Dr. Tanios Bekaii- Saab, MD, Program Head Mayo Clinic answered questions about management of advanced colo-rectal cancer

CancerConnect and The Personalized Medicine Foundation were pleased to provide patients and caregivers the opportunity to ask questions about the management of advanced colo-rectal cancer with Dr Tanios Bekaii-Saab, MD FACP Head-Mayo Clinic Gastrointestinal Cancer Program & Director of Cancer Clinical Research.

Answers to Submitted Questions About Advanced Colon Cancer

My father has been on FOLFOX for 6 months-12 rounds and he just had a CT showing minimal shrinkage of his liver tumors. It has currently only shrunk minimally, and we are quite discouraged. The chemo is causing neuropathy. What should the next steps be?

There is no evidence that total shrinkage of the cancer confers any longer-term benefit than no further growth or minimal shrinkage that remains durable. Often times, the physician may decide to provide the patient with a break from Eloxatin (oxaliplatin) and maintain the patient on less toxic therapy. This seems to maintain the benefit while reducing significantly the risk of side effects.

I was treated with FOLFOX for stage III colon cancer 3 years ago and the cancer has returned in my colon and lungs. My doctor wants to treat me with FOLOX – if it didn’t work the first time why would he use it again? Are there other options?

For chemotherapy in colon cancer, as a general assumption if more than 6-12 months from the last dose of chemotherapy have passed by without evidence of progression of the disease, doctors can reuse the same regimen if there is no evidence of residual side effects. An alternative can be FOLFIRI + Avastin (Bevacizumab). If the cancer originated on the left side of the colon and the absence of KRAS, NRAS, BRAF V600E mutations, or Her2 over expression or amplification, one could consider cetuximab or panitumumab instead of bevacizumab.

I still don’t have a complete response to treatment with FOLFIRI (9 months) and I have worsening neuropathy. My doctor wants to switch to Stivarga and give me a break. Does this make sense? seems like many of the patients I talk to get FOLFIRI or FOLFOX for much longer.

Side effects from chemotherapy is very variable and for every patient differs in terms of timing and severity. Neuropathy is very troublesome side effect and doesn’t always improve. Stivarga (regorafenib) is not technically a chemotherapy drug, but a molecularly targeted precision cancer medicine hitting many of the relevant targets in colorectal cancer. If your physician choses to place you on Stivarga, the preferable approach would be a dose escalation strategy starting with 80 mg orally every day for a week, reassess in a week and go up to 120 mg orally every day for one more week then reassess in a week and if all is well go to 160 mg orally for 1 more week then a week off. This strategy was found to be superior to going straight to 160 mg orally every day for 3 weeks in a row in a study called ReDOS just recently published in the journal Lancet Oncology.

I have recurrent colon cancer in my abdomen and have been treated with both FOLFOX and FOLFIRI and now my cancer is progressing again. Genomic testing revealed no markers that could be treated. Other than a clinical trial what treatment options do I have?

There are 3 options that are available to you. The first is the precision cancer medicine Stivarga The second option would be an agent called Lonsurf (TAS-102) which is a chemotherapy oral agent that belongs to the same family of agents called fluoropyrimidines such as capecitabine and 5FU , but its structure is modified to allow for activity when other fluoropyrimidines stop working. The third option would be to participate in a clinical trial.

I have metastatic colon cancer and am on my 6th treatment with FOLFOX, I have worsening numbness and tingling in my feet. Last two scans show the cancer is in partial remission and stable but no longer improving. What are the next treatment choices?

Often times, the physician may decide to provide a patient with a break from oxaliplatin after 6-8 treatment with FOLFOX maintain them on 5-flurouracil or capecitabine +/- bevacizumab. This seems to maintain benefit while improving significantly the risk of toxicity.

Genomic Biomarker Testing

I have recurrent colon cancer in the liver and abdomen and my doctor wants to start chemo again. I asked if I should be tested for genomics and he said not yet. Other patients I know have been tested and found new treatments – why would he say no and should I insist on getting tested?

Genomic testing has gained significant momentum in the last year or so. It is possible that your physician has already obtained the minimum necessary testing available to decide on your treatment. The most important elements for decision making include assessing for the presence or absence of the KRAS, NRAS and BRAF V600E mutations, Her2 over expression or amplification, Microsatellite stability and later on NTRK fusions. Expanding beyond these clinically useful elements can be performed at any point including later on when more experimental trials are being considered.

Does it matter which biomarker test my doctor uses; he wants to send to the hospital lab but many patients I talk to have used Foundation One or Caris. Are they better than the hospital labs?

