The Impact of Virtual Cancer Care on Chemotherapy Delivery and Clinical Outcomes in Colorectal Cancer Patients Receiving Systemic Therapy: A Pre- and Intra-Pandemic Analysis.

(1) Background: The coronavirus 2019 pandemic has resulted in an abrupt transition to virtual oncology care worldwide. This study's objective is to evaluate chemotherapy delivery and clinical outcomes in patients on systemic treatment for colorectal cancer before and during the pandemic. (2) Methods: Clinical data was collected on patients with colorectal cancer receiving intravenous chemotherapy at The Ottawa Hospital from June 2019 to March 2021. Patients were stratified by whether they were started on chemotherapy pre-pandemic (June 2019-January 2020) or intra-pandemic (February 2020-March 2021). Multiple regression analysis was used to compare outcomes between pandemic periods; (3) Results: There were 220 patients included in this study. The proportion of virtual consultations (1.2% to 64.4%) and follow-up visits (5.2% to 83.3%) increased during the pandemic. There was no difference in the incidence of treatment delays (OR = 1.01, p = 0.78), chemotherapy dose reductions (OR = 0.99, p = 0.69), emergency department visits (OR = 1.23, p = 0.37) or hospitalizations (OR = 0.73, p = 0.43) between pandemic periods. A subgroup analysis revealed no difference in outcomes independent of the presence of metastases; (4) Conclusion: These findings serve as an important quality-care indicator and demonstrate that virtual oncology care appears safe in a cohort of high-risk colorectal cancer patients.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation.

BACKGROUND: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC. METHODS: We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes. RESULTS: Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23-88), 69% were male, and 80% had performance status (PS) 0-1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66-72%) and 79% (95% CI 77-82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR. CONCLUSIONS: NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.

Management of Epidermal Growth Factor Receptor Inhibitor-Induced Hypomagnesemia: A Systematic Review.

BACKGROUND: Despite occurring in 30% of patients, there are no evidence-based guidelines on the management of epidermal growth factor receptor inhibitor (EGFRI)-induced hypomagnesemia. Based on expert opinion, severe hypomagnesemia should be treated by intravenous magnesium replacement. A systematic review of published data of intervention on EGFRI-induced hypomagnesemia was performed. METHODS: Articles from 1960 to March 2015 were identified from Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed using a peer-reviewed systematic search strategy. Eligible studies included randomized controlled trials or observational studies that evaluated management of hypomagnesemia in adult patients treated with EGFRIs. Risk factors for severe hypomagnesemia were also assessed. The quality of included studies was rated using Jadad scores. RESULTS: A total of 1327 references were identified, and 6 studies, involving 486 patients, met inclusion criteria for analysis. There were no randomized controlled trials, and all included studies were of poor quality. From the studies included in this review, severity of EGFRI-induced hypomagnesemia was associated with length of EGFRI treatment, concomitant platinum chemotherapy, increasing age, and baseline magnesium concentration. In most patients with grade 3 or 4 hypomagnesemia, high-dose intravenous magnesium replacement did not achieve sustainable magnesium repletion beyond 72 hours. Oral magnesium supplementation was not effective or tolerable. Severe hypomagnesemia has been associated with tachycardia and mental alteration. After discontinuation of EGFRI therapy, hypomagnesemia generally resolves within weeks to months. CONCLUSIONS: There is an absence of high-quality evidence for the management of EGFRI-induced hypomagnesemia. As hypomagnesemia is often refractory to frequent intravenous or oral replacement, there is a need for prospective trials of new interventions for this common toxicity.

An open-label phase II study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for metastatic colorectal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC-1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR-2, inhibiting VEGFR-2 activation and signaling. METHODS: Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. Endpoints included progression-free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months. RESULTS: Forty-eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6-13.1 months). The objective response rate was 58.3% (95% CI: 43.21-72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8-98.7). Median overall survival was 20.4 months (95% CI: 18.5-25.1 months). The most frequent grade 3-4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest. CONCLUSION: RAM may enhance the efficacy of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.

