The ultimate local failure rate after the watch-and-wait strategy for rectal cancer: a systematic review of literature and meta-analysis.

BACKGROUND: We hypothesise that a high rate of tumour regrowth after the watch-and-wait (w&w) strategy may lead, despite salvage surgery, to a significant impairment of ultimate local control compared with immediate surgery. MATERIALS AND METHODS: To test this hypothesis, we conducted meta-analyses of studies on the w&w strategy (both opportunistic and planned) with an ultimate local failure rate as an endpoint in three patient groups: (1) in all starting radio(chemo)therapy as potential w&w candidates, (2) in a subgroup starting w&w, and (3) in a subgroup with regrowth. RESULTS: We identified eight studies for evaluation of local failure in group 1 (N = 837) and 36 studies in group 2 (N = 1914) and in group 3 (N = 439). The meta-analysis revealed an ultimate local failure rate of 8.0% (95% CI 4.8%-12.1%) in group 1 and 5.4% (95% CI 3.9%-7.1) in group 2. These rates are similar to those reported in the literature following preoperative chemoradiation and surgery. However, in the most unfavourable group 3 (with regrowth), the rate of ultimate local failure was 24.1% (95% CI 17.9%-30.9%), with the most common causes being patients' refusal of salvage total mesorectal excision (TME) (9.1%), recurrence after salvage TME (7.8%), distant metastases (4.1%), frailty (2.4%), and pelvic tumour unresectability (1.7%). CONCLUSION: Nearly 25% of patients with regrowth (unfavourable subgroup) experienced ultimate local failure, primarily due to refusing salvage TME. The risk of ultimate local failure in patients initiating radio(chemo)therapy as potential w&w candidates, or in patients starting w&w, appears comparable to that reported after preoperative chemoradiation and surgery. However, this comparison may be biased, because w&w studies included more early tumours compared with surgical studies.

The importance of measuring baseline tumour volume (or alternatively tumour length along with its rectal circumferential extent) in the watch-and-wait strategy in rectal cancer: a review.

BACKGROUND: The impact of the tumour volume or size on achieving clinical complete response (cCR) after radio(chemo)therapy is poorly understood. MATERIALS AND METHODS: A literature search was performed to gather data on the predictive value of baseline tumour volume or size in achieving cCR. RESULTS: In total, nine reports were identified. In two of three studies evaluating the baseline tumour volumetry, the tumour volume was the most powerful predictor for cCR. In four of six studies evaluating baseline tumour size without volumetry, tumour dimension was significantly associated with cCR, in one study reached borderline significance and in one report was insignificant. In three of four studies where a multivariable analysis was performed, the cT category did not show an independent predictive value for cCR. Because the tumour shape is often (semi)annular, its circumferential rectal extent along with the tumour length probably impact the tumour volume most, and thus, could be considered an acceptable alternative for time-consuming volumetry. CONCLUSIONS: Our review suggests that baseline tumour volume (or alternatively, tumour length along with its circumferential rectal extent) is the most relevant clinical predictor of cCR. Therefore, we postulate assessing and reporting these parameters in studies on the watch-and-wait strategy.

Neoadjuvant chemotherapy with or without oxaliplatin after short-course radiotherapy in high-risk rectal cancer: A subgroup analysis from a prospective study.

AIM: To evaluate the role of oxaliplatin in neoadjuvant chemotherapy delivered after short-course irradiation. BACKGROUND: Using oxaliplatin in the above setting is uncertain. PATIENTS AND METHODS: A subgroup of 136 patients managed by short-course radiotherapy and 3 cycles of consolidation chemotherapy within the framework of a randomised study was included in this post-hoc analysis. Sixty-seven patients received FOLFOX4 (oxaliplatin group) while oxaliplatin was omitted in the second period of accrual in 69 patients because of protocol amendment (fluorouracil-only group). RESULTS: Grade 3+ acute toxicity from neoadjuvant treatment was observed in 30% of patients in the oxaliplatin group vs. 16% in the fluorouracil-only group (p = 0.053). The corresponding proportions of patients having radical surgery or achieving complete pathological response were 72% vs. 77% (odds ratio [OR] = 0.88; 95% confidence interval [CI]: 0.39-1.98; p = 0.75) and 15% vs. 7% (OR = 2.25; 95% CI: 0.83-6.94; p = 0.16), respectively. The long-term outcomes were similar in the two groups. Overall and disease-free survival rates at 5 years were 63% vs. 56% (p = 0.78) and 49% vs. 44% (p = 0.59), respectively. The corresponding numbers for cumulative incidence of local failure or distant metastases were 33% vs. 38% (hazard ratio [HR] = 0.89; 95% CI: 0.52-1.52; p = 0.68) and 33% vs. 33% (HR = 0.78; 95% CI: 0.43-1.40; p = 0.41), respectively. CONCLUSION: Our findings do not support adding oxaliplatin to three cycles of chemotherapy delivered after short-course irradiation.

