Cancer survival

There is a report in today's newspapers in the UK about progress in cancer survival. There has been some improvement but it is not a record of magnificent success. Most of the improvement has come from surgery, particularly with breast and colon surgery - often when combined with adjuvent chemotherapy. Some of the improvement has been because of early diagnosis - not that patients are living longer than they did, merely that are living with the diagnosis for longer. This is particularly true for breast and prostate cancer.

Hormones have made a great impact on cancer survival, particularly for breast cancer.

Chemotherapy has made a great impact on Hodgkin disease and childhood acute leukemia but limited impact elsewhere except in the adjuvent setting. Adult AML has shown little if any benefit from chemotherapy

Monoclonal antibodies have made an impact in CLL, diffuse large cell lymphoma and follicular lymphoma (actually it's all rituximab).

Targeted therapy ahs made an impact on CML, and possibly kidney cancer and a rare form of adenocarcinoma of the lung in Indian female non-smokers. There is some promising news about melanoma.

Bone marrow transplantation has saved some lives but the risk is so great that the butcher's bill is hard to calculate.

Longer survival may come from better disease definition as in some skin cancers and lymphomas.

As for the common solid tumors like lung cancer, pancreatic cancer, brain cancer and the rest, there has been very little improvement since I became and oncologist 37 years ago

More on drug shortages.

From New Scientist:

President Obama has signed an executive order intended to boost drug supply, particularly of cancer treatments and antibiotics

BARACK OBAMA has issued an executive order aimed at easing shortages of prescription drugs in the US. The order allows the US Food and Drug Administration to speed up approval of new drug-making facilities, and requires more companies to warn the FDA of any manufacturing cutbacks. The number of drugs affected by shortages has tripled since 2005, says the White House, which has also called for an investigation into illegal “price gouging” by profiteers selling scarce drugs for inflated prices. The FDA blames demand that is rising faster than manufacturing capacity. Others cite increased reliance on foreign suppliers not meeting FDA standards, and efforts by some companies to impede the manufacturing of older drugs, to boost demand for newer ones.

The number of drugs affected by manufacturing shortages in the US has tripled since 2005. Half of all shortages in the US in 2010 were of sterile preparations for injection, especially for cancer treatments and anaesthesia.

This does not seem to me to have gotten to the root cause of the problem.

Shortage of cancer drugs

There is a shortage of oncology drugs - particularly those that have been around a long time like vincristine, carboplatin, taxotere, doxorubicin and leucovorin. Oncology drugs are usually purchased by the oncologist and sold to the patient or Medicare or an insurer. Since oncology is a knowledge-based specialty rather than a procedure-based specialty, the oncologist makes his income by the mark-up between wholesale and retail prices. Medicare looked at this mark-up and thought it excessive, imposing a limit on it. This has acted as a deterrent to the prescription of generic drugs which would make the practice of treating Medicare patients uneconomic. For example the price of branded carboplatin is $120 a vial whereas generic carboplatin is $3:50. Since Medicare allows only a 6% mark-up it would cost the oncologist money to prescribe the generic.

This is the law of unintended consequences acting. Manufacturers have stopped making generic drugs and even worse, some patients have received a wrong, sound-alike, drug as a consequence. A grey-market has grown up with Indian and Brazilian generics appearing on the market.

This is not much of a problem yet in the UK, but one can see it spreading over here. I have heard of adjunct drugs that are necessary for the administration of some types of chemotherapy being unavailable in hospital pharmacies.

This story is featured in toady's NEJM.

How to reduce the cost of cancer drugs

What could make the cost of new cancer drugs cheaper? In the latest Lancer Oncology, NICE has some suggestions.

1. Recent proposals by an international group of academic clinical investigators suggest that clinical trial costs could be decreased by 40–60% without detriment to their quality. (EL Eisenstein, PW Lemons and BE Tardiff, et al. Reducing the costs of phase III cardiovascular trials. Am Heart J, 149 (2005), pp. 482–488. EL Eisenstein, R Collins and BS Cracknell, et al. Sensible approaches for reducing clinical trial costs. Clin Trials, 5 (2008), pp. 75–84.)

2 Simple measures to reduce costs include electronic data capture, reduction in the length of case-management forms, and modified site-management practices. The latter should include greater use of statistical techniques to detect fraud, rather than over-reliance on site visits by regulators and sponsors.

3 Greater use of Bayesian techniques in the design and analysis of randomised controlled trials holds real promise in reducing trial duration and numbers of patients needed.

4 Oncologists and patient advocacy organisations should start challenging the data requirements demanded by regulatory authorities.

5 Rather than criticise organisations such as NICE for declining reimbursement on grounds of cost-effectiveness, clinicians and patient advocates should start challenging pharmaceutical companies about the high prices they seek for products with modest benefits.

6 We should all be more concerned about the difficulties facing low and middle income countries in accessing affordable cancer care, rather than constantly focusing on the problems facing developed countries.

Two die from pancreatic cancer

By a strange coincidence two famous men died of pancreatic cancer last week. Steve Jobs, the co-founder of Apple succumbed and so did Ralph Steinman, who discovered the dendritic cell. Steinman was awarded the Nobel Prize for medicine, but when the telephone call came he had been dead for three days.

Ironically, Steinman was being treated for his pancreatic cancer with a dendritic cell approach.

So there you have it: pancreatic cancer is so terrible a disease that it cannot be defeated by all the money in the world or by the biggest brains on the planet.

How people with cancer die.

