Onco Chat

What's in Placebos: Who knows? Analysis of randomized, controlled trials

Background: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting.

Purpose: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials.

Data Sources: 4 English-language general and internal medicine journals with high impact factors.

Study Selection: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009.

Data Extraction: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus.

Data Synthesis: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002).

Limitation: Journals with high impact factors may not be representative.

Conclusion: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

via www.annals.org

 

Thanks to Bruce Lehr of the Big Red Biotech Blog for bringing this topic to my attention.

In many trials of new drugs in development such as cardiovascular, dermatology, neuroscience etc, the test agent is typically compared to a placebo with a similar formulation such as a pill, topical cream etc, but as the journal points out, rarely is the composition defined in detail. 

This is not surprising, as the authors of the paper reported that they found that only a paltry 8.2% of the 86 studies they looked at actually stated clearly what the contents of the placebo were.

Does it matter?

Well, you might think it's just a 'sugar pill', but as this article in the LA Times noted, some placebos in cardiovascular trials might consist of olive oil or other polyunsaturated oils, thereby potentially reducing cholesterol and heart disease. Certainly something to think about, as they may have unexpected effects.

Although most cancer clinical trials are typically comparing a new treatment to the standard of care, often placebo is used in the comparator combination. A recent example is the abiraterone trial reported last week at ESMO in men with advanced, castration resistant prostate cancer after prior docetaxel therapy. The study compared abiraterone (a pill) with prednisone (a steroid) to placebo (pill) plus prednisone. Based on the information provided in clinicaltrials.gov, it isn't clear what the placebo actually was.

I liked the quote from the authors in the LA Times article above:

"Perfect placebo is not the aim, rather, we seek to ensure that its composition is disclosed."

Given the placebo could have unexpected effects or at least have an impact, perhaps we should start disclosing what's actually in them.

e-Patient Connections 2010

For all those that asked, my series on learnings from AACR in biomarkers and diagnostics will post Mon-Weds next week as today is heavily tied up with client projects and deadlines.

While I was in Denver, another meeting was taking place in Philadelphia of an entirely different nature, e-patient Connections, hosted by Kevin Kruse of Kru Research.  

For those of you interested in finding out more about this interesting event, here are some resources:

1. Eileen O'Brien of SirenSong posted an excellent summary of the meeting
2. Leigh Householder of What's your digital IQ live blogged the event and I particularly enjoyed reading her post on What physicians think of e-Patients. 
3. Pixels and Pills posted a very moving short interview with artist and poet, Regina Holliday, who vividly reminded us that patients are people.

They're all well worth checking out.

(Hat tip to Phil Baumann for pointing out Regina to me, she's a star)

 

 

The Use of 18F amyloid imaging in Alzheimers Disease

Following my live tweets from the AACR molecular diagnostics and cancer therapeutics meeting here in Denver this week, some interesting offline discussions continued. A big focus here was on biomarkers and systems biology. Several readers observed that oncology seems to be ahead compared to other therapy areas.

What is interesting though, is that while oncology is heavy on science, pathways, targeted therapies and multiple mechanisms of actions, it is surprisingly low on predictive biomarkers. It does fare a little better on prognostic biomarkers, granted. In contrast, Alzheimer's Disease (AD) in many ways, seems to be almost the opposite in that various biomarkers abound, but the field lags in effective targeted drugs and a deep understanding of the underlying biology (relative to oncology that is).

One area where we are likely to see more progress in the near future is in the use of imaging biomarkers for the diagnosis of early Alzheimer’s Disease.

Several companies are currently undertaking clinical trials with imaging biomarkers for AD including Bayer with florbetaben (BAY 94-9172), Avid Radiopharmaceuticals with AV-45 and GE Healthcare with flutemetamol. All three are in phase III development.

Currently the use of Pittsburgh compound B (PiB) in combination with PET allows the imaging of beta-amyloid plaques in the brain that are indicative of AD. However, there are limitations with the use of PiB since it requires use of an on-site cyclotron.

A recent paper by Rik Vandenberghe from the Catholic University Leuven, published in the September edition of the Annals of Neurology caught my attention on this topic. It reported phase 2 trial results from the use of 18F flutemetamol imaging in AD.

In this clinical trial, sponsored by GE Healthcare, blinded visual assessments of 18F- flutemetamol scans were undertaken in 27 subjects with probable early-stage AD and mild cognitive impairment (MCI). The results showed a sensitivity of 93.1% in the ability of the scan to diagnose early AD, as compared to clinical diagnosis as the Standard of Truth (25 out of 27 patients). 18F-flutemetamol was also shown in 20 subjects to have comparable regional standardized uptake value ratios (SUVRs) when compared to 11C-Pittsburgh compound B (11C-PiB). Correlation coefficients ranged from 0.89 to 0.92.

What makes the use of the 18F-labeled PiB derivative interesting is that 18F-flutemamol does not require the use of an on-site cyclotron, unlike 11C-PiB. As the study reports this may make it easier to access PET technology for clinical trials and research into AD.

GE Healthcare have already started a phase 3 trial program with flutemetamol, so it will be interesting to see whether the promising phase 2 results are confirmed when the phase 3 data is available after the study is completed later this year.

Data from other phase III clinical trials make this an area to watch out for. Hopefully the development of imaging biomarkers that allow for early diagnosis, will insoire both more basic research into the underlying biological mechanisms and also stimulate companies develop more targeted drugs for the treatment of what is essentially a horrible, progressive disease.

 

Photo Credit: Avid Radiopharmaceuticals

Top: Elderly Patient Control

Bottom: 18F AV-45 imaging of amyloid plaque in a patient with Alzheimer’s disease

 

References:

Vandenberghe, R., Van Laere, K., Ivanoiu, A., Salmon, E., Bastin, C., Triau, E., Hasselbalch, S., Law, I., Andersen, A., Korner, A., Minthon, L., Garraux, G., Nelissen, N., Bormans, G., Buckley, C., Owenius, R., Thurfjell, L., Farrar, G., & Brooks, D. (2010). 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial Annals of Neurology, 68 (3), 319-329 DOI: 10.1002/ana.22068

 

 

Biomarkers in cancer research - thoughts from AACR in Denver

This week I'm adjusting to the high altitude of Denver while at the American Association of Cancer Research (AACR) meeting on molecular diagnostics and cancer therapeutics. It's a great little meeting, networking opportunities are excellent and I'm learning a lot about what new cutting edge ideas are being explored.

