Still a double standard evaluation

James Fleck & Isabel Goulart: Anticancerweb 12(04), 2019

In locally advanced rectal cancer (LARC), when anterior abdominal resection is no longer feasible, particularly in the mid and lower rectal anatomic segments, standard treatment has been based on total neoadjuvant therapy (TNT) followed by total mesorectal excision (TME) hopefully improving locoregional control. Despite the aggressiveness of the treatment and subsequent impairment in quality of life, this radical intervention still coexist with a third of metastatic progression. Interestingly enough, recent studies using TNT have shown a 30% complete clinical response (cCR), which could represent a suitable subgroup of patients for LARC conservative treatment. However, there are no uniform and reliable criteria for defining cCR and it has been difficult to design a prospective trial testing unpaired arms.

In 2015, the Rectal Cancer Consortium led by the Memorial Sloan Kettering Cancer Center (MSKCC) published in BMC Cancer the design of a LARC randomized phase II trial testing two strategies often used in TNT timing: In arm 1 called induction, patients would be treated with chemotherapy (CT) followed by chemoradiotherapy (CRT), while in arm 2 called consolidation, patients would receive prior CRT and subsequently CT would be administered. Previous studies have pointed out for a potential advantage of TNT consolidation strategy. Both arms, would use the same CT regimen (FOLFOX / CAPEOX). In both arms, after TNT, patients should be evaluated with RDE, endoscopy and MRI. Patients reaching a cCR would be followed up and those expressing residual disease would be treated with TME. Progression-free survival at 3 years (SLP3) was chosen as the primary endpoint. The study will compare SLP3 in two LARC different subgroup of patients: Patients in cCR after TNT versus patients without cCR after TNT and subsequently undergoing TME. The uneven composition of the arms of the study illustrates the methodological difficulty in assessing conservative LARC treatment.

In 2019, the MSKCC publishes in JAMA Oncology a retrospective analysis comparing the outcomes of two subgroups of LARC patients: A subgroup composed of patients who achieved cCR after neoadjuvant treatment and agreed with a watch & wait (WW) strategy and another subgroup of patients who showed complete pathological remission (pCR) after TME. As it was expected in a retrospective evaluation there was no demographic pairing. The WW subgroup included older patients (p <0.001) and tumors closer to the anal verge (p = 0.003), revealing a selection bias. In addition, there was a significant difference in the neoadjuvant treatment, with a predominance of the CRT in patients submitted to TME (p <0.01). Outcomes assessed after a median follow-up of 43 months are seen in the table. About 21% of the patients in the WW subgroup presented local recurrence, 91% were subjected to salvage surgery. Organ preservation was possible in 82% of the WW population. Given double standard evaluation, rectal preservation treatment showed a worsening in survival, especially due to the higher rate of metastatic spread in WW patients who presented local recurrence.

OS = Overall Survival, DFS = Disease-Free Survival, SDS = Specific Disease Survival, WW = Watch & Wait, TME = Total Mesorectal Excision, cCR= Clinical Complete Response, pCR = Pathological Complete Response, LR = Local Relapse

Selection biases do not allow definitive conclusions. In the retrospective study led by the MSKCC, both LARC subgroup (WW and TME) were composed by stage II and III rectal cancer patients. Data provided by US Surveillance, Epidemiology and End Results (SEER) updated in 2017 pointed out for a 71% 5-year overall survival expectancy for regional colorectal cancer, which does not differ from the 73% OS observed in the WW subgroup. The observed 94% OS with TME is justified by a selection bias, since it was only observed in LARC patients which have reached the desired complete pathological response. Maturate results to be obtained in the Rectal Cancer Consortium hopefully will improve the selection of patients for rectal conservative treatment. In a near future, molecular markers may be predictive for pCR. Beyond CEA, preliminary studies with KRAS mutation or KRAS/TP53 combined mutation, EGFR-positivity, ctDNA, micro-RNA (miRNA) signatures, and circulating tumor cells evaluation already point out to promising results.

References:

J. Joshua Smith, Oliver S. Chow, Marc J. Gollub, et al: Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management, BMC Cancer15:767, 2015

J. Joshua Smith, Paul Strombom, Oliver S. Chow, et al: Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients with a Complete Response After Neoadjuvant Therapy, JAMA Oncol, Jan 10, 2019

Mehmet Akce and Bassel F. El-Rayes: Nonsurgical Management of Rectal Cancer, J Oncol Pract15:123-131, 2019