The gentamicin-collagen implant and the risk of distant metastases of rectal cancer following short-course radiotherapy and curative resection: the long-term outcomes of a randomized study.

PURPOSE: A previous randomized study conducted by our group showed that application of gentamicin-collagen implant (GCI) into the pelvic cavity after total mesorectal excision (TME) reduced the incidence of distant metastases. Therefore, we decided to conduct a confirmatory study. METHODS: Patients with rectal cancer were included in the study if they met the following criteria: adenocarcinoma of the rectum, preoperative short-term radiotherapy (5 × 5 Gy), and WHO performance score 0-1. RESULTS: One hundred seventy-six patients were randomly assigned either to an experimental group in which GCI was applied (n = 81) or to a control group without GCI (n = 81). Median follow-up was 80 months. Cumulative incidence of distant metastases at 5 years was higher in the control group compared to the experimental group: 23.5 vs 8.6% (HR 2.4 [95% CI 1.1-5.5], P = 0.005). Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) did not differ between the experimental group and the control group: HR 0.95 [95% CI 0.55-1.70], P = 0.864; HR 0.85 [95% CI 0.50-1.45], P = 0.548, and HR 0.5 [95%CI 0.22-1.22], P = 0.093, respectively. The predefined by the protocol subgroup analysis for yp stage III disease showed better DFS in the experimental group compared to the control group; HR 0.47 [95%CI 0.23-0.97], P = 0.042). CONCLUSIONS: The results confirmed our previous finding that GCI applied in the pelvis significantly reduced the rate of distant metastases in patients after radical rectal cancer resection.

Local Excision Techniques for Rectal Cancer After Neoadjuvant Chemoradiotherapy: What Are We Doing?

BACKGROUND: Recent evidence shows that the majority of rectal cancers demonstrate occult tumor scatter after neoadjuvant chemoradiotherapy that can extend for several centimeters under adjacent normal-appearing mucosa beside the residual mucosal abnormality or scar. OBJECTIVE: This systematic review aimed to determine all of the published selection criteria and technical descriptions for local excision to date with regard to this phenomenon. DATA SOURCES: PubMed, MEDLINE, and Embase were searched using the following key words: rectal cancer, local excision, radiotherapy, and neoadjuvant. STUDY SELECTION: Studies that assessed local excision of rectal cancer after neoadjuvant chemoradiotherapy were included. Duplicate series were excluded from final analysis. INTERVENTION: All of the data points were tabulated and analyzed using Microsoft Excel. MAIN OUTCOME MEASURES: Criteria for patient selection, surgical technique, clinical restaging, pathologic assessment, and indications for completion surgery were analyzed. RESULTS: After exclusions, data from 25 studies that in total evaluated local excision in 1001 patients were included. Compared with the single accepted technique of total mesorectal excision, described techniques for local excision after neoadjuvant therapy demonstrate significant variability in many critical technical issues, such as marking/tattooing original tumor margins before neoadjuvant therapy, using pretreatment tumor size/stage as exclusion criteria, and specifically stating lateral excision margins. Where detailed, the majority of local recurrences occurred in patients with clear pathological margins, yet significant variation existed for pathological assessment and reporting, with few studies detailing R status and some not reporting margin status at all. Significant variability also existed for adverse tumor features that mandated completion surgery, and, importantly, many series describe patients refusing completion surgery where indicated. LIMITATIONS: We were unable to perform meta-analysis because studies lacked sufficient methodologic homogeneity to synthesize. CONCLUSIONS: The observations from this study prompt additional study, standardization of technique, and cautious use of local excision of rectal cancer in the setting of neoadjuvant chemoradiotherapy.

