Cancer.

When I was a young and idealistic graduate student, my supervisor, in one of those melancholic late-night sessions at the pub, opined that he didn’t care how he died as long as it wasn’t from cancer. According to the US National Institutes of Health, a fifth of women in America fear breast cancer more than any other health threat, and nearly 60% of those questioned feared some form of cancer more than anything else (1). Similarly, breast cancer is the biggest health fear for over 40% of British women (2), yet in developed nations heart disease is twenty percent more deadly than all malignant neoplasms combined and accounts for over a quarter of all deaths in the US (3).

What it is it about cancer that makes people fear it so much? Is it the thought of our own bodies turning against us, like some biological fifth columnist? Is it the perceived assault on our masculinity (prostate cancer) or femininity (breast cancer)? Perhaps the reason is more subtle; perhaps cancer has been de-stigmatized too much. Maybe we are too aware of cancer (especially breast cancer) and this knowledge itself makes us unreasonably afraid.

From being a condition that dare not be named, often referred to only as ‘a long illness’, breast cancer has become the ‘biggest disease on the cultural map, bigger than AIDS [...], bigger even than heart disease, lung cancer and stroke' (4). Less than 15% of all women will have breast cancer at some point in their lives, but it affects all of us, from trying to avoid the pink-festooned teddy bears in the shopping mall to compulsory mammography.

After thirty or more years of serious research, there is no reliable cure for cancer. In theory, cancer therapy should be trivial. You discover what class of cell has slipped its leash, figure out what drug kills that cell type faster than it kills the patient, and administer it. But after surgical resection, the increase in long-term survival in response to the best chemo- or radiotherapeutic regimes is disappointingly low (5).

The major problem, and the bane of proud mothers of scientists everywhere, is that all cancers are different. Not just trivially, as in lung cancer versus breast cancer versus prostate cancer; but each different organ or tissue is subject to a bewildering away of malignant subtypes. To take our example of breast cancer, there was great excitement when BRCA1 and, four years later, BRCA2 were discovered: the ‘gene(s) for breast cancer’. However, despite their presence corresponding with a poor prognosis, mutations in these genes account for probably less than 10% of all breast cancer (6). Environmental mutagens are essentially random in their targets – nearly any gene is an oncogene in the right (wrong) conditions. No single drug, no single dose of gene therapy, will be 100% effective against cancer, and although combination therapy does improve a patient’s prognosis, the more drugs you give a person the more ugly are the side effects. We should perhaps not be surprised, then, that against the background of fear and ineffective therapy people are turning to increasingly desperate measures to effect a cure (7).

Against this background, Marnie Schulenburg’s novel asks a brave question – brave not because it deals with cancer up close and personal (the blogosphere is full of that), or that it tackles the infantilization of breast cancer by the Pink Ribbon brigade, but because it simply asks “Why do we treat all cancers the same way?”. Standard cancer therapy consists of trying one drug after another until something good happens. It’s a little bit like trying to solve a crossword puzzle by sticking a pin in a dictionary at random.

A Test of Survival came to me ‘print-on-demand’ from iUniverse. Somewhat larger than a trade paperback, the type is clear, spaced well and with good margins. The paper is thicker than that of most paperbacks on my shelf, and it became dog-eared rather too rapidly for my liking – at US$22 I would have expected the quality to be better. The binding, however, did survive multiple train journeys and two trips to the beach.

The premise of this novel is that it is possible to determine which drugs will prevent a cancer recurring before exposing the patient to months or years of painful and quite probably ineffective chemotherapy. By taking a biopsy of a tumour and testing its response to different combinations of drugs in the laboratory, in an ex vivo assay, it should be possible to determine what will work best for the patient in terms of limiting neoplastic recurrence. The difficulty is that if it were that easy, ex vivo, which has been around for at least 30 years (8), would already be standard practice.

But as anyone who has done serious cell culture will know, cells in flasks die at the slightest thought of mistreatment, which makes testing their survival problematic. Primary cell culture (or ex vivo) also has many other snares to trap the unwary: bacterial contamination, mixed cell populations, aggregation, syncytialization, identification and validation, spontaneous immortalization and so on. Even with a good protocol, appropriate media and experienced handlers, cells excised from a primary tumour and separated from their siblings can lose tumour-specific markers, indicating that they have changed in indeterminate ways.