I will be doing some highlights from each day series later in the week once I've had time to process all the information, as there is a lot to digest here.

What is interesting though, is to look at big picture trends, both in academia and basic research and also what industry are doing in their research teams, since these ideas may well get incorporated into early phase I clinical trials for validation and pilot purposes. More about this later in the week.

Although a lot of the attendees are from the diagnostics end of the business (either academic or industry), there are quite a few serious researchers and thinkers here too. Gordon Mills from MD Anderson gave one of the best talks I've seen at an opening session in a long while. David Parkinson from Nodality also laid out a strategic and thoughtful overview of how things are currently, and how they will continue to change in cancer research with new approaches. 

One thing really struck me here in Denver. While outsiders and FDA become more paranoid about conflicts of interest, it is clear to me that what we actually need is closer and more collaborative relationships between basic and clinical research in order to translate the knowledge and ideas into practice or the clinic more quickly.  To do this requires fresh ideas, a fresh approach and better communication and collaboration. 

By collaboration, I don't just mean between academia and industry, but between labs and between companies, rather than competition. Increasingly, I'm seeing smart researchers presenting data that was generated on behalf of several groups, often in different cities or even countries, each providing different skills and expertise to the research. This used to happen sporadically between friends and former colleagues, but now it's starting to become more commonplace. It's a good sign and a great way to synergies resources and bring more expertise to projects.

Industry are typically very slow to change and tend to see other companies as rivals rather than for collaborative purposes, which is a great shame given that we're all working towards the same goal: fight cancer. 

That said, there are some exciting new, albeit subtle changes afoot. When I think of cancer research, the first two industry research powerhouses I think of are Genentech, who have traditional sought strong relationships with academia and Novartis, who have the Novartis Institute for Biomedical Research (NIBR) and the Genomics Institute of the Novartis Research Foundation (GNF).  

More recent examples include Novartis and GSK, who appear to have been collaborating on research projects and the other major one that surprised many was the Merck-Astra-Zeneca hookup on specific, but related compounds with relevant cancer pathways.

Which brings me to Gordon Mills stirring talk on Monday evening. He made the case that this is the time for systems biology to make it's mark. Rather than looking at adding in a targeted therapy eg an EGFR, a MEK or whatever inhibitor (TKI or monoclonal antibody) to shut off one particular piece of a complex pathway, we need to start looking at a broader concept, which he called 'pathwayness'. That is, we have learned that cancer biology is highly complex and shutting off one aberrant or overexpressed protein, won't shut down the whole engine because either the cancer adapts or other parts continue to function and drive the tumour's survival.

For me, what was spooky about this well thought and well argued talk was that it was eerily similar as a concept to what Frank McCormack was describing earlier this year using PI3K as an example. Both McCormack and Mills are probably ahead of their time.

What we need to see is industry listening to what they have to say and start to think more strategically about what to do with all the inhibitors we already have out there for the 12 critical cancer drivers that Bert Vogelstein discussed at AACR earlier this year.  

Mills argued cogently that we actually have many of the potential tools we need to take a deeper systems biology approach to personalized medicine and by looking at each patients cancer biology we could potential develop a treatment approach relevant to them. He called this 'listening to what the patient tells us'.

This reminded me that recently, there was an article in Forbes about why personalized medicine is bunk, written by a MD at a VC firm. The article annoyed me, mainly for it's lack of critical thinking, fair balance or even a basic understanding of what is happening in medicine and clinical research. Rather than vent in the comments, I turned up at this AACR meeting and was greatly reassured that cancer research is in good hands and we have many excellent people and resources focused on the whole concept of matching treatment to a patients tumour. It will happen. In many ways the revolution has already begun; we just need to get better at it. Every failure tells us something new and important about what to do next.

We have the tools, but there are also a lot of hurdles and challenges to be addressed along the way, not least the regulatory side of things and a different way of thinking about testing and validating the ideas in clinical trials. The good news is that there is much needed activity going on behind the scenes at the policy level, as witnessed by the Cancer Caucus in DC today, where Harold Varmus is kicking off a new era at the NCI. I'm hopeful that the think tank will have open minds and the passion to change the way we think about cancer research.

 

Incyte's INCB018424 looks promising in myelofibrosis

Just before the American Society of Hematology (ASH) meeting last December, I posted an overview of the JAK2 pathway and pipeline inhibitors in development. Things have changed a bit since then, with TargeGen's inhibitor, TG101348, being licensed by sanofi-aventis and the advent of new phase I/II data being published this week in the New England Journal of Medicine on the leading compound in this category, INCB018424 (Incyte/Novartis).

Background

I loved this simple overview from Verstovsek et al., which is hard to improve on for simplicity and logic:

"Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor."

Here's what the pathway looks like, for those interested:

Source: Cell Signal

Currently, there are no approved therapies for the treatment of myelofibrosis, so using a targeted inhibitor is a worthwhile approach to determine whether any clinical benefit will result.

The Patients

In this study, patients were preselected for one of the following characteristics:

• JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis
• post–essential thrombocythemia myelofibrosis
• post–polycythemia vera myelofibrosis.

In all, 153 patients were given INCB018424 as oral therapy for a median duration of more than 14.7 months.  The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated dose (MTD).

Additional doses were also examined, with a clear rationale emerging for a 15 mg twice daily starting dose.

The Results

Skimming through the results section, my attention was immediately drawn to the following:

"61 of 140 patients with an enlarged spleen at study entry (44%) had an objective response (clinical improvement), based on a reduction of 50% or more in palpable splenomegaly within the first 3 months after therapy."

Interestingly, the response rates were highest in patients who took their therapy BID, whereas none of the patients who took INCB018424 once daily showed any clinical improvement.

