External Links

In my continued search for information relating to the treatment of metastatic colorectal cancer I have come across a number of useful reference websites and technical papers. The associated comments and summary notes are all mine and should not be taken as forming advice. That said, I hope that you find something of use to aid your own searches.

Definiteness of purpose is the starting point of all achievement.

The references are provided for the following topics:

General Information (Back to Top)

The National Institute for Health and Care Excellence provides guidance on treatment paths and medication for the treatment of colorectal cancer to the NHS. Information can be accessed by following their links or by performing searches or by downloading a summary of all their guidance to date. The information is particularly useful as the reasoning behind the decisions is also given supporting an assessment against specific situations. A similar summary of FDA approved drugs for cancer can be found here.

Websites such as Wikipedia and encyclopedia can provide useful information but need to be treated with some caution. However, this beating bowel cancer website provides quite a useful summary of colorectal cancer and its treatment. In particular, this last website provides several booklets and factsheets on treating of bowel cancer. They are well worth reading with the following topics; Advanced Bowel Cancer: Treating Metastases, Beyond Bowel Cancer: Living Well, Bowel Cancer Surgery: Your Operation, Bowel Cancer Treatment: Your Pathway, Detect & Diagnose: Understanding Bowel Cancer, Living With Bowel Cancer: Eating Well.

There are three more websites that I would like to recommend as sources of reliable information on medications, natural remedies and supplements. The first one WebMD provides a lot of information on drugs and supplements regarding their use, side effects and interactions with other medication. The next one Drugs.com provides very similar information and is a useful secondary source to cross check the information. The final website is perhaps a bit more controversial as it represents the personal opinion of Dr Weil on many aspects of cancer care. That is the information published on the website has not been subjected to any form of peer review. That said, I have referenced this material on many occasions (mainly relating to natural remedies and supplements) and cross checked with other sources on the internet without identifying any major criticism or significant contradiction.

Pre-diagnostic screening (Back to Top)

This reference provides some information about the problems associated with using colonoscopy as the sole means of detecting cancer whilst also identifying other methods that are currently available for this purpose. This other reference shows the difficulty associated with identification of cancer vs diverticulitis using CT scans.

Once colorectal cancer has been identified, further screening is recommended by oncologists in order to determine the best treatment path. The latest guidelines (draft) can be found here. The main recommendations are aimed at determining the most effective treatment and they are to test for RAS mutations (include KRAS and NRAS), BRAF V600 mutations, deficient mismatch repair (dMMR) and microsatellite instability (MSI) testing for prognostic stratification.

Radiotherapy (Back to Top)

There are two basic types of targeted radiotherapy, external source and internal source. In the case of externally sourced radiotherapy, the radiation is targeted to a greater degree to a region containing the cancer using technology such as CRT and computerised control. More recently technology such as Gamma Knife and CyberKnife have made advances to further limit the damage to nearby tissue and tissue in between the radiation source and the cancer. By better targeting of the radiation, increased dosage can be applied to the cancer with less damage to normal tissue. In the case of internally source radiotherapy, radioactive pellets are delivered to the cancer by T cells.

I am mainly considering the use of Steriotactic Body Radiotherapy (SBRT) that can apply higher dosages than 3D-CRT within smaller radiation fields. This technology is used to treat small isolated tumours in the lung or liver.

Proton beams uses a cyclotron to accelerate protons up to 60% speed of light to deliver dosage mainly at the targeted point and only little dosage is received by the tissue that is in between the equipment and the target. Currently not available in the UK (expected 2018), but NHS does refer some patients to US or Switzerland for treatment.

Photon beams uses a linear accelerator to create high energy X-rays (photons) that are focused on the shape and location of the tumor. Products include: Novalis Tx™, XKnife™, Axesse™ and CyberKnife®.

Gamma radiation (eg Gamma Knife) uses multiple beams (192) of radiation to focus on the tumour. Can use a combination of onboard stereotactic Cone Beam CT imaging and real-time infrared motion detection and management to achieve 0.15 mm treatment accuracy even without a rigid frame.

Immunotherapy (Back to Top)

Overall immunotherapy for colorectal cancer is still at an immature stage and studies have yet to realise the benefits that such treatments appear to offer. This paper provides a useful summary of immunotherapies for colorectal cancer. Recent advances have shown promise for checkpoint block inhibitors for MSI-H cancers and even more recently using dual therapies (MEK, PD-L1) for MSS cancers. The latter case establishes a possible path for further developments such as combining MEK with PD-1 treatments.

The use of adoptive cell transfers and cytokine based treatments have suffered setbacks due to example of high toxicity.

