The following colorectal cancer research updates extend from July 2nd to August 3rd, 2020, inclusive and are intended for informational purposes only.
- Phase II LEAP Clinical Trial to Treat mCRC
- Health Canada approves VITRAKVI (Larotrectinib), first tumour agnostic cancer treatment for advanced solid tumours harbouring an NTRK gene fusion
- A Phase II, Open-Label, Multicentre, Study of an Immunotherapeutic Treatment for the MSI High Colorectal Cancer Metastatic Population
- Phase III Study at the Odette Cancer Centre Comparing Arfolitixorin vs. Leucovorin: Both in Combination with 5FU, Oxaliplatin, and Bevacizumab in Patients with Advanced Colorectal Cancer
- Immunotherapy for Early Stage CRC
- Clinical Trial For KRAS G12C Mutant Patients
- Tumor Mutational Burden Identifies Cancer Responsive to Immunotherapy
- Checkpoint Inhibitor Immunotherapy Delays CRC Progression
- Onvansertib Precision Medicine Being Developed for KRAS mutant Colon Cancers
- CRC With Peritoneal Metastases: CRS-HIPEC Refinements
- Anti-hypertensive Medications Linked to Reduced Risk of CRC
- Entrectinib Results Emphasize Need for NTRK Detection
- Prognostic and Predictive Biomarkers in Metastatic Colorectal Cancer Patients Receiving Regorafenib
- Hepatic Artery Infusion Pump (HAIP) Chemotherapy Program – Sunnybrook Hospital
- Living Donor Liver Transplantation for Unresectable Colorectal Cancer Liver Metastases
- Study Offered at the Odette Cancer Centre to Treat Recurrent Rectal Cancer
- CRC Risk Factors Increasing Among Millennials
- Many Early Onset Colon Cancers are caused by Genetic Mutations Through Families
- Young Adult Colorectal Cancer Clinic Available at Sunnybrook Hospital
- Oral Microbiome Bacterium May Directly Trigger Spread of CRC
- Four Actionable Targets For mCRC That APPs Should Know
- Optimal Nutrition Formulas for Patients Undergoing Surgery for CRC
- Impact of COVID‐19 on Advanced CRC
- Researchers ID 6 COVID-19 Symptom Sets
- Frequently Asked Questions for COVID-19
DRUGS / SYSTEMIC THERAPIES
- Phase II LEAP Clinical Trial For mCRC (Mar.1/20)
The purpose of this study is to determine the safety and efficacy of combination therapy with pembrolizumab (MK-3475) and Levantine (E7080/MK-7902) in patients with triple-negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), or biliary tract cancers (BTC). Participants will be enrolled in initial tumor-specific cohorts, which will be expanded if adequate efficacy is determined. The trial is available at the Odette Cancer Centre and at the Princess Margaret Cancer Centre in Toronto as well as the following Centres throughout Canada: Abbotsford, BC; Winnipeg, MB; CHU de Quebec. For information, visit the link below.
- Health Canada Approves VITRAKVI (Larotrectinib), First Tumour Agnostic Cancer Treatment For Advanced Solid Tumours Harbouring an NTRK Gene Fusion (Mar.5/20)
Bayer announced that there is now a treatment in Canada for tyrosine receptor kinase fusion protein-driven childhood and adult cancers. Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusions can result in the production of TRK fusion proteins that can lead to uncontrolled cell growth and cancer. Health Canada issued a Notice of Compliance with Conditions (NOC/c) for VITRAKVI® (Larotrectinib). VITRAKVI® is approved for the treatment of adult and pediatric patients with solid tumours that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory treatment options. Treatment with VITRAKVI® should be initiated following confirmation of an NTRK gene fusion in a tumour specimen using a validated test.
This is the first time Health Canada has approved a tumour agnostic treatment, such that patients with advanced solid tumours harbouring an NTRK gene fusion may be eligible for treatment with VITRAKVI®, across multiple tumour types and ages. VITRAKVI® is a first-in class oral and highly selective TRK inhibitor that may shrink the tumour or may slow or stop it from growing. In the clinical trials that were the basis for this approval, TRK fusion cancer patients treated with Larotrectinib experienced clinical benefit across numerous tumour types, including lung, thyroid, melanoma, GIST (gastrointestinal stromal tumour), colon, soft tissue sarcoma, salivary gland, and infantile fibrosarcoma. The overall response rate (ORR) was 75% (95% CI, 64%, 85%) with 22% of patients experiencing a complete response (CR) to treatment. The ORR observed was 90% in pediatrics and 69% in adults, and responses were rapid and durable.
What is TRK Fusion Cancer?
TRK fusion cancer is rare and occurs when an NTRK gene fuses with another unrelated gene, producing a TRK fusion protein that becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumours with varying frequency, including lung, thyroid, gastrointestinal cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma). TRK fusion proteins are rare in common cancers (such as colorectal cancer) and common in rare cancers.
NB: The pan Canadian Oncology Drug Review Expert Committee (pERC) has recently issued a funding recommendation in respect of Larotrectinib. It conditionally recommends the reimbursement of Larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with locally advanced solid tumors that have an NTRK gene fusion This recommendation pertains only to adult and pediatric patients with salivary gland tumours, adult or pediatric patients with soft tissue sarcoma (STS) and pediatric patients with cellular congenital mesoblastic nephroma or infantile fibrosarcoma, without a known acquired resistance mutation, that are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory treatment options, only if the following conditions are met:
- Cost-effectiveness being improved to an acceptable level
- Feasibility of adoption (budget impact and access to testing) is addressed
Stay tuned as the expert committee is currently reviewing feedback submissions from various stakeholders.
Please note: the expert review committee has as of October 31st, 2019 issued a final negative funding recommendation in respect of Larotrectinib. Efforts are currently underway to assemble a massive campaign to address this final recommendation by working to secure a sustainable, long-term funding solution for TRK fusion cancer patients.
Another submission will be made by Bayer to CADTH in the fall of 2020.
