The following colorectal cancer research updates extend from March 17 to June 4, 2020, inclusive and are intended for informational purposes only.
CONTENT
- 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
- Efficacy of Immunotherapy in MSI-H or MMR-P CRC
- Trovagene Data Offers Hope for KRAS-Mutant Colon Cancer
- FDA Approves Combination of Encorafenib (Braftovi) and Cetuximab (Erbitux) After Encouraging Results in Phase III Trial
- Neoadjuvant Immunotherapy Has Potential to be a New Standard of Care in Early Stage Colon Cancer
- Addition of Cetuximab to Chemotherapy Shortens OS in Advanced Colorectal Cancer Subset
- Maintenance Therapy Significantly Associated with PFS
- Assessment of Duration and Effects of 3 vs. 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer
- Merck’s Keytruda doubles time to disease progression in certain colorectal cancer patients
- HER2- Targeted Therapy Shows Antitumor Activity in Metastatic Colorectal Cancer
- Three Practice-Changing Clinical Trials in mCRC
- Pembrolizumab doubles PFS for certain patients with mCRC
- Braftovi Gets Approved in the EU for BRAF+ CRC
- Regular Aspirin Use May Reduce Risk for CRC Alongside Other Digestive Tract Cancers
- Durvalumab and Tremelimumab Combination May Prolong OS in CRC
- Hepatic Artery Infusion Pump (HAIP) Chemotherapy Program – Sunnybrook Hospital
- Living Donor Liver Transplantation for Unresectable Colorectal Cancer Liver Metastases
- Wait and Watch Approach in Rectal Cancer
- Study Offered at the Odette Cancer Centre to Treat Recurrent Rectal Cancer
- Importance of Family History-Based Screening of CRC
- Starting Age for Screening in Relatives of Patients with CRC
- Increased Risk of CRC in Individuals With a History of Serrated Polyps
- Single Negative Colonoscopy Predicts Low CRC Risk
- Non-Invasive Blood Assay Can Detect Early CRC
- Young Adult Colorectal Cancer Clinic Available at Sunnybrook Hospital
- Association Between Cannabis and Quality of Life Among CRC Survivors
- Newly Found Link Between Blood Infections and CRC
- Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in CRC
- E. Coli Diversity: Low in CRC
- Turning Colon Cancer Cells Around
- Tumor Mutation and Immune Microenvironment Relationships
- Colon Cancer Signs in Young Adults
- Association Between Mediterranean Diet Adherence and CRC
- 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.
Bayer’s Commitment
- 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.
https://www.bayer.ca/en/media/news/?dt=TmpBPQ==&st=1
- 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.
https://sunnybrook.ca/trials/item/?i=293&page=49335 and https://clinicaltrials.gov/ct2/show/NCT03750786
About Arfolitixorin:
(https://isofolmedical.com/arfolitixorin/ )
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.
- 5. Efficacy of Immunotherapy in MSI-H or MMR-P CRC (May.7/20)
Approximately 5 years ago, the first results of the activity of single-agent pembrolizumab, a programmed cell death-1 (PD-1) antibody, were reported in patients with mismatch repair deficient (MMR-D) and/or microsatellite instable high (MSI-H) metastatic colorectal cancers. In metastatic colorectal cancer, only 4% to 5% of tumors are classified as MSI-H and/or MMR-D; the rest are microsatellite-stable (MSS) or mismatch repair proficient (MMR-P). So far, studies of immunotherapies in MSS and/or MMR-P colorectal cancers have consistently generated disappointing results.
This randomized phase II trial in treatment-refractory metastatic colorectal cancer involves about 180 patients randomized to a combination of durvalumab, a PD-L1 antibody, and tremelimumab, a CTLA-4 antibody, or best supportive care (BSC) alone. The reported median overall survival (OS) was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC, although the progression-free survival showed no difference between arms with 1.8 months and 1.9 months respectively. Only 1 of 119 (0.8%) patients in the treatment arm achieved an objective response, though a potential improvement in disease control rate (22.7% vs 6.6%) was observed. In patients with MSS disease per circulating cell-free DNA (cfDNA) analysis, OS was significantly improved with durvalumab and tremelimumab. Patients with MSS disease with plasma tumor mutation burden (TMB) of 28 variants per megabase or more (21%) had the greatest OS benefit. The combination of durvalumab and tremelimumab was characterized by significant toxic effects with 62% of patients experiencing grade 3 or higher adverse events compared with only 20% on BSC.
The results seen with durvalumab and tremelimumab in treatment-refractory MSS colorectal cancer can only be considered hypothesis generating, and the likelihood of true efficacy of this immunotherapy combination in MSS cancers is low. However, novel combinations of immune checkpoint inhibitors with agents that may further enhance the immune response may be a promising approach, and several clinical trials are ongoing.
https://jamanetwork.com/journals/jamaoncology/article-abstract/2765324
- Trovagene Data Offers Hope for KRAS-Mutant Colon Cancer (Apr.27/20)
The American Association for Cancer Research (AACR) suggests a new route to treating patients with KRAS-mutant colon cancer, including those thought to be undruggable. Trovagene’s PLK1 inihibitor; onvansertib, along with standard of care, has stopped tumors from growing in seven of eight patients with KRAS-mutated colon cancer. According to phase 1b data, tumors of three patients shrank 38%. At the April 1st data cutoff, the combination kept cancer at bay for a median 6.5 months, and six of the patients who responded are still receiving treatment.
The company is testing three dose levels of onvansertib as a second-line treatment in combination with chemo cocktail (Folfiri and Avastin; six on the lowest dose, three on the middle dose and three on the highest). Onvansertib is a “promising therapeutic intervention” for patients, because PLK1, which occurs at high levels in colorectal cancer, is a synthetic lethal pair with the KRAS mutation, said Afsaneh Barzi, M.D., who presented the study at ASCO. Blocking PLK1 in cancer cells where KRAS is inactivated by mutation leads to cell death.
Thus if the data bear out, patients with KRAS-mutant colorectal cancer (about half of all metastatic colorectal cancer patients) could end up with their own targeted therapy.
https://www.fiercebiotech.com/biotech/aacr-early-data-offers-hope-for-kras-mutant-colon-cancer
- FDA Approves Combination of Encorafenib (Braftovi) and Cetuximab (Erbitux) After Encouraging Results in Phase III Trial (Apr.29/20)
The new FDA-approved treatment of encorafenib (Braftovi) and cetuximab (Erbitux) has been proven effective in patients having tumors with BRAFV600E mutation (makes up 8-10% of colorectal cancer patients). BRAF is a protein that helps cells grow and survive and the BRAFV600E mutation causes rapid cell growth, leading to cancer. The treatment helps patients live longer without increasing risk of serious side effects.
