http://scienceblogs.com/insolence/2017/09/25/rigvir-a-cancer-cure-imported-from-latvia-that-cancer-patients-should-avoid/

Rigvir: A cancer “cure” imported from Latvia that cancer patients should avoid

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No, this is not a cancer cure-all.

A dubious Latvian cancer treatment shows up on my radar

Perhaps the language barrier, coupled with its being primarily a treatment from a very small country, is part of the reason why I haven’t discussed a new form of dubious cancer treatment known as Rigvir before. It’s a form of treatment that has been popularized mainly in Latvia, but is also sold in Armenia and Georgia. This situation has made finding sufficient information about Rigvir, the claims made for it, what it is, and what it supposedly does, rather challenging. After all, I don’t speak Latvian, and I don’t know anyone who does. (And, no, having a Lithuanian background on my mother’s side doesn’t help.) I was prodded from my complacency by an article published earlier this month from LSM.lv, “Health ministry defends claimed cancer treatment.” Basically, a Latvian news magazine, De Facto, reported earlier this year that multiple Latvian medical associations had written to the Latvian Health Ministry about Rigvir:

What most grabbed my attention about this article was the response of Health Minister Anda Čakša to inquiries about why the Health Ministry decided the way it did. It’s a response that’ll make a skeptic’s jaw drop:

My reaction was predictable: This is exactly backward! It is up to the company selling a product to provide evidence that it does work for the conditions for which it is marketed, not to critics to show that it doesn’t work! The article also notes that Rigvir is the fifth top selling prescription medicine in Latvia, with growing sales, which is another reason to be concerned. So is the marketing of Rigvir outside of Latvia. For instance, quack cancer clinic in Mexico that I’ve discussed before, Hope4Cancer, offers Rigvir, which it describes in glowing terms:

Not surprisingly, according to Hope4Cancer, Rigvir is fantastic for basically all the common cancers: breast cancer, melanoma, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, liver cancer, and more. Never mind that the only cancer for which there is anything resembling evidence—albeit weak evidence—is melanoma. Rigvir’s proponents claim that it can treat any cancer! The clinic even goes so far as to claim:

No, if Rigvir works, it would be conventional medicine. Viruses that target specific cancers are very much the hot topic now, although results have generally been mixed. The only thing “alternative” about Rigvir is that it is unproven and sold by a quack cancer clinic in Mexico.

Meanwhile, over at the International Virotherapy Center in Latvia, where Rigvir is primarily marketed, there are the sorts of glowing testimonials (complete with a link to the Virotherapy Foundation, which provides even more glowing testimonials) that automatically set my skeptical antennae a’twitching. For instance, here is a woman named Zane who was diagnosed with stage I (yes, stage I) melanoma that was completely surgically excised. Yet Latvian doctors prescribed her “virotherapy” (a.k.a. Rigvir) afterward:

The treatment for stage I melanoma is basically complete surgical excision with an adequate margin of normal tissue around the melanoma, plus examination of the regional lymph nodes through a procedure called a sentinel lymph node biopsy, if the melanoma is stage IB. (Presumably the woman’s lymph nodes were negative, or else she would no longer have stage I melanoma. Rather, she’d have at least stage III melanoma.) There is usually no need for any further treatment. Basically, Zane was exposed to “virotherapy” unnecessarily and massively overtreated for her melanoma. Yet she’s promoted as a success story, who gushes about how she had feared losing her hair and feeling sick but didn’t and how she was able to have a normal baby.

This testimonial is a bit more disturbing:

Basically, it’s a British woman named Nadine who had melanoma in 1999 that recurred in 2009. It sounds as though it’s been metastatic, but there are no details that would allow a cancer surgeon like me to know where it metastasized to, how rapidly it grew, and other critical information. We learn that Nadine has apparently undergone radiotherapy, chemotherapy, and surgery, along with being a “guinea pig” for experimental vaccine therapies, suggesting that she must have been a subject in at least one clinical trial. She’s convinced that Rigvir is helping her, but there’s no way to know for sure. Metastatic melanoma is a strange beast among cancers. It can have an incredibly variable course, rapidly growing and killing some patients, and in others exhibiting a much more indolent behavior. Also, excising melanoma metastases can be curative, if they are single or only a few and can be completely excised surgically. Surgical excision of recurrences and metastases could well have prolonged Nadine’s life greatly, but insufficient information is given for me even to speculate whether this is the case with her.

Basically, there is no way of knowing whether Rigvir helped Nadine or not, but she’s convinced that it did. What’s disturbing is the segment near the end, where Nadine urges patients to “seek alternative therapies.” Near the end, she also states that the melanoma has metastasized “all over my body,” but it’s not clear where that means. Organ metastases are much more serious than skin metastases, for instance. Whatever the case, this one woman is not evidence that “virotherapy” works for melanoma.

There’s a lot more where that came from.

What is Rigvir?