Stage-dependent differential expression of microRNAs in colorectal cancer: potential role as markers of metastatic disease.

MicroRNAs (miRs) are short non-coding RNAs that bind complementary sequences in mRNA resulting in translation repression and/or mRNA degradation. We investigated expression of the reported metastasis-associated miRs-335, 206, 135a, 146a, 146b, 10b, 21, let7a and let7b in normal mucosa, non-metastatic and metastatic colorectal cancer (CRC). Expression of target miRs in micro-dissected paraffin embedded tissues was evaluated in 15 primary tumours with adjacent normal tissue from patients that were disease-free at 4 years (cohort A) and 19 paired primary tumours with corresponding liver metastases (cohort B) by quantitative real-time PCR. Increased expression of miR-21, mir-135a and miR-335 was associated with clinical progression of CRC, while miR-206 demonstrated an opposite trend. The levels of mir-21 did not associate with the expression of PTEN, an important tumour suppressor in CRC and one of many putative targets of miR-21, but interestingly was associated with stage of disease in the PTEN expressing tumours. Surprisingly, let7a, a KRAS-targeting miR, showed elevated expression in metastatic disease compared to normal mucosa or non-metastatic disease, and only in KRAS mutation positive tumors. Finally, a prognostic signature of miR 21,135a, 335, 206 and let-7a for detecting the presence of metastases had a specificity of 87% and sensitivity of 76% for the presence of metastases. In summary, we have shown stage-associated differential expression of five out of nine tested metastasis-associated miRs. We have further found that an analysis of these five miRs expression levels in primary tumors significantly correlates with the presence of metastatic disease, making this a potential clinically useful prognostic tool.

High-grade neuroendocrine carcinoma of the colon, long-term survival in advanced disease.

A 72-year-old man was diagnosed with a poorly differentiated hepatic flexure mass seen on routine screening colonoscopy. He underwent a right hemicolectomy and biopsy of a liver lesion noted at laparotomy. Pathology revealed a high-grade neuroendocrine carcinoma in the primary tumor and the liver lesion. Post-operative imaging revealed an isolated FDG avid liver metastases which had not been appreciated pre-operatively. He was treated with combination platinum and etoposide for extensive stage small-cell carcinoma of the colon. After 6 cycles of chemotherapy, the isolated liver lesion remained FDG avid, albeit less than baseline. Radiofrequency ablation of the avid liver lesion was performed. Further, chemotherapy was given as the lesion remained FDG avid. Ablation was repeated and a subsequent biopsy was positive. Chemotherapy resumed for a total of 10 cycles. Repeat PET scan became negative and the patient remains disease-free 7 years from an initial diagnosis of extensive stage small-cell colon cancer with a negative PET scan. Aggressive locoregional treatment is an option in patients with extensive stage small-cell carcinoma of the colon who are left with an oligometastasis after platinum-based systemic chemotherapy.

EGFR expression variance in paired colorectal cancer primary and metastatic tumors.

