If you would like to subscribe to this blog, click this link and subscribe on the left of the home page. A new article appeared this week with further fuel for those on the side of intervention (and by implication, pro-screening). Let’s remember before we get started, that the two largest trials of screening vs not screening did not show a very big impact, if any, on finding and treating prostate cancer. Moreover, that treatment is toxic to many men who may not have needed it.
The study is about men who HAVE prostate cancer and are randomized to surveillance versus surgery. This is different from the conundrum of screening. These guys were “caught” by whatever means via a biopsy that found cancer. In the NEJM article from Scandinavia, 695 men diagnosed between 1989-99 were randomized to watchful waiting vs. prostatectomy. Their mean age was 65 and 88% of the men had palpable tumors, different from the more common T1c (PSA only) detected in the current era. Here’s a sobering fact: by 2012, 64% of them were dead. Argh….the end is near!
What we care about is their quality of life and how much of that death was attributable to prostate cancer. We are all going to die of something….just don’t torture us please. As regards death, 63/347 (18%) men in the prostatectomy group died from prostate cancer while it was 99/348 (28%) of the surveillance group. However, the overall death rate was 56% vs 69%, so more men in each group died of something else. There are many kinds of additional analyses in the study, including the death rate from low, intermediate, and high risk cancers, effects of age, time on hormonal therapy, and so forth. The benefit of early surgery seems to be greatest in men under 65 with intermediate risk (Gleason 7) cancers. As regards quality of life, more men had metastases in the surveillance group and as the authors state, “The cumulative incidence of the use of androgen-deprivation therapy at 18 years was 42.5% in the radical-prostatectomy group and 67.4% in the watchful-waiting group (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3)” My conclusion is that men who are younger (you pick the age…) and have higher grade tumors (any finding of Gleason 4) are probably better off electing treatment than watching. It is certainly possible that surgery or radiation therapy are equally good choices, but that is not addressed here.
My conclusion is that men should still think carefully about stopping screening as they near 70 unless their parents lived into their late 80′s or 90′s and they enjoy superb health. If they participate in screening and are found to have a Gleason 7 or higher cancer, they should be treated. Those thoughts are not new. The studies also support treatment for lower risk patients, but the preservation of quality of life (potency, continence) and lower impact on the development of metastases or dying, make the decision much tougher.
Long long ago, I had just finished my fellowship in medical oncology and moved from Boston to Denver. In the lab, I was working on an obscure enzyme that seemed to differentiate leukemia from normal cells, cystathionase. In the clinic, we had very few clinical trials, so I wrote a cold call letter to 10 different pharma companies. Only TAP Pharmaceuticals wrote back. They had developed a new drug that ultimately became Lupron, and we had the opportunity to participate in all of the trials that led to its approval. The biggest shock I had in that experience was the cost that TAP charged, although by today’s drug standards, I guess it was a bargain.
A few years later, we were asked to participate in the trials that led to approval of goserelin, or Zoladex™. My anticipation was that if approved, the costs of both drugs would drop as the companies competed for market share. It didn’t happen. There are of course many reasons, the greatest being that physicians generally didn’t worry too much about how much a drug cost….insurance or Medicare picked up the cost. Instead, the two companies competed with favors to physicians. Many urology practices made huge profits from the mark-ups in drug, and ultimately TAP paid one of the largest fines in history for unethical practices.
With the new drugs, notably abiraterone and enzalutamide, there have yet to emerge competitors that are approved. The drugs both work on the androgen stimulation axis, but via different mechanisms I have covered elsewhere. Each is incredibly expensive, around $6000/month. But beyond the above “no compete” story, I am concerned that competitors may never even reach the “podium” to provide competition (whether financial or in marketing). The reason is that prostate cancer is inherently slow and that the FDA requires survival as an endpoint. Add to this, that if a patient is on a new drug with some modest improvement in survival, this can be overwhelmed by patients going onto one of the other actives after they progress (rising psa or new lesions on scans) that will make it difficult to see the contribution to survival by “new drug”. The placebo patients will benefit equally from the new approved drugs. This may well be what happened to orteronel, (TAK 700) that was reported to have missed its survival endpoint needed for approval at last weeks ASCO GU meeting. Although I would like to think that approval would result in lower prices for all of the new drugs, the experience described above makes me skeptical. So how about a new approval process? If a drug is clearly (and I’m not judging whether orteronel is or isn’t the equal of abiraterone here) a comparable, approve it IF the company will provide its “me too” drug to patients at a substantially reduced price. There would still be an advantage for companies to race to be “first to market” and they would enjoy the high profits of being the winner with a new category of drug. On the other hand, competitors could still expect to enter the arena and do well, perhaps competing for first place by price rather than some minor difference in side effects or similar. HOWEVER…this assumes that Medicare, physicians, and insurers would prescribe based on cost savings, something currently forbidden by Medicare but allowed in the VA administration. And then there would be the fancy TV ads trying to convince patients one drug is better than another based on sitting in bath tubs and looking at sunsets….
