It has the potential to change the treatment paradigm for many patients with rectal cancer

This study represents an attempt to investigate, in a multi-institutional setting, the feasibility of rectal preservation in a number of LARC patients who develop a cCR after a novel neoadjuvant therapy protocol. The study design is innovative because it compares 3-year DFS in a group of LARC patients treated according to a protocol incorporating TNT and NOM, to a similar group of historical controls treated according to the standard CRT, TME and ACT protocol. The studies published thus far on the safety of NOM in LARC patients have compared the survival of a selected group of patients with a cCR and NOM, to a selected group of patients with a pCR after TME. While these reports provide an estimate of the safety of NOM, they do not provide accurate information on the impact of selective use of NOM on outcomes in the entire LARC population. Our study will be the first to determine the proportion of patients with LARC who will be candidates for NOM, and the impact of NOM on 3-year DFS in the entire LARC population.

There is now conclusive evidence that tumor response to chemotherapy and radiation requires time, and that some tumors achieve a maximal response only after several months. However, in the studies on NOM published to date, tumor response was assessed a few weeks after completing the standard neoadjuvant protocol. It is possible that many patients who were considered non-responders early on, and were therefore not offered NOM, might actually have been complete responders given a longer observation period. In our study, assessment of tumor response is done only after all neoadjuvant treatment is delivered. In patients completing the entire treatment, final assessment of tumor response-and the decision between NOM and TME-will be done approximately 32 weeks after initiation of therapy.

Therefore, as in patients with stage III colon cancer, current guidelines recommend postoperative chemotherapy for patients with LARC

In the past, LR, likely secondary to inadequate surgery, was the most common form of relapse in patients with LARC. Advances in imaging, surgical technique, and adjuvant therapy have reduced the risk of LR dramatically. Nowadays patients with seemingly localized LARC who die of disease after undergoing treatment with curative intent, succumb to DM (which probably develops from occult micrometastasis present at the time of treatment of the primary tumor). While chemotherapy seems to improve survival compared to no chemotherapy, it is not as effective as would be desired. Although this may be due, in part, to the fact that the agents used are not effective against every single cancer, it is also the case that many rectal cancer patients never start chemotherapy after surgery, and less than half complete the entire treatment [5,18]. In light of our previous experience with neoadjuvant therapy, in this study we will deliver all systemic chemotherapy before assessing tumor response. Delivering systemic chemotherapy in the neoadjuvant setting will not only improve compliance and address the problem of micrometastasis earlier, compared to the standard treatment algorithm of CRT, TME and ACT; it may also contribute to enhanced tumor response. As a result of lengthening the treatment time by administering NACT, this study will provide a closer estimate of the proportion of patients with LARC who will respond to chemotherapy and radiation, and thus be eligible for NOM.

We think this will provide sufficient time for tumor response

There are some potential advantages to using NACT before or after CRT. Delivering NACT before CRT has the advantage of treating occult micrometastasis earlier. As the patients will be treatment naive, compliance with systemic CT may be higher. However, NACT-related toxicity may potentially reduce compliance with CRT. On the other hand, starting treatment with CRT delays delivery of the full dose of systemic chemotherapy used to treat micrometastatic disease, and this may reduce compliance with NACT. An important question is which treatment arm will demonstrate greater tumor response. The results of the TIMING trial compared to the other studies suggest that pCR rates are higher with CRT and CNCT compared to INCT and CRT (see recent work in The Lancet Oncology: PMID: 26187751). The differences between CRT and CNCT versus INCT and CRT may be due to patient selection or delay in the time to aplicaciones de citas para adultos ios assessment of response, rather than treatment effect . However, in patients with squamous cell carcinomas (of various locations) undergoing neoadjuvant therapy, there is evidence that longer duration of treatment, measured from the first day of any therapy to the last day of radiation, is associated with increased local failure and/or decreased survival . In anal cancer patients, overall treatment time, but not radiotherapy time, is associated with a high rate of local failure, suggesting that induction chemotherapy may contribute to local failure by increasing the total treatment time . Our study will test this hypothesis to assess whether the same phenomenon occurs in adenocarcinomas.