The researchers went onto note:

"A total of 28 patients who received 25 mg twice daily or 15 mg twice daily (the most active regimens for splenomegaly reduction) were transfusion-dependent at enrollment. After a median treatment duration of 12 weeks, 4 patients (14%) had transfusion independence (clinical improvement according to the International Working Group) for a median duration of 20 months."

One of the many problems people with myelofibrosis experience is a poor quality of life, so it was reassuring to see some real improvement in practical real life tests.

A small proportion of the patients underwent the 6-minute walk test, with the following improvement in their ability to walk as follows:

• 34 m after 1 month
• 57 m after 3 months
• 71 m after 6 months

I couldn't find the baseline, but we can reasonably assume that it was 34 m or less, judging from this positive trend.

When considering the patients with (n=61) and without (n=11) the JAK2 V617F mutation, there was no difference in response between the groups in the patients who received the most effective doses (ie 15 mg twice daily or 25 mg twice daily). The response rates were 51% and 45%, respectively.

In addition, people with primary myelofibrosis (n=37) had a response rate of 49%, while those with polycythemia vera (n=22), 45%, suggesting that the overall response rates were in the general 45-51% range, irrespective of the type of myelofibrosis.

With regards to serious adverse events, 59 people were affected by JAK2 therapy, of whom 12 had serious adverse events that were considered to be at least possibly related to treatment. Additionally, 3 patients had transformation to AML, but whether this was treatment related, or part of the natural disease progression, wasn't clear from the article.

Insights

The improvements in clinical benefit (response rates, reduction in splenomegaly and exercise endurance) look promising enough for phase III trials to begin. Understanding the mechanisms behind the inflammatory responses and reduction in splenomegaly will be important as more research is undertaken.

In the previous post on JAK2, we discussed how inhibiting JAK2 may influence or block cytokine signalling, which is thought to be responsible for the myelofibrosis. In this study, normalisation of the inflammatory cytokines was noted with INCB018424, suggesting that JAK1 and JAK2 inhibitors may possibly have clinical efficacy in inflammatory diseases such as rheumatoid arthritis (RA).  

Indeed, a trial with another JAK2 inhibitor, INCB028050, from Incyte is ongoing in RA and has already completed recruitment.  The results from this trial may offer proof of concept for JAK2 and cytokine normalisation in inflammatory disease.

The future though, may well involve some form of combination rather than single agent therapy, as the accompanying editorial pointed out:

"One disappointing finding in the trial was the minimal effect on the burden of the V617F-mutated clone; however, this was not entirely unexpected considering the lack of specificity of INCB018424 for mutated protein. Yet, one may question whether the disappearance of the V617F-mutated clone is a reasonable end point for JAK1 and JAK2 inhibitors without causing excessive toxicity, given the essential role of JAK1 and JAK2 in the normal immune system and hematopoiesis."

It is very good news to see that a single agent JAK2 inhibitor has some early efficacy, so we can hope that the phase III trials (COMFORT I and II) will also be positive and confirm the initial phase II results when the data is available in the first half of 2011. In the long run, though, combination approaches may well produce even better outcomes.

 

References

Vannucchi, A. (2010). From Palliation to Targeted Therapy in Myelofibrosis New England Journal of Medicine, 363 (12), 1180-1182 DOI: 10.1056/NEJMe1005856

Verstovsek, S., Kantarjian, H., Mesa, R., Pardanani, A., Cortes-Franco, J., Thomas, D., Estrov, Z., Fridman, J., Bradley, E., Erickson-Viitanen, S., Vaddi, K., Levy, R., & Tefferi, A. (2010). Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis New England Journal of Medicine, 363 (12), 1117-1127 DOI: 10.1056/NEJMoa1002028

 

Sisyphus, oncology R&D and Pharma

Loved this cartoon from Hugh Macleod at Gaping Void that just arrived in my mail box:

Source: Gaping Void

In many ways, this is what drug development can look like on a day to day basis. Scientists repeating experiments, project teams holding endless meetings etc, that sometimes it's hard to see which in a portfolio of agents might actually make it through to market and which will fail along the journey.

Still, eventually, some of those small rocks reach enough critical mass (data) and actually do tip over the edge to be successfully commercialised.  

After all, that's what we all live for - the few that make it to market and make a real difference to the lives of people with cancer.

Celebrate Sisyphus today - it's not the fancy silver lures or cool new toys that makes the difference in the end, but the steadfast daily grind through R&D that eventually pays off big time for everyone.

FDA rejects the Roche Immunogen T-DM1 accelerated approval filing

Interesting news arrived in my email box this morning:

"Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned Roche will continue with its ongoing Phase III EMILIA registration study. Roche will continue to work with the FDA and expects a global regulatory submission of T-DM1 mid 2012.

The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2 positive breast cancer, who had received on average seven prior medicines, including two HER2 targeted agents."

There was a lot of excitement around the initial phase II results (one third of the women experienced tumour shrinkage, for example).  Yet, to much surprise, the application was rejected:

"In their review of the BLA, FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population."

At first reading of the press release, my thoughts centred around:

1. How could the FDA possibly reject such an application?
2. Was an SPA agreed up front?

The first question is easy to be indignant about, but what criteria were used for the trial and what does the data actually show?

Looking at the available clinical trials for T-DM1, this one looks most likely as 100 patients were required and the inclusion criteria stated:

• HER2-positive disease
• Metastatic breast cancer
• Disease progression on the last chemotherapy regimen received in the metastatic setting
• Prior treatment with an anthracycline, trastuzumab, a taxane, lapatinib, and capecitabine in the neoadjuvant, adjuvant, locally advanced, or metastatic setting and prior treatment with at least two lines of therapy (a line of therapy can be a combination of two agents or single-agent chemotherapy) in the metastatic setting
• At least two lines of anti-HER2 therapy must have been given in the metastatic setting as monotherapy or combined with chemotherapy or hormonal therapy. The HER2-targeted agent can include trastuzumab, lapatinib, or an investigational agent with HER2-inhibitory activity.

There are only two approved treatments for HER2-positive breast cancer, trastuzumab and lapatinib, plus others in clinical trials, eg pertuzumab, which was also allowed as one of the prior therapies.  All patients appear to have been refractory to at least two of these drugs, most likely trastuzumab and lapatinib.