What do people with cancer actually die from? It think it is carelessness. I remember reading a book about leprosy. The main problem is that it causes a peripheral neuropathy which means that the leper has to carefully inspect his skin for cuts that might be come infected.

The complications of my cancer and its treatment that I am suffering from are decreased gut motility, a serious pulmonary embolus, proximal myopathy and a peripheral neuropathy. Yesterday afternoon I was trying to strengthen my legs by taking a walk in the garden. I spotted a large weed and stepped onto the flower bed to uproot it. On stepping back to the path, I overestimated my power to take a long stride and the amount of proprioception I had left in my feet. I tripped over the rockery and belly-flopped onto the shingle bath. My goodness, that hurt. I suppose my distended tummy acted like an air-bag, but I was left with superficial bruising on my abdominal wall and a large bruise/hematoma over my tibia (I am fully anticoagulated). After about 10 minutes screaming my wife picked mt up and put me in a chair.

This morning I am uncomfortable but conscious. I have not ruptured my spleen or sustained a cerebral bleed. No lasting damage seems to have been done. That's twice I could have died of carelessness. Perhaps men show too much bravado and this is the reason that women live longer? Perhaps this is why people who choose palliative care live longer than those who choose chemotherapy in some series?

Benefits of Growing as a Person When Dealing With Cancer

David Haas has asked me to post this article on his behalf on my blog and I am happy to do so.

Benefits of Growing as a Person When Dealing With Cancer

Sometimes we look at life like we are entitled to having it easy and carefree. Have you ever been around anyone who hasn't had to earn or work for what they have? If you have, you have seen that they are often shallow people without dimension. Have you seen someone on the television or been around someone who has faced unimaginable hardship and still has a positive outlook? If you have, you will notice they are strong, wise, and people are drawn to them. When you have a serious diagnosis,such as a terminal cancer like mesothelioma, you will need to make a choice. You will need to choose if you will grow as a person or if the diagnosis will destroy you. Choosing to grow will have many benefits.

BENEFITS OF GROWING AS PERSON WHEN BATTLING CANCER

The National Cancer Institute, which is also known as NCI, can provide you with all kinds of statistics about cancer survival, but who knows where you will fit in. There is no way to predict if someone will exceed their life expectancy or not make it past their first treatment. What is known is that everyone can grow as a person while battling cancer. Here are some keywords that people can grow through while dealing with cancer:

Acceptance
Strength
Peace
Patience
Love
Appreciation

Not everyone grows from a serious diagnosis like cancer or other life threatening illness, but the opportunity is there for everyone. Those who choose the high road often survive longer and enjoy a higher quality of life than those who are eaten up with negativity.

YOU CAN'T CONTROL CANCER, BUT YOU CAN CONTROL YOUR ATTITUDE

controlling your view of your own life with cancer is like choosing to get your head out of a trash can and turning around to look at an awesome sunset. You are still in the same spot, but you choose what to keep your eyes on. Job in the Bible experienced undeserved loss, pain, and illness, yet he didn't curse God. It was the growth during that experience that allowed him to be able to develop a level of acceptance that put him in a position to be blessed abundantly.

Every step towards growth is a victory during your battle with cancer or other life threatening illness. It will bring out hidden strengths and skills that will help you survive.

By: David Haas

Do we need different trials for the elderly?

One of the bugbears of clinical trials is that they are usually conducted in younger patients. This is especially relevant in CLL where the median age of presentation is 70. The question has been asked as to whether we should have specific trials for older patients and would they give different answers to the trials that we have now.

There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.

Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.

The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.

The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.

This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.

As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.

This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.

What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.

Vitamin D and cancer

The current New England Journal of Medicine contains an article by Manson, Mayne and Clinton on Vitamin D and cancer prevention. They all served on the Institute of Medicine Committee which recently raised target levels for Vitamin D for the prevention of bony disease. The committee concluded that for outcomes beyond bone health, including cancer prevention, the evidence available is inconsistent and inconclusive. No cause-effect relationship can be established. There has been no randomized controlled trial conducted where cancer has been the primary end point. Most evidence is derived from laboratory studies, ecological correlations, and observational studies. Low vitamin D levels are also linked with confounding factors that are themselves associated with high risk of cancer; for example: obesity, lack of physical exercise, dark skin pigmentation and diet.

Reverse causation may also be a problem - poor health can lead to less sun-exposure or a poorer diet. Vitamin D is like many micronutrients that have been linked with cancer such as beta carotene and selenium; randomized clinical trials for these have been uniformly negative.

The theory that vitamin D can help prevent cancer is biologically plausible. The vitamin D receptor is widely expressed and test tube studies demonstrate that vitamin D can promote cellular differentiation, inhibits cancer cell proliferation, and has anti-inflammatory, proapoptotic and antiangiogenic properties. This might suggest a role in cancer prevention, but, of course, proves nothing.

There have been three vitamin D trials including one that compared vitamin D + calcium to calcium alone that addressed the occurrence of new cancers or cancer mortality as secondary end points, but the results showed no difference. A trial at Oxford of 2686 individuals 833 U/day showed a relative risk of 1.09 (CI 0.86-3.36), a trial in Nebraska of 1179 postmeopausal women showed a relative risk of 0.76 (CI 0.38-1.55) and a big American study of 36,282 postmenopausal women showed a relative risk of 0.98 (CI 0.91-1.05). One study showed that women with the lowest intakes of Vitamin D had the lowest incidence of breast cancer and those with the highest intakes had the highest risk of cancer and in this study both the figures were statistically significant.