How Does The New Treatment Change Outlook for People with This Type of Colorectal Cancer?
It’s a big improvement because this cancer type is very aggressive after it spreads (metastasizes). People whose tumors have BRAFV600E mutation have poor outlook, given that the median survival time after unsuccessful initial therapy is just 4-6 months with uncomfortable symptoms. The trial showed that this combination therapy helps people live longer, can delay development of these symptoms, and improve their quality of life.
How Does The Combination Therapy Work?
Single therapies have not worked well against colorectal cancer because of feedback activation. BRAF strongly activates tumor growth and suppresses the activity of other proteins involved in controlling cell growth. When BRAF activity is blocked, other proteins in the pathway become activated, enabling cancer cells to survive and grow. Encorafenib and cetuximab target different proteins in the BRAF signaling pathway; encorafenib inhibits BRAF, and cetuximab targets EGFR, another protein that is overactive in many colorectal cancers.
Three drugs used to target different parts of the communication pathway in cancer cells with the BRAFV600E mutation.
What did the clinical trial show about the effectiveness of this drug combination?
The international clinical trial involved 665 people with BRAFV600E mutated metastatic colorectal cancer that has returned or continued to grow after at least one type of previous treatment. Patients were split into three groups; a control group received cetuximab + chemotherapy (standard treatment), another received encorafenib + cetuximab, and the third group received the two drugs plus a third (binimetinib).
Results showed that people receiving two-drug combo therapy lived longer than those on the standard. Survival times were 9.3 months on average in the combination group & 5.9 months in the control group. Those who received the combination treatment had their tumors shrink more, had fewer side effects and more likely to have an improved quality of life. The group that received all three had similar survival times to the two-drug group but higher risk of side effects. Both the two- and three-drug regimens have already been added as a treatment option in guidelines put out by the National Comprehensive Cancer Network (NCCN).
https://www.mskcc.org/blog/fda-approval-gives-hope-some-people-advanced-colorectal
- Neoadjuvant Immunotherapy Has Potential to be a New Standard of Care in Early Stage Colon Cancer (Apr.20/20)
Immune checkpoint inhibition could be a new standard of care in patients with mismatch repair (MMR) –deficient (MMR-D) tumors and a subgroup of patients with MMR-proficient (MMR-P) tumors. To date, immunotherapy directed against PD-1 and CTLA-4 proteins has been highly effective in patients with MMR-D colon cancer, while showing poor results in patients with MMR-P.
Researchers treated a group of 40 patients with colon cancer with a single dose of ipilimumab and two doses of nivolumab before surgery; 21 with MMR-D and 20 with MMR-D. All patients underwent radical resection of their tumor and thirty-five of the 40 patients were evaluable for efficacy and translational endpoints. All patients with MMR-D tumors had pathological response; 19 major pathological responses and 12 pathological complete responses. 27% of patients with MMR-P tumors had pathological responses; 3 major and 1 partial response. Researchers acknowledge that the study was small and that larger studies with at least 3 year follow up for disease-free survival will be required.
Image Source: https://jamanetwork.com/journals/jamaoncology/fullarticle/2383147
- Addition of Cetuximab to Chemotherapy Shortens OS in Advanced Colorectal Cancer Subset (Apr.14/20)
According to results of the randomized phase III New EPOC study, cetuximab + chemotherapy resulted in shorter progression-free survival (PFS) & overall survival (OS) compared to chemo alone among patients with KRAS exon 2 wild-type colorectal liver metastases. Detrimental effects of adding cetuximab (an epidermal growth factor receptor antibody) to perioperative systemic chemotherapy appear to be most prominent among patients with more favourable clinical tumor characteristics.
“Although the addition of cetuximab to chemotherapy improves [OS] in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of OS. Cetuximab should not be used in this setting,” John A. Bridgewater, MRCP, PhD, clinical researcher at UCL wrote.
Current analysis (including a long term follow-up & a more complete data set) evaluated effect of the combo on OS among 257 adults with KRAS wild-type resectable or suboptimally resectable colorectal liver metastases. 128 patients were assigned to chemotherapy with oxalipatin, folinic acid and fluorouracil, or oxaliplatin and capecitabine, while the remaining 129 patients received chemo plus cetuximab for 12 weeks before and after liver resection. Cetuximab was administered either through an IV dose (500mg/m2) every 2 weeks or a loading dose (400mg/m2) followed by weekly infusion (250 mg/m2).
During median follow-up of 66.7 months, 180 events occurred. Patients assigned cetuximab demonstrated significantly shorter median PFS than those assigned chemotherapy alone (15.5 months vs. 22.2 months). Median OS was significantly shorter among those assigned cetuximab (55.4 months vs. 81 months). Of the 130 patient deaths that occurred during follow-up, 54 deaths in chemotherapy alone group were disease related vs. 67 disease-related deaths in the cetuximab group. This mature analysis shows that in the perioperative setting, cetuximab shortens OS by 2 years compared with chemotherapy alone.
- Maintenance Therapy Significantly Associated with PFS (Apr.16/20)
Systematic review and network meta-analysis found that maintenance therapy was significantly associated with progression-free survival (PFS) but not overall survival (OS) compared with observation following first-line induction therapy for metastatic colorectal cancer. All three maintenance strategies (fluoropyrimidine, bevacizumab, and fluoropyrimidine plus bevacizumab) significantly improved PFS but not OS, whereas fluoropyrimidine and fluoropyrimidine plus bevacizumab ranked higher than bevacizumab in PFS and OS.
Concerns regarding the methodological aspects of this work;
- Network meta-analysis involves repeated testing of accumulated evidence, leading to inflated type I (false positive) and type II (false negative) errors
- Although authors stated that 11 trials were included in the quantitative analysis, they did not clarify which were ultimately included in the network meta-analysis of PFS or OS
- The included trials were heterogeneous (mixed) in study design and induction chemotherapy backbone
Thus, the authors’ findings regarding the role of maintenance strategies in metastatic colorectal cancer should be interpreted with caution.
https://jamanetwork.com/journals/jamaoncology/article-abstract/2764540
- Assessment of Duration and Effects of 3 vs. 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer (Feb.13/20)
The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage II colon cancer.
The study assesses the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer. Patients were originally randomized in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. 1254 patients with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months. 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm. For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the 6-month arm.
A possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin pair is indicated for treatment of patients with stage II colorectal cancer.