The prior chemotherapies included anthracyclines, taxanes and capecitabine, which is quite heavy pre-treatment and includes all of the considered standards of care for several lines of therapy.  Indeed, the results of the trial presented at the San Antonio Breast Cancer Symposium last December showed that the average number of prior treatments in the metastatic setting was 7.

The others that could be used in the treatment of breast cancer include nab-paclitaxel (Abraxane), which I'm assuming would be covered in the taxane group and ixabepilone (Ixempra), an epothilone approved in by the FDA for metastatic breast cancer following progression on a taxane and anthracyclines, with or without capecitabine.

Ixabepilone is not a taxane or an anthracycline and therefore technically not covered in the inclusion criteria as a prior therapy, although some of the women would likely have received it, but not all.  It is, however, a taxane-like compound in that it targets the microtubules, as described in the PI:

"Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to B-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of aB-II and aB-III microtubules."

If that was the criteria for rejecting the trial as not truly refractory in a very heavily pre-treated setting, I would be surprised.  It's a bit of a technicality and nit-picking. Ixabepilone is not a commonly preferred treatment at all and BMS reported very low sales in 2009.  Most US physicians appear to prefer the well established taxanes such as paclitaxel, docetaxel and nab-paclitaxel rather than a synthetic taxane-like agent and probably consider it as a last resort. It is used as a standalone therapy in the refractory/salvage setting.

However, we're talking about a potential indication for a targeted agent that inhibits HER2 dimerization not a chemotherapy, so I would have thought that most of the important bases were covered by including the most common chemotherapies, trastuzumab and lapatinib in the inclusion criteria.

With regards to the latter question, Twitter chat this morning suggested that no, an SPA wasn't formally agreed upon, but Roche held discussions with the FDA that led them to file for accelerated approval. Thanks to Adam Feuerstein of The Street for being the first to answer that question.

My general opinion is that if you have an agreed Special Protocol Assessment (SPA) and meet the defined targets, it's much easier to move forward and gain approval. If you don't, things may turn into a crapshoot and it can go either way.  And that seems to be what has happened here.

The other factor that comes into play in this discussion is the ongoing discussion of the accelerated approval for Avastin in metastatic breast cancer and the overwhelming negative ODAC opinion last month.  That will not have helped, although one would like to think it shouldn't influence any decision making at the FDA.  We would probably be naive to think otherwise given the full protocol included PFS rather than OS as the endpoint.

To be fair, Roche appear to be addressing this issue, in their announcement this morning:

"Roche will amend the Phase III randomized EMILIA study in order to rigorously evaluate overall survival in addition to progression-free survival and will submit data from EMILIA to support a global regulatory submission in mid 2012."

Overall, I think it's a disappointing decision by the FDA given the heavily pre-treated population and lack of options for women who are refractory to both trastuzumab and lapatinib. Chemotherapy has not been shown to be particularly effective in HER2 disease, and by then the women generally have a poor prognosis. When you look again at the SABCS data, you find an objective response rate (ORR) of approximately 30% and a clinical benefit rate of around 40%, which is quite startling in a heavily pre-treated group.

Meanwhile, for now we'll have to wait another two years to see what the survival data looks like.  That's a rather long time for women who have failed Herceptin and Tykerb to wait for a drug that appears to have significant activity.

{UPDATE: I posted this analysis in a hurry, uncaffeinated, and in a rush to head out to a meeting.  Of course, one remembers later that SPA's apply to phase III not phase II trials, so a formal agreement wouldn't apply here. Thanks also to the two people who gently reminded me of this. Usually though, there are some discussions with FDA around the trial design for accelerated review. Essentially, in layman terms, it means patients are refractory to existing treatments for the disease concerned. Note that Roche, in their press release defined it as, "Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices)." It looks like the FDA are applying it more strictly to ALL therapies, although the number of women who might have taken ixabepilone AND be HER2-positive will likely be miniscule.  I would still maintain that refractory to all available HER2 therapies and most chemotherapies apply for the majority in this case.}

New potential targets in ovarian cancer?

Treatment for ovarian cancer hasn't changed much in the last ten years, reflecting the lack of biomarkers and biochemical targets for the disease. Chemotherapy with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel) has therefore formed the bedrock of therapy, along with other options such as gemcitabine or pemetrexed, as illustrated in the latest NCCN Guidelines.

The good news is that the use of paclitaxel-based combination chemotherapy has been shown to increase progression free survival (PFS) and overall survival (OS) in women with primary peritoneal or ovarian cancers.

While a proportion of ovarian cancers have been shown to be highly chemosensitive, a large number unfortunately fail to respond to primary taxane therapy, leading to the emergence of resistant disease.

The big unanswered questions are therefore why does this happen and what can be done about it to improve outcomes and overall prognosis?

It was with great interest that I read about the findings of a new study just published in Cancer Cell from researchers at MD Anderson (see e-link in the references below).  According to the MD Anderson news alert:

"For the first time, Salt Inducible Kinase 2 (SIK2) has been found to play a critical role in cell division and to regulate the response of some ovarian cancers to chemotherapy."

It's not often when you see the mention of both a potential target and prognostic/predictive biomarker mentioned in the same sentence as ovarian cancer, so this is huge news!  The press release went on to claim:

"Researchers found that depleting SIK2 from ovarian cancers sensitized the cancer cells to paclitaxel, a commonly prescribed chemotherapeutic agent that inhibits cell division, making the drug more effective in stopping the cancer's growth. Levels of the SIK2 protein are increased in approximately 30 percent of ovarian cancers and are associated with poorer survival in women with the disease."

The researchers analysed nearly 780 pools of siRNAs to identify proteins that alter sensitivity to paclitaxel. They found that SIK2 regulates sensitivity to paclitaxel and prevents cell division. This means that SIK2 may offer a useful therapeutic target for pipeline drugs to be developed in ovarian cancer.

What was even more fascinating was that another related article on ovarian cancer from Bast's group appeared in the same journal. In essence, they used siRNA-loaded nanoparticles to stifle a protein, Zeste homolog 2 (EZH2), which is associated with poor survival. This resulted in inhibition of angiogenesis (formation of new blood vessels) to the tumour and caused a steep reduction in the tumour burden in a mouse model of ovarian cancer.