For colorectal cancer, observational studies do support a link. A meta-analysis of 5 studies suggests that patients with serum levels of 25-hydroxy vitamin D of 33 ng/ml or higher had only half the risk of colorectal cancer of those with levels below 12 ng/ml. There have been two studies since; a European prospective study found a similar association, but a Japanese study did not find such an association. Randomized trial evidence is limited. A British study did not find a change in incidence in individuals treated with vitamin D and the WHI trial of vitamin D plus calcium similarly found no reduction in incidence or reduced mortality.

Observational studies for prostate cancer have not supported the idea that vitamin D deficiency is associated with prostate cancer and nested case control studies similarly have been non-supportive of the hypothesis. There has been a large scale Vitamin D pooling project for rarer cancers. These show no association between higher levels of vitamin D and reduced risk of endometrial, esophageal, gastric, pancreatic, or ovarian cancer or NHL. Indeed there are suggestions that higher vitamin D levels might be associated with an increased risk of pancreatic cancer.

The Committee concluded that despite widespread enthusiasm for the idea, the evidence is inconclusive and inconsistent. There are new trials assessing moderate-to-high vitamin D supplementation and these should give us an answer in 5-6 years time.

Wnt pathway and cancer stem cells.

One of the problems in being retired is that medicine moves on. New techniques, new disciplines and new pathways keep appearing until scientific papers become increasingly opaque. The Wnt genes have been around a little while, but because they have hardly impacted on CLL I have ignored them. However, the last CLL paper I looked at mentioned them so I thought that I ought to try and understand them.

The name Wnt was coined as a combination of Wg (wingless) and Int and is usually pronounced as 'wint'. The wingless gene had originally been identified as a recessive mutation affecting wing and haltere development in the fruit fly, Drosophila melanogaster (halteres are small knobbed structures modified from the hind wings in some two-winged insects; they are flapped rapidly and function as accelerometers to help the insect maintain stability in flight). They can be seen on this picture of a crane fly.
It was subsequently characterized as segment polarity gene (genes whose function is to define the anterior and posterior polarities within each embryonic parasegment) in Drosophila melanogaster that functions during embryogenesis and also during adult limb formation during metamorphosis. The INT genes were originally identified as vertebrate genes near several integration sites of mouse mammary tumor virus (MMTV). The Int-1 gene and the wingless gene were found to be homologous, as shown by similar amino acid sequences of their encoded proteins.

Mutations of the wingless gene in the fruit fly were found in wingless flies, while tumors caused by MMTV were found to have copies of the virus integrated into the genome forcing overproduction of one of several Wnt genes. The effort to understand how similar genes produce such different effects has revealed that Wnts are a major class of secreted morphogenic ligands of profound importance in establishing the pattern of development in the bodies of all multicellular organisms studied.

Wnt proteins are therefore known as secreted morphogens that are required for basic developmental processes, such as cell-fate specification(ie what happens to individual cells in development), progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways (see figure which will enlarge when clicked):
the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin.

In the canonical pathway Wnt proteins bind to cell-surface receptors of the Frizzled (FRZ) family, causing the receptors to activate Dishevelled family proteins (Frizzled and Dishevelled are obviously descriptions of fruit flies when these genes are missing) and ultimately resulting in a change in the amount of β-catenin that reaches the nucleus. Cell surface FRZ proteins usually interact with a transmembrane protein called LRP. LRP binds FRZ, Wnt and axin and may stabilize a Wnt/FRZ/LRP/Dishevelled/axin complex at the cell surface (known as the receptor complex). Phosphorylation of the cytoplasmic domain of LRP by CK1 and GSK3 can regulate axin binding to LRP (interaction 1 in Figure). The protein kinase activity of GSK3 appears to be important for both the formation of the membrane-associated Wnt/FRZ/LRP/DSH/Axin complex and the function of the Axin/APC/GSK3/β-catenin complex. β-catenin is able to enter the nucleus and interact with TCF/LEF family transcription factors to promote specific gene expression (interaction 2, Figure).


Wnt binding, inhibits a second complex of proteins that includes axin, GSK-3, and the protein APC (Figure) (APC stands for adenomatous polyposis coli, one of the genes that is involved in bowel cancer). The axin/GSK-3/APC complex normally promotes the proteolytic degradation of the β-catenin intracellular signaling molecule. Several protein kinases and protein phosphatases have been associated with the ability of the cell surface Wnt-activated Wnt receptor complex to bind axin and disassemble the axin/GSK3 complex. The protein kinase activity of GSK3 appears to be important for both the formation of the membrane-associated Wnt/FRZ/LRP/DSH/Axin complex and the function of the Axin/APC/GSK3/β-catenin complex. Phosphorylation of β-catenin by GSK3 leads to the destruction of β-catenin (Figure).

The Wnt pathway is obviously important for morphogenesis and my daughter, who was particularly good at developmental biology, remembers it from her time at Oxford. However, this will not interest most of my readers who will be more concerned with the fact that alterations of Wnts, APC, axin, and TCFs are all associated with carcinogenesis. There are at least 17 members of the Wnt family.

