cetuximab and panitumumab which target EGFR have no adjuvant role even in RAS/RAF wild‐type colon cancer. There was considerable enthusiasm for the poly‐ADP ribose polymerase (PARP) inhibitor veliparib as a radiosensitizer, but unfortunately this was not confirmed by the NRG‐GI002 phase II trial [63].
Immunotherapeutics
The past few decades have witnessed unprecedented advances in the field of cancer immunology. The focus of systemic therapy is developing novel strategies to enhance the ineffective antitumor response of the immune system. Immunotherapy with checkpoint blockade (mainly programed cell death protein 1 [PD‐1]) has had limited efficacy in the vast majority of patients with metastatic colorectal cancer. Durable responses have predominantly been observed in patients with microsatellite instability‐high (MSI‐H) colorectal cancer [64]. The high mutational burden of microsatellite instability (MSI) tumors is thought to provoke a strong intratumoral T‐cell response, which can be further enhanced with anti‐PD‐1 therapy. Pembrolizumab is now accepted as a first‐line standard of care for MSI‐H stage IV colon cancer based on the KEYNOTE‐177 study [65]. There is concern that over one‐third of MSI‐H patients experience rapid disease progression on immunotherapy even though there is a large sustained survival benefit in the majority. RAS mutations and left‐sided tumor origin had less benefit from immunotherapy, but BRAF mutations did not appear to detract from efficacy. Future characterization of blood and tumoral biomarkers may enable precise selection of patients likely to respond to monotherapy and those who require alternative approaches, potentially facilitating the integration of immunotherapy into the neoadjuvant treatment paradigm. There have been some early reports of dramatic responses to neoadjuvant immunotherapy in MSI‐H rectal cancer [66]. While 10–15% of all colon cancer is MSI‐H, only 3–5% of rectal cancer is. The holy grail of colon cancer research is a means by which to enable immunotherapy to benefit patients with microsatellite stable (MSS) disease. Can radiotherapy render MSS rectal cancer vulnerable to immunotherapy? The upregulation of programed cell death‐ligand 1 (PD‐L1) in rectal cancer post‐radiotherapy may be associated with improved outcomes [67, 68]. Several early phase trials are exploring the PD‐L1 antagonists avelumab (AVANA) and atezolizumab (R‐IMMUNE) in combination with preoperative chemoradiotherapy [69–71]. Other studies such as PEMREC combine pembrolizumab with short‐course radiation therapy [72]. In stage III non‐small cell lung cancer, durvalumab is used following definitive chemoradiation based on the PACIFIC trial [73]. Similar approaches in rectal cancer such as the Dutch TARZAN trial (short‐course radiation therapy followed by atezolizumab and bevacizumab) and the Chinese CHINOREC trial (nCRT followed by ipilimumab and nivolumab) are underway. There is no role for immunotherapy in MSS disease outside of clinical trials.
Locally Recurrent Rectal Cancer
The incidence of locally recurrent rectal cancer (LRRC) remains approximately 5%. A negative resection margin, the most important predictor of outcome, may be difficult to achieve due to the anatomical location, involvement of surrounding structures, and the challenges of prior surgery. As a result, upfront chemoradiotherapy may downstage tumors and improve resectability. In patients who have received radiotherapy for treatment of their primary tumor, reirradiation options are limited. Induction chemotherapy has been proposed as a potential means of improving tumor downstaging and clear margin rates. Moreover, it may eradicate occult micrometastases. Development of metastatic disease is common following local recurrence and represents the leading cause of cancer‐related death following successful treatment of local recurrence. Preliminary results of a cohort study in the Netherlands demonstrated R0 and pCR rates of 55 and 17% respectively with induction chemotherapy compared to 49 and 4% with CRT alone (p = 0.506 and p = 0.015 respectively) [57, 74]. Among the induction chemotherapy group, achieving a pCR was strongly associated with improved three‐year DFS (both local recurrence and distant metastases). Two European prospective randomized trials, the French GRECCAR15 and the Dutch PelvEx2 Induction Chemotherapy Trial, aim to determine the optimum preoperative management for LRRC (NCT03879109, Dutch Cancer Society no. 12960/2020–1). GRECCAR15 is comparing induction FOLFIRINOX (six cycles) followed by CRT (30.2 Gy with capecitabine) to induction FOLFIRINOX alone. The primary outcome of interest is the R0 resection rate.
Future Developments
Long‐term outcome data following induction or consolidation chemotherapy are lacking, and whether the total neoadjuvant approach can improve survival remains to be elucidated. Several prospective randomized trials are currently ongoing to evaluate long‐term disease‐specific outcomes, including the PROSPECT and TNTCRT trials [75]. The awaited North American PROSPECT trial will show us if some high‐risk patients who respond well to induction FOLFOX can omit neoadjuvant radiotherapy. GRECCAR12 (lower‐risk patients) is still recruiting and builds on GRECCAR2 comparing neoadjuvant FOLFIRINOX followed by CRT to CRT alone [76, 77]. In both arms, good responders will have local excision of the primary to avoid major surgery. Similarly, the Chinese TNTCRT trial is designed to assess whether induction and consolidation CAPOX, nCRT, and TME improves DFS compared with standard nCRT and TME with adjuvant chemotherapy (NCT03177382). Circulating tumor DNA (ctDNA) is under investigation to guide adjuvant chemotherapy in stage II colon cancer [78, 79]. The DESTINY‐CRC01 trial proved that a drug–antibody conjugate (trastuzumab deruxtecan to target the HER2 receptor) is active against metastatic colon cancer that appropriately express the molecular target [80]. A deeper understanding of radiobiology may lead to molecularly targeted radio‐sensitizing agents [81, 82]. It may become possible to use immunotherapy in MSS LARC.
Summary Box
Early delivery of high-dose systemic chemotherapy represents a promising treatment strategy for both LARC and LRRC.
Favorable short-term outcomes include improved chemotherapy compliance and superior pathological response.
Long-term survival data are limited and interpretation is hampered by marked heterogeneity among neoadjuvant/adjuvant treatment regimes.
Prospective randomized trials will determine whether this approach can improve distant disease control and quality of life, and increase the proportion of patients suitable for non-operative management.
With increasing emphasis on personalized care, the future of rectal cancer management should include risk-adapted strategies incorporating the biomolecular and radiological profile of the tumor.
References
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