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.

Watch-and-wait strategy in rectal cancer: Is there a tumour size limit? Results from two pooled prospective studies.

BACKGROUND: Frequency and predictive factors for a clinical complete response (cCR) in unselected patients are unclear. MATERIAL AND METHODS: Two prospective observational studies were designed and pooled to explore predictive factors for cCR. Both studies evaluated the watch-and-wait strategy in consecutive patients; the first single-institutional study in elderly with a small tumour, the second multi-institutional study in all the patients receiving standard of care preoperative radiotherapy. RESULTS: Four hundred and ninety patients were analysed. Short-course radiotherapy alone, or with consolidation chemotherapy or chemoradiation was given to 40.6%, 40.2% and 19.2% of the patients, respectively. The median interval from the radiation start to the first tumour response assessment was 10.2 weeks for short-course radiation and 13.2 weeks for chemoradiation. Seventy-three patients had cCR and 71 underwent w&w with the median follow-up of 24 months. The regrowth rate was 26.8%. cCR rate was 39.0% for low-risk cancer (cT1-2N0), 16.8% for intermediate-risk (cT3 with unthreatened mesorectal fascia [MRF-] or cT2N+) and 5.4% for high-risk (cT4 or MRF+). In the multivariable analysis, tumour volume (or tumour length and circumferential extent) and cN status were significant predictors for cCR. In circular cancers or with a length ≥7 cm (n = 184), cCR rate was only 2.7%, sustained cCR 1.6% and the sensitivity of cCR diagnosis 23.1%. None of 27 patients with a tumour larger than 120 cm3 achieved cCR. CONCLUSIONS: Considering watch-and-wait strategy is questionable in patients with circular tumours or with tumour length ≥7 cm.

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.

A systematic review and meta-analysis of pT2 rectal cancer spread and recurrence pattern: Implications for target design in radiation therapy for organ preservation.

BACKGROUND: There are no guidelines on clinical target volume (CTV) delineation for cT2 rectal cancer treated with organ preservation. MATERIALS AND METHODS: A systematic review and meta-analysis were performed to determine the extent of distal mesorectal (DMS) and distal intramural spread (DIS), the risk of lateral lymph node (LLN) metastases in pT2 tumours, and regional recurrence pattern after organ preservation. RESULTS: The rate of DMS > 1 cm was 1.9% (95% CI: 0.4-5.4%), maximum extent: 1.3 cm. The rate of DIS > 0.5 cm was 4.7% (95% CI: 1.3-11.5%), maximum extent: 0.8 cm. The rate of LLN metastases was 8.2% (95% CI: 6.7-9.9%) for tumours below or at peritoneal reflexion and 0% for higher tumours. Regional nodal recurrences alone were recorded in 1.0% (95% CI: 0.5-1.7%) of patients after watch-and-wait and in 2.1% (95% CI: 1.2-3.4%) after preoperative radiotherapy and local excision. Thus, the following rules for CTV delineation are proposed: caudal border 1.5 cm from the tumour to account for DMS or 1 cm to account for DIS, whichever is more caudal; cranial border at S2/S3 interspace; inclusion of LLN for tumours at or below peritoneal reflexion. A planning study was performed in eight patients to compare dose-volume parameters obtained using these rules to that obtained using current guidelines for advanced cancers. The proposed rules led to a mean 18% relative reduction of planning target volume, which resulted in better sparing of organs-at-risk. CONCLUSION: This meta-analysis suggests a smaller CTV for cT2 tumours than the current guidelines designed for advanced cancers.

Preoperative radiotherapy and local excision of rectal cancer: Long-term results of a randomised study.

BACKGROUND AND PURPOSE: It is uncertain whether local control is acceptable after preoperative radiotherapy and local excision (LE). An optimal preoperative dose/fractionation schedule has not yet been established. MATERIAL AND METHODS: In a phase III study, patients with cT1-2N0M0 or borderline cT2/T3N0M0 < 4 cm rectal adenocarcinomas were randomised to receive either 5 × 5 Gy plus 1 × 4 Gy boost or chemoradiation: 50.4 Gy in 28 fractions plus 3 × 1.8 Gy boost and 5-fluorouracil with leucovorin bolus. LE was performed 6-8 weeks later. Patients with ypT0-1R0 disease were observed. Completion total mesorectal excision (CTME) was recommended for poor responders, i.e. ypT1R1/ypT2-3. RESULTS: Of 61 randomised patients, 10 were excluded leaving 51 for analysis; 29 in the short-course group and 22 in the chemoradiation group. YpT0-1R0 was observed in 66% of patients in the short-course group and in 86% in the chemoradiation group, p = 0.11. CTME was performed only in 46% of patients with ypT1R1/ypT2-3. The median follow-up was 8.7 years. Local recurrence incidences and overall survival at 10 years were respectively for the short-course group vs. the chemoradiation group 35% vs. 5%, p = 0.036 and 47% vs. 86%, p = 0.009. In total, local recurrence at 10 years was 79% for ypT1R1/T2-3 without CTME. CONCLUSIONS: This trial suggests that in the LE setting, both local recurrence and survival are worse after short-course radiotherapy than after chemoradiation. Because of the risk of bias, a confirmatory study is desirable. Lack of CTME is associated with an unacceptably high local recurrence rate.

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.

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.

Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study.

PURPOSE: To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. METHODS: Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. RESULTS: 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. CONCLUSIONS: The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders: a prospective multicentre study.

