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Treatment Strategy This note is written to serve two purposes; To document my understanding of the cancer and its potential treatments so that these can be confirmed by expert oncologists. To layout a particular strategy in order that research can be confined to a reasonable set of therapies. Otherwise, the research is likely to be spread so widely that it will be ineffective. Preliminary Treatment Initial treatment of the cancer has been a combination of surgical resection and chemotherapy. These are probably the most understood aspects of treatment for colorectal cancer. Surgical resection has the benefits of immediate removal of large proportion of cancerous cells and also providing tissue specimens for analysis. The main disadvantage is that this course of treatment cannot be repeated many times. The chemotherapy regimen of FOLFOX6+Avastin is the most established effective treatment. Established in that its side effects and dosage are well understood. Effective in that genetic testing has indicated that other established regimens using irinotecan and EGRF targeted treatment is likely to be ineffective. Chemotherapy can result in tumour ablation and control of the cancer spreading. There is some documented evidence of colorectal cancer being put into remission or ‘cured’ but it seems to be in a limited number of cases. The problem with chemotherapy is that there is typically a build-up of toxicity in the body requiring the treatment to be suspended (chemo holiday) allowing the body and the cancer time to recover. The second problem is that cancers that initially respond to this treatment can mutate and become resilient to it thus requiring the regimen to be changed or chemo treatment halted. Adjunctive Natural Therapies In addition to the above conventional treatments, there has also been a recourse to more natural therapies to help boost the immune system, recover from surgery, prevent infection, counter chemotherapy side effects, reduce the build-up of toxicity and also help inhibit growth of the cancer. These therapies include regular exercise, nutritionally balanced diet, diet selected to reduce chemotherapy side effects, vitamin supplements, herbal and fungal extracts/supplements. The overall effect is to enable the body to cope with the conventional treatments and also boost the body’s own cancer response. The benefits of some of these therapies are more established than others. But the underlying concept is to keep with natural remedies that have little or no known adverse effects so that less well established remedies can be tried and hopefully benefits can be realised. Colorectal Cancer Difficulties Colorectal cancer can be effectively treated by surgical resection if caught at an early stage (I or II). Once it has spread beyond this, it becomes increasingly more difficult. Literature suggests that there a few basic issues with colorectal cancer that make it difficult to address once it has metastasized. Please check with oncologist. The cancer cells are very similar to normal body tissue thus they don’t elicit a large immune response and they are very difficult to target. The cancer cells express checkpoint blocks to prevent the immune system from targeting them. The cancer cells mutate and can become resilient to current treatments. Cancer Characterisation As noted above, colorectal cancer is particularly good at evading immune response as the cells are very similar to normal cells. Hence the need to identify any genetic differences between the cancer cells and normal cells. These differences can all be considered as potential targets for therapy. Also as noted above, the cancer can mutate hence the need to repeat the genetic assessment during treatment. Finally, although colorectal cancer has proven resilient against immunotherapies, some success has been had with MSI-H cancers and more recently with high overall Tumour Mutation Burden. Note that colorectal increased resilience against immunotherapy implies that specialist advice from an expert in colorectal immunotherapy will be necessary. Evolution of Therapies Initially, treatment was limited to invasive surgery and the use of 5-FU (1950s). Then (2002) Oxaliplatin was added and recently (2004) Avastin has become available. All of these have formed the initial treatment plan. As we can see, current treatment has been available since 2004. The main advances with these specific treatments since 2004 has been the identification of genetic chracteristics of the cancer that are compatible with the drugs effectivity and greater sensitivity and resolution of imaging technologies to detect smaller tumours. 2007 studies indicated that there were benefits in diet and exercise in reducing recurrence of cancer following surgery. More recently other chemo drugs have been identified to offer alternative regimens once FOLFOX6 has run its course. Invasive surgery also now has a number of advanced forms such as keyhole surgery and various forms of targeted radiosurgery and radiotherapy. When combined with advanced high resolution imaging and computer controlled systems this has opened up alternatives for surgical action to remove or destroy tumours. With the exception of drugs like Avastin (a monoclonal antibody that targets VEGF), development of immunotherapy type drugs has met with mixed success. The complete list of currently FDA approved chemotherapy drugs follows: Bevacizumab (eg Avastin) Capecitabine (eg Xeloda) Cetuximab (eg Erbitux) Fluorouracil Injection (eg 5-FU) Irinotecan Hydrochloride (eg Camptosar) Leucovorin Calcium (eg Wellcovorin) Oxaliplatin (eg Eloxatin) Panitumumab (eg Vectibix) Ramucirumab (eg Cyramza) Regorafenib (eg Stivarga) Trifluridine and Tipiracil Hydrochloride (eg Lonsurf) Ziv-Aflibercept (eg Zaltrap) Note that Lonsurf is the latest approved drug (2015). Currently used Candidate Excluded by genetic test Currently used Excluded by genetic test Currently used Currently used Excluded by genetic test Candidate Candidate Candidate Candidate A brief summary of the candidates is provided below: Ramucirumab is a protein that binds to a receptor for VEGF (VEGFR2) like bevacizumab. It enhances the antitumor effect of other chemotherapy drugs. In the United States, it is approved in combination with an irinotecan-based chemotherapy regimen for patients who have previously been treated with bevacizumab plus an oxaliplatin-containing regimen. Can it be used with 5-FU? Aflibercept Intravenous aflibercept represents another method of interfering with a tumor’s blood supply; it is a fusion protein that acts by "trapping" VEGF and preventing it from activating its receptors on the tumor cells. In the United States, aflibercept is approved, in combination with irinotecan-based chemotherapy, for patients whose tumors have progressed while receiving an oxaliplatin-containing chemotherapy regimen, with or without bevacizumab. Can it be used with 5-FU? Regorafenib is a pill form of a drug that blocks several VEGF receptors