In this study, the authors looked at human 180 ovarian cancer tumours and found that the protein was overexpressed in the tumour samples (66%) and in the endothelial cells (67%). It is relevant to note that endothelial cells line the inside of blood vessels and play a crucial role in angiogenesis.

In practice, they found that women with increased EZH2 levels in their tumours had a median survival of 2.5 years compared to 7.33 years for those without. Looking at overexpression in the endothelial cells, the difference was 2.33 years versus 8.33 years for those with normal levels.

Like me, you're probably wondering how these nanoparticles work.  According to MD Anderson:

"The nanoparticles accumulate in the cancer cell and vasculature passively as they circulate in the blood stream. Chitosan nanoparticles are so small that they can flow through tiny holes in the tumor vasculature. They also accumulate in other organs, so the researchers are working to add a targeting molecule that will limit nanoparticle uptake to tumors and their vasculature."

Targeting EZH2 may have application beyond ovarian cancer, since it been associated with the progression and spread of bladder, breast, prostate and gastric cancers and cancer of the pharynx.

All in all, a really interesting pair of papers from Bast's group, which may have clinical promise and real application to the future treatment of ovarian cancer.

 

Ahmed, A., Lu, Z., Jennings, N., Etemadmoghadam, D., Capalbo, L., Jacamo, R., Barbosa-Morais, N., Le, X., Vivas-Mejia, P., & Lopez-Berestein, G. (2010). SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer Cancer Cell, 18 (2), 109-121 DOI: 10.1016/j.ccr.2010.06.018

Lu, C., Han, H., Mangala, L., Ali-Fehmi, R., Newton, C., Ozbun, L., Armaiz-Pena, G., Hu, W., Stone, R., & Munkarah, A. (2010). Regulation of Tumor Angiogenesis by EZH2 Cancer Cell, 18 (2), 185-197 DOI: 10.1016/j.ccr.2010.06.016

Inhibition of mutated, activated BRAF in metastatic melanoma

Hot on the heels of last week's New England Journal of Medicine article on ipilimumab (BMS) comes another article on metastatic melanoma, this time from Keith Flaherty's group in Pennsylvania and Boston on BRAF inhibition with PLX4032, an exciting compound being developed by Plexxikon/Roche (see link below in the references for the article).

I've written a few posts on this interesting compound recently (e.g. here and here), for those interested in getting up to speed on the concept and data.

The basic concept is that a while back it was noticed that some tumours such as melanoma develop the V600E BRAF mutation and induce resistance or a poorer prognosis, so common sense says why not find a targeted agent to inhibit the activity to see what happened?

In the August 26th edition of the NEJM, Flaherty et al., described the updated phase I results in two phases:

• 55 patients (49 with melanoma) in the dose escalation phase
• 32 additional people with metastatic melanoma who had BRAF with the V600E mutation in the extension phase

Now, remember, a phase I trial usually seeks to define the maximum tolerated dose (MTD), which is used in the phase II studies and looks at the general tolerability and side effects.  Efficacy is not the primary end point, but of course, we all secretly look at the activity to see if there is any sign of a response!

First things first.  After some palaver with the crystalline formulation, it was finally settled on a "micro-precipitated bulk powder" since that offered superior bioavailability. I'm paraphrasing a bit and taking liberties here, but no doubt regular readers will sense my excitement and tendency to skip to the bottom line and find out what it all means, although we have all been there with those kind of challenging problems, especially as they add delays and frustrations all around!

Anyway, as a result of these changes, the final recommended dose that emerged for the phase II studies was 960mg BID, with increases in the dose limited by grade 2 or 3 rash, fatigue or arthralgia. These kind of side effects are fairly typical of oral TKI's and very different from what we saw with last week's NEJM article on immunotherapy with ipilimumab in a similar population.

Potentially, the biggest concern is the appearance of squamous-cell carcinoma that appeared in 10 of 32 patients (31%) in the dose escalation cohort.  While normally well differentiated and of low invasive potential, it is something to note.  The authors noted that recent data earlier this year (see references below) suggest BRAF inhibitors can activate the MAP kinase pathway in cells that lack a BRAF mutation and may explain some of the peculiar side effects seen with PLX4032.

Previously, Flaherty et al., reported nine responses in the second PLX4032 cohort and median PFS of 6 months.  For comparison with the updated data, see the last report before reading on. Over half of the people in both cohorts had received 2 or more therapies, so these are a mix of relapsed and refractory patients:

• In the first cohort of 55 people, there were 16 with the BRAF V600E mutated melanoma and received 240mg or more of PLX-4032.  The efficacy?  Well, there were 10 partial response and 1 complete response (69%).
• In the extension cohort of 32 people, 24 were partial responders and 2 had a complete response (81%), which is pretty impressive all around.  No wonder Dr Flaherty was very excited when interviewed for an article in the NY Times earlier this year!

My first reaction was slight disbelief, after all, this is a very difficult to treat and highly aggressive disease, thus sadly, people do tend to relapse early. In short, if there were three cancers I absolutely wouldn't want to get, this would be one of them.

On closely checking the data carefully including the 81% response rate in the second cohort (yes, it's correct!), I noticed that the researchers reported across all patients in the phase I study, the median progression free survival (PFS) was now improved to 7 months.  That means that 50% did worse and 50% did better than 7 months, way better than one might expect so early in a trial.  I did double check again and pinch myself, as it was late on Tuesday night when I penned the draft.

If you are interested in this area, do check out the link to the article below because the water plots and anti-tumour responses over time are well worth looking at, especially as some people are clearly achieving responses approaching a year, despite having advanced disease.

"Responses were observed at all sites of the disease, including the bone, liver, and small bowel."

Yes, it is still very early, but how awesome is it to read that?

As an aside, a number of readers have written asking why sorafenib hasn't shown to be effective in melanoma, despite inhibiting BRAF.  Flaherty et al., had an answer for that. They suggested that  because it also inhibits other pathways, it may well be that the non-BRAF effects of the drug mediate side effects that limit the ability to achieve enough drug concentration and thus the drug concentration isn't high enough to effectively inhibit the V600E BRAF mutation.  An interesting theory that also speak to the idea that several specific inhibits may be more effective that more promiscuous multi-kinase inhibitors.

