Clarifying immunotherapy

- Updated on 16 March 2017 -

Friday, 3 March 2017

WE read with great interest the article “A case for immunotherapy” (Sunday Star, Feb 12). Firstly, we would like to congratulate Chin (nasopharyngeal cancer) and Wong (prostate cancer) on improvements in their condition and for their successful struggle against cancer. Many like these two men are increasingly facing up to the reality of a cancer diagnosis as its prevalence rises in the Asia-Pacific region. However, upon reading the article we also noted several disturbing points regarding their treatment which we would like to highlight here.

Firstly, immunotherapy is indeed emerging as a new and exciting breakthrough in our treatment armamentarium against cancer. Immunotherapy aims to harness or enhance the ability of our own immune system to recognise and mount an immune response against cancer cells. Indeed, over the past few years, several immune therapies such as PD-1 and PDL-1 checkpoint inhibitors have now received licensing approval from major health authorities such as the US Federal Drug Agency (FDA) and European Medicines Agency (EMA). Much time, cost and effort have gone into performing clinical trials involving thousands of patients in order to prove that these treatments are superior to current available treatments and can be safely given with acceptable side effects. Not least as these treatments are usually very costly, we need to be sure that they work before they are offered to the public.

In contrast, the HITV (Hasumi Immunotherapeutic Vaccine) treatment in combination with radiotherapy is not an FDA or EMA approved therapy. There are no large phase 2 or phase 3 clinical trials (such trials are a necessary requirement before new therapies can be approved by the regulatory authorities) that have been performed to prove that it works any better than conventional chemotherapy, radiotherapy or targeted therapy alone. Indeed, the clinical trials to explore whether cellular immunotherapy treatment such as HITV are effective are currently only in an initial stage of development and it is premature to suggest that these treatments should be offered widely to the public.

Regarding the specific cases discussed, it is already well known that radiotherapy alone can cure up to 80% of patients with stage 2 or 3 nasopharyngeal cancer. It is highly questionable whether HITV immunotherapy would have provided any additional benefit on top of highly effective treatment with radiotherapy.

In the case where prostate cancer had spread to the pelvic bone (which incidentally would make the patient stage 4 cancer, not stage 3 as reported), the article omitted to report whether the patient was receiving hormonal therapy. We would be very surprised if the patient was not receiving hormonal therapy as it is the standard treatment for stage 4 prostate cancer and is over 90% effective in controlling this disease. Coupled to radiotherapy, which confers further benefit, this makes this combination approach extremely effective for the vast majority of prostate cancer patients. Again, it would be questionable whether HITV treatment would have provided any additional benefit to this patient.

As health professionals, we fully empathise with the dilemma and plight of cancer patients who are beginning their struggle with cancer. In the midst of the shock of receiving the news of the diagnosis, frequently they will also receive conflicting advice from well-meaning friends and relatives.

Often times, patients would recoil at the mention of the word “chemotherapy” and do everything in their power to find alternative solutions. This well-meant advice, however, may not necessarily be beneficial nor accurate.

We would caution patients to consider whether any proposed treatment is backed up by proof. Claims that a particular therapy, be it immunotherapy or alternative therapy, which may act as an “adjunct” to conventional therapy must be substantiated by proof. Claims that a particular treatment is effective due to the existence of limited laboratory data is inadequate to bring it into clinical practice that requires scientific rigour.

Claims, no matter how plausible, for example the use of radiotherapy or chemotherapy to release tumour antigens to sensitise dendritic cells, must ultimately be backed by proof, which MUST come in the form of phase 3 clinical trials whereby one group of patients is exposed to the treatment and one group is not, and the former group must record an improvement in survival and/or quality of life.

Some therapies claim proof in the form of a handful of anecdotal patients who have benefited, which is insufficient and subject to bias from the person offering the therapy. Claims that a particular treatment is preferable because of minimal side-effects over conventional therapy is insufficient to justify it being recommended for use. Furthermore, many of these non-conventional immunotherapy and supplemental therapy are very costly.