- Merck’s Keytruda doubles time to disease progression in certain colorectal cancer patients (May.28/20)
Keytruda kept cancer at bay for 16.5 months in previously untreated patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (MMR-D) colorectal cancer that had either spread or couldn’t be surgically removed. That’s compared with 8.2 months for chemo, delivered with or without other targeted therapy, which means Keytruda cut the risk of disease worsening or death by 40%.
Keytruda not only kept cancer away longer, but also in a larger proportion of patients. At the 12-month mark, 55.3% of patients on the Merck drug hadn’t seen their cancer worsen, versus just 37.3% of chemo patients. At the 24-month mark, that difference was more pronounced, with cancer still at bay in 48.3% of Keytruda patients and 18.6% of chemo patients. 11% of Keytruda patients saw their cancer vanish completely, compared to 3% of chemo patients. 83% of those who responded to Keytruda saw their benefits last more than 2 years, versus just 35% of those who responded to chemo.
The new data should bring Keytruda earlier into treatment for the 5% of metastatic colorectal cancer patients with MSI-H tumors, which has been “a tough patient population” to treat. Right now, Keytruda is cleared for previously treated patients with MSI-H tutors, no matter their location in the body. BMS (New York drugmaker) is working on the second-line treatment setting pertaining to MSI-H or MMR-D colorectal cancer rather than all MSI-H or MMR-D tumors. So far it has no indication for previously untreated patients, although they are working on it. In October 2018 their phase 2 data showed its Opdivo-Yervoy duo could spur responses in 60% of front-line MSI-H or MMR-D colorectal cancer patients.
ASCO: Merck’s Keytruda doubles time to disease progression in certain colorectal cancer patients
- HER2-Targeted Therapy Shows Antitumor Activity in Metastatic Colorectal Cancer (May.30/20)
According to findings of the phase 2 DESTINY-CRC01 study, trastuzumab deruxtecan demonstrated durable benefit among patients with HER2-expressing metastatic colorectal cancer. Trastuzumab deruxtecan is a novel antibody-drug conjugate composed of 3 components — an anti-HER2 immunoglobin G1 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload.
Early studies have shown promising activity in advanced HER2-expressing tumors. Interstitial lung disease appeared to be an important risk that requires careful recognition and intervention, researchers noted. The DESTINY-CRC01 trial included 78 patients (median age, 58.5 years; range, 27-79) with HER2 expressing RAS wild-type metastatic colorectal cancer. All patients received at least two prior lines of treatment and 20.5% had prior anti-HER2 therapy.
The study consisted of 3 cohorts;
- Cohort A = 53 patients who were HER2-positive
- Cohort B included seven patients with immunohistochemical 2-positive/ in situ hybridization-negative disease
- Cohort C included 18 patients with immunohistochemical 1-positive disease
All patients received 6.4-mg/kg trastuzumab deruxtecan IV every 3 weeks.
Median treatment duration was 3.5 months overall & 4.8 months in cohort A, with 38.5% of patients remaining on study treatment (41% discontinued due to disease progression and 9% due to clinical progression). Results showed a confirmed ORR in cohort A of 45.3%, which includes 1 complete response & 23 partial responses. Twenty patients achieved stable disease, for a disease control rate of 83%. Researchers observed no responses in cohorts B or C. Among those who received prior anti-HER2 therapy, researchers observed an ORR of 43.8%. Median PFS was 6.9 months and median OS was not reached.
HER2-targeted therapy shows antitumor activity in metastatic colorectal cancer
- Three Practice-Changing Clinical Trials in mCRC (May.30/20)
Autumn J McRee, MD, associate professor of medicine, The University of North Carolina at Chapel Hill, presented three clinical studies of targeted therapies in unique niches of metastatic colorectal cancer (mCRC) at ASCO.
First Study
Dr McRee showcased the DESTINY-CRC01 study – a phase II, multicenter, open-label study of an antibody drug conjugate (T-DXd) in patients with HER2-expressing disease. Please see article number thirteen above. Patients in the study had unresectable or metastatic disease, had received at least two prior lines of therapy, and were RAS/BRAF wildtype. They were divided into three cohorts, the first of which included 53 patients who were HER2-positive and treated with T-DXd (6.4 mg/kg). ORR was recorded as 45.3% in the experimental cohort, and there seemed to be an improvement regardless of prior treatment. Dr McRee noted that adding T-DXd to the treatment paradigm offers an improvement in progression-free survival (PFS) as well as higher response rates.
Second Study
Dr McRee discussed the updated survival results from the BEACON trial – a randomized, three-arm, phase III study, involving patients with BRAF V600E-mutated metastatic disease with progression after at least one prior regimen. Please see article number seven above. They received encorafenib plus binimetinib and cetuximab (Arm A) encorafenib plus cetuximab (Arm B) or FOLFIRI plus cetuximab, or irinotecan plus cetuximab (Control Arm). Updated survival curves showed identical median OS for Arm A and Arm B (9.3 months) compared with that of Control Arm (5.9 months). Response rates were also higher in Arm A and Arm B than in Control Arm. “This trial shows how our poorest prognostic group in colorectal cancer now has viable options,” Dr McRee stated, and is “immediately practice-changing, given the FDA approval of encorafenib and cetuximab.”
Third Study
Lastly, Dr McRee introduced the PANDA study – a non-comparative randomized clinical trial of older patients (median age, 77 years) with RAS/RAF wildtype metastatic disease. Patients received either FOLFOX plus panitumumab (Arm A) or 5FU/LV plus panitumumab (Arm B) for up to 12 cycles followed by panitumumab maintenance. Primary objective of the study was PFS of each arm compared with a literature-based historic control of less than or equal to 6 months. The PFS endpoint was met in both arms of the study, Dr McRee stated; the median PFS was 9.6 in Arm A and 9.1 in Arm B. Both arms had promising response rates of greater than 50%. While encouraging response rates were observed in the first-line setting in both treatment arms, further overall survival and geriatric assessment data are needed.
- Pembrolizumab doubles PFS for certain patients with mCRC (May.29/20)
First-line pembrolizumab extended progression free survival (PFS) vs. chemotherapy for patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer (mCRC). An estimated 5% of patients with metastatic colorectal cancer have high microsatellite instability, characterized by a high level of mutations. In microsatellite instability-high/mismatch repair-deficient disease, DNA repair is compromised, leading to an even higher number of mutations. This subgroup of patients is less likely to respond to conventional chemotherapy and, therefore, prognosis typically is poor.