Avoiding radical surgery improves early survival in elderly patients with rectal cancer, demonstrating complete clinical response after neoadjuvant therapy: results of a decision-analytic model.

BACKGROUND: In elderly and comorbid patients with rectal cancer, radical surgery is associated with significant perioperative mortality. Data suggest that a watch-and-wait approach where a complete clinical response is obtained after neoadjuvant chemoradiotherapy might be oncologically safe. OBJECTIVE: This study aimed to determine whether patient age and comorbidity should influence surgeon and patient decision making where a complete clinical response is obtained. DESIGN: Decision-analytic modeling consisting of a decision tree and Markov chain simulation was used. Modeled outcome parameters were elicited both from comprehensive literature review and from a national patient outcomes database. SETTINGS: Outcomes for 3 patient cohorts treated with neoadjuvant therapy were modeled after either surgery or watch and wait. PATIENTS: Patients included 60-year-old and 80-year-old men with mild comorbidities (Charlson score <3) and 80-year-old men with significant comorbidities (Charlson score >3). MAIN OUTCOME MEASURES: Absolute survival, disease-free survival, and quality-adjusted life years were measured. RESULTS: The model found that absolute survival was similar in 60-year-old patients but was significantly improved in fit and comorbid 80-year-old patients at 1 year after treatment where watch and wait was implemented instead of radical surgery, with a survival advantage of 10.1% (95% CI, 7.9-12.6) and 13.5% (95% CI, 10.2-16.9). At all of the other time points, absolute survival was equivalent for both techniques. There were no short- or long-term differences among any patient groups managed either by radical surgery or watch and wait in terms of either disease-free survival or quality-adjusted life years. LIMITATIONS: Oncologic data for the watch-and-wait approach used for this study is derived from only a small number of studies pertaining to a highly selected group of patients. The 90-day postoperative mortality rate derived from the United Kingdom population-based study might be lower in other countries or individual institutions. CONCLUSIONS: This study suggests competing effects of oncologic and surgical risk when using watch-and-wait management and that elderly and comorbid patients have the most to gain from this approach.

Early rectal cancer: the European Association for Endoscopic Surgery (EAES) clinical consensus conference.

BACKGROUND: The last 30 years have witnessed a significant increase in the diagnosis of early-stage rectal cancer and the development of new strategies to reduce the treatment-related morbidity. Currently, there is no consensus on the definition of early rectal cancer (ERC), and the best management of ERC has not been yet defined. The European Association for Endoscopic Surgery in collaboration with the European Society of Coloproctology developed this consensus conference to provide recommendations on ERC diagnosis, staging and treatment based on the available evidence. METHODS: A multidisciplinary group of experts selected on their clinical and scientific expertise was invited to critically review the literature and to formulate evidence-based recommendations by the Delphi method. Recommendations were discussed at the plenary session of the 14th World Congress of Endoscopic Surgery, Paris, 26 June 2014, and then posted on the EAES website for open discussion. RESULTS: Tumour biopsy has a low accuracy. Digital rectal examination plays a key role in the pre-operative work-up. Magnification chromoendoscopy, endoscopic ultrasound and magnetic resonance imaging are complementary staging modalities. Endoscopic submucosal dissection and transanal endoscopic microsurgery are the two established approaches for local excision (LE) of selected ERC. The role of all organ-sparing approaches including neoadjuvant therapies followed by LE should be formally assessed by randomized controlled trials. Rectal resection and total mesorectal excision is indicated in the presence of unfavourable features at the pathological evaluation of the LE specimen. The laparoscopic approach has better short-term outcomes and similar oncologic results when compared with open surgery. CONCLUSIONS: The management of ERC should always be based on a multidisciplinary approach, aiming to increase the rate of organ-preserving procedures without jeopardizing survival.

HDR brachytherapy for the reirradiation of cervical and vaginal cancer: analysis of efficacy and dosage delivered to organs at risk.