Dendritic cell vaccines show promise for the future as they seem to cause low toxic effects, but to date their success rates still seem to be variable with such treatment being expensive. A search of literature on the internet has identified a number of reasons that could be behind this lack of response to the DCV and the relatively slow rate of progress in establishing best practice. The slow rate of progress would seem to be the result of research effort being diluted by multiple approaches to all aspects of the DCV including its preparation and administration. This is further exacerbated by there being three underlying approaches to the DCV; generation of dendritic cells from monocytes ex vivo, harvesting of dendritic cells from the blood and injecting target antigens directly into the body to activate the dendritic cells in vivo.

Lack of response to DCV has been put down to a number of hypotheses. The time taken to mature and activate the dendritic cells ex vivo, non-optimal selection of the cultures used to differentiate the monocytes to form dendritic cells and to mature the dendritic cells, the dendritic cells not migrating to the lymph nodes to cause an immune response, the cancer escaping the immune response and the tumour microenvironment suppressing the immune response.

A consequence of this uncertainty, is that Ken has decided to research into Dendritic Cell Vaccines. This research is to be focused on the path that has been most researched to date.

  • Monocytes harvested from the blood and differentiated ex vivo to form Dendritic Cells.
  • Dendritic cells to be primed with tumour lysate. (This offers the best chance of the activated DCs targeting all of the cancer.
  • Pre-vaccine depletion of Treg (immune suppression) by application of low doses of Temozolomide.

Chemotherapy (Back to Top)

An excellent website that covers the basics of chemotherapy can be found at Chemocare. It provides substantive information on the types and characteristics of chemotherapies, each drug and how to manage side effects.

The established and approved drugs for the treatment of mCRC are: 5-fluorouracil, Capecitabine (an oral form of 5-FU), Oxaliplatin, Irinotecan, Bevacizumab, Cetuximab and Panitumumab. More recent additions are Ramucirumab, Regorafenib, Trifluridine & Tipiracil Hydrochloride and Ziv-Aflibercept.

The efficacy of each drug can be affected by the characteristics of the cancer. The following links provide examples of such dependencies.

Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase

Irinotecan and potentially Oxaliplatin require medium to high levels of topoisomerase-1 to be effective. See Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.

Panitumumab or Cetuximab require KRAS wild and BRAF wild genes to be effective. See Wildtype BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer, Panitumumab: in metastatic colorectal cancer with wild-type KRAS and KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.

For many more examples of genetic mutations and gene expression levels affecting the benefit of specific chemotherapy drugs, refer to the 'references' section of a Caris report on the Treatment page of this website.

Natural Remedies (Back to Top)

I have encountered many websites that recommend a whole range of natural remedies. I believe that the adoption of any of these should remain a personal choice but the ones that I have chosen to take on or at least carefully consider seem to have a degree of support from the medical profession and oncologists. The use of moderate exercise (about 5 hours walking per week), ensuring that my daily intake of vitamin D is maintained, trying to establish and keep to a nutritionally balanced diet (not always easy given stoma and chemotherapy side effects see here for ideas) and daily supplements of extracts from certain mushrooms (Turkey Tail, Maitake, Reishi , Agaricus blazei) see advice from Dr. Weil, ginger and turmeric.

Note that the therapeutic effects of vitamin D are well reported, including the anticancer benefits. Of greater note is the study into how vitamin D analogs can enhance the effectivity of 5-FU in colon cancer.

The following websites provide additional information on foods and supplements that may help in the fight against cancer.

Imaging/Scanning (Back to Top)

The ability to detect and image tumours at an early stage (resolution as small as 2mm) so that they can either be surgically removed or otherwise destroyed is an important aspect of the overall treatment of mCRC. The other uses of imaging are to guide the application of many treatments such as SBRT and laser ablation and to monitor the progress of a treatment. There are three important aspects to achieving high quality imaging; the equipment, imaging or contrast agent and the analyst. Note that the analyst plays an important role and should remain the same over multiple scans if they are to be used to monitor disease progression.

There are many types of equipment available for imaging each with their own advantages; PET, CT, MRI, Ultrasound and latterly PET/CT and PET/MRI.

PET scans have the main advantage that it is based on the uptake of glucose (bearing the radioactive element) by tissue and hence differentiates between tissues that are absorbing energy at higher rates. This typically will be the tumour. Recent advances in CT equipment has resulted in high fidelity imaging with lower and more controlled radiation doses. Latest advances in PET and PET/CT scanners are discussed in this paper. Whereas PET/CT and PET/MRI scanners are available in the UK, currently they are used for research purposes only and have not yet used for clinical diagnostics (2016).