Phase II studies showed pembrolizumab improved response and prolonged survival for patients with microsatellite instability-high metastatic colorectal cancer compared to chemotherapy. Randomized, phase 3 KEYNOTE-177 trial assessed the efficacy and safety of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) vs. standard chemotherapy as first-line treatment for patients with microsatellite instability-high, mismatch repair-deficient mCRC. Of the 307 patients with measurable disease, Researchers randomly assigned 153 patients to pembrolizumab dosed at 200 mg every 3 weeks, while the other 154 patients received investigator’s choice of one of six standard chemotherapy regimens selected prior to randomization. This included modified FOLFOX-6, which consists of 5-FU, leucovorin and oxaliplatin; modified FOLFOX-6 plus bevacizumab; modified FOLFOX-6 plus cetuximab; FOLFIRI, which consists of leucovorin, 5-FU and irinotecan; FOLFIRI plus bevacizumab; or FOLFIRI plus cetuximab. Treatment continued until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, or completion of 35 cycles.
Results of the final PFS analysis were presented based on median follow-up of 32.4 months. The results showed a near-doubling of median PFS with pembrolizumab (16.5 months vs. 8.2 months) and a higher percentage of patients assigned pembrolizumab remained progression free at 12 months (55.3% vs. 37.3%) and 24 months (48.3% vs. 18.6%). Researchers also reported a higher ORR in the pembrolizumab group (43.8% vs. 33.1%), as well as higher rates of complete response (11.1% vs. 3.9%) and partial response (32.7% vs. 29.2%). More than twice as many patients assigned pembrolizumab remained in response for 2 years or longer (83% vs. 35%). Although the majority of both groups experienced treatment-related adverse events, a considerably lower percentage of patients assigned pembrolizumab experienced grade 3 to grade 5 treatment-related adverse events (22% vs. 66%). The most common adverse events reported among pembrolizumab-treated patients included diarrhea (any grade, 25% for pembrolizumab vs. 52% for chemotherapy; grade 3 or higher, 2% vs. 10%). The study will continue so researchers can assess OS outcomes.
Image Source: https://www.primeoncology.org/primelines/watch-and-wait-rectal-cancer-2/
- Braftovi Gets Approved in the EU for BRAF+ CRC (June.4/20)
The European Medicines Agency (EMA) has approved Pierre Fabre’s Braftovi for the treatment BRAF-positive colorectal cancer (BRAF+ CRC), making it the first drug specifically approved for this type of cancer in the EU. BRAF inhibitor Braftovi (encorafenib) has been cleared in a regimen alongside Merck KGaA’s EGFR-targeting antibody Erbitux (cetuximab) for second-line treatment of BRAF+ CRC patients previously treated with other systemic therapies.
Braftovi was approved for the same indication in April in the US particularly for its potential as a CRC treatment, and is sold by Pfizer – and was one of the key elements in the Big Pharma company’s $11.4bn takeover of Array Biopharma last year. Braftovi is already approved to treat BRAF+ melanoma (form of skin cancer) and analysts at EvaluatePharma think that colorectal cancer will account for more than $700m of the drug’s predicted global sales in 2024. Pfizer claimed approval for the colorectal cancer indication from the FDA in April.
The latest EU approval follows the BEACON CRC trial, which according to Pierre Fabre is the first and only phase 3 study to test a BRAF combination targeted therapy in BRAF+ colorectal cancer. It showed that Braftovi/Erbitux significantly improved overall survival (OS) by 40% compared to Erbitux and irinotecan-based chemotherapy, with a median OS of 9.3 months and 5.9 months, respectively. The trial has established Braftovi and Erbitux as a standard therapy for second-line BRAF-mutant colorectal cancer, but trials are already underway that will try to move the combination into the front-line setting. The phase 2 ANCHOR CRC trial, which started in 2018, is testing triple therapy with Braftovi/Mektovi plus Erbitux or another EGFR inhibitor – Amgen’s Vectibix (panitumumab) – as a chemotherapy-free option for patients. Results are due to generate this month.
- Regular Aspirin Use May Reduce Risk for CRC Alongside Other Digestive Tract Cancers (May.21/20)
Researchers used random effects models to estimate the pooled response rate (RR) of cancer with regular aspirin use (at least one to two tablets per week) vs. nonuse and investigated dose- and duration-risk relationships when possible. Results showed associations between regular aspirin use and reduced risk for colorectal cancer (CRC) (95% response rate of 45 studies), squamous cell esophageal cancer, adenocarcinoma of the esophagus and gastric cardia, stomach cancer, and pancreatic cancer. Researchers also observed increased benefit with longer duration of aspirin use, and increased doses appeared to further reduce risk for CRC. They found that an aspirin dose of 75 mg to 100 mg per day lead to a 10% reduction in risk for colorectal cancer, whereas a dose of 325 mg per day lead to a 35% reduction and a dose of 500 mg per day lead to a 50% reduction. However, the estimate for high-dose aspirin should be interpreted with caution because it is based on only a few studies. These findings suggest there’s a beneficial effect of aspirin in the prevention of bowel and other cancers of the digestive tract.
Image Source: https://financialtribune.com/articles/people/64508/aspirin-not-effective-for-atrial-fibrillation-treatment
- Durvalumab and Tremelimumab Combination May Prolong OS in CRC (May.20/20)
A phase II trial published in JAMA Oncology suggested that combination immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged overall survival (OS) in patients with advanced refractory colorectal cancer (CRC). Analysis suggested that tumor mutation burden (TMB) from cell-free DNA (cfDNA) analysis could be a possible biomarker for benefits from immune checkpoint inhibitors. The trial was conducted in 27 cancer centers across Canada between August 2016 and June 2017. Patients eligible for the study had histologically confirmed adenocarcinoma of the colon or rectum, and received all available standard systemic therapies, including:
- Fluoropyrimidines, oxaliplatin, irinotecan (Camptosar), and bevacizumab (Avastin), if appropriate
- Cetuximab (Erbitux) or panitumumab (Vectibix), if the patient has RAS wild-type tumors
- Regorafenib (Stivarga), if available
Patients received either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg of durvalumab every 28 days, or best supportive care (BSC) alone. With an average follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC. Progression-free survival (PFS) was 1.8 months and 1.9 months, respectively. In those who were microsatellite stable (MSS), OS was significantly improved with the combination of durvalumab and tremelimumab. However, patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) saw the greatest OS benefit.
Grade 3 or 4 adverse events (AEs) were found to be significantly more frequent with immunotherapy – 75 (64%) patients in the treatment group had at least 1 grade 3 or higher AE vs 12 (20%) in the BSC group. Incidences of all grades were significantly higher in the treatment group for fatigue, nausea, constipation, insomnia, cough and diarrhea. Results seen with the combination of durvalumab and tremelimumab in treatment-refractory MSS colorectal cancer can only be considered hypothesis generating, and the likelihood of seeing actual efficacy from this immunotherapy combination is low. Novel combinations of immune checkpoint inhibitors with agents that may further enhance the immune response may be a more promising approach, and several clinical trials are ongoing.