OBJECTIVE: To evaluate the efficacy and toxicity of HDR brachytherapy (BT) for the reirradiation of cervical or vaginal cancer arising within a previously irradiated area with a special focus on dosage delivery to organs at risk. METHODS: Twenty consecutive patients with cervical (N = 19) or vaginal (N = 1) cancer were reirradiated with curative intent using BT with or without external beam irradiation and hyperthermia. The median biologically equivalent dose in 2 Gy fractions (EQD2), assuming α/ß = 10, for reirradiation was 48.8 Gy (range: 16.0-91.0 Gy), and the median cumulative EQD2 (for primary treatment and reirradiation) was 133.5 Gy (range: 96.8-164.2 Gy). The median follow-up after retreatment was 31 months (range: 6-86 months). RESULTS: The 3-year overall survival (OS) rate was 68% (95% confidence interval [CI]: 44%-91%). The 3-year disease-free survival (DFS) rate was 42% (95% CI: 19%-65%). The 3-year local control (LC) rate was 45% (95% CI: 22%-69%). For nine patients who received 3D treatment planning, the median cumulative EQD2 to 2 cm(3) of rectum was 94.4 Gy (range: 67.1-118.8 Gy) and to 2 cm(3) of bladder was 99.3 Gy (range: 70.4-122.3 Gy). Grade 3 late toxicity was observed in 3 patients (15%). An interval between primary RT and reirradiation of ≤ 12 months and a tumor diameter >3 cm were significant prognostic factors adversely affecting OS, DFS and LC. CONCLUSIONS: HDR BT is a valuable method for the reirradiation of cervical cancer. A cumulative EQD2 of approximately 100 Gy was safely delivered to 2 cm(3) of the bladder and the rectum.

Neoadjuvant radiotherapy (5 × 5 Gy): immediate versus delayed surgery.

GOALS: To evaluate the role of length of the interval between 5 × 5 Gy and surgery. METHODS: PubMed was searched to perform a systematic review. RESULTS: There were 10 studies on 5 × 5 Gy with delayed surgery (no of patients (n) = 1343), and six studies on 5 × 5 Gy with consolidation chemotherapy delivered over a long interval prior to surgery in a tight sequence (n = 244). In total, there were four randomized studies, five phase II studies, and seven retrospective studies. Trials that compared immediate with delayed surgery after 5 × 5 Gy showed a benefit in terms of lower rate of severe acute post-radiation toxicity (4.2 % absolute difference) in the immediate-surgery group. However, this benefit was counterbalanced by the increase in minor postoperative complications (13 % of absolute difference) in the group with immediate surgery compared with that with the delayed surgery. The pathological complete response (pCR) rate was about 10 % higher in the delayed-surgery group. There were no differences in sphincter preservation and R0 resection rate between the two groups. Small studies suggest no differences in the oncological outcomes. Regarding elderly patients who were unfit for chemotherapy, short-course radiotherapy with delayed surgery produced favourable outcomes for "unresectable" cancer or for small cancer after full-thickness local excision. A watch-and-wait policy in complete responders after short-course radiotherapy is feasible. A pCR of over 20 % was recorded after short-course radiotherapy and consolidation chemotherapy compared with about 10 % after 5 × 5 Gy and delayed surgery. Favourable outcomes after short-course radiotherapy and consolidation chemotherapy were observed in patients with potentially resectable stage IV disease. CONCLUSIONS: Evidence showed that 5 × 5 Gy with delayed surgery can be used routinely for the management of elderly patients who are unfit for chemotherapy in case of "unresectable" cancer or early cancer prior to local excision. Short-course radiotherapy with consolidation chemotherapy is a promising treatment that can be used routinely for potentially resectable stage IV disease.

Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: A narrative review.

Overall survival benefit of total neoadjuvant treatment (TNT) remains unconfirmed. Thus, in our opinion, the main rationale for using TNT is a planned watch-and-wait (w&w) strategy to improve patients' long-term quality of life through organ preservation. The OPRA randomized trial, which examined a planned w&w strategy using TNT, showed a higher organ preservation rate but also a higher regrowth rate compared to studies on the opportunistic w&w strategy. Higher rates of complete clinical response with TNT did not improve disease-free survival compared to historical controls. Therefore, the gain in organ-sparing capability might not be balanced by the increased oncological risk. The ultimate local failure rate in the intention-to-treat analysis of the OPRA trial was 13% for induction chemotherapy and 16% for consolidation chemotherapy, which seems higher than expected compared to 8% in a meta-analysis of w&w studies or 12% after TNT and surgery in the PRODIGE-23 and RAPIDO trials, which enrolled patients with more advanced cancers than the OPRA trial. Other studies also suggest worse local control when surgery is delayed for radio-chemoresistant cancers. Our review questions the safety of the planned w&w strategy using TNT in unselected patients. To reduce the oncological risk while maintaining high organ preservation rates, we suggest that the planned w&w strategy using TNT requires a two-tier patient selection process: before treatment and after tumor response assessment at the midpoint of consolidation chemotherapy. These robust selections should identify patients who are unlikely to achieve organ preservation with TNT and would be better managed by preoperative chemoradiotherapy (without consolidation chemotherapy) and surgery, or by discontinuing consolidation chemotherapy and proceeding directly to surgery.