- Bayer has launched a testing program called FastTRK. As per an information sheet that may be obtained from CCRAN, FastTRK is a clinical testing program for the diagnosis of NTRK gene fusions. Sponsored by Bayer, this is a complimentary service for clinicians to determine whether their patients’ cancer has an NTRK gene fusion. Solid tumour samples from eligible patients (in the form of a solid tumour block or prepared slides) will be tested by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). Currently, Bayer has partnered with LifeLabs and the Kingston Health Sciences Centre (KHSC) to provide NTRK gene fusion testing services for Canadians. The FastTRK program will be supported at least until the end of 2021.
- Bayer will continue to offer the therapy to patients who are identified to have TRK fusion cancers and who are responding to the therapy.
- Bayer will provide a TRAKTION Patient Support Program to assist patients while on the therapy.
- A Phase 2, Open-label, Multicenter, Study of an Immunotherapeutic Treatment for the MSI High Colorectal Cancer Metastatic Population (Mar.12/20)
The purpose of this study is to look at the effectiveness of the vaccine DPX-Survivac in combination with the drugs cyclophosphamide and the immunotherapy Pembrolizumab in patients with solid cancers who are identified to be MSI-High. All patients will receive combination therapy of DPX-Survivac, cyclophosphamide, and pembrolizumab. Patients participating will know which treatment they are receiving. The trial is currently hosted at the Odette Cancer Centre, and a new site is opening at Mt. Sinai Hospital.
- Phase III Study at the Odette Cancer Centre Comparing Arfolitixorin vs. Leucovorin in Combination with 5FU, Oxaliplatin and Bevacizumab in Patients with Advanced Colorectal Cancer (Mar.12/20)
The purpose of this study is to look at the effectiveness of the drug Arfolitixorin in combination with 5-fluorouracil (5FU), oxaliplatin, and bevacizumab in patients with colorectal cancer. Patients with advanced/metastatic colorectal cancer who meet certain criteria may be able to participate. There will be two groups of patients participating in this study;
- one group will receive Arfolitixorin in combination with 5FU), oxaliplatin, and bevacizumab,
- while the other group will receive the drug Leucovorin in combination with 5FU, oxaliplatin, and bevacizumab (standard of care).
The doctor and study staff will not know which group a patient is in. Patients will be randomized to receive one treatment or the other.
Arfolitixorin is Isofol’s proprietary drug candidate being developed to increase the efficacy of standard of care chemotherapy for advanced colorectal cancer. The drug candidate is currently being studied in a global Phase 3 clinical trial. As the key active metabolite of the widely used folate-based drugs, arfolitixorin can potentially benefit all patients with advanced colorectal cancer, as it does not require complicated metabolic activation to become effective.
Treating cancer patients with arfolitixorin – The goals:
- When treating colorectal cancer, for example, arfolitixorin is administered in combination with 5-FU to increase cell mortality in circulating cancer cells and in cancerous tumours.
• Arfolitixorin is administered in conjunction with rescue therapy after high-dose treatment with the cytotoxic agent, methotrexate, in order to suppress the cytotoxic effect in surrounding healthy tissue. The treatment is used for certain types of cancer, such as osteosarcoma, a type of bone cancer. This involves administering arfolitixorin separately, 24 hours after the chemotherapy.
- Immunotherapy for Early Stage CRC (Jun.15/20)
The development of immune checkpoint inhibitors (ICI) (immunotherapies) for early stage colorectal cancer (CRC) is accompanied by specific challenges:
- The selection of patients who are likely to benefit from these treatments, [i.e., patients with tumors harbouring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/MMR-D), or other potential parameters (increased T cell infiltration using Immunoscore or others, high tumor mutational burden, POLE mutation)]
- The selection of patients at risk of disease recurrence (poor prognostic features)
- The choice of an accurate clinical trial methodological framework
MSI/MMR-D has now become a major predictor for the efficacy of ICI. Given its frequency in localized colon cancer (CC) (10–15% compared to 5% of metastatic CRC), the development of ICI in adjuvant setting may concern a sizeable group of patients. Due to the high efficacy of ICI in MSI/MMR-D CRC, one question concerns what should the experimental arm of a study be for this population of patients: ICI alone or combined with chemotherapy? To conduct a study of adjuvant ICI therapy, with a reasonable chance to improve disease free survival (DFS), it is more feasible to focus on patients with T4 or N2 MSI/MMR-D CC, for whom the expected magnitude of effect is high. Concerning MSI/MMR-D rectal cancers, neoadjuvant strategies with ICI and/or chemoradiotherapy need to be evaluated in clinical trials.
- Clinical Trial For KRAS G12C Mutant Patients (Jul.28/20)
This phase I dose-escalation and dose-expansion study will evaluate the safety, pharmacokinetics (PK), and preliminary activity of GDC-6036 in patients with advanced or metastatic solid tumors with a KRAS G12C mutation. Targeted conditions/diseases include non-small cell lung cancer, colorectal cancer (CRC), and advanced solid tumors. This trial is specific to stage 4 CRC patients who have KRAS mutant tumors and don’t qualify for anti-EGFR therapies.
The clinical trial will include an estimated 108 patients, 18 years and older, with a histologically documented advanced or metastatic solid tumor with KRAS G12C mutation. Participants in Phase I (dose-escalation) will receive GDC-6036 administered orally once daily. The dose will be increased in successive cohorts until a safety threshold is observed. Participants with select solid tumors will be treated with GDC-6036 PO QD in Phase II (dose expansion).
Primary Outcome Measures Include:
- Percentage of Participants With Adverse Events (AEs) [Time Frame: From baseline up until 28 days after the final dose
- Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Time Frame: Days 1-21 of Cycle 1 (a cycle is 21 days)]
- Percentage of Participants With Changes From Baseline in Targeted Vital Signs [Time Frame: From baseline up until 28 days after the final dose]
- Percentage of Participants With Changes From Baseline in Targeted Clinical Laboratory Test Results [Time Frame: From baseline up until 28 days after the final dose
- Percentage of Participants With Changes From Baseline in Targeted ECG Parameters [Time Frame: From baseline up until 28 days after the final dose]
The Estimated Study Completion date is August 31, 2023.
