Oliver S Chow

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

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

Peritoneal carcinomatosis in patients with gastric cancer, and the role for surgical resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy

BACKGROUND The aims of this study were to create a model of peritoneal carcinomatosis in patients with gastric cancer and to evaluates outcomes in patients with gastric cancer treated using surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS A single-institution cohort of patients with gastric cancer was analyzed according to the development of gastric cancer with peritoneal carcinomatosis (GCPC). Variables were evaluated using regression analysis. Kaplan-Meier analysis was used to evaluate outcomes after surgical resection, cytoreductive surgery, and HIPEC. RESULTS Age ≤60 years and local tumor stage (T3/T4) were significantly associated with GCPC (odds ratio, 3.95 and 3.94, respectively). Thirty-six-month survival was 57% for patients without peritoneal disease and 39% for patients with GCPC. There was no significant trend of improved survival after surgical management or HIPEC. CONCLUSIONS Age ≤60 years and T3/T4 tumor stage are risk factors for GCPC. Intermediate-term survival of patients with GCPC treated with surgical resection or cytoreductive surgery and HIPEC was not improved, though future research should address the possible benefits of aggressive approaches to the treatment of GCRC.

Integrated genomic profiling identifies microRNA-92a regulation of IQGAP2 in locally advanced rectal cancer.

Locally advanced rectal cancer (LARC) is treated with chemoradiation prior to surgical excision, leaving residual tumors altered or completely absent. Integrating layers of genomic profiling might identify regulatory pathways relevant to rectal tumorigenesis and inform therapeutic decisions and further research. We utilized formalin‐fixed, paraffin‐embedded pre‐treatment LARC biopsies (n=138) and compared copy number, mRNA, and miRNA expression with matched normal rectal mucosa. An integrative model was used to predict regulatory interactions to explain gene expression changes. These predictions were evaluated in vitro using multiple colorectal cancer cell lines. The Cancer Genome Atlas (TCGA) was also used as an external cohort to validate our genomic profiling and predictions. We found differentially expressed mRNAs and miRNAs that characterize LARC. Our integrative model predicted the upregulation of miR‐92a, miR‐182, and miR‐221 expression to be associated with downregulation of their target genes after adjusting for the effect of copy number alterations. Cell line studies using miR‐92a mimics and inhibitors demonstrate that miR‐92a expression regulates IQGAP2 expression. We show that endogenous miR‐92a expression is inversely associated with endogenous KLF4 expression in multiple cell lines, and that this relationship is also present in rectal cancers of TCGA. Our integrative model predicted regulators of gene expression change in LARC using pre‐treatment FFPE tissues. Our methodology implicated multiple regulatory interactions, some of which are corroborated by independent lines of study, while others indicate new opportunities for investigation.

Anorectal function and quality of life in patients with early stage rectal cancer treated with chemoradiation and local excision

BACKGROUND: Little is known about anorectal function and quality of life after chemoradiation followed by local excision, which is an alternative to total mesorectal excision for selected patients with early rectal cancer. OBJECTIVE: The purpose of this study was to prospectively assess anorectal function and health-related quality of life of patients with T2N0 rectal cancer who were treated with an alternative approach. DESIGN: This was a prospective, phase II trial. SETTINGS: The study was multicentric (American College of Surgeons Oncology Group trial Z6041). INTERVENTIONS: Patients with stage cT2N0 rectal adenocarcinomas were treated with an oxaliplatin/capecitabine-based chemoradiation regimen followed by local excision. MAIN OUTCOME MEASURES: Anorectal function and quality of life were assessed at enrollment and 1 year postoperatively with the Fecal Incontinence Severity Index, Fecal Incontinence Quality of Life scale, and Functional Assessment of Cancer Therapy-Colorectal Questionnaire. Results were compared, and multivariable analysis was performed to identify predictors of outcome. RESULTS: Seventy-one patients (98%) were evaluated at enrollment and 66 (92%) at 1 year. Compared with baseline, no significant differences were found on Fecal Incontinence Severity Index scores at 1 year. Fecal Incontinence Quality of Life results were significantly worse in the lifestyle (p < 0.001), coping/behavior (p < 0.001), and embarrassment (p = 0.002) domains. There were no differences in the Functional Assessment of Cancer Therapy overall score, but the physical well-being subscale was significantly worse and emotional well-being was improved after surgery. Treatment with the original chemoradiation regimen predicted worse depression/self-perception and embarrassment scores in the Fecal Incontinence Quality of Life, and male sex was predictive of worse scores in the Functional Assessment of Cancer Therapy overall score and trial outcome index. LIMITATIONS: Small sample size, relatively short follow-up, and absence of information before cancer diagnosis were study limitations. CONCLUSIONS: Chemoradiation followed by local excision had minimal impact on anorectal function 1 year after surgery. Overall quality of life remained stable, with mixed effects on different subscales. This information should be used to counsel patients about expected outcomes.