Endoscopic resection of residual rectal neoplasia after definitive chemoradiotherapy for rectal cancer.

The conventional approach to treating locally advanced rectal cancer, commonly defined as cT3 or cT4 primary tumors or with nodal metastases, involves chemoradiation (CRT) followed by surgical resection. There is a growing recognition of the potential for nonsurgical management following CRT or total neoadjuvant therapy (TNT), which allows for organ preservation. "Watch and wait" strategy may be considered if complete clinical response is achieved. In cases when adenoma or superficial cancer is present, a novel approach known as "salvage endoscopic resection of the residual disease" is emerging as a viable nonsurgical option for carefully selected patients. This review discusses available evidence and future potential for endoscopic management of residual neoplasia after oncological treatment of rectal cancer.

Which tumour factors preclude organ preservation in patients with rectal cancer?

BACKGROUND: cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes, extramural vascular invasion (EMVI) and mesorectal fascia threatening (MRF+) have been utilized as exclusion criteria in several studies on the watch-and-wait (w&w) strategy. Here, our aim was to validate these criteria through a post hoc analysis of two pooled prospective studies on w&w following routine radio(chemo)therapy. METHODS: A review of baseline magnetic resonance imaging was performed in a subgroup of 223 patients treated at a single institution. Of these, 17.9 % started w&w, 12.6 % achieved clinical complete response (cCR) and 9.0 % sustained cCR during median follow-up of 54 months. RESULTS: The multivariable logistic analysis showed that the proportion of circumferential bowel involvement and EMVI significantly influenced the chance of sustained cCR; odds ratios were 0.063 (95 % confidence interval [CI] 0.008-0.489, p = 0.008), and 0.109 (95 % CI 0.014-0.850, p = 0.034), respectively. Sustained cCR was observed in none of the 57 patients with 90 %-100 % circumferential bowel involvement and in only one of the 89 patients with EMVI. In contrast, cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes or MRF+ were not independently associated with sustained cCR. Among the subgroups of patients with these features but without (near-)circular tumour or EMVI+, sustained cCR was observed in 12 %-25 % of patients. CONCLUSION: Sustained cCR after routine preoperative radio(chemo)therapy is unlikely in patients with (near-)circular tumour or EMVI, whereas patients with cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes and MRF+ should not be denied w&w.

Definitive radical external beam radiotherapy for rectal cancer: evaluation of local effectiveness and risk of late small bowel damage.

AIM: To present a retrospective analysis of results of definitive radiotherapy for rectal cancer. MATERIAL AND METHODS: Forty-one consecutive patients with rectal cancer (32% primary, 61% pelvic recurrence and 7% after R2 resection) who could not be treated with surgery underwent external beam radiotherapy. A median tumour dose of 64 Gy was given with 1.8-2.5 Gy per fraction using 2D or 3D technique. In 46% of patients, concurrent 5-Fu-based chemotherapy was given. The median follow-up was 54 months. RESULTS: Clinical complete response was achieved in 39% of patients. Five-year cumulative incidence of local failure, overall survival and cancer specific survival were 76%, 26% and 30%, respectively. Of 11 patients with local control, in five cases the tumour was larger than 5 cm and in the other five the tumour was fixed. Two patients, regarded as locally controlled had non-progressive tumour without local symptoms at the last follow-up of 54 and 118 months post-radiotherapy. Late toxicity occurred in 22% of patients, all with acceptable severity. There was no bowel obstruction requiring surgery despite that in 18 patients the small bowel dose was >60 Gy to a mean volume of 51 cm(3). CONCLUSION: Definitive radio(chemo)therapy provides a chance for local control even in patients with large fixed or recurrent rectal cancer.

Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review.

BACKGROUND: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. METHODS: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. RESULTS: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. CONCLUSION: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.