Surgery (St Vincent's) - Research Publications
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ItemAssociation between imaging response and survival following neoadjuvant chemotherapy in patients with resectable colorectal liver metastases: A cohort study(WILEY, 2021-04)BACKGROUND: The association between the imaging response (structural or metabolic) to neoadjuvant chemotherapy (neoCT) before colorectal liver metastasis (CRLM) and survival is unclear. METHOD: A total of 201 patients underwent their first CRLM resection. A total of 94 (47%) patients were treated with neoCT. A multivariable, Cox proportional hazard regression analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between response groups. RESULTS: Multivariable regression analysis of the CT/MRI (n = 94) group showed no difference in survival (OS and PFS) in patients who had stable disease/partial response (SD/PR) or complete response (CR) versus patients who had progressive disease (PD) (OS: HR, 0.36 (95% CI: 0.11-1.19) p = .094, HR, 0.78 (95% CI: 0.13-4.50) p = .780, respectively), (PFS: HR, 0.70 (95% CI: 0.36-1.35) p = .284, HR, 0.51 (0.18-1.45) p = .203, respectively). In the FDG-PET group (n = 60) there was no difference in the hazard of death for patients with SD/PR or CR versus patients with PD for OS or PFS except for the PFS in the small CR subgroup (OS: HR, 0.75 (95% CI: 0.11-4.88) p = .759, HR, 1.21 (95% CI: 0.15-9.43) p = .857), (PFS: HR, 0.34% (95% CI: 0.09-1.22), p = .097, HR, 0.17 (95% CI: 0.04-0.62) p = .008, respectively). CONCLUSION: There was no convincing evidence of association between imaging response to neoCT and survival following CRLM resection.
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ItemSurvival benefit of neoadjuvant chemotherapy and surgery versus surgery first for resectable colorectal liver metastases: a cohort study(WILEY, 2021-06)BACKGROUND: There is continued debate about the survival benefit of neoadjuvant chemotherapy (neoCT) in patients with resectable colorectal liver metastases (CRLM). METHODS: In this retrospective cohort study, we included 201 patients with metastatic colorectal cancer who underwent their first CRLM resection and achieved resection of all sites of disease. We compared the overall survival (OS) and progression-free survival (PFS) between patients who received neoCT prior to CRLM resection with those who underwent CRLM upfront. A multivariable Cox proportional hazard regression analysis was performed to adjust for potential confounders. RESULTS: A total of 101 of 201 (51.2%) patients received chemotherapy prior to CRLM resection and 100 of 201 had surgery upfront. Multivariable Cox proportional hazard regression showed no statistically significant difference in the hazard of death for those given neoCT prior to resection of CRLM compared with surgery first for both OS and PFS (OS: hazard ratio 1.74, 95% confidence interval 0.85-3.55, P = 0.127, PFS: hazard ratio 1.42, 95% confidence interval 0.93-2.19, P = 0.107). CONCLUSION: In our series of patients with metastatic colorectal cancer who achieved surgical resection of all sites of disease, neoCT prior to CRLM resection was not associated with any survival benefit.
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ItemTreatment of peritoneal carcinomatosis with hyperthermic intraperitoneal chemotherapy in colorectal cancer(WILEY, 2017-09)The peritoneum is the second most common site of metastasis after the liver and the only site of metastatic disease in approximately 25% of patients with colorectal cancer (CRC). In the past, peritoneal carcinomatosis in CRC was thought to be equivalent to distant metastasis; however, the transcoelomic spread of malignant cells is an acknowledged alternative pathway. Metastasectomy with curative intent is well accepted in patients with liver metastasis in CRC despite the paucity of randomized trials. Therefore, there is rationale for local treatment with peritonectomy to eliminate macroscopic disease, followed by hyperthermic intraperitoneal chemotherapy to destroy any residual free tumour cells within the peritoneal cavity. The aim of this paper is to summarize the current evidence for cytoreduction and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis in CRC.