Blood/Serum Tests (Back to Top)

The most widely reported biomarker for colorectal cancer is CEA. In this report the study indicates that high levels of CEA prior to surgery tends to imply that the cancer has metastasized, but it also shows that a slow rate of decrease (long half-life) in the level post-surgery is also indicative of metastatic CRC even with low initial levels. In my case I had an initial level of 10ng/ml and a half-life of 5.8 days. This data placed me right in the middle of cases with/without metastasis. Subsequent assessments have confirmed that my cancer has metastatic tumours in the liver.

This report provides an extensive list of potential biomarkers for colorectal cancer. Although the report is written with the intention of identification of biomarkers for screening of colorectal cancer, they have the potential to be used to monitor cancer progression during treatment. Primary additional candidates would be CA19.9, TIMP1, CCSA-2, CCSA-3 and CCSA-4.

Another approach to monitor the progress of the cancer treatment is provided by Chronix Biomedical where the instability of the DNA copy number is used as a predictor of the effectivity of the current treatment.

Tumour and Liquid Biopsy Tests (Back to Top)

As the specific characteristics of colorectal cancer can have significant impact on the effectiveness of any specific medication or therapy I took on the approach to gather as much information as possible. Because I was aware that the cancer is probably heterogenous, I wanted to analyse both the primary tumour and liver metastases. Additionally, I decided to cross check the results with two independent assessments. The profiling of the tumours was performed by Caris and Foundation and the results can be found on the Treatment webpage.

With the longer-term objective of tracking any change to the cancer characteristics, and recognising that it is not always possible to perform the profiling of a tumour, profiling of the cancer cells circulating in the blood stream was undertaken using Guardant Health.

Finally, we are actively seeking to collaborate with Immunovative Therapies Ltd, in the analysis of tumour and blood specimens to establish characteristics of the immune system response. In this collaboration, the oncologist provides tumour and liquid biopsies and agrees that the results of the tests can be shared with Immunovative Therapies and their associated companies. In return, all test results are provided back to the oncologist. These results can form the foundation for monitoring of the response of the immune system to a selected form of immunotherapy.

Managing Treatment Side Effects (Back to Top)

So far, the treatment side effects have been the result of chemotherapy, surgery and the ileostomy. The main problems that have been experienced to date are nausea, pain, high stoma output, hernia and infections.

Whilst I would not like to say that I've been all that successful with managing these problems, it is worth providing some references to other websites that provide supportive information.

Managing the side effects of chemotherapy - Best website is again Chemocare.

Ileostomy High output Stoma - many websites on this issue, this is one example. The main advice is that excessive stoma output can quickly lead to other problems and medical advice is to be sought if it continues for more than 24 hours.

Hernia prevention - Hernias can be caused by lifting heavy weights such as a briefcase or groceries within a few weeks of surgery or whilst a stoma is fitted.

As chemotherapy has continued, one of the more debilitating side effects has been diarrhoea. A very useful publication that discusses the cause of chemotherapy induced diarrhoea and the many treatments can be found here. The report mentions that loperamide can become ineffective but that other treatments should be considered; Levofloxacin, Budesonide (can also be used concomitantly with loperamide), combination of Lactobacillus rhamnosus and fibre, activated charcoal (highly compliant and tolerant, Octreotide (some evidence that it is more effective than loperamide but higher cost. Successfully dealing with severe diarrhoea is not only beneficial to quality of life but also it helps to maintain the chemotherapy dosage at the required level.

Additional Medication (Back to Top)

Aspirin is widely reported as having medicinal benefits such as the possible reduction of the excess risk of venous thromboembolism during chemotherapy. It is also associated with assisting with the reduction in cancer tumours. A recent study has indicated that this second benefit might be restricted to those tumours that show mutation in PIK3CA, HLA class I antigen, or show COX-2 over-expression. But the study still recommends that prophylactic anticoagulants should be considered in all patients with cancer because of the first benefit and because its findings regarding the anticancer benefits require further independent research to be substantiated.

Other additional medications have been taken but only under doctor's prescription and supervision to manage pain, boost the immune system and prevent blood clots forming post-surgery. These include Tramadol, Loperamide and Clexan.

The 'ReDo Project' aimed at repurposing drugs in Oncology has started the lengthy process of assessing selected drugs for their potential anti-cancer benefits. The primary drug for metastatic CRC that is very well tolerated is Mebendazole. The drug is relatively cheap and readily available.

Methylsulfonylmethane (MSM) is again typically very well tolerated and is mentioned in many cancer related websites. Typically, it is taken orally, diluted in water (1:14 by weight). A recent publication has shown that it can be effective with certain Colon cancer cell lines and is independent of p53 status.

