Adjuvant Chemotherapy for Older Patients With Stage III Colorectal Cancer: A Real-World Analysis of Treatment Recommendations, Treatment Administered and Impact on Cancer Recurrence.

BACKGROUND: A substantial proportion of patients with stage III colorectal cancer (CRC) are older than 70 years. Optimal adjuvant chemotherapy (AC) for older patients (OP) continues to be debated, with subgroup analyses of randomized trials not demonstrating a survival benefit from the addition of oxaliplatin to a fluoropyrimidine backbone. PATIENTS AND METHODS: We analyzed the multisite Australian ACCORD registry, which prospectively collects patient, tumor and treatment data along with long term clinical follow-up. We compared OP (≥70) with stage III CRC to younger patients ([YP] <70), including the proportion recommended AC and any reasons for not prescribing AC. AC administration, regimen choice, completion rates, and survival outcomes were also examined. RESULTS: One thousand five hundred twelve patients enrolled in the ACCORD registry from 2005 to 2018 were included. Median follow-up was 57.0 months. Compared to the 827 YP, the 685 OP were less likely to be offered AC (71.5% vs. 96.5%, P < .0001) and when offered, were more likely to decline treatment (15.1% vs. 2.8%, P < .0001). Ultimately, 60.0% of OP and 93.7% of YP received AC (P < .0001). OP were less likely to receive oxaliplatin (27.5% vs. 84.7%, P < .0001) and to complete AC (75.9% vs. 85.7%, P < .0001). The probability of remaining recurrence-free was significantly higher in OP who received AC compared to those not treated (HR 0.73, P = .04) but not significantly improved with the addition of oxaliplatin (HR 0.75, P = .18). CONCLUSION: OP were less likely than YP to receive AC. Receipt of AC reduced recurrences in OP, supporting its use, although no significant benefit was observed from the addition of oxaliplatin.

Biology and Clinical Implications of Fecal Occult Blood Test Screen-Detected Colorectal Cancer.

BACKGROUND: Fecal occult blood test (FOBT)-based screening for colorectal cancer (CRC) reduces mortality, with earlier stage at diagnosis a prominent feature. Other characteristics of FOBT screen-detected cancers and any implications for clinical management have not been well explored. METHODS: We examined a multisite clinical registry to compare the characteristics and outcomes of FOBT screen-detected CRC via the Australian National Bowel Cancer Screening Program (NBCSP), which is offered biennially to individuals aged 50-74 years, and age-matched non-screen-detected CRC in the same registry. All statistical tests were 2-sided. Odds ratios (ORs) were calculated using the Baptista-Pike method, and hazard ratios via the log-rank method. RESULTS: Of 7153 registry patients diagnosed June 1, 2006, to June 30, 2020, 4142 (57.9%) were aged between 50 and 74 years. Excluding 406 patients with non-NBCSP screen-detected cancers and 35 patients with unknown method of detection, 473 (12.8%) were screen detected via the NBCSP, and 3228 (87.2%) were non-screen detected. Screen-detected patients were younger (mean age = 62.4 vs 64.2 years; P < .001) and more medically fit (OR for ASA score 1-2 = 1.91, 95% confidence interval [CI] = 1.51 to 2.41; P < .001). Pathologic characteristics within each stage favored the screen-detected patients. Stage III screen-detected colon cancers were more likely to receive adjuvant therapy (OR = 3.58, 95% CI = 1.52 to 8.36; P = .002). Screen-detected patients had superior relapse-free (hazard ratio = 0.41, 95% CI = 0.29 to 0.60; P < .001) and overall survival (hazard ratio = 0.22, 95% CI = 0.15 to 0.35; P < .001), which was maintained in matched stage comparisons and multivariable analysis. CONCLUSIONS: Beyond stage at diagnosis, multiple other factors associated with a favorable outcome are observed in FOBT screen-detected CRC. Given the substantial stage-by-stage differences in survival outcomes, if independently confirmed, individualized adjuvant therapy and surveillance strategies could be warranted for FOBT screen-detected cancers.