SURGICAL THERAPIES
- Hepatic Artery Infusion Pump (HAIP) Chemotherapy Program — Sunnybrook Odette Cancer Centre (Feb.24/20)
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.
http://sunnybrook.ca/content/?page=colorectal-colon-bowel-haip-chemotherapy
- Living Donor Liver Transplantation for Unresectable Colorectal Cancer Liver Metastases (Mar.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.”
https://clinicaltrials.gov/ct2/show/NCT02864485
- Wait and Watch Approach in Rectal Cancer (Apr.29/20)
What is the Innovation?
A watch-and-wait (WW) approach for patients with rectal cancer after a clinical complete response (cCR) to neoadjuvant therapy (NAT) is the innovation. The Clinical complete response means no rectal tumor is found by digital examination, endoscopy, and magnetic resonance imaging (MRI). As for the WW response, it gives the patient an opportunity to preserve the rectum & avoid surgery. Patient demand has increased for watch-and-wait as a cCR can occur in approximately 30% of patients treated with a total neoadjuvant therapy (TNT) approach and can occur in some patients receiving ChemoRadiation Therapy (CRT) alone. One of the largest studies conducted to date has been at Memorial Sloan Kettering in New York City.
What are Key Advantages Over Existing Approaches?
Rectal cancer is a complex disease to treat, given multimodal care (i.e. neoadjuvant chemoradiation [CRT], rectal resection, adjuvant chemotherapy). After neoadjuvant therapy, standard treatment proceeds to total mesorectal excision (TME), which places patients at risk for bowel, bladder, or sexual dysfunction as well as a stoma and other potential postsurgical complications (eg, anastomotic leak or wound dehiscence). For patients with no clinical evidence of residual tumor, WW approach offers significant advantages, including avoiding TME and maintaining an excellent quality of life. The potential downside is seen in WW patients who do not have a sustained complete tumor response, are at risk for developing local regrowth and thus require delayed TME and face the potential for increased metastasis risk and oncologic outcome compromise.
How Will This Affect Clinical Care?
Patients opting for WW must undergo strict surveillance for at least 5 years, where they are observed for 8 to 12 weeks post-neoadjuvant therapy (NAT) to determine their tumor response. For patients treated off protocol by WW at Memorial Sloan Kettering Cancer Center (New York), an agreement is made between the surgeon and the disease management team to proceed with this nonstandard approach. For one to accept the risks of local regrowth and in possible need for salvage surgery and potential local and/or distant spread. Patients who cannot handle uncertainty or return for follow-up visits will not be good WW candidates. TME is the best option for those who want to be absolutely certain there is no remaining cancer in the rectum.
Is There Evidence Supporting the Benefits of the Innovation?
For WW in selected patients with a sustained cCR compared with pathological complete response (pCR), for patients who underwent TME, there were no differences in overall survival between the groups. Deferral of surgery was safe in the cCR group, and local regrowths could be salvaged with total mesorectal excision (TME). Nonetheless, WW is an alternative treatment strategy. Their work which evaluates 113 patients achieving cCR after NAT reflects the largest North American WW assessment & demonstrated 4 key points. First, cCR patients accepted WW and were willing to take risks to preserve their rectum. Secondly they have observed a high rate of rectal preservation (79% at 5 years) in those achieving a cCR. Third, WW with careful surveillance and timely surgical salvage after local regrowth detection obtained local control in 20 of 22 patients who underwent salvage surgery (90%) and 111 of 113 (98%) overall. Lastly distant metastases developed in 8% of WW patients.
What Barriers to Implementing This Innovation More Broadly?
A main barrier is lack of expertise with the surveillance strategies. Knowledge of the clinical appearance of cCR by endoscopy, and dedicated radiologists who can assess and reliably interpret rectum and MRI findings after NAT. Challenges to patient adherence include travel for surveillance examinations, life interruption, and anxiety associated with surveillance. The barrier in the community is the lack of insurance coverage for interval endoscopy and MRI because there is not a solid WW endorsement by the National Comprehensive Cancer Network in the US. Some other hurdles to broad implementation include non-uniform response definitions regarding cCR, surveillance protocol variations, multiple NAT regimens used, and short follow up in the retrospective studies to date. Finally, refining patient selection and lowering local regrowth rates would improve acceptance and make this approach more generalizable.
In What Time Frame Will This Innovation Likely Be Applied Routinely?
The Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II trial is evaluating 3-year disease-free survival in patients with rectal cancer treated with CRT plus induction or consolidation chemotherapy and TME orWW. MRI-staged patients with clinical stage 2 or 3 rectal cancer amenable to TME are randomized to receive systemic chemotherapy in an induction or consolidation approach (pre-/post-CRT). TME is required if a residual tumor remains; if no tumor is detected, then WW is used. OPRA will illuminate the best way to get patients to cCR; however, it is only a phase II trial, and the findings must be validated in an adequately powered phase III trial. It will be 3 to 4 years before additional level-1, prospective data will be available to validate this approach.
https://jamanetwork.com/journals/jamasurgery/article-abstract/2764558
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:
SCREENING
- Importance of Family History-Based Screening for CRC (Apr.20/20)
Colorectal cancer develops in the large intestine as a small noncancerous clump of cells (polyps), that form on the inside of the colon and turn cancerous over time. Regular screening tests can help prevent the disease by identifying these polyps so they can be removed, but not everyone is screened early enough. This study concluded that almost all adults included in the analysis, who were diagnosed with colorectal cancer between 40 and 49 years of age, could have been diagnosed earlier if they had been screened according to current family history-based screening guidelines. Family history of the disease is one of the most important risk factors for colorectal cancer, according to the American Cancer Society, those with a parent, sibling, child who was diagnosed have 2-4 times the risk of developing the cancer compared to those without family history. It’s recommended that individuals with an average risk of colorectal cancer consider screening around age 50 while people with a higher risk should consider getting screened sooner.
Samir Gupta, lead author of the research and professor of clinical medicine at the University of California conducted an analysis of the information in the Colon Family Registry on individuals aged 40 to 49 years, investigators found that 25% of patients with colorectal cancer and 10% of those without colorectal cancer met the criteria for family history-based early screening. Almost 98% of patients with colorectal cancer, who met the early screening criteria, should have been screened at a younger age than when their cancer was diagnosed, meaning that their cancer could’ve been diagnosed earlier or even prevented.