The WNT/ β-catenin pathway is activated by WNT1, WNT3, WNT3a, WNT7a, and WNT8. In the absence of Wnt signaling, β-catenin is destined for destruction. Several genes have now been identified as the target of β-catenin /TCF transcriptional regulation. These include MMP7 (Matrix Metalloproteinase-7), UPAR (Urokinase-type Plasminogen Activator Receptor), CD44, c-Myc, c-Jun, FRA1 (Fos-Related Antigen-1), CcnD1 (Cyclin-D1), PPAR-Delta (Peroxisome Proliferative Activated Receptor-Delta), TCF1 (Transcription Factor-1), Fibronectin , Slug , Gastrin, Cox2 (Cyclooxygenase-2) and the Gamma2 chain of Laminin5. Many of these genes, including CcnD1 and c-Myc have crucial roles in cell growth, proliferation and differentiation, and are inappropriately activated in colon cancer, Burkitt's lymphoma and mantle cell lymphoma as well as many other tumors. c-Myc gene induced by β-catenin may induce expression of p53, and p53 upregulated p21WAF1 and p130/RB2, resulting in growth arrest. Another target of β-catenin is Vimentin, a protein involved in cell migration. Vimentin is a direct target of the β-catenin /TCF transactivation pathway in human breast cancer cells. WNT signaling can prevent apoptosis by up-regulating anti-apoptotic proteins, such as the caspase inhibitor, survivin, and stimulate angiogenesis via up-regulation of VEGF (Vascular Endothelial Growth Factor). Several proteases capable of degrading extracellular matrix, such as Matrilysin/MMP7 and MMP26, as well as cell adhesion molecules such as CD44 and NRCAM (Neuronal Cell Adhesion Molecule) are WNT targets that could aid the tumour cells in invasion and metastasis. The Canonical WNT signaling cascade also regulates the NRSF/REST and ENC1 (Ectodermal-Neural Cortex (with BTB-like domain)-1) genes, thereby controlling the progenitor cells. Cldn1 (Claudin-1) is also involved in the Ctnn-Beta -TCF/LEF signaling pathway, and increased expression of Cldn1 may have some role in colorectal tumorigenesis.

One of the interesting recent developments in cancer has been the recognition of cancer stem cells (CSCs). Recent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells (CSCs) which are thought to be responsible for recurrence of cancer. One of the characteristics of CSCs is their ability to form floating spheroids under anchorage-independent conditions in a serum-free defined media. Last September an investigation was published of reporting an examination of the role of Wnt/β-catenin pathway in regulating the growth and maintenance of colonospheres using the human colon cancer cell line HCT-116. Colonospheres formed by HCT-116 cells show over 80% of the cells to be CD44 positive, compared to ≤ 1% in the corresponding parental cells. Additionally, colonospheres showed reduced membrane bound β-catenin but had increased levels of total β-catenin, cyclin-D1 and c-myc and down regulation of axin-1 and phosphorylated β-catenin. Increased expression of β-catenin was associated with a marked transcriptional activation of TCF/LEF. The latter was greatly decreased following down regulation of β-catenin by the corresponding siRNA.

Cancer stem cells that are resistant to conventional chemotherapy seem to be one possible reason that cancer returns after complete remissions. Speculation suggests that this is true not only for epithelial tissues like the colon, but also for leukemias and lymphomas. It may be that therapy targeted to the Wnt/β-catenin pathway will be effective in eliminating this population.

Yet more good news.

I last wrote about ALK in June 2008. I first came upon it when sitting at the feet of Professor Dennis Wright who gave us weekly tutorials on lymphomas while I was working in Bournemouth. Anaplastic large cell lymphoma needs to be distinguished from Hodgkin's disease (both of which show CD30 positivity) and can be so distinguished because of a chromosomal translocation which produces the NPM-ALK fusion protein.

However ALK can have many other partners in lots of different cell types. The important thing about ALK is that it is a tyrosine kinase like Glivec and could be inhibited therapeutically.

In this week's New England Journal of Medicine there are a series of reports where this has happened. The new TKI (tyrosine kinase inhibitor) is called Crizotnib and the tumor it works in is non-small cell lung cancer. Like Glivec, its efficacy became apparent after a small phase I trial. This type of non-small cell lung cancer is a small subtype, comprising only 5.5%, but this might mean over 10,000 candidates a year in the USA alone. Most of this group are non-smokers with adenocarcinomas. They had mostly already had best available chemotherapy, so a 57% response rate in these patients is impressive. It is early days yet, but this represents another step along the pathway to tailored therapy for cancer.

Baby's breath for cancer?

Baby's Breath flower can boost anti-leukaemia drugs by up to a million times

So read the headline in the Daily Mail.

The article refers to work done in Southampton by David and Bee Flavell with antibodies tagged to Saponin. This couple have been beavering away for more than 20 years ever since they lost their child, Simon, to acute lymphoblastic leukemia.

Here is an abstract of their work from a presentation at the American Association for Cancer Research last month.