Increasingly, oncologists are witnessing patients who are suffering from financial burden due to their expenditure on cancer care. We have encountered many patients who have expressed regret having spent large sums of money over ineffective cancer treatments only to be left without resources for subsequent effective therapy.

There is a huge industry revolving around the sale of non-licensed “adjunct” medical therapies or supplements and we would like to remind patients that these are fundamentally commercial entities. We strongly advise patients to be judicious when choosing the appropriate therapy for their illness and to consult an oncologist accredited in their respective national specialty register.

The good news is that as cancer therapies are becoming increasingly sophisticated, our results are improving in great strides and the side-effects are reducing significantly. The guiding principle behind modern oncology care is to prolong life while maintaining good quality of life.

In view of this, we hope patients will continue to seek professional help from their local accredited oncologist. If in doubt over a particular therapy, we simply advise patients to demand phase 3 clinical trial proof that the treatment works. Otherwise, you may just be buying hope and a feel-good placebo effect.

MALAYSIAN ONCOLOGICAL SOCIETY

In conjunction with Dr Ravindran Kanesvaran

President, Singapore Society of Oncology

http://www.thestar.com.my/opinion/letters/2017/03/03/clarifying-immunotherapy/

Friday, 10 March 2017

Keeping an open mind on ‘unproven’ treatments

Friday, 10 March 2017

Keeping an open mind on ‘unproven’ treatments

I AM writing in response to the joint letter by the Malaysian Oncological Society and the President of the Singapore Society of Oncology (The Star, March 3).

Your letter is generally well written, offering sensible cautionary advice to cancer patients about “unproven” treatments.

While I cannot offer the breadth of data you demand (“clinical trials involving thousands of patients”) I will share one data point in an in-depth manner, in the hope that you see prima facie evidence that maybe Human Initiated Therapeutic Vaccine (HITV) works after all.

And since I am “replying” to oncologists, I will convey facts accurately from medical reports and supplemented by personal notes. I hope that laymen readers will bear with me.

My mother’s recent journey with cancer started with a transurethral resection of a bladder tumour (TURBT) to remove a low-grade bladder tumour in June 2012. Soon after, she noticed blood in her urine and this led to surgery to remove her left kidney and some surrounding tissues three weeks after the TURBT.

“Invasive high-grade transitional cell carcinoma of left renal pelvis....Resected margins are free from tumour,” the histopathology report concluded. While the surgeon was confident he had excised all the at-risk tissues, my mother was offered chemotherapy as a precaution.

After completing the cycles of carboplatin and gemcitabine chemotherapy, the CT scan radiologist reported on Jan 10, 2013 a “lymph node consistent with metastatic node. This is a new finding.”

A presumably stronger regime of chemotherapy involving taxol was given and once again the CT scan three months later showed the lymph node had grown.

A third concoction of chemo was administered (taxol and ifosfamide for four months).

Half way through, the oncologist prepared us for the worst, saying that if this chemo failed, then she could only offer hope to slow disease progression with future treatments.

Cure would be out of the question and future chemo would involve experimental drugs which the patient could import personally with the right paperwork.

I decided to check out the treatment at a clinic in Bangsar. I had no idea they offered immunotherapy, having heard only vague accounts through a friend that they had an alternate cancer treatment.

I went there (without my mother because I didn’t want to overload her with too much information), with an open mind and very inquisitive. I learnt that they offered P53 gene therapy and HITV.

I asked for scientific literature and explanation. While literature was skimpy the scientific explanation resonated with me and I also liked the idea that they did not entail serious side effects because they did not involve drugs.

Subsequently, a clinical response paper involving 167 patients was published in October 2013.

This paper showed very good success. It, however, did not influence our decision because it was published after my mother underwent HITV.

Getting back to the treatment time line, I decided (and my mother agreed) to try P53 mid-way through her third concoction of chemo. This was disclosed to the chemo oncologist.