Stage dependent recurrence patterns and post-recurrence outcomes in non-metastatic colon cancer.

BACKGROUND: Multiple meta-analyses have demonstrated that routine surveillance following colorectal cancer surgery improves survival outcomes. There is limited data on how recurrence patterns and post-recurrence outcomes vary by individual tumor stage. METHODS: Using a multi-site community cohort study, we examined the potential impact of primary tumor stage on the sites of recurrence, management of recurrent disease with curative intent, and post-resection survival. We also explored changes over time. RESULTS: Of 4257 new colon cancers diagnosed 2001 through 2016, 789 (21.1%) had stage I, 1584 (42.4%) had stage II, and 1360 (36.4%) had stage III colon cancer. For consecutive 5-year periods (2001-2005, 2006-2010, 2011-2016), recurrence rates have declined (23.4 vs. 17.1 vs. 13.6%, p < 0.001), however, the resection rates of metastatic disease (29.3 vs. 38.6 vs. 35.0%, p = 0.21) and post-resection 5-year survival (52.0 vs. 51.8 vs. 64.2%, p = 0.12) have remained steady. Primary tumor stage impacted recurrence rate (3.8 vs. 12 vs. 28%, p < 0.0001 for stage 1, 2, and 3), patterns of recurrence, resection of metastatic disease, (50 vs. 42 vs. 30%, p < 0.0001) and post-resection 5-year survival (92 vs. 64 vs. 44%, p < 0.001). CONCLUSION: In this community cohort we defined significant differences in recurrence patterns and post-resection survival by tumor stage, with a diminishing rate of recurrence over time. While recurrence rates were lower with stage I and II disease, the high rate of metastatic disease resection and excellent post-resection outcomes help to justify routine surveillance in these patients.

Real-world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer.

BACKGROUND: Neoadjuvant chemoradiation therapy is standard-of-care treatment for locally advanced rectal cancer (LARC). A pathological complete response (pCR) following chemoradiation therapy is an early indicator of treatment benefit and associated with excellent survival outcomes, with capecitabine largely replacing infusional 5-fluorouracil as the choice in routine care of LARC. AIMS: To analyse the uptake of capecitabine usage over time, and on the back of clinical trial data demonstrating equivalence between fluoropyrimidines, confirm that efficacy is maintained in the real-world setting. METHODS: We analysed data from a prospectively maintained colorectal cancer database at three Australian hospitals including patients diagnosed from January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5-FU or capecitabine. RESULTS: A total of 657 patients was analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine-treated patients and 118/380 (23.7%) that received 5-FU (P ≤ 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, P < 0.01). Two-year progression-free survival was similar (84.9% vs 88.0%, P = 0.34). CONCLUSIONS: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation.

Results of phase II trial of intensified neoadjuvant treatment with interdigitating radiotherapy and chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid in patients with locally advanced rectal cancer (PROARCT trial).

BACKGROUND AND PURPOSE: The chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. MATERIALS AND METHODS: Eligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3-5, and weeks 8-10. Surgery was performed 4-6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. RESULTS: Median age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. CONCLUSIONS: Delivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.

Impact of anastomotic leak on recurrence and survival after colorectal cancer surgery: a BioGrid Australia analysis.