Lymph node yield in right colectomy for cancer: a comparison of open, laparoscopic and robotic approaches

Studies have demonstrated a relationship between lymph node (LN) yield and survival after colectomy for cancer. The impact of surgical technique on LN yield has not been well explored.

Can We Predict Response and/or Resistance to Neoadjuvant Chemoradiotherapy in Patients with Rectal Cancer?

The current management of locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. Response to CRT varies significantly, and the ability to predict responsiveness, so that treatment modalities can be tailored to the tumor biology of the individual patient, remains a pressing goal. Although many studies have reported promising findings, no markers of response or resistance have been validated and widely incorporated into clinical use. However, many ongoing prospective clinical trials have the potential to dramatically change the standard of care for rectal cancer. This review summarizes the current understanding of predictors of response to CRT, ranging from patient-specific factors to radiologic modalities, with a special emphasis on the rapidly expanding field of molecular biomarkers derived from genomic data.

Maximizing Neoadjuvant Treatment Response and Watch and Wait

Neoadjuvant therapy has been a keystone supporting the advances we have made in the treatment of rectal cancer. The reason for maximizing tumor response to neoadjuvant treatment is clear: as response improves, the consideration of less invasive treatment options such as local excision and “watch-and-wait” (nonoperative) strategies can be explored. Tumor response is closely correlated with long-term oncologic outcome, and the optimization of tumor response to neoadjuvant therapy is thought to improve long-term outcomes as well [1–3]. Maximizing neoadjuvant treatment response is therefore expected to have profound effects on both oncologic outcomes and quality of life.

Reply to Cristóbal and Co‐authors' comment, deregulation of miR‐92a in locally advanced rectal cancer

We thank Crist obal et al. for their interest and comment on our recently published manuscript. As we noted in our discussion and as the commentators recognized, there are additional studies that can be used to elucidate further the direct regulatory relationships between miRNAs and their putative targets. Our goal, however, was to perform in vitro experiments to corroborate the association identified as meaningful through our sparse regression model, which takes statistical advantage of the fact that aberrantly expressed miRNAs can have broad but subtle effects and contribute to small changes in expression across a large number of downstream genes, both directly and indirectly. The commentators note that without a perfect match between miRNAs and its seed, the target mRNA is not degraded and thus mRNA level changes would not be observed. We could have further elaborated that the presence or absence of a direct regulatory relationship between miR-92a and KLF4 cannot be supported by our studies alone, but we felt that this was clear from our discussion. We at no point claimed a direct regulation of IQGAP2 and KLF4 by miR-92a in our paper. We agree with Crist obal et al.’s comment that our regression model suggests that further work assessing the functional relevance of IQGAP2 and KLF4 deregulation is warranted. As our group is most interested in rectal cancer response to chemoradiation, we aim to leverage our integrative model to characterize the differences in regulatory pathways between tumors that are highly responsive to chemoradiation and those that are resistant.

To the editor, in reply to Cristóbal and co‐authors' comment, “Deregulation of miR‐92a in Locally Advanced Rectal Cancer”

We thank Crist obal et al. for their interest and comment on our recently published manuscript. As we noted in our discussion and as the commentators recognized, there are additional studies that can be used to elucidate further the direct regulatory relationships between miRNAs and their putative targets. Our goal, however, was to perform in vitro experiments to corroborate the association identified as meaningful through our sparse regression model, which takes statistical advantage of the fact that aberrantly expressed miRNAs can have broad but subtle effects and contribute to small changes in expression across a large number of downstream genes, both directly and indirectly. The commentators note that without a perfect match between miRNAs and its seed, the target mRNA is not degraded and thus mRNA level changes would not be observed. We could have further elaborated that the presence or absence of a direct regulatory relationship between miR-92a and KLF4 cannot be supported by our studies alone, but we felt that this was clear from our discussion. We at no point claimed a direct regulation of IQGAP2 and KLF4 by miR-92a in our paper. We agree with Crist obal et al.’s comment that our regression model suggests that further work assessing the functional relevance of IQGAP2 and KLF4 deregulation is warranted. As our group is most interested in rectal cancer response to chemoradiation, we aim to leverage our integrative model to characterize the differences in regulatory pathways between tumors that are highly responsive to chemoradiation and those that are resistant.

Innominate artery injury from disseminated tuberculosis.

A 49-year-old man presented with chest pain and was found to have hemorrhage and drainage from a chest wound secondary to disseminated tuberculosis involving the sternum and ankle. He then developed acute hemorrhage from an innominate artery pseudoaneurysm originating just below a severely diseased sternoclavicular junction. A staged approach was used to manage his pathology given the life-threatening bleeding and his debilitated condition. He underwent endovascular stent grafting to exclude the pseudoaneurysm, followed by aggressive debridement of the affected sternal area.