The Bangsar clinic was quite upfront about the probability of success, or the lack of it. The post-chemo imaging report CT scan (PET scan this time) revealed that the “hypermetabolic left para-aortic nodal mass has increased in size. Neither chemo nor P53 worked.

We then abandoned further chemo, although the paperwork for the experimental drug was in order. In short, HITV commenced about a year after chemo was started.

The first PET CT, about three months after HITV treatment, reported: “The left para-aortic hypermetabolic nodes are gone, but there are other mildly hypermetabolic lesions situated more cranially and laterally” showed complete remission. As you rightly alluded in your letter, this is no proof that immunotherapy worked, given that high dose radiotherapy was administered.PET CT were done at three-month intervals, subsequently relaxed to six-month intervals. I’m happy to say that all these scans did not detect any cancer tumours. The latest scan is 38 months after HITV treatment.

Now, please recall how aggressive this cancer was – a new tumour in the para-aortic lymph node swelled it to 2.5 x 2cm in a span of about five months.

Take note also that HITV involves intratumoral injection of immature dendritic cells, a process that risks seeding tissues adjacent to the injection pathway with cancer cells.

By logical deduction, the radiotherapy part of HITV cannot have provided the systemic protection required to keep the patient free of any new tumours for 38 months, especially in the context of the aggressiveness of this cancer (my opinion).

Whereas the activated immune system could and probably did. To be clear, she received no cancer treatment other than HITV during this period.

Lastly, while clinical trial is a gold standard to aim for, you probably also know that it is very costly and a long journey. Meanwhile, the clock ticks for many cancer sufferers.

Just as my mother was allowed to import an experimental chemo drug, so too should patients have the option of HITV. I have certainly received more information on HITV than on the experimental chemo drug we were offered.

I believe doctors are taught the principle primum non nocere (Latin for first, do no harm). On this score, HITV does well with minimal side effects. One cannot say the same for the experimental chemo drug we were offered or FDA-approved immunotherapy drugs such as keytruda.

HITV was honed to its present state over decades by Dr Kenichiro Hasumi in Japan. Evidently America has cottoned on to this idea; former President Barack Obama launched the Moonshot 2020 programme last year to find “vaccine-based immunotherapies” against cancer! Wow, Obama was so specific when there are so many different approaches in immunotherapy.

Some background on me. I come from a family with strong history of cancer. My brother succumbed to colon cancer at only 32.

I would like to think that his premature death has a purpose for it spurred the rest of the family to do regular colonoscopy.

Several years later, we all went for genetic testing which revealed I have the HNPCC gene mutation.

With that, I undergo colonoscopy annually (for the past 20 years), and latterly annual ultrasound and biennial MRI as well.

These efforts paid off when I discovered a colon tumour (1997 at age of 38) and bladder tumour (2016) in very early stages and dealt with them successfully.

GAN TEE JIN

Kuala Lumpur

http://www.thestar.com.my/opinion/letters/2017/03/10/keeping-an-open-mind-on-unproven-treatments/

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Letters

Thursday, 16 March 2017

Cancer patients deserve better

 

WE would like to thank Gan Tee Jin for the letter “Keeping an open mind on unproven treatments” (The Star, March 10). We appreciate the effort to describe his family’s experience with HITV (Hasumi Immuno-Therapeutic Vaccine) and are glad that his mother has had a successful outcome after her treatment.

His mother is a living testimony that cancer is not always a death sentence, which sadly is an all too common perception among Malaysians.

We welcome feedback to our previous letter, “Clarifying immunotherapy” (The Star, March 3), and are keen to explain our position regarding oncology and evidence-based medicine.

The Malaysian Oncological Society (MOS) regards educating the public on cancer as one of our primary objectives and we strongly believe that the practice of oncology should be based on the best scientific evidence.

Gan’s letter raises several interesting points that continue to be debated in medicine, and science in general. Firstly, what kind of evidence is required to “prove” that something works? Is one successful case sufficient proof? Can we rely on our own, often flawed, observations to form judgements?