BACKGROUND: There is conflicting evidence regarding the oncological impact of anastomotic leak following colorectal cancer surgery. This study aims to test the hypothesis that anastomotic leak is independently associated with local recurrence and overall and cancer-specific survival. METHODS: Analysis of prospectively collected data from multiple centres in Victoria between 1988 and 2015 including all patients who underwent colon or rectal resection for cancer with anastomosis was presented. Overall and cancer-specific survival rates and rates of local recurrence were compared using Cox regression analysis. RESULTS: A total of 4892 patients were included, of which 2856 had completed 5-year follow-up. The overall anastomotic leak rate was 4.0%. Cox regression analysis accounting for differences in age, sex, body mass index, American Society of Anesthesiologists score and tumour stage demonstrated that anastomotic leak was associated with significantly worse 5-year overall survival (χ 2 = 6.459, P = 0.011) for colon cancer, but only if early deaths were included. There was no difference in 5-year colon cancer-specific survival (χ 2 = 0.582, P = 0.446) or local recurrence (χ 2 = 0.735, P = 0.391). For rectal cancer, there was no difference in 5-year overall survival (χ 2 = 0.266, P = 0.606), cancer-specific survival (χ 2 = 0.008, P = 0.928) or local recurrence (χ 2 = 2.192, P = 0.139). CONCLUSION: Anastomotic leak may reduce 5-year overall survival in colon cancer patients but does not appear to influence the 5-year overall survival in rectal cancer patients. There was no effect on local recurrence or cancer-specific survival.

Survival Impact of Adjuvant Chemotherapy for Resected Locally Advanced Rectal Adenocarcinoma.

BACKGROUND: Recent data has created uncertainty regarding the benefit of adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy. PATIENTS AND METHODS: This is a retrospective analysis of patients with LARC, diagnosed between January 1, 2003 and December 31, 2014 at 3 Melbourne health services. Patients were identified from the Australian Comprehensive Cancer Outcomes and Research Database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence, and survival were analyzed. RESULTS: A total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. Four hundred fifty-two of 555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy group and 20 (19%) in the surveillance group had relapsed. Five-year relapse-free survival was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no significant difference on univariate analysis (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.58-1.51; P = .780). No significant impact on relapse-free survival was seen for either pCR or non-pCR patients. Five-year overall survival (OS) was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a nonsignificant trend towards OS benefit (HR, 0.62; 95% CI, 0.37-1.05; P = .074). A significant OS benefit favoring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR, 0.49; 95% CI, 0.28-0.86; P = .014). CONCLUSION: A high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 5-year OS only in the patients with a non-pCR.

Impact of Surgical Complications Following Resection of Locally Advanced Rectal Adenocarcinoma on Adjuvant Chemotherapy Delivery and Survival Outcomes.

BACKGROUND: Surgical complications after resection for locally advanced rectal cancer may influence adjuvant treatment outcomes and survival. Few studies have examined this effect. OBJECTIVE: This study aimed to examine the impact of surgical complications on adjuvant therapy delivery and survival in patients with locally advanced rectal cancer treated with long-course chemoradiation followed by surgery. DESIGN: This is a retrospective analysis of a prospectively collected multicenter colorectal cancer database. SETTINGS: Data were collected from the Australian Comprehensive Cancer Outcomes and Research Database. PATIENTS: All patients who completed neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer between January 2003 and December 2014 were selected. MAIN OUTCOME MEASURES: We examined the types and frequency of surgical complications and their impact on the delivery of adjuvant chemotherapy and survival. RESULTS: Data were available for 517 patients, of whom 147 (28%) had a surgical complication. Patients with a surgical complication were less likely to commence adjuvant chemotherapy (33% vs 66%; p = 0.0005) and more likely to have adjuvant treatment commencing more than 8 weeks from surgery (71.8% vs 21.2%; p = 0.004). Wound-related complications (p = 0.001), return to operating theater (p = 0.004), and readmission within 30 days (p = 0.02) had the most significant negative impact on the delivery of adjuvant chemotherapy. Surgical complications were significantly more likely in males (31.6% vs 20.8%, p = 0.003) and laparoscopic converted cases (47.8% vs 21.8%, p = 0.03). For the entire patient population, adjuvant chemotherapy compared with surveillance was not associated with an improved recurrence-free survival (HR, 1.06; p = 0.83) but was associated with an improved overall survival (HR, 0.53; p = 0.04). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Surgical complications in patients having surgery following neoadjuvant chemoradiotherapy for locally advanced rectal cancer were associated with significantly reduced uptake and delays to receiving adjuvant therapy. Surgical complications, however, were not associated with either significantly reduced recurrence-free or overall survival. Adjuvant chemotherapy delivery was associated with improved overall survival.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.

Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing-based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Comparing oncological outcomes of laparoscopic versus open surgery for colon cancer: Analysis of a large prospective clinical database.

BACKGROUND: Oncological outcomes of laparoscopic colon cancer surgery have been shown to be equivalent to those of open surgery, but only in the setting of randomized controlled trials on highly selected patients. The aim of this study is to investigate whether this finding is generalizable to real world practice. METHODS: Analysis of prospectively collected data from the BioGrid Australia database was undertaken. Overall and cancer specific survival rates were compared with cox regression analysis controlling for the confounders of age, sex, BMI, ASA score, hospital site, year surgery performed, procedure, tumor stage, and adjuvant chemotherapy. RESULTS: Between 2003 and 2009, 1,106 patients underwent elective colon cancer resection. There were differences between the laparoscopic and open cohorts in BMI, procedure, post-operative complication rate, and tumor stage. When baseline confounders were accounted for using cox regression analysis, there was no difference in 5 year overall survival (χ(2) test 1.302, P = 0.254), or cancer specific survival (χ(2) test 0.028, P = 0.866). CONCLUSION: This large prospective clinical study validates previous trial results, and confirms that there is no difference in oncological outcome between laparoscopic and open surgery for colon cancer.

Initial impact of Australia's National Bowel Cancer Screening Program.

OBJECTIVE: To examine the initial impact of the National Bowel Cancer Screening Program (NBCSP), which was launched in May 2006 and offers faecal occult blood testing to Australians aged 55 or 65 years. DESIGN AND SETTING: Review of data on colorectal cancer (CRC) cases diagnosed between May 2006 and June 2008 from a prospective database used at 19 Australian hospitals, linked and analysed by BioGrid Australia. MAIN OUTCOME MEASURES: Number of CRC cases detected through the NBCSP or symptomatic presentation, and differences by sex, stage at diagnosis, tumour location and level of socioeconomic disadvantage. RESULTS: 1628 cases of CRC were identified; 1268 had information on the patients' test status as part of the NBCSP, and 40 of these (3.2%) were recorded as being detected by the NBCSP. Of 75 CRC cases in patients aged 55 or 65 at diagnosis, 22 were NBCSP-detected. Overall, there was no difference in NBCSP-detected cases by sex. The distribution of tumour locations was similar between NBCSP-detected cases and symptomatic cases, but NBCSP-detected cancers were diagnosed at an earlier stage than symptomatic cancers (stage I, 40% v 14%; stage IV, 3% v 15%, respectively). Of patients diagnosed through the NBCSP, 63% were from areas of least socioeconomic disadvantage (deciles 8-10) and 18% were from the most disadvantaged areas (deciles 1-4) (P=0.0375). CONCLUSION: Initiation of the Australian NBCSP has had a measurable impact on CRC stage at diagnosis, and an improvement in survival would be anticipated. The lower uptake among people from disadvantaged areas is of concern.

Outcomes and prediction of hospital readmission after intestinal surgery.

BACKGROUND: Clinical care pathways reduce postoperative stay after major bowel operations. Concerns about unexpected early readmissions and delays in diagnosis of complications remain unanswered. The objectives of this study were determination of readmission rate and outcomes for patients undergoing intestinal operations. STUDY DESIGN: Patients readmitted (PR) within 30 days of discharge after intestinal operations were compared with patients who were not readmitted (NR). Variables that might predict readmission were evaluated. RESULTS: Of 553 patients, 56 (10.1%) were readmitted after 10 days (interquartile range [IQR] 4.5 to 15.5 days). PR and NR groups had similar age, gender, diagnosis, preoperative comorbidities, and index operations. Discharge hemoglobin level, white cell count, antibiotic use, or presence of stoma did not affect readmission. PR had a greater frequency of steroid use (p = 0.03) during index admission. Median length of stay for the index hospitalization was 5 days (IQR 4 to 8 days) for the NR and 6 days (IQR 4.8 to 9 days) for the PR group (p = 0.049). Duration of readmission was 4 days (IQR 2 to 9 days) in the PR group, with equal total median length of stay identical for PR and NR patients with complications (median 12 days). Clinical outcomes for PR patients and NR patients with complications were similar. CONCLUSIONS: Early readmission is an unpredictable sequel of major bowel operations; it does not correlate with shorter hospital stay. Identification of unpredictable complications after discharge that require later invasive intervention does not adversely affect clinical outcomes. Readmission within 30 days of a patient who has attained standardized discharge criteria may not be a valid indicator of poor quality of care.