Saponins are a highly diverse group of glycosides of plant origin containing either a steroidal or triterpenoid aglycone to which one or more sugar chains are attached. They have been variously described as enhancing the cytotoxic activity of ribosome-inactivating proteins (RIPs) and ligand-directing conjugates constructed with these for eukaryotic cells. Saponins are thought to facilitate the entry of RIPs into the cytosol across the membranes of intracellular vesicular structures. This characteristic of saponins therefore makes them of interest as molecules that could be useful in improving the therapeutic index of immunotoxins (IT) in a clinical setting. In the current study we used a protein synthesis inhibition assay based on leucine incorporation together with cell proliferation studies in culture to demonstrate that saponins from Gypsophila paniculata L. potentiate the cytotoxicity of the anti-CD19 and CD38 saporin-based immunotoxins (BU12-SAPORIN and OKT10-SAPORIN, respectively) by several thousand-fold for the human lymphoma cell line Daudi. Various experiments revealed that the enhancing effect of saponins on immunotoxin activity did not appear to be dependent on extra cellular pH in the assay system we used. Kinetic studies further revealed that saponin at a predetermined optimal concentration of 2 μg/ml reduced the t10 (time taken to reduce protein synthesis to 10% of the level seen in control Daudi cells) for OKT10-SAPORIN at 0.1μg/ml from 50 hours without saponin to 12.5 hours with saponin. In blocking experiments using OKT10-SAPORIN IT at the IC50 concentration in combination with saponin together with a gross excess of native OKT10 antibody we established that the immunospecific cytotoxic activity of OKT10-SAPORIN was fully retained when leucine incorporation was used as the surrogate measure of cytotoxicity but only partially so when thymidine incorporation was used. This observation of a partial uncoupling of protein and DNA synthesis as a measure of cytotoxicity was further supported by cell proliferation experiments in culture which were undertaken in parallel. If saponins are to be of any clinical value as candidate molecules for improving the therapeutic index of immunotoxins it is imperative that the immunospecificity of IT activity is fully retained. Whilst this study clearly demonstrates that saponins from G. paniculata L. do indeed significantly potentiate IT activity it seems that this effect may only be partially immunospecific. Nevertheless, the dramatic improvements that saponins confer on IT activity argue in favor of in vivo experiments in transgenic animal models of human lymphoma combined with additional studies to explore other strategies that might be employed to improve the immunospecific effect achievable.

I have written about these 'immunotoxins' at length in the past and we published a small series back in the 1990s:

Lancet. 1995 Jul 22;346(8969):223-4.

Treatment of B-cell lymphomas with combination of bispecific antibodies and saporin.
French RR, Hamblin TJ, Bell AJ, Tutt AL, Glennie MJ.

Tenovus Research Laboratory, Southampton General Hospital, UK.

Abstract
We report the use of a bispecific F(ab')2 antibody to target the ribosome-inactivating protein saporin to the surface antigen CD22 in the treatment of low-grade, end-stage, B-cell lymphoma. Four patients were treated. Toxic effects were minimal (grade I), with mild fever, weakness, and myalgia for 1-2 days after treatment. One patient showed an antibody response to mouse Fab' and saporin. All patients showed rapid and beneficial responses to treatment with improvements in most disease sites and in peripheral blood cytopenia. The responses were short-lived (less than 28 days) but further study of this targeting system is warranted.
We need to distinguish between saporin and saponin. Saporin is a ribosome-inactivating protein similar to ricin, that needs an antibody to hitch a lift on to get into the cell. Saponins are a group of plant compounds which seem to enhance the activity of immunotoxins.

It is important to recognize that these experiments, while promising, are still at the stage of killing cells in a test tube. Many substances kill cells in test tubes, the acid test comes when you put them into patients. We found that the OKT10-saporin conjugate caused transient blindness when given to patients with myeloma.

Human breast milk as an anti-cancer agent

One of my correspondents claimed that her CLL improved after she started drinking human breast milk. In today's Telegraph there is a report of a study which seems to confirm that breast milk has anti-cancer properties.

The article suggests that a component of human breast milk, Human Alpha-lactalbumin Made Lethal to Tumour cells or HAMLET, could be a common cancer treatment for adults within five years. Human trials have shown HAMLET can kill bladder cancer and laboratory tests have found it kills 40 different types of cancer, but it is harmless to normal cells. the work is that of Assistant Professor Roger Karlsson, of the University of Gothenburg.

Human trials on male bladder cancers sufferers showed tumours were reduced without side effects within just five days of treatment. However the compound had to be infused into the bladder through a catheter and the professor does not see the compound being infused intravenously or given orally.

Researching this report, I see that it refers to an article in the International Journal of Cancer from 2007, so this may well be old news triggered by a new review.

In fact there is a paper in this month's Journal of Urology which is probably the source of the Telegraph article.

Here is a summary of what it says.

HAMLET is a complex of α-lactalbumin and oleic acid that kills a wide range of tumor cell lines in in vitro conditions. Embryonic cells are intermediately sensitive to HAMLET but healthy differentiated cells tested to date remained viable. The therapeutic potential of HAMLET was established in vivo in patients with skin papilloma. Topically applied HAMLET caused a significant reduction in lesion size. Local infusion of HAMLET into rat brains with invasively growing human glioblastoma xenografts delayed tumor development and prolonged survival. Apoptosis was mainly confined to the tumor area, although HAMLET diffused throughout the infused hemisphere.

In patients with superficial bladder cancer HAMLET instillations recently reduced tumor size and caused apoptosis-like death of tumor cells but the study was not designed to examine a therapeutic effect. Thus, we evaluated the therapeutic effects of HAMLET for bladder carcinoma in a murine bladder cancer model. Results suggest that HAMLET delays tumor growth and cell death mainly occurs in tumor tissue.

Drug resistance

This paper has just appeared in Cell.

A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sreenath V. Sharma et al Cell 2010 DOI 10.1016/j.cell.2010.02.027

Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly ‘‘drug-tolerant’’ cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells
transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

In other words some cancer cells can only become resistant to anti-cancer agents by using a little-used pathway to keep alive. Block that pathway and they die. Some evidence that drug resistance in cancer cells may be reversible.

Screening for cancer.

