Rectal Sparing Approach After Preoperative Radio and/or Chemotherapy in Patients With Rectal Cancer

The proposed study is an observational, prospective, multicenter study of patients undergoing neoadjuvant therapy for medium-low rectal cancer. Recently the investigators have published the findings of a multicenter Italian phase II study showing that the rate of local recurrence, with a 3 year follow-up, is less than 5% in patients with baseline T2-3 mid-low rectal cancer who, after preoperative chemoradiotherapy (pCRT), showed a major clinical response and underwent a transanal local excision. Based on these results, an organ-sparing approach for patients showing a major clinical response is feasible without reducing the good results obtained with the standard treatment. While a phase III trial is the best way to compare the standard treatment with the organ-sparing approach (local excision or wait-and-see) it is impracticable and likely unethical. An observational study is therefore one of the best way to evaluate the impact that an organ-sparing approach may have on oncological outcomes, quality of life, and bowel function for patients with rectal cancer who, after a pCRT, show a clinical major/complete response. This phase II trial is designed to test the hypothesis that conservative treatments, in patients with low-mid rectal cancer who undergo a major or complete clinical response after neoadjuvant treatment, will be safe and effective compared to standard surgery. The investigators will compare rectum-sparing approaches to standard surgery, firstly in terms of rate of organ preservation at 2 years. Additionally they will compare survival outcomes (DFS, OS), stoma rates, clinical and tumor factors related to pathological complete response, correlation between major and complete clinical response. To add value, the investigators will measure QoL in patients treated with rectum-sparing approaches in comparison to patients treated with standard surgery (TME or abdomino-perineal amputation). Rectum-sparing approach can be considered clinically acceptable if percentage of conservation of the rectum at two years is not less than 50%. The collected data on 164 patients who underwent "rectum-sparing" allow to test the hypothesis that the rectum is preserved in 60% of patients with 80% power (exact binomial test for proportions, alpha = 5 %, 1 tail) and the study will be considered positive if it obtains a frequency of conservation of the rectum of not less than 87 cases. The analysis results will be reported in accordance with STROBE guidelines (von Elm et al., 2008). For all analyzes, continuous variables are described using the mean and standard deviation of position and appropriate measures when appropriate. Categorical variables will be described using the contingency tables.

Sex

All

Minimum age

18 Years

All patients underwent neoadjuvant therapy for rectal cancer will be registered provided that they satisfy the following requirements:

1. histologically documented adenocarcinoma of the rectum;
2. Up to 12 cm from the anal verge to rectoscopy;
3. Minimum age 18 years old;
4. Able to undergo both neoadjuvant treatment, TME than conservative treatment;
5. For which RT and/or CT fluoropyrimidine ± oxaliplatin or biologic drugs regimens are expected;
6. Able to understand risks and benefits of the protocol.

Criteria for inclusion in the rectum-sparing group (study group):

Of patients registered, they will be eligible for the study rectum-sparing those who have all of the following requirements:

1. Major or complete clinical response at restaging after 7-8 weeks from the end of neoadjuvant therapy, confirmed at second restaging (after 11-12 weeks from the end of neoadjuvant therapy);
2. Written informed consent (after 2nd restaging). Note: They will be subject to wait-and-see approach only patients with cCR.

Criteria of esclusion from protocol:

At restaging after 7-8 weeks and/or after 11-12 weeks, patients who show one of the following characteristics:

1. palpable mass on digital rectal examination;
2. deep ulcer with surface \> 2 cm in diameter or obvious signs of endoscopic residual disease;
3. presence of metastatic lymph nodes at MRI (\> 5 mm along short axis).

Inclusion criteria to be included to EL or wait- and-see approach:

1. Patients with mCR or cCR at restaging performed after 11-12 weeks after the end of radiotherapy;
2. Ability to understand the protocol;
3. Acquisition of written informed consent.

Inclusion and exclusion criteria to be observed (just follow-up) after LE:

The LE local will be considered as proper treatment if histological assessment will document:

1. ypT0 (cCR);
2. ypT1 but with a TRG degree \< 3 and with a differentiation degree of G1-2;
3. histologically margins not involved.

LE will be considered as excessive handling and patients will be advised to undergo TME if histological assessment will document the presence of cancer with at least one of the following characteristics:

1. ypT ≥ 2;
2. Positive margins;
3. TRG ≥ 3;
4. Poor differentiation degree (G3).

Indications to wait-and-see approach This approach, that consists only in observation after neoadjuvant therapy, is reserved only to those patients who show cCR at restaging, as defined previously.

• DERIVEDBarina A, De Paoli A, Delrio P, Guerrieri M, Muratore A, Bianco F, Vespa D, Asteria C, Morpurgo E, Restivo A, Coco C, Pace U, Belluco C, Aschele C, Lonardi S, Valentini V, Mantello G, Maretto I, Del Bianco P, Perin A, Pucciarelli S. Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study. Tech Coloproctol. 2017 Aug;21(8):633-640. doi: 10.1007/s10151-017-1665-1. Epub 2017 Jul 28. PMID 28755256