Colonic diverticular disease.

BACKGROUND: Diverticular disease of the colon is common and the spectrum is broad, ranging from asymptomatic diverticulosis to perforation and massive haemorrhage requiring emergency colectomy. OBJECTIVE: This article discusses the epidemiology, pathophysiology, symptomatology and management of common presentations of diverticular disease including a brief review of surgical management. DISCUSSION: Management is based on the patient's symptoms and signs with assistance from findings at colonoscopy, computerised tomography scanning and occasionally bleeding localisation studies. For minimally symptomatic patients, a high fibre diet is the mainstay of management. Those with diverticulitis require antibiotics and bowel rest, and hospitalisation may be required. Surgery is indicated for recurrent diverticulitis, complicated diverticulitis, perforation and severe bleeding. This involves resection of the affected colon segment and can be performed laparoscopically or open.

Extent of mesorectal invasion is a prognostic indicator in T3 rectal carcinoma.

BACKGROUND: The aim of this study was to determine if local recurrence (LR) rates in patients with minimally invasive and advanced T3 rectal cancer are different. This may influence the use of adjuvant therapy. METHODS: Consecutive patients with T3 rectal cancer undergoing curative surgery were classified into minimally invasive or advanced groups. Minimally invasive T3 was defined as a tumour that had invaded beyond the muscularis propria on microscopic examination only, whereas advanced T3 tumours had invasion beyond the muscularis propria that was obvious on macroscopic examination and confirmed histologically. Local recurrence rates of the two groups were compared by construction of Kaplan-Meier curves. The log-rank test was used to determine equivalence, and Cox regression to estimate the hazard ratio. The Grambsch- Therneau test and graphical comparison of predicted and observed Kaplan-Meier curves was used to test the proportional hazards assumption. RESULTS: There were 222 patients in total, 74 in the minimally invasive group and 148 in the advanced. The overall LR rate was 11.2%. The LR rates in the minimally invasive and advanced groups were 5.4% and 14.2%, respectively. The log-rank test gives a P value of 0.042 for equivalence, with the minimally invasive patients doing significantly better. The hazard ratio estimated by Cox regression was 0.35 (early relative to advanced), 95% confidence intervals (0.12, 1.0). There was no evidence of confounding by age at surgery, pathology type, gender or postoperative adjuvant therapy. CONCLUSIONS: The extent of invasion into the mesorectum appears to be an independent prognostic variable. If oncologically sound surgical techniques are employed, the LR rate of patients with minimal invasion is low. Adjuvant therapy may not confer additional benefit in this group.

Colon trauma: Royal Melbourne Hospital experience.

BACKGROUND: Recent studies from the USA and South Africa suggest that primary repair or resection and primary anastomosis have become the recommended treatment for most traumatic colon injuries. The aim of the present review is to determine the applicability of these studies to the urban Australian setting. METHODS: All patients with colon injuries operated on at the Royal Melbourne Hospital from March 1989 to March 1999 were identified. Data were collected by a retrospective chart review. RESULTS: A total of 20 patients sustained 26 injuries to the colon. Blunt injuries were more common than penetrating injuries (14 vs 6). Significant other injuries occurred in 15 patients. Colostomies were performed in four patients. The overall mortality rate was 10%. There were no anastomotic leaks. Primary repair or resection and primary anastomosis were not associated with any increase in intra-abdominal complications. CONCLUSION: Evidence from large trauma centres supporting primary repair or resection and primary anastomosis is also applicable to regions that have a low rate of traumatic colon injury.