All these problems are probably tractable given sufficient time and effort (9,10). However, as surgical resection aims to remove all malignant cells from the site of a tumour, and subsequent therapy (i.e. radiation and/or drugs) is directed at killing cells that have escaped and therefore by definition are different from primary tumour cells (metastasis itself representing a significant change in a tumour cell’s life), a big question mark remains over the interpretation of any tests performed on the original, cultured biopsy.

This is the core of Schulenburg’s story. The protagonist is Gus Ephraim, a rather unlikeable physician-turned scientist-turned lab technician who hawks his testing laboratory across the US in an effort to gain respect and recognition for ex vivo testing of anti-cancer drugs. Along the way he nearly breaks up with his wife, teeters on the brink of an affair with his first wife, is reconciled to his estranged son, is thoroughly humiliated, fights the powerful director of a cancer research hospital (and loses), fights him again (and wins – through blackmail), somehow manages to get powerful lawyers on his side, and all the while is the only person qualified to analyse the actual assay upon which his and his (current) wife’s livelihoods depend.

Despite the rather stark opening chapter, this not a book about science. It continues bleakly (for this reviewer, it was rather hard going until about half-way through) but the science does not. Even believers in ex vivo technology (the method is not scientifically unrespectable, despite the somber appraisal of the disinterested characters in the novel, and is in fact the focus of ongoing research [11-14]) would laugh at the assay endpoint as described – as one character remarks, bleach kills cells; but that does not mean Domestos is an appropriate chemotherapy agent. And they would have a fit when they found out that Ephraim is the only person who can read the assay. When his ex-wife asks for details on the drugs that the assay flags as being appropriate in her own case, she admonishes Ephraim for not explaining the science, but then falls asleep while he explains; and we, the readers, are similarly unenlightened.

Unfortunately, much of the book consists in unexplained details and minor irritants (side effects, maybe?). There is the character who is Scottish, but strangely not ‘a Brit’ and says ‘ass’. ‘Data’ is treated as a singular noun. Colours as adjectives are much abused, and while Schulenburg can report, there is an aching journalistic dryness in her atmospherics (“Just the facts, ma’am”?):

The office smelled of rotten apples, vaguely sweet. The wastebasket was plugged with the brown hour-glass skeletons of several chewed-up apple cores. Gus moved through food favorites, specializing in one for months and then abandoning it.

We have interminable shopping lists of people’s names and what they’re wearing, yet in the middle of a descriptive passage about a county court room and the people trickling in, the author seems to get bored and mentions ‘another woman’. The inconsistency is jarring.

And there is a problem with the characterization in general: Gus Ephraim might be unappealing, but he’s also uninteresting. His son develops in ways that seem quite incredible for a teenager. Apart from the bogeyman of the piece, only one other character seems to have any spark; yet as she was getting interesting her ultimate demise is telegraphed well in advance. So by the time of her casual rape, and heartbreak, and death, I was as utterly disinterested as the cancer itself.

The story does pick up pace in the later stages, and we learn that our protagonist is not wholly jejune; he’s actually quite nasty. The blackmail apparently comes from nowhere, and rather annoyingly the reader ends up feeling sympathy for Ephraim’s opponent. Although I am no clinical scientist, I became incredibly vexed at the depiction of an untractable conflict between ex vivo and clinical trials. This is the theme of the book, and unfortunately for the story it is a false dichotomy. Ephraim seems to realize this, belatedly, but only after I had been screaming at him for several pages. Shoehorning these rather subtle and interesting issues into a single either/or question is too simplistic. Culturing neoplasms outside the body and subjecting them to various drugs is not a treatment for cancer. It is – or could be, or might be – a diagnostic tool to tell an oncologist what kind of cancer the patient has.