BACKGROUND: Previous studies indicate that drugs targeting the Epidermal Growth Factor Receptor (EGFR) signaling pathways can induce objective responses, prolong time to progression and improve survival of patients with metastatic colorectal cancer (mCRC). EGFR expression in the primary tumour may not predict response to these agents and data is conflicting regarding the correlation of EGFR expression in the primary tumour with the metastatic site. In other tumour sites, the presence of EGFR mutations was associated with efficacy in a subset of patients. OBJECTIVES: The goal of this study is to correlate tumour EGFR expression between primary and liver metastatic sites, and to assess the mutational status in the EGFR kinase domain. METHODS: This is a single center retrospective study of patients who underwent surgical resection of CRC, for whom paired paraffin-embedded tissue blocks of primary tumours and resected liver metastases were available. EGFR immunostaining and mutation analyses were preformed. RESULTS: Fifty six paired colorectal primaries and metastases were available for analysis. EGFR was detectable in 96.6% of the primary samples and in 89.7% of the metastatic samples. Perfect concordance in the intensity score between the primary and the metastases was found in 46.5% of the cases. While individual pairs were poorly concordant for intensity, the proportion of primaries with intense staining was similar to the proportion with intense staining in the metastatic samples. Overall survival did not correlate with either EGFR expression in the primary tumour, or with EGFR expression in the metastasis. There were 2 cases with mutations in the EGFR kinase domain. Both mutations were found in exon21 C>T. CONCLUSIONS: In this analysis, EGFR expression in the primary tumor site was not predictive of its level in the metastasis. EGFR expression levels in the primaries and in the metastases do not appear to be useful prognostic markers.

Safety and efficacy of panitumumab following cetuximab: retrospective review of the Memorial Sloan-Kettering experience.

There are two highly selective antibodies to the epidermal growth factor receptor (EGFR) now available for use in metastatic colorectal cancer (mCRC). In KRAS wild type patients, cetuximab (Cmab)-an IgG1 chimeric molecule--has activity alone and in combination with chemotherapy for the first, second and third-line settings. Panitumumab (Pmab)--a fully humanized IgG2 molecule--has activity as a single agent in chemorefractory mCRC and shows promising activity in combination with chemotherapy. It remains unclear which antibody to use. This retrospective review of our experience with Pmab in 13 EGFR antibody-naive patients and in 22 patients previously treated with Cmab for mCRC highlights a lack of hypersensitivity reactions (HSR) with Pmab, even in patients who experienced HSR to Cmab. In patients who received Cmab, 22% developed grade 3-4 HSR. There were no HSR on subsequent treatment with Pmab. We demonstrate similar activity in 95% of cases, between Cmab and Pmab both alone and in combination with chemotherapy in the treatment of mCRC. In one case we report unique sensitivity to Pmab after progression with Cmab.

Overview of systemic therapy for colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and second leading cause of death from cancer in North America. The authors provide an overview of the indications for both chemotherapy and targeted therapy, as well as discuss the efficacy and toxicity of systemic therapy. They highlight the key studies that lead to the initial historical use of fluorouracil (5FU) based chemotherapy in the adjuvant and metastatic setting, the recent adoption of 5FU plus leucovorin (LV) and oxaliplatin (FOLFOX) chemotherapy over 5FU when treating adjuvant patients, and the use of FOLFOX or 5FU plus LV and irinotecan (FOLFIRI) in metastatic patients. They also review the role of chemotherapy in treating rectal cancer and resectable liver metastatic disease. Future areas of research focus for systemic therapy of colorectal cancer are highlighted.

A Case of Appendiceal Adenocarcinoma with Clinical Benefit from FOLFOX and Bevacizumab.

A 44-year-old woman presented with lower abdominal pain and bilateral ovarian masses on ultrasound. Exploratory laparotomy revealed extensive peritoneal and intra-abdominal disease and an abnormal appendix. Bilateral salpingo-oophorectomy, infracolic omentectomy, ileocolic resection and primary anastomosis were performed. Final pathology revealed a primary appendiceal adenocarcinoma, poorly differentiated, of signet ring cell type. CT scan postoperatively revealed gross residual disease. The patient was treated with FOLFOX chemotherapy combined with bevacizumab. Repeat CT scan showed a decrease in residual disease and the patient clinically improved. After her treatment has been continued for 13 months, she remains clinically well and her CT scan shows sustained disease stability. Disseminated appendiceal carcinoma is generally considered to be refractory to 5-FU-based chemotherapy and, to our knowledge, this is the first reported case of a patient with appendiceal adenocarcinoma demonstrating clinical benefit and sustained stability of disease with combination chemotherapy plus bevacizumab.