Image Source: https://www.waynefleming-illustrator.com/ngg_tag/pharmakokinetics-digestive-system/
- Tumor Mutational Burden Identifies Cancer Responsive to Immunotherapy (Jul.29/20)
The Food and Drug Administration (FDA) granted accelerated approval to Keytruda® (pembrolizumab) for the treatment of adult and paediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) cancers that have progressed following prior treatment and who have no satisfactory alternative treatment options.
High levels of microsatellite instability (MSI-high) occur in about 10% to 15% of colorectal cancers (CRCs). Research has demonstrated that about 50% of MSI-high patients with advanced colon cancer respond to treatment with immune checkpoint inhibitor medications like Keytruda, which improves survival compared to chemotherapy.
Research suggests that the tumor mutational burden (TMB) may help further predict which patients with MSI-high disease can be optimally treated with immune checkpoint inhibitors. Tumor cells with high TMB may have more novel antigens (targets) which are associated with an increase in cancer-fighting T cells to direct an anti-cancer response. The presence of MSI-high is associated with higher TMB, however TMB does not guarantee the presence of MSI-high.
Doctors have evaluated TMB in colon cancer patients and found a very strong association between TMB and response to treatment. Researchers estimated the optimal predictive cut point for TMB to be between 37 mutations/megabyte and 41 mutations/megabyte. Patients who fall outside of the cut-point range may be less likely to benefit from checkpoint inhibitor immunotherapy therapy. The best approach to these patients is still being determined. This data supports the integration of a TMB score as a potential decision tool in the sequencing of checkpoint inhibition and chemotherapy.
- Checkpoint Inhibitor Immunotherapy Delays CRC Progression (Jun.30/20)
Checkpoint inhibitors are a type of precision cancer immunotherapy that helps to restore the body’s immune system to fight the cancer. In doing so they release checkpoints that the cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand, these drugs restore an immune cells’ ability to recognize and fight colon cancer cells.
Keytruda (pembrolizumab) and Opdivo (nivolumab) are “checkpoint inhibitors” with significant anti-cancer activity in advanced colorectal cancer (CRC) patients with mismatch repair deficient (MMR-D) and microsatellite instability high (MSI-high) abnormalities. The Phase 3 Keynote-177 trial evaluated first-line treatment with Keytruda for patients with MSI-high or MMR-D in 307 patients with unresectable or metastatic CRC (mCRC). Keytruda treated patients survived on average 16 months without cancer progression compared to 8.2 months for those treated with standard chemotherapy. At 24-months follow up, progression-free survival (PFS) was 55.3% with Keytruda compared to 18.6% with chemotherapy. All patients with colon cancer should undergo genomic biomarker testing to determine whether they have MSI-high or either markers that can help determine optimal treatment.
Image Source: https://www.pharmaceutical-journal.com/news-and-analysis/features/immune-checkpoint-inhibitors-bring-new-hope-to-cancer-patients/20067127.article?firstPass=false
- Onvansertib Precision Medicine Being Developed for KRAS Mutant Colon Cancers (Jul.02/20)
The FDA granted Fast Track Designation to Onvansertib, an orally administered, highly selective PLK1 inhibitor that is being developed in patients with KRAS-mutated metastatic colorectal cancer (mCRC). KRAS mutations are the most common oncogenic alteration in all of human cancers and there are currently no effective treatments available for patients with KRAS-mutant cancers.
Onvansertib is being developed by Cardiff Oncology who recently announced an Expanded Access Program (EAP) to access onvansertib in combination with standard-of-care FOLFIRI and bevacizumab for second-line treatment of patients with KRAS-mutated mCRC who are not be able to participate in the ongoing clinical trial. The trial will enroll up to 44 patients with a KRAS mutation and histologically confirmed metastatic and unresectable disease. In addition, patients must have failed treatment or be intolerant of FOLFOX (fluoropyrimidine and oxaliplatin) with or without bevacizumab.
An EAP provides a potential pathway for patients with a serious or life-threatening condition to gain access to an investigational drug for treatment outside of a clinical trial, particularly when no comparable or satisfactory alternative therapy options are available. The Cardiff Oncology EAP is intended for use in combination with FOLFIRI and bevacizumab for the second-line treatment of patients with KRAS-mutated mCRC that has progressed on prior FOLFOX (with or without bevacizumab) therapy.
- CRC With Peritoneal Metastases: CRS-HIPEC Refinements (Jul.06/20)
Patients with colorectal cancer (CRC) who have peritoneal metastases should only be treated in a specialized referral centre and given systemic chemotherapy before cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Researchers noted that the choice of intraperitoneal chemotherapy may not affect overall survival (OS), with both oxaliplatin and mitomycin C.
Monica M. Bertagnolli, MD, professor of surgery at Harvard Medical School, explained that about 5% of patients with CRC present with peritoneal carcinomatosis (CRPC) and another 5% develop metachronous CRPC. She mentioned that there is agreement that CRPC is “best managed in a specialty centre” and that the “best long-term survival” is offered by cytoreductive surgery plus chemotherapy. However, there is “controversy” over whether HIPEC or systemic therapy is the best chemotherapeutic approach.
Bertagnolli summarized the findings of four new studies:
- There was no significant difference in survival outcomes between HIPEC patients given mitomycin C vs. those receiving oxaliplatin in a Dutch observational study.
- The addition of adjuvant systemic chemotherapy after CRS-HIPEC significantly improved OS when compared with active surveillance on a propensity score matched analysis of a Dutch nationwide registry.
- Results from a centralized program in Barcelona underlined how optimal patient selection and defined clinical pathways and protocols can achieve excellent results. The team reported a median OS after CRS-HIPEC of almost 43 months in patients with peritoneal CRC metastases.