Work by Daniel Kahneman and Amos Tversky, recipients of the Nobel Prize in Economics in 2002, showed that men and women are inherently predisposed to errors in thinking. Mistakes due to errors in judgement have led to the tragedies caused by thalidomide and eugenics.

Medicine has wrestled with this problem for decades and thus evidence-based medicine was developed as a solution. Under this method, a new treatment is required to show strong evidence that it is effective before it is accepted by the medical community as valid.

Evidence should come from well-planned research, the observations meticulously recorded and audited independently and the results then analyzed, discussed and often debated and criticized to ensure its validity. This process is a component of evidence-based medicine and forms the foundation of modern oncology.

Another very interesting point is whether we can decide on a course of action if the scientific explanation makes sense. Thomas Huxley famously said that the great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.

Unfortunately, the history of medicine is littered with the corpses of beautiful hypotheses that turned out to be wrong or even harmful.

Angiogenesis (the formation of blood vessels to feed the cancer) was shown to be vital in the growth of cancer cells. Drugs to stop or suppress this process were shown to be highly effective in stage 4 kidney and colon cancers.

Previously, oncologists believed that it should be even more effective in earlier stage cancers as the metastatic cancer cells have not had a chance to grow or spread. However, clinical trials involving thousands of patients and doctors across multiple cancer centres did not show any benefit in adding these drugs to standard treatment.

If we had treated patients based on scientific theory that sounded reasonable without strong supportive evidence then our patients would have received ineffective therapy and be burdened with the high costs of treatment and potential side-effects. Is this acceptable to the public?

Dr Kenichiro Hasumi’s paper published in the journal Oncoimmunology in 2013 was mentioned in the letter. This paper described their experience with HITV in 167 patients with advanced cancer.

Patients received intra-tumoural injections of dendritic cells followed by high dose radiotherapy and activated T cell infusions. In patients who were treated according to their protocol, i.e. less than 5 metastases and each less than 3 cm, the clinical response rate at 1 year was 75.7%.

Fairly impressive results but this only applies to 37 out of 167 patients in the case series. Was the PETCT assessments audited by an independent external party to confirm its accuracy?

The remaining 130 patients with more extensive disease had clinical response rates of 7-13% with HITV. This is slightly better than placebo.

Are these results sufficient to be regarded as successful? If so, that is a fairly low bar. Small metastases in a limited number of sites are known as oligo-metastases. These oligo-metastases can be treated with surgery, radiofrequency ablation or high dose radiotherapy with local control rates of 70-90%.

If good response rates can be achieved with such therapies then how much can we say is due to HITV? If further distant metastases do not appear after effective local treatment in oligo-metastatic disease then we should consider the possibility that there were no metastases in other distant organs to begin with.

Therefore, the absence of relapse after high dose radiotherapy of a local recurrence in one patient is not evidence of the effectiveness of HITV.

Only a randomized clinical trial can help to answer these questions. Yes, it is costly and time consuming but it can be done. Malaysian oncologists have been participating in a clinical trial to test a virus specific T cell immunotherapy for metastatic nasopharyngeal cancer developed by a Singaporean biotechnology company. If we insist on this kind of evidence from drug companies, why should we settle for anything less from others?

The former US president Barack Obama launched the Cancer Moonshot in January 2016 with the aim of accelerating cancer research to achieve the goal of making a decade’s worth of cancer research progress in five years.

Prior to Obama’s initiative, a joint program called the Cancer Moonshot 2020 was launched by private companies and academic cancer centres aimed at developing vaccine-based immunotherapy to combat cancer. These are exciting times for oncology and we look forward to the results from their meticulous research.

We are grateful for Gan’s letter as the various thoughtful points he raised gave us the opportunity to discuss the issues we grapple with daily. The Malaysian Oncological Society is committed to insisting on the best scientific evidence to guide medical practice. Our patients have entrusted us with their lives. They deserve nothing less.

DR MUHAMMAD AZRIF

Honorary Secretary

The Malaysian Oncological Society

http://www.thestar.com.my/opinion/letters/2017/03/16/cancer-patients-deserve-better/