The American Cancer Society is urging a more cautious approach to screening for prostate cancer. Among its recommendations is the advice that men with a life expectancy of less than 10 years should not be offered screening. The chairman of the committee said that two decades into the the PSA era of prostate cancer screening, the overall value of early detection in reducing the morbidity and mortality from prostate cancer remains unclear. One interesting statistic was that for each man who experienced the presumed benefit of screening, more than 20 had to be diagnosed with prostate cancer. This represents the most optimistic view assuming that the entire decline in prostate cancer mortality is due to screening. In fact the benefit ratio could be as poor as 1 in 50.

Raised PSA levels are frequently caused by benign prostatic hypertrophy or by a low grade malignancy that is unlikely to cause problems during the lifetime of the indidividuals. These people still have to undergo prostatic biopsy (which can be painful) and if it indicative of a low grade cancer they have the worry of deciding whether or not they should be treated. If they decide not to be treated then the horrors of watchful waiting beset them.

If it is deemed necessary to try and treat the prostate cancer surgically, the patient does not have a smooth passage. Apart from the immediate complications of bleeding and urinary stricture, the two primary longer term adverse effects of surgery are urinary and sexual. Data would suggest that long-term incontinence rates after surgery are from 12% to 16%. Long-term rates of erectile dysfunction after surgery in contemporary series ranged from 19% to 27%. It has been recently reported that, as with urinary incontinence, there is a higher rate of erectile dysfunction with minimally invasive radical prostatectomy compared with radical retropubic prostatectomy.

Radiation therapy is also not without toxicity. Acute toxicities that can present during treatment in up to 50% of men include urgency, dysuria, and nocturia, loose bowel movements or diarrhea, and hemorrhoidal and anal irritation. As with surgery, the most commonly encountered late toxicity is erectile dysfunction, which affects up to 50% of men.

Prostate cancer is very sensitive to the removal of a testosterone drive. Among the most common types of side effects of hormonal therapy are increased risk for weight gain, obesity, and diabetes; cardiovascular disease; breast enlargement and tenderness; sexual problems, including diminished sex drive and erectile dysfunction; emotional changes, including anger, sadness, and, in many, a generalized sense of fatigue; osteoporosis; loss of muscle strength and mass, which also increases the risk of falls in older men, predisposing them to bony fractures; anemia, which also contributes to fatigue; and cognitive changes, such as impaired thought processes and memory loss.

Similar fears have been raised about breast cancer screening. The authors of this report come from the Nordic Cochrane Center (the word 'Cochrane' usually implies a sensible approach to the statistics of health care). The report is in response to a report from the UK NHS Breast Cancer Screening Program which celebrates the 20th anniversary of cancer screening in the UK with the statement that the program saves 1400 lives a year

The authors regard this as propaganda, and since it is in line with the British government's expectation I would say that it just plain lying. No other breast screening program makes such claims. For example the Swedish mammography service claims to save 1 woman in 1000 screened, not the 2.8 per 1000 claimed here. It is easy to prove that the claim is nonsense. The decline in breast cancer mortality since 1989 in women who were screened (ie aged between 50 and 64) was 35%. But for women aged 40-49 (who weren't screened) the decline was 41% and for those aged 65-69 (who weren't screened until 2001) the decline was 38%. It would be special pleading to suggest that some other factor was responsible for the better outcome in those women who weren't screened, while the slightly smaller improvement in those who were screened was because they were screened. Moreover the improvement in survival began a couple of years before screening began. It is more likely that treatment has improved, most likely because of tamoxifen.

The most serious hazard of mammography is the overdiagnosis and overtreatment of healthy women who would not have acquired breast cancer in their lifetime had they not attended screening. It has been estimated that as many as a third of breast cancers picked up by screening are unnecessary diagnoses. That amounts to about 7000 breast cancer diagnoses a year in the UK.

In 2007 there were 83,728 recalls after initial screening in the UK. Of these, 14,753 were eventually found to have cancer - in other words 70,000 women were worried unnecessarily. About 40% of those recalled (about 34,000) undergo needle biopsy. There are about 2500 excision biopsies every year of which nearly 1700 will show a benign lesion. It has been estimated that screening leads to an extra 20% mastectomies each year, but some of these will be for carcinoma-in-situ (this is the breast cancer version of monoclonal B-cell lymphocytosis). 29% of carcinoma-in-situ cases were treated by mastectomy. Now perhaps 40% of cases of carcinoma-in-situ cases will progress to full blown carcinoma, but which 40%? There is no knowing whether they will include any of the 29% operated on.

Many of my readers will know what it is like to walk around with a cancer diagnosis, even if the doctors tell you that no treatment is necessary. The problem with screening is that it assumes that 'cancers' picked up by screening will behave in the same way as cancers picked up when they present in the normal way. There is quite a lot of evidence that they do not. Nor should it be assumed that a cancer patient who survives 12 years after diagnosis following screening has done any better than the patient who dies 8 years after diagnosis is a conventional way. Both might have died exactly the same length of time after the first cancer cell appeared; it's just that the first patient has known about it longer.

Last year the diagnostic criteria for CLL changed. No longer do 5000 lymphocytes define the disease; you have to have 5000 B-lymphocytes. B-lymphocytes normally comprise 10-18% of all lymphocytes, so you see that the threshold has been raised considerably. Patients who last year thought they had leukemia have now been told that they have a benign condition. Unlike other forms of leukemia, CLL is very similar to other cancers that occur predominately in older people. It may well be true that there are other cancers for which a relatively benign form exists. If we have very sensitive forms of diagnosis we may well end up diagnosing all sorts of cancer that never needed diagnosis.