- Pilot phase results from the ongoing randomized phase 3 trial known as CAIRO6, which is comparing CRS-HIPEC plus perioperative systemic therapy vs. CRS-HIPEC alone, indicated the systemic therapy induces radiological and pathological tumor responses.
She concluded that, “The results today show us that by standardizing treatment, tracking outcomes, and collaborating to conduct high-quality clinical trials, we can expect to see a better future of outcomes for these special patients”.
- Anti-hypertensive Medications Linked to Reduced Risk of CRC (Jul.06/20)
Treating hypertension with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) was associated with a reduced risk for colorectal cancer (CRC). In this latest study, the use of ACE inhibitors/ARBs was associated with a 22% lower risk for CRC developing within 3 years after a negative baseline colonoscopy. With a cohort of more than 185,000 patients, the study is designed to suggest a significant protective effect for these two common antihypertensive medications.
The risk of developing CRC decreased with longer duration of ACE inhibitor/ARB use, with a 5% reduction in adjusted hazard ratio risk for each year of use. However, this effect was limited to patients who had negative colonoscopies within a 3-year period and did not extend beyond that point.
There has been considerable debate about the potential carcinogenic effects of ACE inhibitors and ARBs, and the relationship with “various solid organ cancer risks have been unsettled”. A recent study reported that ACE inhibitors, as compared with ARBs, increased risk for lung cancer by 14%. The risk for lung cancer increased by 22% among those using ACE inhibitors for 5 years, and peaked at 31% for patients who took ACE inhibitors for 10 years or longer.
Image Source: https://www.shutterstock.com/image-photo/kyiv-ukrainejune-20-2018-diuretic-drug-1233217231
- Entrectinib Results Emphasize Need for NTRKDetection (Jul.07/20)
Although fusions in the neurotrophic receptor tyrosine kinase (NTRK) gene are rare in gastrointestinal carcinomas (found in fewer than 5% of cases), they should be looked for. Researches have said that treatment with the TRK inhibitor entrectinib can achieve robust and durable responses. Entrectinib and similar agents that act on NTRK fusion genes are described as tumor agnostic, which are biomarkers that define the cancer rather than the organ of origin.
Combining results of three studies of entrectinib, researchers identified 12 gastrointestinal carcinoma patients among 74 adults with locally advanced/metastatic NTRK fusion-positive, TRK inhibitor-naive solid tumors who had undergone at least 6 months of follow-up. 58% of these 12 patients had colorectal cancer (CRC) and 24% had pancreatic cancer.
The median progression-free survival (PFS) was 7.1 months across the whole cohort. It was 8.0 months for pancreatic cancer patients and 12.0 months for the patient with cholangiocarcinoma. The median overall survival (OS) was 16 months. The majority of adverse events were of grade 1/2. The most common event was change in taste, which occurred in 37.3% of patients. There were no treatment-related deaths.
“The main take-away point from this abstract is that, though they are rare, if we identify patients with NTRK fusions during the course of the disease, we can offer them benefit from entrectinib, and I would argue that…we should be screening patients for NTRK fusions much more frequently,” said Manish R. Patel, MD, Department of Medicine, University of Minnesota, in Minneapolis.
In the second study, researchers performed immunohistochemistry (IHC) analysis followed by next-generation sequencing on samples of biliopancreatic cancers to determine the prevalence of NTRK fusions. Results show that, “consistent” with their low frequency in solid tumors, NTRK gene fusions are “also rare” in biliopancreatic cancers. Given this low frequency, testing and identification are of high clinical importance, due to possible treatment with pan-TRK inhibitors. A two-step diagnosis can preselect patients suitable for next-generation sequencing assay.
- Prognostic and Predictive Biomarkers in Metastatic Colorectal Cancer Patients Receiving Regorafenib (Aug.03/20)
Regorafenib is a tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of chemotherapy-refractory metastatic colorectal cancer (mCRC) patients. Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity.
LCCC1029 is a randomized, placebo controlled, phase II trial of chemotherapy ± regorafenib in second-line mCRC patients. 20 soluble protein biomarkers were assessed in the plasma of 149 patients from the trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects.
Six markers were found to be prognostic for PFS and nine markers were prognostic for OS. Higher baseline levels of OPN, VCAM-1, and PDGF-AA markers appeared to predict PFS benefit from regorafenib compared to placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared to placebo.
The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit while multiple protein markers may be prognostic of outcome in mCRC patients.
- Hepatic Artery Infusion Pump (HAIP) Chemotherapy Program — Sunnybrook Odette Cancer Centre (July 16/20)
The HAIP program is a first-in-Canada for individuals where colon or rectal cancer (colorectal cancer) has spread to the liver and cannot be removed with surgery. The program involves a coordinated, multidisciplinary team approach to care, with close collaboration across surgical oncology, medical oncology (chemotherapy), interventional radiology, nuclear medicine, and oncology nursing. The Hepatic Artery Infusion Pump (HAIP) is a small, disc-shaped device that is surgically implanted just below the skin of the patient and is connected via a catheter to the hepatic (main) artery of the liver. About 95 percent of the chemotherapy that is directed through this pump stays in the liver, sparing the rest of the body from side effects. Patients receive HAIP-directed chemotherapy in addition to regular intravenous (IV) chemotherapy (systemic chemotherapy), to reduce the number and size of tumours. Drs. Paul Karanicolas and Yooj Ko are the program leads and happy to see patients eligible for the therapy.
Presently at Sunnybrook Odette Cancer Centre, HAIP is being used in patients with colorectal cancer that has spread to the liver that cannot be removed surgically and has not spread to anywhere else in the body. Patients who have few (1-5) and very small tumors in the lungs may be considered if the lung disease is deemed treatable prior to HAIP. If you believe you may benefit from this therapy and/or would like to learn more about the clinical trial, your medical oncologist or surgeon may fax a referral to 416-480-6179. For more information on the HAIP clinical trial, please click on the link provided below.