as well as other proteins referred to as kinases. In the United States, regorafenib is approved as a single agent for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens as well as other targeted therapies. Trifluridine-tipiracil–is an oral agent that contains two components, trifluridine and tipiracil, each of which have different properties. In the United States, trifluridine-tipiracil is approved for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens as well as other targeted therapies. Immunotherapy There are two main areas of immunotherapy that are showing promise; checkpoint inhibitors and Dendritic cell vaccines. Others such as cytokine injection have resulted in severe toxic response or are still seen as immature/risky. The most recent progress on checkpoint inhibitors is to a stage III trial is for a combination of MEK and PD-1 checkpoint inhibitors. This is likely to result in many other similar approaches being trialed. This approach shows some success with MSS and MSI-L cancers. Other studies have shown that TMB is a better assessor of success for some therapies than MSI-H. Dendritic cell vaccines Probably the first use of Dendritic cell vaccines was at Stanford Cancer Institute where Dendritic cells (DCs) were isolated from patients with non-Hodgkin´s lymphoma. The DCs were loaded with immunoglobulins from the patients´ cancer cells. After re-injection a significant response was obtained from the T-cells and out of 6 patients, two had a complete response, with complete cancer regression. Stanford say that the treatment ´represents a promising and safe form of immunotherapy´. There are a number of potential therapies that are available (privately) and some that are maturing through the clinical trials process. The applicability of these candidate therapies will depend on characteristics of the cancer. Since these therapies are provided privately it is probably in the clinic’s interest to ‘sell’ treatments without complete regard to probability of success and side effects. Hence it is thought necessary to employ the independent advice of a scientific advisor to check the claims and applicability to the specifics of the cancer. This advisor needs to be expert in immunotherapies as applied to colorectal cancer. Cost can be high outside of clinical trials. There are clinics in US and Europe that offer this treatment but it is not yet clear how successful the approach is with colorectal cancer. Other forms of immunotherapy are also becoming available (eg Issels Clinic and private clinics in Europe) but further research is required to establish the reality of these approaches. Summary The overall treatment plan can be considered in five parts. Natural remedies that can become part of your lifestyle providing health benefits throughout any other treatments and afterwards to deter any cancer resurgence. Importantly these can be continued even when other forms of therapy are suspended due to toxicity. Characterisation and testing. Genetic testing of the cancer and immune system combined with blood tests and PET/CT or PET/MRI scans can remain as part of the treatment plan even when the cancer is in remission or deemed cleared. The main difference will be the frequency of such scans or tests. Planned therapy. Currently this is the chemo regimen FOLFOX6+Avastin and surgical resection. The actual form of the active therapy may change with time for example different chemo drugs or radiosurgery and may even be temporarily suspended. In the main the active treatments will be based on approved drugs and techniques as these are best understood (how likely to succeed and known side effects) and more widely available. The planned therapy consists of the current treatments and identified treatments that can be activated when conditions are appropriate. Research into future treatments. Consisting of information search, advice from recognised experts and trialing of prospective treatments (in mice or models). There is some potential to engage with PhD student or cancer research group for specific detailed research. Research can identify new treatments that can become part of the active therapy plan, identify clinical trials or non-approved treatments that are worth detailed consideration. Non-Approved Treatments/Clinical Trials. Some treatments have not yet been approved for colorectal cancer but have either been shown to succeed with other cancers or are still going through initial trials. Joining a clinical trial can have the benefit of the treatment being free but otherwise on a personal basis can be negative (no control over treatment, if not phase IIB non randomized then you might not actually receive treatment. Some non-approved treatments are still available privately. Near Term Plan Within the current treatment, there are two major milestones that are important to note. The first is the completion of the FOLFOX6 treatment. This treatment consists of 12 cycles each of 2 weeks starting in 10th August 2016 and finishing mid-January 2017. This might finish early if toxicity signs increase significantly. The second milestone is the availability of mice to commence testing. The preparation of the mice commenced post-surgery (mid July 2016) and is due to take about 5 months to complete. This implies that they will be ready at about the same time as the chemo is finished. This raises two issues. What treatment can continue on completion of the chemo? (Internet blogs suggest that typically a wait and see approach is taken.) Which treatments should be trialed with the mice? Whilst both issues can be answered by the oncologists on the team, it is also useful to form an independent opinion on them. Many actions are already in place or even completed to help answer these questions. Establishment of natural remedies regimen. Consisting of moderate exercise, nutritionally balanced diet but adjusted to cope with the chemotherapy and additional food/vitamin/mineral supplements. PET/CT imaging to identify new tumours. Genetic analysis of tumour samples and liquid biopsies. Immune response analysis using ELISPOT. Information search on approved and new treatments Identify expert on colorectal immunotherapy with links to clinics and research groups (or university research departments). If possible, it would be beneficial to also visit selected clinics and research organisations to further assess their capabilities and willingness to help. Given that these near term activities all complete then we should be in a position to answer these questions. Which alternative chemo regimens might be successful given the known genetic characteristics of the cancer? If there are any new tumours do we need to leave them to the chemo, destroy using radiosurgery (or similar) or take biopsies to study/use? Which new immunotherapy treatments appear candidates for future use? What are the expert opinion on these, given characteristics of the cancer and the immune system response? Can these treatments be further evaluated (eg by modelling)? Are they clinically available?