It is now a year since I was diagnosed with cancer. In retrospect six months previously a small enlarged lymph node was detected on CT scan. It was known from colonoscopy to be situated somewhere near the junction of small and large bowel. At operation no primary tumor was found, but the lymph node was found to contain well-differentiated adenocarcinoma. I was given 9 course of chemotherapy on an intense schedule. At the end of this a residual and inoperable was 75% smaller than before the chemotherapy. Three months on the node was unchanged on CT scan and I am due another scan shortly. My CEA test gave an answer of 3 at the time of the operation, which does not indicate a large amount of cancer, but now it is <1. I have nothing to suggest that my disease has recurred.

Even though my cancer had spread at diagnosis, this clearly does not mean that it was an advanced disease. With breast cancer we know it to be a systemic disease even at an early stage of diagnosis. Bowel cancer may well be the same. Now I begin to ask myself the question as to whether my screening test was wise. I certainly had no symptoms prior to diagnosis and I have suffered quite a lot in the ensuing year. Perhaps I should have had the disease for many years before it drew attention to itself; perhaps it never would have done and I would have had my coronary in bed at the age of 90. On the other hand, perhaps it has behaved so well because I had a hefty dose of chemo while it was still small. I guess I will never know.

Second cancers in CLL

I have been thinking about the question of second malignancies in patients with CLL. This will not be the definitive article but I want to set out the hazards in attempting such an analysis.

It has long been assumed that second malignancies were common in CLL. When I was first appointed in 1974, one of my colleagues, David Beresford pointed out that he had written an article in 1951 which detailed 100 patients with CLL who had also had a second malignancy.

Here are some of the reasons that a patient with CLL might also have another cancer.

1] It might be a coincidence of old age. One in three of us is going to develop cancer, usually in old age. If we live long enough with one cancer we still have a one in three chance of getting a different tumor. People with CLL often live long enough.

2] CLL impairs immunity. If cancers are caused by a virus then impaired immunity to that virus might make a cancer more likely.

3] There might be immune surveillance against mutations that lead to cancers. This immune surveillance might be impaired in CLL along with other immune functions.

4] Both radiotherapy and chemotherapy may be oncogenic and could conceivably induce second cancers.

5] Chemotherapy is immunosuppresive and this might reduce immune surveillance.

6] There might be an unknown oncogenic or genetic factor that induces both CLL and other cancers.

7] There might be something about CLL that causes it to transform into another type of cancer.

8] CLL is hard to diagnose accurately. Perhaps patients had lymphoma all along, but a spillover into the blood was misdiagnosed as CLL.

Epidemiological studies might be expected to solve some of these puzzles but there are hazards in interpreting genetic studies:

1] CLL is usually undiagnosed until the individual has a blood test. Cancer patients have frequent blood tests but random controls do not. Therefore one would expect that cancer patients would have their CLL diagnosed while controls would not.

2] CLL patients see doctors regularly so if a cancer is present it is likely to be found, whereas controls don't see doctors regularly and therefore they may die of something else with their cancer undiagnosed.

Therefore, as I look at the published studies over the next few weeks I must be careful that I am not being hoodwinked.

Treatment holiday

I spoke to my oncologist yesterday. The CT scan after 8 courses shows no improvement on that after 5 courses. What does that mean? It could mean that I have residual disease that is resistant to this chemotherapy, but against this there has been no progression and the only remaining evidence for cancer is a distortion of the ileocecal valve where the presumed primary was. This distortion does not mean cancer - it could just as easily represent scar tissue from where the cancer was. The truth is that a CT scan is not sensitive enough to detect minimal residual disease. I have no systemic marker to detect smaller amounts of disease; my CEA level is in the normal range. I have no symptoms other than chemotherapy-induced ones.

Therefore the decision is that I have a treatment holiday with the presumption that my cancer is in remission. It's rather like watch and wait in CLL. We know that the cancer, while it had spread beyond the bowel into lymph nodes and peritoneal surface, was not extensive. We know that its growth rate was slow. For all we know, all traces of the cancer have gone. I have had at least 4 courses of chemo since the maximal response was achieved. It seems at this point that toxicity is outweighing benefit.

How do I feel? Certainly relieved that I don't have to go through any more chemotherapy for the time being. Anxious about the future. The oncologist is going to take my scans to show the surgeon to discuss the possibility of a second-look laparotomy and possible right hemicolectomy. That will be a difficult decision. If the last operation is a template, the post-operative course is a disincentive to further surgery.

The other option is to forget about the last 6 months and get my life back to normal, doing the things that I normally do. My daughter is getting married on October 3rd and that will provide sufficient distraction to keep me occupied.

Anemia in cancer patients

Why have a blood transfusion? Is it a] to raise your hemoglobin? b] to improve your color? c] to improve the oxygen carrying capacity of your blood?

The answer, of course, is c] but while it will do both a] and b] it won't do c] immediately. Oxygen is carried by hemoglobin and is released to the tissues where it is needed. It is helped to do this by a chemical called 2,3,DPG. In order to release oxygen, its place on the hemoglobin molecule must be taken by this chemical. 2,3,DPG is manufactured by all cells from the burning of glucose (the process is known as glycolysis and the biochemical pathway is known as the Emden-Myerhoff pathway. The particular trick of producing 2,3,DPG is known as the Rapaport-Leubering Shuttle). If a cell is not metabolising glucose then it won't make any 2,3,DPG, and this is what happens when blood is stored in a fridge. So when you receive blood from the blood bank it has very little 2,3,DPG and therefore the hemoglobin molecules cling on to their oxygen. That's why someone who has been transfused gets no immediate benefit from it; it can't release its oxygen to the tissues until it regenerates 2,3,DPG, which takes a couple of days.