The Rigvir website describes the treatment thusly:

I perused what passes for a product information sheet. Rigvir is provided as a 2 ml frozen solution of an adapted and selected ECHO-7 virus strain, Picornaviridae family, Enterovirus genus, Enteric Cytopathic Human Orphan (ECHO) type 7, group IV, positive-sense single-stranded RNA virus produced under GMP. The titer is not less than 106 – 108 TCID50/ml. (TCID50 is a measure of active viral particles.) A brief word is in order here. “Orphan” indicates a virus not known to be associated with any disease. (Since the discovery of ECHO viruses, they have been linked with diseases to the point where most ECHO viruses are no longer considered orphan viruses. Even so, the name stuck.) Echoviruses were first isolated from the feces of asymptomatic children in the context of epidemiological studies of polioviruses and are now known to be one of the leading causes of acute febrile illnesses in children. 90% of ECHO virus infections are asymptomatic, but in the 10% that produce symptoms those symptoms can range from mild to severe, depending on the age, gender, and immune status of the host and the subgroup, serotype, and enteroviral strain. We’re talking anything from a nonspecific febrile illness to aseptic meningitis to respiratory symptoms to myocarditis.

What I find most implausible about Rigvir is the claim that it attacks only cancer cells and leaves normal cells alone. It takes a look into the history of Rigvir to get an idea where this claim came from.

Aina Muceniece: Discoverer of Rigvir

The story of Rigvir began several decades ago with a Latvian immunologist Professor Aina Muceniece. Discovering unbiased information on Prof. Muceniece and her discovery of Rigvir is damned near impossible these days, because searches on her name will produce a host of links related to laudatory descriptions of Rigvir and/or associated with the International Virotherapy Center. However, one article does describe the origin of Rigvir thusly:

A PubMed search on Prof. Muceniece’s name doesn’t turn up very much, just two Russian language articles and a frequently touted clinical study from 2015, to which her name must have been added posthumously given that she died in 2010 at the age of 85. Of course, given the time period of the discovery of what is now called Rigvir (the height of the Cold War), it is perhaps not too surprising that there are few publications indexed in PubMed about it. Be that as it may, the peer-reviewed English literature is not a good place to find out very much about the origin of Rigvir, although there is a 2012 review article on oncolytic (cancer destroying) viruses that gives some hints. I find this passage rather telling:

From what I can tell synthesizing the evidence that I’ve been able to find, Dr. Muceniece made an interesting discovery in the early 1960s in which she observed that some ECHO viruses appeared to have cytolytic effects on tumor cells (i.e., caused them to lyse, or break apart), but the effect was weak, observed in only a few patients, and attenuated by the rapid development of immunity to the virus. In other words, lost in the mists of scientific history, this is an interesting dead end that appeared to go nowhere. Moreover, assuming this account is reasonably accurate, it certainly casts into doubt the stories of “miracle cures” of patients with stage IV cancer, given that those early trials apparently only looked at patients with stage IV cancer and Rigvir didn’t work in them. There are anecdotes from surviving contemporaries of Dr. Muceniece that in melanoma Rigvir produced “such excellent results that all medical staff involved were astonished,” but no published data, and, pointedly, many of her contemporaries are happy to express their admiration for her but decline to evaluate the medication that she is credited with developing.

Unfortunately, the only primary literature referenced are publications by Dr. Muceniece in Latvian. I searched and could not find any published results of these alleged phase III trials begun in 1988 showing that Rigvir prolongs survival in cancer. Neither could Eduards Ritums, who wrote an extensive article in Latvian translated into English about Rigvir. Ritums notes:

So what evidence is there for Rigvir’s anticancer activity? As you will see, it’s pretty weak and unconvincing. Even so, somehow Rigvir was approved by the Latvian version of the FDA in 2004 and even more mysteriously found its way onto the list of Latvian state-reimbursed medicines in 2011.

Evidence for Rigvir’s anticancer activity: Thin gruel indeed

I did PubMed searches and Google Scholar searches, and, as anyone who tries the same will discover, rapidly found that the published data on Rigvir in the peer-reviewed scientific biomedical literature is incredibly sparse. Ritums notes this in his article:

Indeed, if you look at the Virotherapy Center’s page of clinical studies, you won’t be surprised to see how thin it is. The early studies are described thusly glowingly, but without enough detail or evidence to judge how convincing the data are. No mention is made of whether the studies were randomized (I get the impression that they were not), how the cases were matched, and survival rates are reported as ranges, which makes me wonder how on earth the investigators were determining their survival rates. For instance, it is claimed that in melanoma patients the three year survival rate for patients treated with surgery alone was between 46% and 58%, while it was 57% to 84% for those treated with surgery plus Rigvir. I assume that the Virotherapy Center is pooling multiple trials, but this sure isn’t any meta-analysis. Without a lot more detail, it’s impossible to tell what the investigators did several decades ago.

