The authors review the main evidence from the literature on neoadjuvant approaches in locally advanced rectal cancer, starting with the use of radiotherapy only in the pre–total mesorectal excision (TME) era, through fluorouracil(Drug information on fluorouracil) (5-FU)–based chemoradiation in the TME era, to the most modern administration of “targeted therapy” in association with radiotherapy and traditional chemotherapy.
This analysis focuses on the main paradox of the neoadjuvant approaches. On one hand, these strategies seem to offer an increasingly less important contribution to treatment. Whereas in the Swedish trial, preoperative radiation yielded a significant improvement of local control and survival, since the introduction of TME, the contribution of preoperative chemoradiation has been relegated to local control with minimal or no impact on survival (even if the absolute 5‑year survival rate has moved from 40% in the 1970s to 60%–65% in recent years).[1-3]
On the other hand, pathologic complete response (pCR) rates approaching 30% seem to identify a subset of patients with a more favorable prognosis associated with neoadjuvant treatments.[5-6] Furthermore, 30% to 35% of rectal cancer patients treated with multimodality therapy still die from cancer (ie, distant metastases) in spite of the 4% to 8% absolute benefit of 5-FU–based adjuvant chemotherapy. This seems to nullify ongoing efforts to optimize local treatments (surgery and radiotherapy) and improve delivery of chemotherapeutic agents.
New Study Landscape
To try to overcome this paradox, it may be time to design studies wherein resectable rectal cancer is considered as a heterogeneous disease within each stage group, with one-third of patients being those who die from distant metastases, receiving insufficient therapies, and two-thirds those who benefit from locoregional therapies alone, such as the combination of chemoradiation and surgery.[2,3] Within this latter group of patients can be recognized a subpopulation achieving a pCR after preoperative chemoradiation. A recent European joint analysis of 566 pCR patients treated with preoperative chemoradiotherapy demonstrated a 1.6% local recurrence rate, an 8.9% incidence of metastases, a 5-year cancer-related survival of 94%, and a 5-year disease-free survival of 85%.
The new landscape that we need to explore is one where we tailor treatment according to tumor behavior, which we should identify biologically or clinically. We need to overcome the tendency to treat all resectable locally advanced rectal cancers with the same neoadjuvant approach, by designing studies and generating data based on the modulation of treatments according to tumor behavior.
For example, we should explore different surgical options. Sphincter-saving surgery represents a debatable endpoint for neoadjuvant treatments in rectal cancer. Data that support the positive impact of neoadjuvant approaches in promoting sphincter preservation are scattered and not easily comparable due to differences in the evaluation of the distance between the tumor and the anus, the lack of declaration by the operating surgeon about the surgical approach required before the start of preoperative therapy, and inconsistencies in how surgeons behave with regard to sphincter-saving feasibility.
Sometimes sphincter function in patients submitted to low-anterior resection is poor, giving patients problems such as frequent evacuation, gas, and/or stool incontinence, with resultant limitations on social life. The possibility of preserving the sphincter and its function by performing a local excision in patients with a pCR after preoperative chemoradiation could offer a great advantage in terms of quality of life. Local excision would avoid impairing sphincter function and overcome the contradictory results on sphincter preservation that have been so highly debated in the literature.
But how many studies address the reliability of such an approach, which requires the modulation of surgery according to tumor response? Furthermore, how should we manage patients from the end of preoperative therapy to the time of surgery if they do not show a major response to neoadjuvant therapy at early evaluation?
We agree with the authors that researchers should be focused on clinically relevant endpoints, but they need to design studies that account for the heterogeneity of tumor behavior and to modulate the intensity of treatments according to data from biologic profiles, molecular images, and clinical observations. Rather than always designing studies that test the maximum tolerable treatment for all patients, in this time of tailored therapies, we need studies that test the minimum effective treatment for different subgroups.
—Vincenzo Valentini, MD
—Maria Antonietta Gambacorta, MD
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