- Living Donor Liver Transplantation for Unresectable Colorectal Cancer Liver Metastases (July 12/20)
Approximately half of all colorectal cancer (CRC) patients develop metastases, commonly to the liver and lung. Surgical removal of liver metastases (LM) is the only treatment option, though only 20-40% of patients are candidates for surgical therapy. Surgical therapy adds a significant survival benefit, with 5-year survival after liver resection for LM of 40-50%, compared to 10-20% 5-year survival for chemotherapy alone. Liver transplantation (LT) would remove all evident disease in cases where the colorectal metastases are isolated to the liver but considered unresectable.
Image Source: https://www.slideshare.net/AhmedAdel65/preoperative
While CRC LM is considered a contraindication for LT at most cancer centers, a single center in Oslo, Norway demonstrated a 5-year survival of 56%. A clinical trial sponsored by the University Health Network in Toronto will offer live donor liver transplantation (LDLT) to select patients with unresectable metastases limited to the liver and are non-progressing on standard chemotherapy. Patients will be screened for liver transplant suitability and must also have a healthy living donor come forward for evaluation. Patients who undergo LDLT will be followed for survival, disease-free survival, and quality of life for 5 years and compared to a control group who discontinue the study before transplantation due to reasons other than cancer progression. Despite the trial’s negative outcome, investigation of HIPEC, and other strategies to prevent peritoneal metastasis, should continue, they concluded in Lancet Gastroenterology & Hepatology. “The 21% peritoneal recurrence noted in the overall study population indicates the magnitude of the clinical problem in locally advanced colon cancer, and therapeutic strategies have to be further explored,” they said. “Outcomes of other trials investigating adjuvant HIPEC are eagerly awaited.”
RADIATION THERAPIES/INTERVENTIONAL RADIOLOGY
- Study Offered at the Odette Cancer Centre to Treat Recurrent Rectal Cancer (Mar.12/20)
Magnetic resonance-guided focused ultrasound (MRg-FU) is a noninvasive, outpatient modality being investigated for the thermal treatment of cancer. In MRg-FU, a specially designed transducer is used to focus a beam of low-intensity ultrasound energy into a small volume at a specific target site in the body. MR is used to identify and delineate the tumour, focus the ultrasound beam on the target, and provide a real-time thermal mapping to ensure accurate heating of the designated target with minimal effect to the adjacent healthy tissue. The focused ultrasound beam produces therapeutic hyperthermia (40-42°C) in the target field, causing protein denaturation and cell damage. Currently, there is no prospective clinical data reported on the use of MRg-FU in the setting of recurrent rectal cancer. Recurrent rectal cancer is a vexing clinical problem. Current retreatment protocols have limited efficacy. The addition of hyperthermia to radiation and chemotherapy may enhance the therapeutic response. With recent advances in technology, the investigators hypothesize that MRg-FU is technically feasible and can be safely used in combination with concurrent reirradiation and chemotherapy for the treatment of recurrent rectal cancer without increased side-effects. The study is being offered at the Odette Cancer Centre. Here is the link to the study protocol:
- CRC Risk Factors Increasing Among Millennials (Jul.20/20)
According to the Blue Shield Association, the rates of Crohn’s disease and ulcerative colitis are up 14% among adults ages 22-37. The rates of diabetes and diagnosed obesity are up 35% and 100%, respectively. People with Crohn’s and ulcerative colitis have almost double the risk of developing colorectal cancer (CRC). Those with diabetes or diagnosed obesity have a 1.7 and 1.3 times greater risk, respectively.
This trend among millennials could lead to a spike in CRC cases, which stresses the importance of early screening. A previous BCBS report found that millennials have a higher prevalence rate for type 2 diabetes, Crohn’s disease and ulcerative colitis than Generation X did at the same age. Though the overall colon cancer incidence rate is falling, it is rising among younger adults.
The U.S. Preventive Services Task Force recommends that CRC screening begin at age 50, but people with Crohn’s disease or other risk factors should get screened earlier. CRC prevalence rates increase by 50% from age 50 to 55. Regular screenings can identify polyps before they become cancerous and CRCs at an earlier stage, thereby improving treatment outcomes. The most common screening tests are colonoscopies. Other options include Fecal Immunochemical and Fecal Occult Blood tests, both of which test for blood in stool.
Image Source: https://medicalxpress.com/news/2017-10-colorectal-cancer-screening.html
- Many Early Onset Colon Cancers are caused by Genetic Mutations Through Families (Mar.28/20)
One in every six colorectal cancer (CRC) patients (16%) diagnosed under age 50 has at least one inherited genetic mutation that increases his/her cancer risk and many of these mutations could go undetected with the current screening approach.
A new analysis reported the prevalence of specific mutations in 25 genes associated with inherited cancer syndromes in an unselected series of CRC patients. “The prevalence of hereditary cancer syndromes among early-onset CRC patients was quite high, which presents a tremendous opportunity for us to save lives through early detection based on genomic risk factors,” says Heather Hampel, MS, CGC, and principal investigator of the statewide study. The research team recommends genetic counselling and a broad, multi-gene panel test of cancer susceptibility genes for all early-onset CRC patients, regardless of family history or the results of tumor screening for Lynch syndrome. This differs from current professional guidelines, which recommend all CRC patients be screened for Lynch syndrome, with referral for genetic counselling and Lynch syndrome-specific genetic testing if the tumor-screening test is abnormal. The team’s findings, however, showed that 33% of patients found to have an inherited cancer syndrome did not meet established testing criteria for the gene in which they were found to have a mutation.
The spectrum of mutations in early-onset CRC is much broader than anticipated. Thus, complete genetic testing for all early-onset CRC patients could save lives by identifying at-risk families so that they can benefit from intensive cancer surveillance and prevention options.
