Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial

Abstract

Summary Background Local excision is an organ-preserving treatment alternative for patients with stage I rectal cancer. However, local excision alone is associated with a high risk of local recurrence and inferior survival compared to transabdominal rectal resection. Here we investigate the oncologic and functional outcomes of neoadjuvant chemoradiotherapy and local excision for T2N0 rectal cancer. Methods This was a prospective, multi-institutional, single arm phase 2 trial for patients with clinically-staged T2N0 distal rectal cancer, treated with neoadjuvant chemoradiotherapy consisting of capecitabine (original dose 825mg/m2, twice daily, on days 1-14 and 22-35) , oxaliplatin (50mg/m2 weeks 1, 2, 4, 5), and radiation (5 days/week at 1.8 Gy/day for 5 weeks to a dose of 45 Gy, then a boost, for a total dose of 54 Gy) followed by local excision. Due to adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg /m2, twice daily, 5 days/week, for 5 weeks, and the total dose of radiation to 50.4 Gy. Patients were followed at scheduled intervals and evaluated for recurrence and survival. Anorectal function (ARF) and quality of life (QOL) were assessed at baseline and one year after surgery, using validated instruments. The primary endpoint was 3-year disease-free survival for all eligible patients and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumors, and negative resection margins. This trial is registered with ClinicalTrials.gov, number NCT00114231. Findings Seventy-nine eligible patients were accrued to the trial, and started nCRT. Three patients did not complete nCRT or LE per-protocol. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Median follow-up was 56 months. Of the 79 patients, five (6%) developed distant recurrence, and three (4%) recurred locally. All but two underwent salvage surgery. Three-year disease-free survival and overall survival for the entire group were 88% (0.88 (95% CI: 0.81, 0.96) and 95% (95% CI: 0.90, 1.00), respectively. Overall 14 (29%) of 79 patients had grade 3-4 gastrointestinal adverse events, 12 (16%) of 79 patients had grade 3-4 pain as an adverse event, 12 (16%) of 79 patients had grade 3-4 hematological adverse events, and 9 (11%) of 79 patients had grade 3 dermatologic adverse events during chemoradiation. Six (8%) of the 77 patients who had surgery had grade 3 pain, 3(4%) of 77 patients had grade 3-4 hemorrhage, 3 (4%) of 77 patients had gastrointestinal adverse events, 2 (3%) of 77 patients had infectious/febrile neutropenia, 2 (3%) of 77 patients had hematological adverse events, and one (1%) had neurological adverse events. The rectum was preserved in 72 of the 79 (91%) patients. ARF and QOL were unchanged one year after surgery compared to baseline. Interpretation Most patients with T2N0 rectal cancer treated with nCRT and LE achieved organ preservation without deterioration of their quality of life. The estimated 3-year DFS rate wa...

Organ Saving Treatment of Rectal Cancer

“…Если прини-мать во внимание тот факт, что вероятность полного клини ческого ответа при «раннем» раке существенно выше, чем при стадиях Т3-4, применение подобного подхода может быть обосновано у данных пациентов на этапе первичной диагностики. Подтверждением тому являются данные исследований CARTS [23], ACOSOG Z6041 [24], в которые включали пациентов с раком прямой кишки стадий Т1-Т3а-bN0 в пре делах 10 см от ануса. Пациентам проводили пролонгирован-ную ХЛТ с оценкой эффекта лечения через 8-12 нед и локальным иссечением с применением трансанальной эндомикрохирургии остаточной опухоли у пациентов с хорошим клиническим ответом.…”

“…Необходимость до-полнительного лечения определяли по результату пато-морфологического заключения. По результатам иссле-дований CARTS, ACOSOG Z6041 органосохраняющее лечение удалось выполнить у 55 и 66 % больных соот-ветственно [23,24].…”

Complete Clinical Response in Rectal Adenocarcinoma: Review of Treatment Options

“…The multi-institutional ACOSOG Z6041 trial [38] consisted of 79 patients with T2N0 rectal cancer, less than 4 cm in diameter within 8 cm of the anal verge who received nCRT (capecitabine, oxaliplatin and radiation) followed by LE. Seventy-two patients comprised the per-protocol group with a median follow-up of 56 months.…”

Technological advances in radiotherapy of rectal cancer: opportunities and challenges

“…This last year has seen considerable progress in the field with the publication of several prospective studies (44,45) as well as a large retrospective series (46) (60,61). MRI is especially interesting as a modality for daily imaging for rectal cancer radiotherapy, as the primary tumour is challenging to visualize using on-board CT. MRI-guidance would allow for much more accurate daily delivery of dose-escalated treatments, but could potentially also be used for daily treatment adaptation.…”

“…Consequently, standard clinical practice in many parts of the world is to treat locally advanced disease with long-course CRT, with delayed surgery after 6-12 weeks. The typical long-course CRT regimen consists of [45][46][47][48][49][50] Gy to the primary tumour and the regional lymph node stations, delivered over 5-6 weeks in daily 1.8-2.0 Gy fractions, with concomitant fluorouracilbased chemotherapy. However, neoadjuvant treatment strategies are increasingly individualised; in terms of treatment modality, radiotherapy dose and schedule, details of treatment technique, and choice of chemotherapy regimens (4).…”