Systemic therapy for colon cancer.

Colorectal cancer (CRC) is a common and frequently fatal disease in North America. A multidisciplinary approach to the prevention, diagnosis, and treatment of this disease is essential. There have been many advances in the surgical and medical treatment of CRC over the last 10 years. This article reviews the indications, efficacy, and toxicity of chemotherapy and targeted therapy for patients who have CRC.

Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials.

PURPOSE: This study analyzed patients enrolled in two large, prospectively randomized trials of systemic chemotherapy (adjuvant/palliative setting) for non-small-cell lung Cancer (NSCLC). The main objective was to determine if age and/or the burden of chronic medical conditions (comorbidity) are independent predictors of survival, treatment delivery, and toxicity. PATIENTS AND METHODS: Baseline comorbid conditions were scored using the Charlson comorbidity index (CCI), a validated measure of patient comorbidity that is weighted according to the influence of comorbidity on overall mortality. The CCI score (CCIS) was correlated with demographic data,(ie, age, sex, race), performance status (PS), histology, cancer stage, patient weight, hemoglobin, alkaline phosphatase, lactate dehydrogenase, outcomes of chemotherapy delivery (ie, type, total dose, and dose intensity), survival, and response. RESULTS: A total of 1,255 patients were included in this analysis. The median age was 61 years (range, 34 to 89 years); 34% of patients were elderly (at least 65 years of age); and 31% had comorbid conditions at randomization. Twenty-five percent of patients had a CCIS of 1, whereas 6% had a CCIS of 2 or greater. Elderly patients were more likely to have a CCIS equal to or greater than 1 compared with younger patients (42% v 26%; P < .0001), as were male patients (35% v 21%; P < .0001) and patients with squamous histology (36% v 29%; P = .001). Although age did not influence overall survival, the CCIS appeared prognostic (CCIS 1 v 0; hazard ratio 1.28; 95%CI, 1.09 to 1.5; P = .003). CONCLUSION: In these large, randomized trials, the presence of comorbid conditions (CCIS > or = 1), rather than age more than 65 years, was associated with poorer survival.

Genitourinary small cell carcinoma: a retrospective review of treatment and survival patterns at The Ottawa Hospital Regional Cancer Center.

OBJECTIVE: To review patients with genitourinary (GU) small cell carcinoma (SCC) treated at a regional cancer centre, as due to its rarity and aggressive nature, GU SCC remains a therapeutic challenge. PATIENTS AND METHODS: The charts of patients managed at a regional cancer centre between 1991 and 2002 for any GU diagnosis were manually reviewed to identify GU SCC. Demographic, staging, treatment and outcome data were extracted. The Veterans Administration small cell lung cancer staging classification of "limited" or "extensive" disease was adapted for SCC of the prostate and bladder (with "limited" defined as disease localized to the true and false pelvis, and "extensive" as disease beyond the pelvis). RESULTS: In all, 555, 858 and 5066 new cases of primary renal, bladder and prostate cancer, respectively, were identified. Of these patients, 22 had GU SCC (12 bladder and 10 prostate; there were no cases of SCC of the kidney). Eight of 12 patients with bladder SCC had limited disease; five of 12 are alive (all with limited disease at diagnosis), and the median survival was 19.8 months. Surviving patients received similar therapy, with transurethral resection of the bladder tumour, platinum-based chemotherapy, etoposide (4-6 cycles), and radical radiotherapy (56-60 Gy). Two of 10 patients with SCC of the prostate had limited-stage disease, but all 10 died, the median survival being 9.5 months. Survival by stage for both types combined was 59 months for limited disease and 8 months for extensive disease. CONCLUSIONS: These results indicate that GU SCC is an aggressive cancer; limited-stage SCC of the bladder or prostate, when treated with platinum/etoposide chemotherapy and radical radiotherapy, has a more favourable outcome than that of extensive GU SCC.