The good news is that for now at least, we seem to be on the right track with PLX4032 and ipilimumab in metastatic melanoma.  It will be interesting to see what the mechanisms of resistance are down the road, and whether we have some options in the works for either combination or sequencing of different targeted agents for this disease.

 

Flaherty, K., Puzanov, I., Kim, K., Ribas, A., McArthur, G., Sosman, J., O'Dwyer, P., Lee, R., Grippo, J., Nolop, K., & Chapman, P. (2010). Inhibition of Mutated, Activated BRAF in Metastatic Melanoma New England Journal of Medicine, 363 (9), 809-819 DOI: 10.1056/NEJMoa1002011

Heidorn, S., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J., Springer, C., & Pritchard, C. (2010). Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF Cell, 140 (2), 209-221 DOI: 10.1016/j.cell.2009.12.040

Poulikakos PI, Zhang C, Bollag G, Shokat KM, & Rosen N (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464 (7287), 427-30 PMID: 20179705

Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B., Anderson, D., Alvarado, R., Ludlam, M., Stokoe, D., Gloor, S., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K., Jaiswal, B., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L., & Malek, S. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth Nature, 464 (7287), 431-435 DOI: 10.1038/nature08833

Is the cancer research paradigm changing?

Over the weekend, a reader (a scientist in translational medicine) kindly sent me the link to a paper on PARP inhibition and asked:

"Is this a sign of the new wave of oncology drug development? Rather than basing treatment on cancer tissue type (eg. breast, prostate, colorectal), the underlying genetic mutation regardless of tissue of origin will be used for targeted agents. Imagine a randomized Ph2 trial of all BRCA1/2 deficient patients vs. non-mutated patients. Of course, this same rationale would have not worked for K-ras mutation patients with EGFR inhibitors in NSLCLC vs. Colorectal."

My short answer is basically, yes.

It may, however, take a while for this to evolve fully clinically, but you can already see the movement starting at AACR meetings, where they organise topics around pathways.

Unfortunately, at ASCO and ASH things are still discussed in cancer specific sessions, which I increasingly find more difficult to follow and plan for.  For example, suppose I'm interested in pipeline PI3-kinase inhibitors.  There might be something at 8.45am in North Hall A on one tumour type, but another at 9.00am on the other side of the convention centre in Room 330A in the East Building on a different cancer.  Ugh, no wonder we all joke about the #blisterwalks and increasingly lack of time for networking at conferences - we're all too busy dashing between sessions in highly frazzled, rather than leisurely fashion!

I do believe the translational medicine and scientists are right in the pathway over tumour approach though and have been advocating for a pathway driven approach for some time on this blog.  If you haven't read it yet, the short four part series on pathways and treatment in lung cancer earlier this year may be useful (see posts here, here, here and here) for examples of how lung cancer specialists (translational scientists and clinicians together) are leading the way in pioneering this concept.

In the example my correspondent gave, PARP inhibitors are being tested in BRCA1 and 2 positive tumours for olaparib (AstraZeneca), i.e. breast and ovarian cancers, whereas looking at the clinical trials database, Sanofi-Aventis are taking a more traditional approach with iniparib (BSI-201) and looking at different tumour types without the BRCA mutation.

Meanwhile, Abbott are also taking a very creative approach with their PARPi, veliparib (ABT-888), by not only looking at BRCA-positive cancers but also getting involved in the I-SPY2 neoadjuvant trial in breast cancer, which was a very smart move in my opinion.  You can read more about the agents in that groundbreaking study protocol from the interview with Dr Sue Desmond-Hellmann.  It's a great example of seeking to treat women diagnosed with early breast cancer with different therapies based on their underlying biology of their tumour, thereby enabling us to see what works and what doesn't earlier than we would normally.

It's going to be interesting to see how all these different R&D strategies work out commercially.  For the record, I think olaparib may well be the first targeted agent to show benefit in patients with cancers that result from BRCA1 or BRCA2 gene mutations.  That's quite exciting in itself, and hopefully, AZ have also learned considerably from the mistakes made with gefitinib (Iressa).  Whether the specific targeted and scientific approach will win over a more commercial strategy, we'll have to wait and see.

The advantage of a specific targeted strategy is that if you get the biomarker right, the people who are most likely to respond to a therapy will more likely receive it plus the response rates and outcomes, in theory, should be better.  Those who are less likely to respond are spared of the systemic exposure and false hope.

Some marketers will also argue that it may also, however, limit your market commercially, but my argument is that a highly targeted agent will actually get more prescriptions in the long run because it will be easier for an oncologist to choose therapy accordingly and good results reinforce usage and loyalty. Standing out from the crowd with superior efficacy in a well defined population is a much more elegant approach to this marketer :)

In a catch-all strategy, you may believe that by targeting a bigger market you will win more commercially, but the risk is that the response rates will be lower in a heterogeneous population (the wins and losses will cancel out to some extent). Thus if a competitors more targeted approach actually works, they win and you have no biomarker to answer with to allow oncologists to choose between the agents. Increasingly, they are reluctant to treat everyone willy nilly because of high costs, whether in terms of patient co-pays for oral therapies or more draconian restrictions for iv therapies from insurers.

Developing targeted agents is very different from traditional chemotherapy. Oncologists now want to know who is most likely to respond to a given therapy and treat those subsets accordingly rather than randomly treat and expose everyone to not insignificant systemic side effects of therapy.  One of the best concepts we have right now is to have multi-functional research and clinical practice that marries identifying the key pathways and mutations with targeted therapies designed to knock out or shutdown the aberrant cell signalling.

We have a ways to go, but the tide is already turning.

 

Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, & Carmichael J (2010). Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet, 376 (9737), 235-44 PMID: 20609467

Michael Douglas has throat cancer?

This afternoon I was chatting with a Pharma friend via IM when she sent me a surprise link:

Michael Douglas to Undergo Chemo for Tumor in Throat Cancer

Oof, he was one of my favourite actors growing up as a child - I just loved the Streets of San Francisco!  He also made Gordon Gekko famous in Wall Street.