“Colon cancer has strong genetic and environmental components… about 20% of people who get diagnosed with colon cancer will report some sort of family history of colon cancer,” said Gupta. Jeffrey Meyerhardt, medical oncologist and co-director of colon and rectal cancer center at Dana-Farber Cancer Institute said, there’s no uniform way of ensuring that all health care providers are not only asking patients for their family history as a part of standard practice, but that this information is updated over time in medical records. The study emphasized the importance of increasing public awareness of the risk factors for colorectal cancer alongside efforts to ensure individual medical records are updated with any sign of family history
- Starting Age for Screening in Relatives of Patients with CRC (Apr.7/20)
There is limited information on how many years earlier high-risk individuals should be screened; current practice is based on weak evidence. The data was collected from nationwide family-cancer datasets in Sweden and calculated risk-adapted starting ages of screening for individuals with different family histories of colorectal cancer (CRC). During a follow up of 12,829,251 individuals with genealogy information, 173,796 developed CRC, the 10-year cumulative risk for the average-risk population at age 50 y (guideline-recommended age for screening) was 0.44%, the individuals with different family histories of CRC attained this equivalent 0.44% risk 3-32 y earlier than their peers without such a family history where individuals with 1 affected first-degree relative diagnosed before age 45 reached the corresponding risk level 16 y earlier. These findings might be used in counselling individuals about the appropriate age to start CRC screening, to optimize screening practice, and to supplement guidelines for CRC screening.
- Increased Risk of CRC in Individuals With a History of Serrated Polyps (Apr.8/20)
Serrated polyps (SPs) are precursors to 20%–30% cases of colorectal tumors, but patients’ long-term risk after removal of SPs is poorly understood. The study investigates the risk of colorectal cancer (CRC) in individuals with a history of SPs. Participants were categorized based on the size and location of SPs. The study included 233,393 individuals, of whom 445 developed incident CRC, at 10 years, cumulative incidence rates of CRC (per 1000 persons) for individuals with no polyp = 4.7, proximal small SPs = 14.8, proximal large SPs = 30.2, distal SPs = 5.9. In patients with SPs, risk of CRC was not increased until 3 y or more after the first colonoscopy. The presence of synchronous adenomas increased the risk for CRC.
https://www.sciencedirect.com/science/article/abs/pii/S0016508520304674
- Single Negative Colonoscopy Predicts Low CRC Risk (May.26/20)
New study concludes that a single negative screening colonoscopy is associated with long-lasting, significant reductions in the incidence of, and mortality from, colorectal cancer (CRC). The population-based study showed a reduction in CRC risk over 17.4 years of follow-up, findings confirm that a 10-year interval between high-quality screening colonoscopies [as is currently recommended] is safe and that there is no benefit from more frequent screening. This interval could even be prolonged, provided the baseline colonoscopy is of high quality, it is emphasized that only high-quality colonoscopy provided a durable reduction in mortality risk and that low-quality colonoscopy was associated with a significantly increased risk of CRC death after the first 5 years following the examination.
Polish Colonoscopy Screening Program
The study included 165,887 average-risk patients who had a single negative screening colonoscopy between October 2000 and December 2011. The negative colonoscopy was defined as an examination where no evidence of any neoplastic lesion was found. This being said a high-quality screening colonoscopy was defined by three key properties, cecal intubation, adequate bowel preparation, endoscopist’s adenoma detection rate (ADR) of 20% or greater calculated on a yearly basis. A total of 505 different endoscopists performed the colonoscopies over a median follow-up of 10.1 years. Compared with the general population, among individuals with a negative colonoscopy, the incidence of CRC was 72% lower and CRC mortality was 81% lower over a period of 5.1 to 10 years. Beyond 10 years of follow-up, reductions in CRC incidence and mortality were similar to those observed for the earlier period of 5.1 to 10 years but only for participants who had had a high-quality screening colonoscopy.
Subgroup Analyses
Subgroup analyses showed that high-quality colonoscopy — although not those of low-quality — effectively reduced the incidence of, and mortality from, CRC in women and in the proximal colon. Previous studies have suggested that women may not benefit from screening colonoscopy to the same extent as men. Where as research suggests a reduced CRC risk in the proximal colon relative to that in the distal colon, for the first time, the findings showed that when you have high-quality colonoscopy, women benefit from screening colonoscopy as much as men. High-quality screening colonoscopy was associated with a 50% reduction in mortality in the proximal colon throughout the 17.4-year follow-up, whereas there was no decrease in mortality with low-quality colonoscopies. Lesions in the proximal colon are subtler and are harder to detect. It’s also more difficult to achieve good bowel preparation in the proximal colon. Women are more prone to develop lesions in the right (proximal) side of the colon and appear to have more pain with colonoscopy than men. They showed that high-quality is a prerequisite for safe intervals between colonoscopies, so if, at a certain age, a patient has a negative colonoscopy of high-quality, a negative colonoscopy is highly predictive of a very low future risk of CRC.
Single Negative Colonoscopy Predicts Low Colorectal Cancer Risk
- Non-Invasive Blood Assay Can Detect Early CRC (May.21/20)
Doctors recommend certain screening tests for healthy people with no signs or symptoms in order to look for signs of colon cancer or noncancerous colon polyps. Finding the cancer at its earliest stage provides the greatest chance for a cure. Medical Scientist at the Stanford University Medical Center (Stanford, CA, USA) evaluated a novel blood-based assay in a single-center, blinded study. The study included 354 patients with no prior colorectal cancer (CRC) diagnosis who were scheduled for colonoscopy. 86% of these patients were asymptomatic and 14% had symptoms or a positive fecal immunochemical test.
Prior to colonoscopy, investigators drew blood samples to be analyzed by the test FirstSightCRC. This test focuses on three biomarkers, circulating gastrointestinal epithelial cells, somatic mutations and methylation of cell-free DNA. Scientists developed a quantitative age- and sex- adjusted composite CMx Score from 0 to 100. The test achieved a specificity of 90% and sensitivity of 100% for the detection of CRC and 76% for detection of advanced adenomas. It also found an association between the CMx Score and disease severity.
The study included several patients who had elevated CMx Scores but had negative colonoscopies. After reviewing patient histories, the investigators found a prior history of advanced adenoma removal in most cases. Shai Friedland, MD, a professor of medicine and the senior study author, said, “The blood test has the potential to fill an unmet need by giving patients a highly sensitive, convenient option for colorectal cancer screening”. Patients are continually being enrolled to validate the blood test, as results look extremely promising.
