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Treatment Strategy
This note is written to serve two purposes;
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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.
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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:
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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.
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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.
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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.
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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.
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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?