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ItemOutcomes from cytoreduction and hyperthermic intraperitoneal chemotherapy for appendiceal epithelial neoplasms(WILEY, 2019-09-01)Background Appendiceal epithelial neoplasms are rare cancers. Management of peritoneal disease from appendiceal neoplasms has historically been with debulking surgery. In recent decades, the advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care. Here, we report our single institution 10‐year experience with CRS and HIPEC for appendiceal neoplasms. Methods This is a retrospective review from 1 January 2008 to 1 June 2017 of all patients undergoing CRS and HIPEC for appendiceal neoplasms. Institutional ethics approval was granted for this project. Results One hundred and seventy‐two patients underwent 208 CRSs during this time. Overall, 83.72% of patients had one CRS and HIPEC procedure. Pseudomyxoma peritonei from a perforated appendiceal mucinous neoplasm accounted for 67.9% of cases. The median peritoneal carcinomatosis index (PCI) was 14, with complete cytoreduction achieved in 74.2% of patients. Fifty‐four percent of patients had at least one complication, with one (0.5%) peri‐operative mortality in our cohort. For the entire cohort, the median overall survival was 104 months and a 5‐year survival of 75%. In those having a complete cytoreduction, 5‐year survival was 90%, with a median disease free interval of 63 months. PCI and completeness of cytoreduction were independent predictors of overall survival. Conclusion Our results demonstrate that CRS and HIPEC for appendiceal neoplasms are safe and effective. Despite carrying some morbidity, it offers patients an excellent disease free and overall survival.
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ItemA clinical trial with protracted infusion 5-fluorouracil and mitomycin C for localized squamous cell carcinoma of the anus(WILEY, 2019-02)PURPOSE: Mitomycin C (MMC) plus standard 5-fluorouracil (FU) infusion in weeks 1 and 5 often contributes to radiotherapy interruptions and possibly less-than-ideal outcomes in anal cancer. This study was to evaluate alternative strategies for chemotherapy delivery that might be less toxic or more efficacious, and outcomes of patient-initiated treatment interruption for severe acute toxicity. MATERIALS AND METHODS: This was a prospective, nonrandomized study for patients with T1-4N0-3M0 anal squamous carcinoma. Radiotherapy of 54 Gy in 30 fractions over 6 weeks was given with infusion FU 300 mg/m2 /day for 96 hours/week for 6 weeks plus bolus MMC at 10 mg/m2 on D1. RESULTS: Fifty patients were recruited (72% female). Median age was 60.5 years (35-84). Forty-seven patients (94%) received 54 Gy. Median duration of chemoradiation was 39 days (37-105). Grade 3 and 4 acute toxicity were observed in 66%. Thirty-one percent with severe acute toxicity developed severe late toxicity. Of those who experienced severe late skin toxicity, 29% did not have severe acute toxicity. Disease-free survival at 5 years was 74% (95% confidence interval [CI], 60-84), and at 9 years 61% (95% CI, 46-74). Overall survival at 5 years was 84% (95% CI, 71-92), and at 9 years 67% (95% CI, 50-81). Colostomy-free survival at 5 years was 70% (95% CI, 56-81), and at 9 years 57% (95% CI, 40-72). CONCLUSION: It is feasible to deliver chemoradiation with bolus MMC and protracted infusion FU for anal cancer. Efficacy and toxicity of this regimen seem similar to conventional chemoradiation with FU/MMC. Acute skin toxicity is not a reliable predictor of severe late skin toxicity.
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ItemPrognostic value of tumour regression grade in locally advanced rectal cancer: a systematic review and meta-analysis(WILEY, 2018-07)AIM: The current standard of care for locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. There is a spectrum of response to neoadjuvant therapy; however, the prognostic value of tumour regression grade (TRG) in predicting disease-free survival (DFS) or overall survival (OS) is inconsistent in the literature. METHOD: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was undertaken using Ovid MEDLINE, Embase and Google Scholar. Inclusion criteria were Stage II and III locally advanced rectal cancer treated with long-course CRT followed by radical surgery. The aim of the meta-analysis was to assess the prognostic implication of each TRG for rectal cancer following neoadjuvant CRT. Long-term prognosis was assessed. The main outcome measures were DFS and OS. A random effects model was performed to pool the hazard ratio (HR) from all included studies. RESULTS: There were 4875 patients from 17 studies, with 775 (15.9%) attaining a pathological complete response (pCR) and 719 (29.9%) with no response. A significant association with OS was identified from a pooled-estimated HR for pCR (HR = 0.47, P = 0.002) and nonresponding tumours (HR = 2.97; P < 0.001). Previously known tumour characteristics, such as ypN, lymphovascular invasion and perineural invasion, were also significantly associated with DFS and OS, with estimated pooled HRs of 2.2, 1.4 and 2.3, respectively. CONCLUSION: In conclusion, the degree of TRG was of prognostic value in predicting long-term outcomes. The current challenge is the development of a high-validity tests to predict pCR.