There is no evidence that any of the commercial tests (Caris, F1, Tempus or others) confer a significant advantage versus a well validated local hospital laboratory. Many large institutions provide the same depth and wealth of information you will get from commercial tests. The most important elements for decision making include assessing the presence or absence of KRAS , NRAS and BRAF V600E mutations , Her2 over expression or amplification, Microsatellite stability and later on NTRK fusions. Expanding beyond these clinically useful elements can be performed at any point including later on when more experimental trials are being considered.

Questions About Management of Metastases

Individuals with colon cancer and mets only to the liver seem to have a chance with liver-resection. It seems like individuals with lung mets are underserved… what is on the horizon for treatment of lung mets?

Every patient with metastatic colon cancer may have a shot at resection or local therapy if the disease is organ limited (liver, lung, peritoneum etc..). This is not limited to the liver only. The decision for feasibility of a local therapy approach usually comes from the multidisciplinary group meeting (tumor board) that every institution or center holds to discuss these types of cases.

Is RFA HIPEC or other liver treatments better than surgery if the cancer can be removed by surgery?

HIPEC is a treatment offered for select patients with peritoneal metastatic disease only. As for RFA vs. surgery, it is unknown if one confers an advantage vs. the other. Both are operator dependent and experience matters quite a bit for success. My preference for my patients is typically for surgery if reasonable, feasible and patient willing.

How are peritoneal mets from colon cancer best treated (especially if I am not eligible for HIPEC/PIPAC)?

HIPEC is a treatment offered for select patients with peritoneal metastatic disease only. HIPEC on its own is not a good option without surgical resection of all visible lesions. On the other hand, for most colon (non-appendix) cancer that are limited to the peritoneum, systemic therapy +/- surgery (if feasible and reasonable) is a reasonable option . For all other patients, systemic therapy is their best and only option.

Is radiation therapy an effective treatment option for stage 4 colon cancer metastasized to right pelvic mass, internal mammary node and peritoneum? I can’t find much information to suggest radiation makes sense.

Radiation therapy has very limited role in stage 4 colon cancer. On rare occasions it is used in certain specific settings such as brain, bone and/or spinal cord involvement.

Questions about Research and Clinical Trials

What are the key ongoing clinical trials in colon cancer that patients should be aware of?

Current research is focused on identifying which patients can be treated with a precision cancer medicine targeting specific cancer driving mutations in patients with metastatic and stage III colon cancer.

COLOMATE: Using a Liquid Biopsy in CRC to Select a Molecularly Targeted Therapy.

The primary objectives of the COLOMATE trial are “to perform blood-based genomic profiling on patients with treatment-refractory metastatic colorectal cancer to facilitate access to specific targeted treatments based on the molecular profiles of their cancers. Patients with specific cancer driving genomic alterations such as RAS/BRAF wild-type, HER2-amplified, FGFR-altered, and RAS-mutated, abnormalities will be eligible to be treated with precision cancer medicines in development that target these mutations. https://clinicaltrials.gov/ct2/show/NCT03765736

I was wondering if you might know of any research about the scientific rationale for using a BRAF inhibitor with an ICI for BRAF V600e MSS patients? I’ve seen the Consensus Molecular Subtype research and it seems very compelling re BRAF being more likely to be immunogenic. But I suspect there is so much related research in melanoma with BRAF inhibitors (Dr. Flaherty, maybe Dr Ribas). I know CRC is different from melanoma (and that so much of the current work is to find answers) but I could use an assist in any published research or ASCO abstracts re BRAF(i) + ICI.

Research regarding the use of BRAF(i) + ICI in MSI/BRAF V600E mutated tumors makes sense. It is unclear (and unlikely) that ICI + BRAF (i) will have any efficacy in patients with MSS/BRAF V600E mutated cancers.

The addition of DHA Synergistically Enhances the Efficacy of Stivarga for Kidney Cancer Therapy. Has anyone looked at similar synergism for CRC? Do you think diet, especially consumption of Omega-3 rich seafood among the Japanese had any effect on the response rate seen with Stivarga in that population? What in your opinion could be responsible for the 36% response rate in the Japanese MSS CRC patients to Stivarga ? Is the pathogenesis of HFSR in Stivarga treated patients similar to HFS seen in capecitabine treated patients?

There is no clinical evidence that DHA adds value to Stivarga in any cancer. Overall, Japanese CRC patients seem to have very similar benefits than their Western counterparts. The response rate you are referring to is very preliminary and involved combining Opdivo to stivarga. This is now being confirmed in a phase 3 study. HFSR and HFS are different in their pathogenesis.

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