Yesterday was a travel day but thanks to gippy wifi and a packed day, I didn't have the opportunity to post about some interesting articles on prostate cancer published in the NEJM, which I read and digested on the train up to Boston. Now that the embargo has lifted, we can all talk and write about the data publicly.

Kantoff et al., have reported the full results of the IMPACT trial data for sipuelucel-T (Provenge) from Dendreon (a client), which led to the vaccine being approved by the FDA for the treatment of asymptomatic prostate cancer recently.   The results are not new and contain no surprises as they are already well represented in the prescribing information (PI), which are available online for anyone to read and have been presented ad nauseum at recent meetings at the American Urology Association (AUA) and American Society of Clinical Oncology (ASCO).

For those who missed the meetings, the data can be summarised by the following quotes from the article:

"This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group." 

"The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group." 

"Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache."

What can conclude from this is that the vaccine helped men with asymptomatic prostate cancer live longer without the known significant toxicities seen with chemotherapy such as alopecia (hair loss), severe myelosuppression, neutropenias, anemias, febrile netropenias and infectious complications. That would be a win in most people's books because people want to know whether their relative with cancer will live longer, feel better than they do and have a reasonable quality of life with their families. The price might be a bit of a sticker shock, but insurers seem to be covering it to date without any major hiccups.

The accompanying editorial, however, from Dan Longo, a cancer researcher and Scientific Director, National Institute on Aging, National Institutes of Health in Maryland, was probably well meaning, but rather surprising and a little harsh at times.

Science is about the pursuit of truth and in this case, finding out whether men with an advanced cancer would live longer, which they clearly did, so to grumble about the lack of tumour shrinkage is a little odd. Oncologists have for years focused on this as an indication of response rate through a measurement system known as RECIST although whether the patient lived any longer was somewhat moot.  In Longo's editorial, he noted:

"It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression."

This is rather old school thinking and as we develop new therapeutic approaches, the end points and surrogate biomarkers may well change.

There have been far too many studies in cancer that showed that traditional chemotherapy could shrink a cancer (great) while toxically poisoning everything in its wake as well (not so great), making many of us wonder whether this was actually a useful approach if survival wasn't impacted. By this, I mean are we measuring the right thing in the first place? 

In full disclosure, my own Father passed away from this disease 10 years ago this month, so it possible that I'm biased in my thinking have gone through his experience with him.  It was a very stressful time for all of us, him especially, although he held up well and maintained his dignity until the end.  Still, I think I would rather know that a new therapy would help a male relative of mine lived longer (improved overall survival) and felt better (less sickness and pain). Then we could all enjoy their last few years together in dignity with quality time than go through the hell that is chemotherapy, which he chose not to do because after many discussions, because if it wasn't going to cure him he saw no point in putting my Mother through that agony.

Sometimes, we need a more humanistic approach to oncology and to remember that these are people's lives we are talking about, not a number on a stat sheet. Tumour shrinkage?  "Pshaw, what does that mean?!" was my Dad's cynical reaction.  Looking back, he was instinctively right.

Another question that was raised in the editorial was the study design, ie was the control group an ideal one? Well, to be fair the time for input into those issues is during the protocol design stage when many people's input is sought before a trial even begins enrolling. Grouching about it after the event seems a little churlish at best. 

Could the control group have experienced some stimulatory effect?  Possibly, but then when you look at the data, the survival time is not out of kilter with those from other control groups previously reported versus chemotherapy who mostly received best supportive care, ie usually pain medications and growth factor support. Perhaps had that approach been taken the difference between the control group and the sipuleucel-T group would have been even greater.

"As the authors point out, differences in subsequent treatments (e.g., docetaxel) do not appear to account for the survival differences, but methods for assessing such effects are imperfect. New prognostic variables such as statin use, the duration of the first off-treatment interval, circulating tumor cells (as assessed as EpCAM+CK+CD45− objects), and new prognostic algorithms may need to be accounted for in assessing therapeutic effects."

Well quite, but I'm sure we'll hear more about further meta analyses of the data at some point. There are a number of other vaccines in phase II/III trials and as we learn more about how this therapeutic approach works, which markers to measure and what impact they have on both the immune system and the natural course of the disease, so our scientific and clinical knowledge will improve and hopefully, patient outcomes as well.

Promising phase II data doesn't always translate into significant phase III data, as we have seen more compounds and vaccines than I remember over the years. For now, we have two new therapy options for men with prostate cancer at different stages of the disease, more choice can only be a good thing, as is having a active pipeline for treatment of prostate cancer, offering hope for many that progress is being made after years of stagnation.

{UPDATE: I spotted Adam Feuerstein's (The Street) and Matthew Herper's (Forbes) excellent articles on this topic after writing this blog post, so they are linked for further information and background reading for those interested.

Kantoff, P., Higano, C., Shore, N., Berger, E., Small, E., Penson, D., Redfern, C., Ferrari, A., Dreicer, R., Sims, R., Xu, Y., Frohlich, M., & Schellhammer, P. (2010). Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 411-422 DOI: 10.1056/NEJMoa1001294 

Longo, D. (2010). New Therapies for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 479-481 DOI: 10.1056/NEJMe1006300