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ItemSurgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process(SPRINGER, 2018-04)Surgery remains the curative treatment modality for colorectal cancer in all stages, including stage IV with resectable liver metastasis. There is emerging evidence that the stress response caused by surgery as well as other perioperative therapies such as anesthesia and analgesia may promote growth of pre-existing micro-metastasis or potentially initiate tumor dissemination. Therapeutically targeting the perioperative period may therefore reduce the effect that surgical treatments have in promoting metastases, for example by combining β-adrenergic receptor antagonists and cyclooxygenase-2 (COX-2) inhibitors in the perioperative setting. In this paper, we highlight some of the mechanisms that may underlie surgery-related metastatic development in colorectal cancer. These include direct tumor spillage at the time of surgery, suppression of the anti-tumor immune response, direct stimulatory effects on tumor cells, and activation of the coagulation system. We summarize in more detail results that support a role for catecholamines as major drivers of the pro-metastatic effect induced by the surgical stress response, predominantly through activation of β-adrenergic signaling. Additionally, we argue that an improved understanding of surgical stress-induced dissemination, and more specifically whether it impacts on the level and nature of heterogeneity within residual tumor cells, would contribute to the successful clinical targeting of this process. Finally, we provide a proof-of-concept demonstration that ex-vivo analyses of colorectal cancer patient-derived samples using RGB-labeling technology can provide important insights into the heterogeneous sensitivity of tumor cells to stress signals. This suggests that intra-tumor heterogeneity is likely to influence the efficacy of perioperative β-adrenergic receptor and COX-2 inhibition, and that ex-vivo characterization of heterogeneous stress response in tumor samples can synergize with other models to optimize perioperative treatments and further improve outcome in colorectal and other solid cancers.
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ItemColorectal peritoneal metastases: pathogenesis, diagnosis and treatment options - an evidence-based update(WILEY, 2020-09)Peritoneal metastases confer the worst survival among all sites in patients with metastatic colorectal cancer. They develop largely through transcoelomic spread, with a sequence of events that allow cells to first detach from primary tumours, survive in the peritoneal environment, attach to the peritoneal surface of organs and migrate into the submesothelial space to create a microenvironment conducive to metastatic growth. Diagnostic challenges have previously hindered early identification of peritoneal metastases. While advances in diagnostic modalities have improved our ability to identify peritoneal metastases, lesions under 0.5 cm remain challenging to detect. The advent of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases a favourable long-term survival. Recent trials, however, have cast doubts on the efficacy of HIPEC, with the recent PRODIGE 7 trial showing no benefit from oxaliplatin based HIPEC in addition to good quality cytoreductive surgery in resectable disease. While peritoneal recurrence can be reliably predicted from high-risk features in primary tumours such as a perforated cancer, ovarian metastases or T4a cancers, the use of prophylactic second look surgery with HIPEC or adjuvant HIPEC failed to demonstrate any survival benefit in high-risk cases in recent clinical trials, raising further questions about the efficacy of HIPEC. With high failure rates from systemic chemotherapy in unresectable disease, novel surgical techniques such as pressurized intraperitoneal aerolized chemotherapy are being investigated in clinical trials worldwide. Further collaborative research is needed to explore newer avenues of treatment for this poor prognostic cohort.
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ItemPrognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis(WILEY, 2020-11)AIM: Peritoneal metastases from colorectal cancer confer the worst survival among all metastatic sites. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with isolated colorectal peritoneal metastases (CRPM) a favourable long-term survival. There are numerous factors postulated to influence survival in patients undergoing CRS and HIPEC. The aim of this study was to identify the key perioperative prognostic factors that influence survival in patients undergoing CRS and HIPEC for isolated CRPM. METHOD: A systematic review and meta-analysis were conducted to evaluate prognostic factors influencing survival in patients undergoing CRS and HIPEC for isolated CRPM. RESULTS: Thirty-three studies fitted the inclusion criteria for the systematic review, with 25 studies included in the meta-analysis. On pooled analysis, incomplete cytoreduction, increasing peritoneal carcinoma index (PCI) and lymph node involvement were significantly associated with a worse survival. Additionally, a rectal primary [hazard ratio (HR) 1.93, 95% CI 1.10-3.37], adjuvant chemotherapy (HR 0.71, 95% CI 0.54-0.93) and perioperative grade III/IV morbidity (HR 1.59, 95% CI 1.17-2.16) were also found to significantly influence survival. Notably, tumour differentiation and signet ring cell histology did not influence survival on pooled analysis. CONCLUSION: This meta-analysis confirms that in patients undergoing CRS and HIPEC for isolated CRPM, incomplete cytoreduction, high PCI and lymph node involvement have a negative influence on survival. In addition, a rectal primary, adjuvant chemotherapy use and grade III/IV morbidity are important factors that also significantly influence survival.
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ItemFDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy(NATURE PUBLISHING GROUP, 2011-08-09)BACKGROUND: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.