Image Source: https://geneticliteracyproject.org/2018/04/02/understanding-genetic-mutations-why-do-some-cause-disease-while-others-dont/
- Young Adult Colorectal Cancer Clinic Available at Sunnybrook (Mar.12/20)
A recent study led by the University of Toronto doctors has observed a rise in colorectal cancer rates in patients under the age of 50. The study mirrors findings from the U.S., Australia and Europe. The growing colorectal cancer rates in young people come after decades of declining rates in people over 50, which have occurred most likely due to increased use of colorectal cancer screening (through population-based screening programs) which can identify and remove precancerous polyps. Patients diagnosed under the age of 50 have a unique set of needs, challenges and worries. They are unlike those diagnosed over the age of 50. Dr. Shady Ashamalla (colorectal cancer surgical oncologist), and his team at the Sunnybrook Health Sciences Centre understand the needs of this patient population.
Dr. Ashamalla belongs to a multidisciplinary team of experts in the Young Adult Colorectal Cancer Clinic who will work with young colorectal cancer patients, regardless of disease stage, to create an individualized treatment plan to support each patient through their cancer journey. Their needs and concerns will be addressed as they relate to:
- Fertility concerns and issues
- Young children at home
- Dating/intimacy issues
- Challenges at work
- Concerns about hereditary cancer
- Relationships with family and friends
- Psychological stress due to any or all of the above
The team of experts consists of:
- Oncologists (medical, surgical, radiation)
- Social workers
- Nurse navigator
Should a patient wish to be referred to Sunnybrook, they may have their primary care physician, or their specialist refer them to Sunnybrook via the e-referral form, which can be accessed through the link appearing below. Once the referral is received, the Young Adult Colorectal Cancer Clinic will be notified if the patient is under the age of 50. An appointment will then be issued wherein the patient will meet with various members of the team to address their specific set of concerns.
- Oral Microbiome Bacterium May Directly Trigger Spread of CRC (Jul.22/20)
Virginia Tech researchers have discovered that a species of bacteria commonly found in the mouth can migrate around the body via the blood and trigger existing colorectal cancer (CRC) cells to spread, or metastasize. New findings indicate that Fusobacterium nucleatum (F. nucleatum) may also directly and indirectly modulate immune and cancer cell signaling and migration. This is vital information because 90% of cancer-related deaths result from non-primary tumors or sites that have metastasized to somewhere else in the body.
Over recent years, multiple studies have shown that the bacterium directly invades colon tumors. The bacteria is believed to predominantly travel through the blood to different sites in the body where they are also associated with serious infections of the brain, liver, and heart, as well as preterm birth in pregnant women. Poor oral hygiene could cause the bacteria to migrate to other parts of the body where cancers exist.
According to researchers, there was no evidence that the bacterium was directly initiating cancer, and it did not appear to be releasing molecules that would cause the cancer cells to migrate. The studies have shown that F. nucleatum can stick to and even enter cancer cells using the protein Fap2, which docks with sugars overrepresented on the surface of cancer cells. This causes cancer cells to release cytokines that play critical roles in immune system activation against infections. One infected cell could be affecting multiple neighboring cells, so there does not have to be a widespread infection within a tumor for it to be influencing a large surrounding area. Through paracrine signaling (communication of cells over short distances), F. nucleatum interactions with CRC cells could be releasing factors that create not only a metastatic environment but also one that provides protumor inflammation.
The newly reported results also hint that blocking the release of cytokines could feasibly combat metastasis induced by bacteria. This is an attractive alternative to using antibiotics to kill F. nucleatum, as antibiotics might also kill beneficial bacteria. It is vital for researchers to identify if there are other important bacteria that could be working in synergy with F. nucleatum to drive cancer. This could be important for F. nucleatum, given that it is classified as a non-motile bacterium, lacking the machinery, such as flagella, that drives movement.
Image Source: https://www.sciencedirect.com/science/article/pii/S2213453018301642
- Four Actionable Targets For mCRC That Advanced Practice Providers (APPs) Should Know (Jul.10/20)
Treatment options for patients with metastatic colorectal cancer (mCRC) are limited and, therefore, many clinicians and researchers are focused on identifying predictive and prognostic molecular targets for this disease. This article identifies four actionable mutations — microsatellite instability (MSI-high), BRAF V600E, HER2 and neurotrophic tyrosine receptor kinase (NTRK) — that APPs should be aware of and incorporate into the evaluation and management of this patient population.
Microsatellite Instability – High (MSI-high) and mismatch repair deficient (MMR-D) status are well-known biomarkers for colon cancer and patients with Lynch syndrome. Data presented at this year’s ASCO20 Virtual Scientific Program served as the basis for the FDA approval of pembrolizumab in the first-line setting for patients with MSI-high or MMR-D status. The KEYNOTE-177 study compared pembrolizumab with investigator’s-choice chemotherapy among 307 patients with MSI-high mCRC. Results showed improved median progression free survival (PFS) (16.5 months vs. 8.2 months) and a higher overall response rate (ORR) (43.8% vs. 33.1%) with pembrolizumab.
BRAF V600-positive or mutant CRC has been known to portray a poor prognosis, with lack of response to EGFR therapy (such as cetuximab or panitumumab) and median overall survival (OS) of 4 to 6 months after failure of previous therapy. Updated results of the phase 3 BEACON CRC trial, presented during this year’s ASCO20 Virtual Scientific Program, showed an OS of 9.3 months in the triplet arm of encorafenib, binimetinib and cetuximab compared with 5.9 months with cetuximab-irinotecan or cetuximab-FOLFIRI. This prompted the newest FDA approval of the two-drug targeted therapy combination of encorafenib and cetuximab for previously treated patients with BRAF V600E-mutant mCRC.
HER2 amplification is typically identified by next-generation sequencing or immunohistochemical testing. The MyPathway trial evaluated pertuzumab in combination with trastuzumab for HER2-positive mCRC. Results showed a 32% ORR with these drugs among a previously treated population with a median of four prior lines of therapy. Median duration of response was 5.9 months, with some patients responding for longer than 12 months. The patients most likely to respond to HER2 antibody therapy were those with KRAS wild-type disease.