Another remedy that appears in multiple cancer websites is Curcumin. A scientific assessment of Curcumin and its effects on cancer has been published. Because of its high tolerance, a daily dose of Curcumin has commenced. One significant issue is to improve the body's ability to absorb the Curcumin so it is normally taken with perperine. Also noteworthy is that since it is the Curcumin that we are after then 95% pure Curcumin is taken rather than Turmeric that often has only 15% Curcumin.

One interesting approach to a more natural therapy to control metastatic cancer is the combination of Hyperbaric Oxygen Treatment combined with a Ketogenic diet and Ketone supplements. This form of therapy has been subject to scientific assessment in mice. In this publication the following chart indicates the potential benefit of this therapy.

Tumor Growth Image

Note that the success of the Ketogenic diet is assessed in terms of the ratio of glucose and ketone levels in the blood. A state of Ketosis is achieved when the ratio is approximately 1:1 or higher in favour of ketones see this publication.

Genomic Databases (Back to Top)

Once the genetic mutations of the cancer have been identified through genetic analysis of tissue or liquid biopsy, these mutations can be investigated on the internet to determine their interpretation, their location and related information on drugs. Accessing these databases is simple but the information is highly technical.

The first source for information is The Precision Medicine Knowledgebase (PMKB) which is a project of the Institute of Precision Medicine (IPM) at Weill Cornell Medicine. This database is currently in the Beta state. This database returns the interpretation of any known mutation and cites references for this information.

The same mutation can also be investigated in the Colorectal Cancer Atlas yielding information about the mutation such as its type and DNA effect.

Further assessment of the mutation and its impact on choice of treatment can be performed using the COSMIC database. The initial search returns a list of drugs, their target and effectivity. The individual entries can be followed for more information about the drug.

However in the case of TP53 gene mutations, there is a separate database provided by the International Agency for Research on Cancer.

Liver Metastases Treatment (Back to Top)

The most common location for metastatic tumours for colorectal cancer is the liver. To date Ken's distant tumours have been confined to this organ. Fortunately, the liver is the one organ that will regenerate making surgical resection the primary treatment as it is the only one that guarantees the removal of the entire tumour. However, there are many other treatments that can be adopted for situations where resection is not an option. A very useful guide to treating liver metastases is provided at the Beating Bowel Cancer website.

  • Transarterial Chemoembolization (TACE). A specialized form of chemotherapy uses special catheters to deliver chemotherapeutic drugs directly into the artery supplying the liver. This procedure focuses the anti-cancer effect on the metastatic lesions in the liver, and tends to have fewer side effects commonly seen with systemic chemotherapy.
  • Radiofrequency Ablation. Small metastatic tumours can be treated with radiofrequency ablation (RFA). A specially designed probe is radiographically guided into the liver tumour, and radiofrequency energy is used to destroy tumour cells.
  • SIRT. Millions of very tiny 'beads' (microspheres) are injected into the major blood vessel that supplies the liver. These beads reach the tiny blood vessels in and around the active tumours, where they give out concentrated doses of direct radiation.
  • Hepatic Arterial Infusion. Delivers chemotherapy (typically Floxuridine) directly to liver tumours. The chemotherapy is supplied through a pump to the hepatic artery of the liver. Note treatment requires gallbladder to be removed.
  • Cryotherapy. An extremely cold gas is passed through a probe that has been placed directly into a liver tumour through a small incision. The gas freezes and destroys the cancer. Sometimes the freezing process is repeated. It is suitable for tumours up to 4 cm.
  • Percutaneous ethanol injection. A needle injects ethyl alcohol directly into the liver tumour to kill cancer cells and shrink the tumour.
  • Radiation therapy. This is not often used to treat liver metastases as it can damage the liver. But there are different forms.
    • Radioembolization. A catheter carries the radioactive beads through the hepatic artery to the liver delivering radiation only to the tumour. They also block the blood supply to the tumour.
    • Stereotactic body radiation therapy. (See Radiotherapy) May be used when there are 1- 3 small liver metastases and may require multiple sessions.
  • Microwave ablation. Uses microwave radiation to heat and destroy cancer cells. The technique is quicker than RFA allowing multiple lesions to be treated in the same session.
  • Hepatic artery chemoembolization. A chemotherapy drug mixed with an oily liquid is injected via a thin plastic tube that has been inserted into the hepatic artery. The chemotherapy stays in contact with the tumour for several hours.
  • Laser ablation. A flexible tube which carries the laser light is inserted through the skin over the liver and into the center of each tumour. The high-powered beam of light is used to destroy cancer cells by heating them to high temperatures and can be used on tumours of up to 5cm in size.

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