Role of COnsolidative RADiotherapy in bulky and/or extra-nodal DLBCL (CORAD-DLBCL) with complete metabolic response (CMR) after R-CHOP regimen: A Randomized Controlled Trial

Diffuse large B cell lymphoma (DLBCL) consists of 60-70% of Non-Hodgkin’s Lymphoma (NHL) patients in India (Nair R et al, Oncology 2016). Immuno-chemotherapy incorporating Rituximab, Cyclophosphamide, Doxorubicin, vincristine and Prednisolone (R-CHOP) is the current standard regimen for treatment of DLBCL. A proportion of DLBCL patients present with relapse after successful treatment, and a multitude of factors have been associated with the same. PET CT-based response assessment using a 5-point Deauville’s score is one predictive factor, with clinical implication.

Presence of bulky lymph nodes (defined as >5 cm to >10 cm in different studies) and extranodal disease at presentation is another risk factor for relapse. Use of local radiotherapy (RT), to the site of bulky or extranodal disease, is practiced by multiple groups across the world, to abrogate this risk. However, there is concern about potential acute and especially long-term toxicities of RT, due to expected long-term survivorship of these patients. Thus, a fine balance between the potential benefit and risk is crucial.

The evidence so far, to guide clinicians about the need of RT in DLBCL is very sparse. There were randomized studies in the pre-Rituximab and/or pre-PET era comparing chemotherapy alone (CT) versus combination of CT and RT; which showed superiority of combined regimen (namely the analysis of National Cancer Database (NCDB), SWOG 8736, the ECOG 1484, the GELA LNH 93-1 and 93-4 study). In addition to the issues with design and patient characteristics, the applicability of those studies in the present era is questionable.

Retrospective studies in the Rituximab and PET era showed benefit in PFS with consolidative RT. Possibility of inherent bias, lack of details about the RT portals and toxicities limit adopting those results in current clinical practice. The prospective studies include the RCT by Aviles et al. (Precis. Radiat. Oncol. 2019) showing benefit in OS in the RT arm (flaws being non-usage of PET CT for response assessment and use of 14-day cycles of R-CHOP), the comparison of RICOVER and RICOVER NoRTh groups by Held et al (JCO 2013) showing benefit in EFS with consolidative RT (however was not used as a response assessment tool and patients included partial responders also).

The UNFOLDER study (published in abstract form) had randomized patients after R-CHOP to RT versus observation; and reported significant benefit in EFS with RT; leading to closure of the RT arm. However, 11% of patients in this study had partial response to immuno-chemotherapy, which makes applicability of the results to patients having CMR quite challenging. The OPTIMAL-60 study (Am. Soc. Clin. Oncol. 2017) concluded no detriment in outcomes, if RT was omitted in elderly poor-risk patients.

There are prospective single arm studies attempting a PET based omission of RT mainly from the British Columbia group (Sehn et al, Blood 2019, Freeman et al, Blood 2021) where there were excellent outcomes in patients observed after CMR. The FLYER trial (ref) also showed non-inferiority of lesser cycles of R-CHOP in favorable risk patients and none of the patients received consolidative RT.

Gaps in the evidence:

1. When a patient with bulky or extranodal disease at presentation obtains CMR after 6 cycles of R-CHOP, does consolidative RT to the bulky site improve outcomes?
2. Sites of RT used differ across studies; some using IFRT to only the bulky site while others irradiated all sites irrespective of baseline extent of disease. The latter is often technically and practically (higher anticipated toxicities) challenging. Whether benefits of consolidative RT only to the baseline bulky disease adds benefit, is yet to be defined.

To address the above lacunae in scientific evidence, in the specified patient population, we are planning this RCT.