There's a lot of throat cancer in the news lately.  The most recent was Alex Higgins, the incredible Irish snooker player who was a truly sensational player from my childhood.

I wrote about him recently here.  Be warned - the before and after pictures are a little shocking.

A recent photo of Michael Douglas on ABC News was also a shock, as he looks much more haggard than I remember :(

Lately, I've been watching re-runs in the evenings of the classic gritty but violent English detective drama from the 1970's, The Sweeney, starring John Thaw and Dennis Waterman.  Idly clicking through to IMDB, I wondered what had become of Thaw, who also starred in Inspector Morse, only to discover that he, too, had passed away in 2002 - from throat cancer.

What is common with these three men? Well, alcohol and cigarette smoking contributed no doubt, as the American Cancer Society lists both of these as two of the potential risk factors for laryngeal and hypopharyngeal cancer, the medical term for throat cancer, which is often referred to as oesophageal cancer in the UK.  The median age of diagnosis is round 65, so Douglas, Thaw and Higgins were all around the peak of the age range bell curve (60-65).

Hopefully, Michael Douglas's cancer has been picked up early and he will make a full recovery from chemotherapy.  I really hope so, it's very sad to see one's favourite childhood heroes dropping :(

 

Photo Credits:

Manny the Movie Guy

The Sweeney Info

Circulating IGF-I levels and pancreatic cancer risk

A couple of new papers will be reviewed this week, thanks to everyone who sent in links and suggested topics for discussion.  I'll try and cover one a day, although there were so many worthy of consideration!  Please do keep the ideas coming, they are much appreciated.

For today, here's one I came across last week in one of the American Association of Cancer Research (AACR) journals, Cancer epidemiology, biomarkers & prevention. The article discusses the evidence surrounding overexpression of insulin-like growth factor (IGF)-I and how that is implicated in human pancreatic tumours. To look at this concept further, the researchers decided to use longitudinal data from a study involving 187 cases and 374 controls, a not insignificant number as a starting point:

"We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk."

For those needing some background, I've covered the IGF pathway and some of the therapeutic inhibitors being developed in cancer before (see here, here, here and here for examples).

Michael Pollak, one of the authors from McGill University in Montreal, is a recognised authority on the subject and gave a fascinating talk on the science and biology behind the topic at the AACR Lung cancer meeting back in January this year. It's a particularly interesting pathway, not only because of the potential for cross-talk between pathways, but also feedback and feedforward loops, especially with the insulin receptor (IR), as Pollak elegantly illustrated.

It was therefore with great curiousity that I downloaded and read the paper (see the clickable journal link in the reference below), wondering what they found in the broader study.  Essentially, they concluded that:

"A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which may be a risk factor for pancreatic cancer."

Thus, rather than the absolute levels per se, the ratio may turn out to be a useful biomarker of the disease because the individual levels were not found to be helpful by the researchers, who:

"confirmed the nonsignificant associations for IGF-I, IGF-II, and IGFBP- 3 and risk of pancreatic cancer from previous studies."

As many of you know, pancreatic cancer is rather nasty, typically being diagnosed late because the symptoms can be subtle to detect and diffential diagnosis from other conditions associated with general malaise is hard.  A new biomarker would be clearly be helpful, although the findings will need to be validated in future large scale longitudinal studies or from pooled analysis from other prospective trials.

Mind you, this research on pancreatic cancer reminded me of the phase I Merck study in the same tumour type, reported earlier this year, with a combination of different therapies including IGF-1R and EGFR inhibitors.

As far as I can remember, Merck also included the use of metformin in the protocol to manage hyperglycemia, which would also potentially block the IGF-1R - IR feedback loop seen in the figitumumab trial.  Still, it would be interesting to know whether the IGF-I/IGFBP-3 molar ratio and free IGF were higher in the people with pancreatic cancer in that study.

Clearly, if IGF-I/IGFBP-3 turns out to be a valid biomarker of disease risk then it may be possible to identify, monitor and ultimately treat people with pancreatic cancer earlier, as well as develop better pipeline drugs, since we learn more about the biology of the disease in the process.

That can only be a great thing in the long run for improved outcomes.

 

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371

Chemoprevention in Prostate Cancer - do 5alpha-reductase inhibitors make things worse?

There's a lot of media coverage today surrounding use of 5alpha-reductase inhibitors such as finasteride (Merck) and dutasteride (GSK) and their generic equivalents for chemoprevention of prostate cancer following publication of a study on finasteride by the American Association of Cancer Research (AACR) and one earlier this year on dutasteride in the New England Journal of Medicine (see references below for sources and the journal articles).

So what do these drugs do?

The drugs in the 5alpha-reductase class were developed for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

• Improve symptoms
• Reduce the risk of acute urinary retention
• Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

Fair enough, but how does this relate to prostate cancer?

Well, testosterone is the major circulating androgen in men and is converted to the major intracellular androgen, dihydrotestosterone, by steroid 5alpha-reductase isoenzymes, designated as type 1 and type 2.  Finasteride inhibits the type 2 isoenzyme, whereas dutasteride inhibits both.

Many of you will be aware that in early stage prostate cancer, most men are hormone sensitive and respond to androgen deprivation therapy (ADT), which effectively acts as chemical castration to suppress the growth of the tumour of the prostate.  Later, when castration resistance sets in (CRPC), the disease is more advanced.  These days, if they are asymptomatic or mildly symptomatic, then a vaccine called sipuleucel-T (Provenge) can be considered or if metastatic and symptomatic, then chemotherapy with docetaxel (Taxotere) can be considered as a first-line option or cabazitaxel (Jevtana) after docetaxel has failed.

The goal of using the 5alpha-reductase inhibitors early was therefore to prevent or at the very least delay the development of malignant prostate cancer, essentially reducing the risk of developing the disease later.  Several studies have been published over the last decade to answer this question.

The big question is does this approach actually work?

My thinking was if it was that obvious, then surely urologists and primary care physicians would be rushing to prescribe either therapy?  Trouble is, they're not, as this succinct AACR press release shows.