Cancer treatment as it stands is the pin in the dictionary. If you’re a cynic you might say that this state of affairs suits the pharmaceutical companies just fine; they can sell their drugs in ever-increasing doses and in countless combinations, knowing that the clinical trials say at least 80% of the patients will survive for ten years. They might not have their hair or bladder control, and maybe 60% would have survived that long without the treatment, but you don’t know who they are and the executives certainly have no interest in finding out (which, incidentally, is part of the reason too few people have heard of pharmacogenomics [15]).

But if you can identify the precise type of cancer, if you can predict with reasonable confidence what will kill (or prevent) metastases in any given patient, then you can start the process of individually tailored chemotherapy, using drugs that have been tested for safety and efficacy in clinical trials. The diagnostic technique at the heart of this story should be judged in this light, and the scientific jury is still sitting.

References

1. http://www.nhlbi.nih.gov/health/hearttruth/press/fear_doubled.htm

2. http://www.breastcancercampaign.org/mediacentre/news/0100/

3. http://www.cdc.gov/nchs/data/dvs/LCWK2__2004.pdf

4. http://bcaction.org/index.php?page=welcome-to-cancerland-2

5. For example:

5.1. Early Breast Cancer Trialists' Collaborative Group 2005. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. The Lancet 365(9472): 1687-1717.

5.2. Lallya BE, Urbanica JJ, Blackstocka AW, Millerb AA, and Perry MC, 2007. Small Cell Lung Cancer: Have We Made Any Progress Over the Last 25 Years? The Oncologist 12(9): 1096-1104.

5.3. Zuckerman DS and Ryan, DP, 2007. Adjuvant therapy for pancreatic cancer: a review. Cancer, Published Online: 29 Nov 2007. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&TermToSearch=18050292.

5.4. Early Breast Cancer Trialists' Collaborative Group 1998. Polychemotherapy for early breast cancer: an overview of the randomised trials. The Lancet 352(9132): 930-942.

6. Szabo CI and King MC, 1995. Inherited breast and ovarian cancer. Human Molecular Genetics 4: 1811-1817.

7. See, for example: “Lab Rat? Sam Hutchison has cancer. His father is seeking a cure beyond the edge of medicine”, http://online.wsj.com/article/SB119759308934528357.html

8. Balls, M and Monnickendam MA (Eds.), 1976. Festschrift for Dame Honor Fell. FRS. Cambridge University Press; Organ Culture in Biomedical Research.

9. Peehl, DM, 2005. Primary cell cultures as models of prostate cancer development. Endocrine-Related Cancer 12(1):19-47.

10. Heinzman JM, Brower SL, Bush JE, Silverman JF, 2007. Ex vivo enrichment of malignant carcinoma cells in primary culture. Pathology 39:491-494.

11. Kurbacher, CM and Cree IA, 2005. Chemosensitivity Testing Using Microplate Adenosine Triphosphate–Based Luminescence Measurements. In: Chemosensitivity Vol I 101-120 (series Methods in Molecular Medicine 110, Humana Press, NJ, USA).

12. Lang DS, Droemann D, Schultz H, Branscheid D, Martin C, Ressmeyer AR, Zabel P, Vollmer E and Goldmann T, 2007. A novel human ex vivo model for the analysis of molecular events during lung cancer chemotherapy. Respiratory Research 8:43.

13. Dollner R, Granzow C, Werner JA, Dietz A, 2004. Is There a Role for Chemosensitivity Tests in Head and Neck Cancer? Onkologie 27:310-315.

14. Pirnia F, Frese S, Gloor B, Hotz MA, Luethi A, Gugger M, Betticher DC, and Borner MM, 2006. Ex vivo assessment of chemotherapy-induced apoptosis and associated molecular changes in patient tumor samples. Anticancer Research 26(3A):1765-72.

15. The use of ex vivo in this context faces similar challenges in terms of testing, regulation and profiteering as the field of pharmacogenomics:

15.1. A primer from the NCBI http://www.ncbi.nlm.nih.gov/About/primer/pharm.html

15.2. Report in Scientific American and the disincentive of the profit motive:

http://www.sciam.com/article.cfm?chanID=sa004&articleID=0006C064-7701-12ED-B70183414B7F0000

15.3. The Pharmacogenomics Journal: http://www.nature.com/tpj/index.html

Related information

A Test of Survival can be purchased from the author's website or from Amazon.com.