The FDA approved larotrectinib (Vitrakvi) for patients with NTRK gene fusions based on data showing an overall response rate (ORR) of 79% and median duration of response of 35.2 months with this agent across solid tumors. Entrectinib — another potent inhibitor of tropomyosin receptor kinase — also is an option for NTRK gene fusion-positive mCRC.
Please note: there is data to support mcrc patients who are MSI-H/MMR-D and BRAF wild type appear to harbor these NTRK gene fusions with greater amplification.
- Optimal Nutrition Formulas for Patients Undergoing Surgery for CRC (Jul.21/20)
Patients with colorectal cancer (CRC) are prone to malnutrition, which may be due to decreased intake, impaired digestion, malabsorption of nutrients and increased nutritional requirements. Malnutrition is a key factor associated with the dysfunction of homeostasis and the immune system, which may lead to poor outcomes of surgery, such as postoperative complications, delay of wound healing and prolonged hospital stay. Optimal nutrition formulas for CRC patients who underwent surgery remain uncertain.
A study including 1032 CRC patients that underwent surgery assessed comparative efficacy of different immunonutrition formulas and standard nutrition. The comparison confirmed the potential improvement of arginine-based immunonutrition on infectious complications (IC), glutamine on noninfectious complications (NIC) and omega-3 polyunsaturated fatty acids on length of hospital stays (LOS). Results indicated that glutamine had the highest probability of reducing complications and hospital stays. As for CRC patients who underwent surgery, this indirect comparison suggested some superiority of glutamine.
- Impact of COVID‐19 on Advanced CRC (Jul.24/20)
The COVID‐19 pandemic has significantly impacted the delivery of surgical care despite efforts to maintain essential cancer care during this time. This has necessitated significant re‐organization in the way cancer care is delivered including the provision of ‘cold’ sites.
In the U.K. 14, 000 patients are diagnosed with rectal and rectosigmoid cancer annually. Of these, approximately 10% of cancers are locally advanced at the time of presentation and require a beyond TME approach, while a further 5–10% of patients with rectal cancer develop local recurrence following surgery. Without surgical intervention, the survival of patients with local recurrence is extremely low.
A population study examining locally recurrent rectal cancers found that no patients treated with systemic chemotherapy alone or best supportive care had survived up to 5 years. 57% of patients treated with potentially curative resection were alive at 5 years. 30–40% of patients who have undergone exenteration suffer major complications, have a long hospital stay (median 17 days) and are more likely to be readmitted. Such risks must be balanced with long-term quality of life (QoL) and the survival advantage from pelvic exenteration. It is suggested that by 2–9 months after surgery, QoL returns to preoperative levels. Patients with locally advanced or recurrent rectal cancer who do not undergo surgery have a sustained decline in QoL compared to those who undergo exenteration (total removal of all organs from a body cavity).
Pelvic exenterations are resource‐intensive procedures with longer operating times involving multidisciplinary teams and a greater need for critical care support. The resource needs, as well as a perception of generally poorer outcomes, resulted in COVID‐19‐related guidance to recommend that such extended surgery should be de‐prioritized and therefore deferred. The backlog of deferred cases and the probable continued clinical capacity issues will mean patients on the complex cancer waiting lists will have to be prioritized. This should not replace efforts to develop the necessary capacity to deliver care and minimize the number of patients that may come to harm due to delays.
- Researchers ID 6 COVID-19 Symptom Sets (Jul.31/20)
COVID-19 presents differently in people. Some experience mild or no symptoms, while others may experience widespread inflammation along with life threatening lung and kidney damage. Additionally, most people will be able to recover on their own at home, but a small percentage of those who develop a severe infection will need to get supportive care at the hospital. With the disease presenting itself differently from person to person, it can be tricky for doctors to predict how the disease will play out in any given patient.
New research has discovered there are primarily six different symptom “sets” or “clusters” of COVID-19.
- Flu-like with no fever: headache, loss of smell, muscle pain, cough, sore throat, chest pain, and no fever
- Flu-like with fever: fever, loss of appetite, headache, loss of smell, sore throat, hoarseness
- Gastrointestinal: diarrhea, headache, loss of smell, loss of appetite, sore throat, chest pain, no cough
- Severe level 1, fatigue: fatigue, headache, loss of smell, cough, fever, hoarseness, chest pain
- Severe level 2, confusion: confusion, headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, muscle pain
- Severe level 3, abdominal and respiratory: shortness of breath, diarrhea, abdominal pain, headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain
A research team found just 1.5% of those with the 1st cluster (Flu-like with no fever), 4.4% of people with the 2nd (Flu-like with fever), and 3.3% in the 3rd (Gastrointestinal) needed respiratory support when hospitalized. Severity increased with the latter half of the clusters, which tended to include people who were frailer, older, and had underlying health conditions (i.e. diabetes or lung disease). With cluster 4 (Severe level 1), 8.6% of people needed breathing support. Additionally, early 10% in cluster 5 (Severe level 2) and 19.8% in cluster 6 (Severe level 3) needed breathing support.
Earlier diagnosis and intervention in patients with COVID-19 may potentially help to reduce the risk for requiring mechanical ventilation, decrease length of hospital stay, and risk for developing thrombotic complications.
Image Source: https://www.npr.org/sections/goatsandsoda/2020/05/06/850707907/from-loss-of-smell-to-covid-toes-what-experts-are-learning-about-symptoms
- Frequently Asked Questions for COVID-19
Q: What is COVID-19 (or novel Coronavirus Disease – 19)?