PURPOSE: To assess local control after preoperative radiation and local excision and to determine an optimal radiotherapy regimen. METHODS: Eighty-nine patients with G1-2 rectal adenocarcinoma <3-4 cm; unfavourable cT1N0 (23.6%), cT2N0 (62.9%) or borderline cT2/cT3N0 (13.5%) received 5 × 5 Gy plus 4 Gy boost (71.9%) or 55.8 Gy in 31 fractions with 5-FU and leucovorin (28.1%). Local excision (traditional technique 56.2%, transanal endoscopic microsurgery 41.6%, Kraske procedure 2.2%) was performed 6-8 weeks later. If patients were downstaged to ypT0-1 without unfavourable factors (good responders), this was deemed definitive treatment. Immediate conversion to radical surgery was recommended for remaining patients. RESULTS: Good response to radiation was seen in 67.2% of patients in the short-course group and in 80.0% in the chemoradiation group, p = 0.30. Local recurrence at 2 years (median follow-up) in good responders was 11.8% in the short-course group and 6.2% in the chemoradiation group, p = 0.53. In the total group, a lower rate of local recurrence at 2 years was observed in elderly patients (>69 years, median value) when compared to the younger patients; 8.3% vs. 27.7%, Cox analysis hazard ratio 0.232, p = 0.016. A total of 18 patients initially managed with local excision required conversion to abdominal surgery but either refused it or were unfit. In this group, local recurrence at 2 years was 37.1%. CONCLUSIONS: This study suggests an acceptable local recurrence rate after preoperative radiotherapy and local excision of small, radiosensitive tumours in elderly patients.

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.

Prospective evaluation of the palliative effect of whole-brain radiotherapy in patients with brain metastases and poor performance status.

BACKGROUND/PURPOSE: The benefit of whole brain radiotherapy (WBRT) for RTOG RPA (Radiation Therapy Oncology Group Recursive Partitioning Analysis) class 3 patients with brain metastases is not well established. The aim of this study was to determine whether WBRT has any benefit in terms of symptoms palliation in such patients. Evaluation of patients' preferences for WBRT, changes in performance and neurological status were secondary aims. METHODS: Ninety-one RTOG RPA class 3 patients were included. All patients received WBRT (20 Gy in 5 fractions) and were asked to complete a questionnaire about their symptoms before and one month after WBRT. The patient's symptom checklist comprised 17 items scored from 0 to 3; a higher score meant a greater symptom intensity. The mean scores at baseline and after treatment were compared. Karnofsky performance status (KPS) and neurological status before and one month after WBRT were also recorded. Patients were asked to express their preference as to the WBRT undergone. RESULTS: Forty-three (47%) patients completed both symptom checklists. The mean scores on the symptom checklist were 18.21 and 21.09 at baseline and one month after WBRT, respectively (p = 0.02). The KPS was estimated after WBRT in 42 patients: 57% of patients improved, 26% worsened, and 17% did not change from the baseline KPS score (p = 0.06). Neurological status did not change from baseline to one month after WBRT (p = 0.44). Only 7% of respondents would not have consented to the WBRT undergone. CONCLUSION: Our results challenge the palliative value of the WBRT in RPA class 3 patients.

Delineation variation of lymph node stations for treatment planning in lung cancer radiotherapy.

PURPOSE: To assess the variability among clinicians in the delineation of mediastinal and hilar lymph node stations (LNS) according to the published recommendations in the treatment planning of elective nodal irradiation for lung cancer. METHODS: Nine observers delineated on axial CT scans of five cases the LNS according to the guidelines of the published Atlas. Next, the Volumes of Consensus (VC)--fitting strictly the guidelines--for each LNS and case were collectively defined. Volume of Intersection (VI) as the overlap of the Delineated Volume (DV) for each LNS, case and observer with respective VC was computed. The Concordance Index (CI) for respective LNS and observers was defined as "VI/VC x 100%". The Discordance Index (DI) for respective LNS and observers was defined as "(1-VI/VD) x 100%". RESULTS: Mean values of CI and DI for all observers were 69% and 36%, respectively. For five radiation oncologists who used to work as a team the ways of delineation were similar. The poorest reproducibility was shown for LNS 5, 7, 10R, and 10L. CONCLUSIONS: Although detailed guidelines are used there is still substantial room for improvement. More training in the use of the Atlas is recommended.

Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial.

BACKGROUND AND PURPOSE: Patients (N=316) with resectable cT3-4 low-lying and mid-rectal cancer were randomised to receive either preoperative 5x5Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8Gy per fraction plus boluses of 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. No differences were found in sphincter preservation, survival, local control and late complications. Early complications were less frequent in the short-course group. The aim of this report is to find out whether large doses per fraction of short-course schedule result in more severe anorectal and sexual dysfunction and quality of life (QoL) impairment. MATERIALS AND METHOD: Patients who were free of disease were asked to answer the QLQ-C30 and those without stoma were, additionally, asked to fill in a questionnaire of anorectal (19 items) and sexual function (1 item). RESULTS: Two hundred and twenty-two patients (86% response rate) completed the QLQ-C30 and 118 (86% response rate) the anorectal-sexual function questionnaire. The median time from surgery to filling in the QLQ-C30 questionnaire was 12 months, and to filling in the anorectal-sexual function questionnaire - 13 months. We did not find significant differences between the randomised groups regarding QoL and the anorectal and sexual functions. Approximately two-thirds of patients had anorectal function impairment. Approximately 20% of patients stated that this considerably influenced their QoL. CONCLUSIONS: QoL and the anorectal and sexual functioning did not differ in patients receiving short-course radiotherapy, as compared to those receiving chemoradiation.