This is one of the reasons that patients are dissatisfied with blood transfusion. That and the risk of transmitting viruses, or prions, or making their cancer worse by suppressing their immunity. In fact blood transfusion is very safe. Blood is screened for HIV, hepatitis B and C and a host of other possible infections. It cannot be screened for prions, but the risk of developing new variant CJD from transfusion is vanishingly small. The greatest risk of a transfusion is that some idiot will give you the wrong blood.

The alternative is EPO. Lots of cancer patients have been given it, but the unfortunate fact is that it shortens life. A recent meta-analysis published in the Lancet looked at 53 separate trials involving 13,933 patients. Although the effect was not great (a hazard ration of 1.06) it was statistically significant. Partly this effect is because EPO may raise the hemoglobin too much and the thrombotic complications of polycythemia come into play, but also there is the worrying fact that EPO is a growth factor for some tumors.

With so much to worry about we need to look at anemia again. In some cases the problem can be sorted with iron therapy. (Oral iron is best; there is no evidence that intravenous or intramuscular iron is more likely have a response or have a quicker response.) But we need to be able to recognise iron deficiency (which is almost always caused by bleeding). The easiest way is to look at the mean cell volume on the blood count. If this is below 80 fl then iron deficiency is the most likely diagnosis. Thalassemia trait can cause a low MCV and this is an important catch for people of Mediterranean background, but the only other cause of a low MCV is the anemia of chronic disorders (ACD).

I have bee surprised recently by how little even hematologists know about ACD. They seem to be unaware that it can cause a low MCV. I can only think that they have never looked at the blood counts of patients with rheumatoid arthritis, ulcerative colitis and Crohn's disease, let alone people with chronic infections or disseminated cancer. The serum iron in ACD can be as low as it is in iron deficiency, as can the MCV. The difference is that the iron binding capacity or the blood (or the serum transferrin) is raised in iron deficiency and lowered in ACD. Serum ferritin is low in iron deficiency and raised in ACD.

What happens in ACD is that the macrophages are over active and snaffle all the iron in the body and won't release it to the newly formed red blood cells. We now know that a chemical called hepcidin, a small peptide produced by the liver that inhibits both iron absorption and release of iron from the macrophages. Patients with excess hepcidin will not respond to more iron, whether oral or intravenous, nor to EPO. Only blood transfusion will raise the hemoglobin.

High hepcidin levels are found in association with high sed rates, high CRPs, high IL-6 levels and other indicators of inflammation.

The message of medians

Stephen J Gould's article, "The Median is not the Message" is a must read for everyone with any sort of cancer.

Results of particular treatments are usually reported as median survivals. This means the time at which 50% of people are dead and 50% are still alive. Medians are sensible figures when calculated on populations based on a normal distribution as represented by my second curve. But survival curves, as can be seen from the first illustration, do not look like this. They are extremely right skewed.

The median of the whole population is pressed up against the left hand edge of the graph at zero days because the normal distribution would contain all those who were going to get the cancer that we don't (and can't) know about. So we start on the downward slope from the time that the cancer is diagnosed. But that is a time some way into the disease. Some people are only diagnosed on the day that they die, having had the disease for many years undiagnosed. For CLL, we know that virtually all cases have had a long period when they had MBL before the diagnosis was makeable, and even when the diagnosis was makeable with a blood test, most people don't have blood tests.

On the survival curve, those with the most advanced and drug-resistant disease die soonest. By the time you get to the median survival the survivors are mainly those who had good prognostic factors at the beginning: low white count, no lymph nodes or spleen, mutated IgVH genes, low ZAP-70, low CD38 and del 13q14 on one chromosome. We know that some patients with these characteristics live out beyond 20 years and that they tend to die from old age. Indeed the ACOR list reported a man in New Mexico who had had the disease for 52 years. That survival curve had a very long tail indeed. As far as CLL is concerned the tail is abbreviated by the fact that everybody dies and that CLL patients cannot live longer than life itself. It is also a snapshot of the time it was drawn and it cannot take account of treatments that will appear in the next 20 years.

As far as my cancer is concerned, the median survival on this treatment is given as 22 months. But the 50% who die in this time are those who are really ill when they present, including those with massive liver secondaries, ascites, and bowel obstruction. I have all the good prognostic features: a primary so small as to be unfindable, localized spread, no liver involvement and no ascites, a well differentiated histology, low CEA levels, no symptoms and a 6 month observation which showed no progression on the CT scan. I should be on the right hand edge of the tail of that survival curve.

Fourth Course

Today I start my fourth course. When I finish this I will be a third of the way through. looking back, the third course was the worst so far. Not in terms of the side effects which I am beginning to come to terms with, but more because of my mental state. I was beset by doubts as to whether the chemo would be effective, of whether I could possibly last six months of this and of whether the side effects would ever remit. I would not say that I was depressed, but I cam pretty near to it.

As it is I feel better this morning and ready to start again without dose reduction. The remaining symptom is a sore nose for which I am applying naseptin. I have not really been blogging much, and to cap it all I have lost my internet connnection. I am using my daughter's computer for this blog