A: Coronaviruses are a large family of viruses that can cause illnesses in humans and animals. Coronaviruses can cause illnesses that range in severity from the common cold, to more severe diseases such as Severe Acute Respiratory Syndrome (SARS) and most recently, COVID-19. COVID-19 or novel coronavirus originated from an outbreak in Wuhan, China in December 2019. The most common symptoms associated with COVID-19 can include fever, fatigue, and a dry cough. Though additional symptoms have now been linked with the disease, which may include aches and pains, nasal congestion, runny nose, sore throat, diarrhea, skin rash and vomiting. It is also possible to become infected with COVID-19 and not experience any symptoms or feeling ill. The spread of COVID-19 is mainly through the transmission of droplets from the nose or mouth when a person coughs, exhales or sneezes. These droplets land on surfaces around a nearby person. COVID-19 can be transmitted to that nearby person who may end up touching the surface contaminated with COVID-19 and then end up touching their nose, mouth, or eyes. A person can also contract COVID-19 through inhaling these droplets from someone with COVID-19. Although research is still ongoing, it is important to note that older populations (over the age of 65), those with a compromised immune system and those with pre-existing conditions including heart disease, high blood pressure, lung disease, diabetes or cancer may be at a higher risk of severe illness due to COVID-19.
Q: What can I do to avoid getting Coronavirus?
A: There are various ways in which we can reduce our risk of contracting COVID-19. Below are some measures suggested by the World Health Organization
- Keep at least 2 metres (or 6 feet) between yourself and other people. This will reduce the risk of inhaling droplets from those infected with COVID-19.
- Regularly clean your hands for at least 20 seconds with warm water and soap, or an alcohol-based hand rub. This will kill any viruses on your hands.
- Avoid touching your eyes, nose and mouth. If the virus is on your hands, it can enter the body through these areas.
- Follow good respiratory hygiene by covering your mouth and nose with a tissue or elbow when you cough and sneeze. This prevents the droplets from settling on surfaces or being released into the air around you.
- Stay home as much as possible, especially if you are feeling unwell. If you think you may have the Coronavirus, please see “What should I do if I think I have Coronavirus?” section.
- Please wear a face covering or mask in public when physical distancing is not possible.
Q: Are there any treatments available for Coronavirus?
A: People with cancer are at a higher risk of severe illness due to COVID-19 as cancer is considered a pre-existing health issue. Some cancer treatments including chemotherapy, radiation and surgery can weaken the immune system, making it harder for the body to fight infections and viruses, such as Coronavirus. It is important to diligently follow the World Health Organization’s recommendations above to reduce the risk of contracting COVID-19. If you have any concerns about your risk, it is best to contact your doctor or healthcare team.
There are currently no treatments available for COVID-19 but trials are underway to determine how to best treat and manage those afflicted with the virus. Vaccine candidates are being vigorously tested in a number of countries around the world, Canada included. The US government is funding 3 major phase 3 trials on potential COVID-19 vaccines and all 3 trials are being conducted by 3 different pharmaceutical companies looking at different vaccine candidates. The hope is to have a vaccine by the end of the year!
Q: Are there special precautions that people with cancer can take?
A: People with cancer (and other chronic ailments such as heart disease, diabetes, high blood pressure and lung disease) are at a higher risk of severe illness due to COVID-19 as cancer is considered a pre-existing health issue. Some cancer treatments including chemotherapy, radiation and surgery can weaken the immune system, making it harder for the body to fight infections and viruses, such as Coronavirus. It is important to diligently follow the World Health Organization’s recommendations above to reduce the risk of contracting COVID-19. If you have any concerns about your risk, it is best to contact your doctor or healthcare team.
Will anything change with regards to my cancer related medical visits? As each patient and treatment plan is unique, it is always best to contact your health care provider for updated information about your treatment plan. In some cases, it is safe to delay cancer treatment until after the pandemic risk has decreased. In other cases, it may be safe to attend a clinic that is separate from where COVID-19 patients are being treated. Oral treatment options could be prescribed by your care provider virtually, without the need to attend the clinic. Finally, some follow-up appointments or discussions could be held virtually (via skype or zoom for example) or over the phone to minimize your risk. As we know, conditions and protocols are changing daily due to the nature of the COVID-19 outbreak, and vary based on location, therefore, the best first step is to reach out to your care provider for guidance.
Should you wish to contact your local public health agency, please see below.
COVID-19 info for Albertans
Social media: Instagram @albertahealthservices, Facebook @albertahealthservices, Twitter @GoAHealth
Phone number: 811
British Columbia COVID-19
Social media: Facebook @ImmunizeBC, Twitter @CDCofBC
Phone number: 811
Social media: Facebook @manitobagovernment, Twitter @mbgov
Phone number: 1-888-315-9257
New Brunswick Coronavirus
Social media: Facebook @GovNB, Twitter @Gov_NB, Instagram @gnbca
Phone number: 811
Newfoundland and Labrador
Newfoundland and Labrador COVID-19 information
Social media: Facebook @GovNL, Twitter @GovNL, Instagram @govnlsocial
Phone number: 811 or 1-888-709-2929
Northwest Territories coronavirus disease (COVID-19)
Social media: Facebook @NTHSSA
Phone number: 811
Nova Scotia novel coronavirus (COVID-19)
Social media: Facebook @NovaScotiaHealthAuthority , Twitter @healthns, Instagram @novascotiahealthauthority
Phone number: 811
Nunavut COVID-19 (novel coronavirus)
Social media: Facebook @GovofNunavut , Twitter @GovofNunavut, Instagram @governmentofnunavut
Phone number: 1-888-975-8601
Ontario: The 2019 Novel Coronavirus (COVID-19)
Social media: Facebook @ONThealth, Twitter @ONThealth , Instagram @ongov
Phone number: 1-866-797-0000
Prince Edward Island
Prince Edward Island COVID-19
Social media: Facebook @GovPe, Twitter @InfoPEI,
Coronavirus disease (COVID-19) in Québec
Social media: Facebook @GouvQc, Twitter @sante_qc
Phone number: 1-877-644-4545
Social media: Facebook @SKGov, Twitter @SKGov
Phone number: 811
Yukon: Find information about coronavirus (COVID-19)
Social media: Facebook @yukonhss, Twitter @hssyukon
Phone number: 811