OTHER
- 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
- Psychologists
- Geneticists
- 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.
http://sunnybrook.ca/content/?page=young-adult-colorectal-cancer-clinic
- Association Between Cannabis and Quality of Life Among CRC Survivors (May.3/20)
As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptoms. This study aims to determine the prevalence of cannabis use among colorectal cancer (CRC) survivors and its associations with quality of life (QoL) and cancer-related symptomatology. 13, 089 people ≥18 years old with diagnosed colorectal cancer from 2010 through 2016 were given a survey of patient-reported QoL outcomes and behaviours.
Of the 1784 respondents, 293 (16.4%) reported cannabis use following CRC diagnosis. Current tobacco smokers & greater alcohol use was associated with cannabis use. Cannabis use was more likely in patients diagnosed with stage 3 or 4 CRC than stage 1 or 2 CRC. The study also found that people who used cannabis had significantly lower QoL than people who did not use cannabis. Clinicians should inquire about cannabis use among their patients and provide evidence-based recommendations for cancer-related symptoms.
- Newly Found Link Between Blood Infections and CRC (May.1/20)
A study has concluded that anaerobic bacterial blood infections are associated with an increased risk of developing colorectal cancer, which may help clinicians better screen for colorectal cancer. Anaerobic bacteria do not require oxygen in order to function. It’s a normal part of the body and exists in various locations.
Of 2 million participants, the team gathered data on 45,760 blood infections, including information about the type of pathogens present in the participants’ bloodstreams. They looked for new cases of colorectal cancer, especially those that developed following a blood infection from any of the bacteria already associated with colorectal cancer. Of the 45,760 people, 492 (1.1%) later developed colorectal cancer. Of these, 241 (0.5%) were within the first year of the bacterial blood infection.
The study found that, in people with blood infections caused by anaerobic bacteria, the risk of developing colorectal cancer was increased by up to 42 times compared with people with blood infections caused by aerobic bacteria such as E.coli. The Study’s co-author Dr. Ulrik Justesen, from Odense University Hospital in Denmark stated “At this stage, we are not sure if the bacteria are directly causing cases of colorectal cancer, or if the blood infection with these bacteria itself was caused by the cancer.” He says: “Our follow-up research of this study will focus on the specific bacteria from [people with cancer] to see if we can identify specific characteristics that could be implicated in cancer development. If this is the case, it could be of great importance when it comes to screening and treatment of colorectal cancer.” Details about the full methodology and results are not yet available, as this research is awaiting presentation.
- Mucinous Histology, BRCA1/2Mutations, and Elevated Tumor Mutational Burden in CRC (Apr.25/20)
An increased risk of colorectal cancer has been demonstrated in germline (hereditary) BRCA1/2 mutation carrier. BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of mucinous carcinoma (MC) tumors. MC tumors have a tendency to develop in young patients and are associated with late diagnosis at advanced stages, possibly because their typical location in the proximal (right-sided) colon is associated with less symptomatic presentation and a faster disease progression. A limited response to systemic therapy in metastatic disease has been reported. MC histology has, therefore, been considered as an unfavorable prognostic indicator of CRC.
This study investigates the relationship between BRCA mutations and mucinous histology in colorectal cancer patients. Using both an existing cohort of sequenced colorectal tumors and a prospective case-control study comparing MC and conventional adenocarcinoma (AC), patients tested for BRCA mutations. Analysis showed a significantly higher incidence of BRCA mutations as well as a higher average mutation count in the MC tumors compared to AC. The strongest predictor of the mutation count was mucinous histology, independently of other variables. Finally, they observed a higher tumor mutational burden (TMB) in MC tumors compared with AC tumors. The association between MC histology, BRCA mutations, and increased TMB may open the door to the utilization of simple tests to detect patients who may benefit from immunotherapy in colorectal cancer.
https://www.hindawi.com/journals/jo/2020/6421205/
- E. ColiDiversity: Low in CRC (Apr.6/20)
Pathogenic E. coli have different types, causing intestinal or extra-intestinal infections. New types associated with colorectal cancer have continually been reported. 2280 E. coli isolates were collected from healthy individuals in three age groups, who did not have intestinal or extra-intestinal illnesses (preschool children, university students, and seniors), and of CRC patients for comparative studies. Based on their genomic differences, the bacteria was laid out into distinct genome types (genotypes).
The general diversity of the E. coli populations went up with age in the groups of healthy subjects but the CRC patients of all ages had the lowest diversity. E. coli isolates from CRC patients could suppress the growth of E. coli bacteria isolated from healthy controls under nutrient-limited culture conditions. These results suggest that the coexistence of multiple benign E. coli lineages in the same microbiota may help create a beneficial microbial environment for human health. The low diversity of E. coli bacteria may be associated with unhealthy microenvironment in the intestine and hence facilitate the pathogenesis of diseases such as CRC.
Image Source: https://www.canceractive.com/article/colorectal-cancer-link-to-food-poisoning-and-ecoli
- Turning Colon Cancer Cells Around (Apr.7/20)
According to findings by University of California, Irvine biologists, using a modified natural substance along with current approaches could improve colon cancer treatment. 80% of colon cancers stem from a genetic mutation of the protein adenomatous polyposis coli, or APC. Majority of people with that mutation will develop polyps, while only some of the polyps will become cancerous.
The research team decided to investigate non-genetic factors that could propel the disease, focusing on the role of the amino acid glutamine. Cancer cells consume a great amount of glutamine to multiply, but depriving them of glutamine doesn’t kill all the tumor cells. Researchers found that a drop in cellular levels of the metabolite alpha-ketoglutarate after glutamine starvation accompanied the transition from benign to cancerous cells.
Conducting further investigation into the metabolite’s role, they provided a modified version of alpha-ketoglutarate to animal models with APC mutation and the results were significant. 23% of those given the modified metabolite developed rectal bleeding (an indication of intestinal tumours), compared to 90% of the animal models that did not receive it. It also curbed tumour growth and protected against disease-associated conditions such as weight loss.
“Supplementation of the modified alpha-ketoglutarate inhibits a key cancer-development signalling pathway in colon cancer cells, turning them into more normal cells,” said researcher Thai Q. Tran. By mixing it into drinking water, the metabolite was easy to take & did not affect overall health. “We believe this new knowledge shows great potential for using less-toxic and natural approaches in combination with current therapies to more successfully treat colon cancer while better protecting patients’ overall wellbeing,” said Molecular Biology and Biochemistry Associate Professor Mei Kong.
https://ecancer.org/en/news/17622-turning-colon-cancer-cells-around
- Tumor Mutation and Immune Microenvironment Relationships (May.26/20)
An international research team has uncovered apparent ties between tumor mutational patterns and immune features in the surrounding microenvironment in dozens of colorectal cancer (CRC) patients from Korea and Belgium. Researchers profiled expression patterns in more than 91,100 individual cells from tumor samples from 23 Korean individuals with CRC and six CRC patients from Belgium. Molecular features in the tumor and its microenvironment could both help in selecting the most appropriate treatment for a patient with CRC. It is beneficial to understand if, and how, tumor features interact with immune and other cells in the microenvironment.