One of the problems is that the original Prostate Cancer Prevention Trial (PCPT) study back in 2003, a large randomized controlled trial consisting of 18,000 men, appeared to have conflicting results, since it showed:

• a 25 percent reduced risk of prostate cancer.
• a 27% increased risk in high-grade tumours, which was highlighted in the accompanying editorial.

This fact seems to have created doubt and concern amongst urologists and PCP's.

Subsequently, there have been other reported studies with finasteride in 2008 (reanalysis of the 2003 data) and with dutasteride in the NEJM earlier this year, suggesting in both cases that the risk did not exist.  The doubt, however, still lingers as the AACR press release highlighted:

"64 percent of urologists and 80 percent of primary care physicians never prescribe finasteride for chemoprevention.

When asked for reasons for their decision, 55 percent said they were concerned about the risk of high-grade tumors and 52 percent said they did not know it could be used for chemoprevention."

Another issue is the conflicting consequence of PSA suppression, which is still used by many urologists as the main biomarker for diagnosis and ADT treatment.  The NEJM editorial earlier this year noted the challenge:

"Among men without cancer, both finasteride and dutasteride treat lower urinary tract symptoms, produce dramatic prostate shrinkage, and reduce serum levels of PSA by 50% or more.

However, for the patient who believes that he is taking a drug to prevent prostate cancer, this decline in PSA level can lead to a false sense of security."

Why is this?  The editorial went on to explain:

"Data from the PCPT indicate that finasteride produces a progressive suppression of PSA for the duration of treatment. To estimate what the “true” PSA level would be if finasteride were not taken, it is necessary to multiply the PSA level by 2.0 for the first 2 years, by 2.3 for years 2 through 7, and thereafter by 2.5.

However, if the PSA level ever begins to rise at all, a biopsy should be performed, because with an increase in PSA level, the risk of cancer is increased by a factor of 3 and the risk of high-grade disease is increased by a factor of 6.

In the Finnish study, men who received finasteride for more than 4 years had a risk of high-grade disease that was increased by a factor of 2.6."

After reading all of the evidence in the various studies (cited below), I can see why physicians might be:

1. Confused
2. Concerned

It's hard to make solid sense of the real impact of all the research, even as an unbiased scientist given the data that has emerged.  My overall takeaway from all the articles was as follows:

• Dutasteride and finasteride do not prevent prostate cancer.
• They do shrink tumours that have a low potential for being lethal.
• They do not reduce the risk of a positive biopsy in patients who have an elevated PSA level or an abnormal digital rectal examination.
• Use of these drugs for prevention may be controversial because PSA levels are suppressed, giving a false sense of security.
• If prostate cancer develops, the diagnosis may be thus delayed (by artificially low PSA levels) until they have high-grade aggressive disease that may be more difficult to cure.

My final observation is that perhaps we should be monitoring other markers of disease such as circulating tumour cells (CTCs) in the blood rather than PSA. Whether this would be a better measure of disease or not remains to be elucidated, but would certainly be worth looking at in future studies to see if it is a more accurate biomarker in early prostate cancer.

 

Hamilton RJ, Kahwati LC, & Kinsinger LS (2010). Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699373

Andriole, G., Bostwick, D., Brawley, O., Gomella, L., Marberger, M., Montorsi, F., Pettaway, C., Tammela, T., Teloken, C., Tindall, D., Somerville, M., Wilson, T., Fowler, I., & Rittmaster, R. (2010). Effect of Dutasteride on the Risk of Prostate Cancer New England Journal of Medicine, 362 (13), 1192-1202 DOI: 10.1056/NEJMoa0908127

Walsh, P. (2010). Chemoprevention of Prostate Cancer New England Journal of Medicine, 362 (13), 1237-1238 DOI: 10.1056/NEJMe1001045

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, & Coltman CA Jr (2003). The influence of finasteride on the development of prostate cancer. The New England journal of medicine, 349 (3), 215-24 PMID: 12824459

Lucia, M., Darke, A., Goodman, P., La Rosa, F., Parnes, H., Ford, L., Coltman, C., & Thompson, I. (2008). Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention Cancer Prevention Research, 1 (3), 167-173 DOI: 10.1158/1940-6207.CAPR-08-0078

Murtola, T., Tammela, T., Määttänen, L., Ala-opas, M., Stenman, U., & Auvinen, A. (2009). Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial British Journal of Cancer, 101 (5), 843-848 DOI: 10.1038/sj.bjc.6605188

Tufts and raising funding for pediatric cancer research

This year I'm participating in the 14th Annual Cycle for Life on Saturday 11th September, which benefits the Floating Hospital for Children's Cancer Center. The basic idea is that the fundraising from the riders provides direct support for young patients and their families.

The organisation is based at Tufts Medical Center and offers a unique approach, which appeals to me:

"The pediatric cancer program at Floating Hospital for Children offers complete hematology and oncology services for children.  Floating Hospital physicians have developed novel protocols for the aggressive treatment of cancer, including autologous bone marrow transplantation and new approaches to administering chemotherapy.

Floating Hospital for Children's Cancer Center stresses a team approach to the management of pediatric cancer patients, working closely with pediatric surgeons and radiation oncologists.  The Center has received national recognition for its innovative patient and family support programs and provides state-of-the-art cancer treatment."

Source: Cycle for Life

Over the last couple of years, my Twitter buddy Alicia Staley has organised a team and off they go in their free time one Saturday morning in the fall, 25 or 50 miles round Marblehead, Massachusetts.

The last two years have seen a bit of rain, so I'm hoping the weather Gods will play nicely this year since I rashly agreed to join the Staley's Riders team, as did Marian, one lunchtime when we all met up in NY :).

To date, I'm about a third of the way towards my target, so if any of you readers or your organisation would like to chip in for a good cancer cause, here's the link.

It will be interesting to see how effective social media is at helping to fund raise.  All donations are warmly appreciated in advance!

 

Are people with cancer 'smoothened men'?

Wednesday afternoon humour:

The 'smoothened men' bit on the left hand side gave me much amusement when looking at the Wordle of most frequently used words on this blog lately!