What about more recent evidence? As Ritums notes, there is nothing more to be found besides three retrospective studies carried out post-registration, as a perusal of the Virotherapy Center’s page on its post-registration studies shows. For instance, there is this 2015 study published in Melanoma Research by Donina et al, Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Basically, it is as the title says, a retrospective, unrandomized study that looked at 79 patients who had undergone excision of their primary melanoma and classified as stage IA, IB, IIA, IIB, or IIC according to surgical findings. The rationale was as follows:

So let me get this straight. This is the rationale? No post-surgical therapy is generally recommended for melanomas Stage IIA and below; so let’s just give them Rigvir, instead. This is not a randomized trial. Patients were all offered Rigvir, were treated, and then a retrospective analysis was done after treatment. There was no blinding. There was no evidence of rigorous inclusion criteria. We have no way of knowing whether the Virotherapy Center included all the patients it treated for melanoma of the selected stages during the given time period or if it excluded cases in a way that could bias the results. Also, quite tellingly, no treatment/observation group is, on average, ten years older than the Rigvir group, and has proportionally over twice as many in the stage IIB group, which would have a worse prognosis than earlier stage melanoma. Basically, this study is worthless. I’m disappointed that Melanoma Research, normally a very good journal, published this dreck.

The rest isn’t any better. For instance, there is a 2016 paper with three case reports of patients with stage IV melanoma, stage IIIA small cell lung cancer, and a stage IV histiocytic sarcoma, all of whom were treated with Rigvir and all of whom have survived longer than expected. Of course, case reports can be useful for hypothesis generation, but do not generally show efficacy. Another study is listed (but not linked to). It’s a retrospective study published in Latvijas Ārsts (Latvian Doctor) that looked at the progression-free period for stage II melanoma patients and observed that patients treated with surgery and observed were 6.7 times more likely to recur than those treated with oncolytic virotherapy after surgery. This study suffers from the same problems as the 2015 study. It’s not randomized. It’s retrospective. We have no way of knowing how the cases were selected.

All of this leads to the question: Does Rigvir have anticancer activity, particularly against melanoma? My answer is simple: Damned if I know given the lack of valid, rigorous clinical trial evidence, but I tend to doubt it strongly. Rigvir might have weak activity in melanoma (although I doubt even that), but there’s no way Rigvir is curing patients with stage IV cancers and it’s incredibly unlikely that it is active against the range of cancers for which it is used.

Rigvir is most likely cancer quackery

There are many aspects to the Rigvir story that strongly suggest that Rigvir is probably cancer quackery. First, there is its mysterious origin story. As I read more about Rigvir, I couldn’t help but hear echoes of the story of Stanislaw Burzynski, with the exception that there is no evidence of which I’m aware that Dr. Muceniece ever supported the uses to which Rigvir has been put since its registration in Latvia in 2004. The echoes I heard, however, were distinct and came from the lack of information about the origin of this therapy, which goes back even further than the 1970s origin of Stanislaw Burzynski’s antineoplastons. True, the parallel is not anywhere near airtight, but it’s troubling.

Next, there is the way Rigvir is marketed, which is straight out of the cancer quack playbook. There are slickly produced videos on the International Virotherapy Center website full of appealing patients singing the praises of how Rigvir saved their lives in personal anecdotes and even a foundation that promotes Rigvir, again with glowing testimonials. This is definitely a red flag.

Then there’s how the International Virotherapy Center has represented the registration of Rigvir. In brief, it tries very hard to make it sound as though the drug was registered in accordance with European Union standards when it wasn’t. Again, Ritums tells the tale:

Then, like many dubious clinics, the Virotherapy Center disparages conventional medicine and portrays Rigvir as “natural”:

Others have noted that Rigvir, when first sold, was inexpensive, but with its growing popularity the price has gone up. A telling quote comes from the Medical Director of the center, Dace Baltina, who was quoted in the magazine Ir as saying, “We do not promise to heal”, but “a patient is ready to pay believing the recovery will happen.” Sound familiar? And that doesn’t even take into account the association the Virotherapy Center now has with what is without a doubt a quack clinic in Mexico, Hope4Cancer. As I documented before, in addition to Rigvir, H4C offers high dose intravenous vitamin C, alkalinization, coffee enemas, juice fasting, near infrared saunas, detox routines, and more quackery. None of this has stopped the EU from providing support under Horizon 2020 for a “feasibility” study as a prelude to a phase 2 trial to support registration with the European Medicine Agency. Somehow I doubt Rigvir will make it that far. At least, I sincerely hope that it doesn’t, unless of course rigorous clinical trials show that it actually works, which is, based on my reading of the existing data, highly doubtful, albeit not impossible.

What we have in Rigvir is yet another example of alternative medicine co-opting an interesting treatment from history that had been largely abandoned, resurrecting it, and riding it to profits. Immunotherapy, including the use of oncolytic viruses to target cancer, is all the rage these days in oncology; so a treatment like Rigvir is easy to sell based on its supposed immunological mechanism. Never mind that there is such a paucity of evidence that it actually works. Cancer patients, beware.

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