due to CHT) had a fatal course, whereas those pts who developed secondary solid tumors (usually due to RT) had a 5-yr OS of 85%.