- By exploring the cellular landscape and reconstructing the interaction network between tumor cells and their microenvironment, researchers were able to decode how these diverse cellular components jointly determine CRC molecular subtypes in individual patients. They identified expression-based clusters representing cell types in the microenvironment, including stromal, epithelial, myeloid, and mast cells, along with T cells and B cells, in samples collected from different parts of the large intestine. Those clusters were then used to find tumor features that corresponded to heightened or damped down immune responses (i.e. tumors in a consensus molecular subtype (CMS) called CMS2 had TP53 or APC driver mutations and had relatively low levels of immune cells and stromal cells).
The authors noted that the genetic alterations found in the tumors did not fully line up with molecular features in the samples, suggesting still other environmental, microbiome, or molecular features contribute to the such interactions
- Colon Cancer Signs in Young Adults (Jun.3/20)
Young adults are often not aware they can get colon cancer, and doctors are often late to diagnose it in younger patients. While the overall rates of colorectal cancer declined by 3.6% annually among adults 55 and older from 2007 to 2016, it increased by 2% annually in that time period among those under age 55, the American Cancer Society says. In 2020, the American Cancer Society estimates there will be nearly 108,000 cases of colorectal cancer (CRC) diagnosed, with 53,200 deaths.
Ronit Yarden, PhD, an adjunct associate professor of oncology at Georgetown University School of Medicine did an online survey, launched via social media channels in which 885 patients and survivors finished the questionnaire. The median age at diagnostic was 42, lower than the American Cancer Society’s recommended age of 45 to start screening for average-risk people. 63% of respondents said they were not aware that CRC can affect people younger than 50. Yarden says that may explain why most waited more than 3 months after noticing symptoms to see their doctors and 23% waited more than 12 months.
Once they visited the doctor, diagnosis was poor. 75% said they visited two or more doctors before getting a diagnosis and 11% of those visited 10 or more doctors before hearing what was wrong. Many patients felt that the doctors saw and dismissed their symptoms. 68% of respondents reported blood in the stool and 49% had rectal bleeding, both of which are of a direct correlation to this type of cancer. 77% of patients reported being diagnosed with advanced disease and they were treated with aggressive therapies that affected their quality of life. Many of the youngest patients said their doctors did not discuss fertility preservation before treatment. 29% reported some family history of CRC and 6% were diagnosed with Lynch syndrome, a type of inherited cancer syndrome linked with a tendency to get colon cancer.
It is important to test any patients with symptoms that suggest colorectal cancer regardless of age. Patients and doctors need to become more aware that CRC can happen at any age. The American Cancer Society recommends people at average risk of colorectal cancer start screening at age 45 and those with a family history or inherited conditions (i.e. Lynch syndrome) may need to start earlier.
Image Source: https://www.medifee.com/blog/colon-cancer-the-easiest-cancer-to-prevent/
NUTRITION/HEALTHY LIFESTYLE
- Association Between Mediterranean Diet Adherence and CRC (May.2/20)
Many studies have been conducted to investigate the inverse association between following a Mediterranean diet (MD) and colorectal cancer (CRC) incidence and mortality. This meta-analysis leveraged eligible studies from PebMed, Embase and Web of Science. A random-effects model was used to estimate summary RRs and 95% CIs.
This meta-analysis included 13 prospective cohort studies, of which 9 reported CRC incidence and 5 reported CRC mortality. The summary RR of CRC incidence was 0.90 (95% CI: 0.84, 0.96) for highest compared with lowest MD adherence and 0.96 (95% CI: 0.94, 0.99) per 2-score increase in MD adherence. The summary RRs for highest compared with lowest MD adherence were 0.82 for rectal cancer (95% CI: 0.71, 0.95), 0.94 for proximal (right-sided) colon cancer (95% CI: 0.87, 1.02), and 0.91 for distal (left-sided) colon cancer (95% CI: 0.79, 1.04). Neither the summary HR of overall mortality for highest compared with lowest pre- and postdiagnosis MD adherence, nor the summary HR of CRC-specific mortality for highest compared with lowest prediagnosis MD adherence achieved a value with statistical significance.
This meta-analysis supports the inverse association of MD adherence with CRC incidence, but not with overall mortality or CRC-specific mortality among those diagnosed with CRC.
Image Source: http://directorynews.weebly.com/blog/what-is-the-mediterranean-diet-definition
COVID-19 UPDATES
- 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.
https://www.who.int/news-room/q-a-detail/q-acoronaviruses)
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.
https://www.who.int/news-room/q-adetail/q-a-coronaviruses
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!
Source: https://www.who.int/news-room/q-a-detail/q-acoronaviruses
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.
https://www.cancer.gov/contact/emergencypreparedness/coronavirus
Should you wish to contact your local public health agency, please see below.
Alberta
COVID-19 info for Albertans
Social media: Instagram @albertahealthservices, Facebook @albertahealthservices, Twitter @GoAHealth
Phone number: 811
British Columbia
British Columbia COVID-19
Social media: Facebook @ImmunizeBC, Twitter @CDCofBC
Phone number: 811
Manitoba
Manitoba COVID-19
Social media: Facebook @manitobagovernment, Twitter @mbgov
Phone number: 1-888-315-9257
New Brunswick
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
Northwest Territories coronavirus disease (COVID-19)
Social media: Facebook @NTHSSA
Phone number: 811
Nova Scotia
Nova Scotia novel coronavirus (COVID-19)
Social media: Facebook @NovaScotiaHealthAuthority , Twitter @healthns, Instagram @novascotiahealthauthority
Phone number: 811
Nunavut
Nunavut COVID-19 (novel coronavirus)
Social media: Facebook @GovofNunavut , Twitter @GovofNunavut, Instagram @governmentofnunavut
Phone number: 1-888-975-8601
Ontario
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,
Quebec
Coronavirus disease (COVID-19) in Québec
Social media: Facebook @GouvQc, Twitter @sante_qc
Phone number: 1-877-644-4545
Saskatchewan
Saskatchewan COVID-19
Social media: Facebook @SKGov, Twitter @SKGov
Phone number: 811
Yukon
Yukon: Find information about coronavirus (COVID-19)
Social media: Facebook @yukonhss, Twitter @hssyukon
Phone number: 811
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