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These two questions are among the most commonly asked in my clinic, particularly from patients who are recently diagnosed with prostate cancer. Numerous studies have been done on adding various supplements to the diet, and anyone who reads this blog has already seen my thoughts on pomegranate, milk thistle, green tea, soy, etc. You can find dozens if not hundreds of references and small studies purporting to show a beneficial effect on cancer.
Further, there are studies that show the likelihood of cancer patients using supplements is higher among those with the most education (and probably with more disposable income). I have contributed my own body to this question by participating in the Physician’s Health Study II. For more than a decade I faithfully took first 3, then 2, then one pill daily that was either placebo or a vitamin/multivitamin. The results of this study so far are a big, fat ZERO. Moreover, in looking at this study along with many others, it is very hard to see any benefit from most supplements. An exception might be Vitamin D since those of us who are cancer phobic do such a good job of wearing sunscreen. And patients on androgen suppression may benefit from calcium supplements, although this, too, is controversial.
In the most recent Annals of Internal Medicine, there is further evidence of futility in the 28 BILLION dollar/year vitamin industry. “This review included 26 studies (24 randomized, controlled trials and 2 cohort studies) that examined the benefits and harms of using vitamin and mineral supplements for primary prevention of CVD, cancer, or all-cause mortality in healthy individuals without known nutritional deficiencies. We found no consistent evidence that the included supplements affected CVD, cancer, or all-cause mortality in healthy individuals without known nutritional deficiencies.” The accompanying editorial is entitled “Enough is enough: Stop wasting money on vitamin and mineral Supplements”
So, you can read it and weep, or save your money and buy more veggies and exotic fruits and nuts and enjoy your diet. It’s all up to you (and maybe how many years you went to school after you “grew up” and could critically analyze data). Remember, the more schooling, the higher the tendency to buy/take vitamins. Welcome to dreamland! What you CAN do is exercise and avoid fat.
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Men who have metastatic prostate cancer at presentation are now quite rare. In the days before psa screening (which clearly works, but picks up way too many patients with low grade disease whom we don’t need to find…see multiple blogs elsewhere) we used to see 70 year old men come in with new bone pain, and then it turned out to be prostate cancer. In any case, since the discovery of the taxanes (docetaxel and cabazitaxel), the first drugs to prolong survival after castrate resistant disease sets in, we have all wondered if they were used earlier whether there would be an advantage. The earliest they could be used would be immediately after surgery – but the trial that attempted to study this was abandoned after 2 years because not enough men/doctors would sign their patients up. (see blogs on this elsewhere as well)
So… what about using taxanes at the time hormone therapy is first started? (This could be after surgery or radiation…many years…or when a rare patient first presented with metastatic disease. They HAD to have metastases, however, not just a rising psa. The study (which we called CHAARTED – and my colleagues at CU and I offered this trial to many patients and we treated quite a few who were willing) randomized to hormone treatment alone vs hormone treatment (ADT) combined with 6 cycles over 18 weeks of docetaxel. The trial has been reported now in preliminary form and shows significant improvement in survival in the men who received the docetaxel. This is really a trial between “early vs late” docetaxel, since I am relatively certain the men who got ADT alone would have eventually received docetaxel as well when they became castrate resistant. This is a BIG deal. It means that we have a shot at eliminating some of the cells that don’t fully die off from ADT alone right at the start. It also paves the way to go back and look at doing similar treatment right at the time of surgery or radiation, like we tried to do a decade ago. And if we add the newer hormonal agents (abiraterone, enzalutamide, Tak700, etc) up front, the results could be even better (please lobby the companies who make these agents to provide them for free to men willing to be treated in such trials)
Hats off to the men who agreed to this practice changing trial and to their physicians. And congratulations to my good friend Chris Sweeney who headed up the trial. (He and I have had some great times together over the years) Gentlemen, this is what our sisters did to advance breast cancer treatment 30 years ago! Don’t ever tell me it isn’t good to sign up for randomized trials, or that just doing what we always have done is adequate. Support research! Only 4% of U.S. cancer patients participate in clinical trials. Let’s work together to beat this disease. Happy holidays!
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For journal club last week, I selected an article that looks at length of telomeres as a prognostic variable for prostate cancer. Telomeres are DNA protein complexes that are added to the tips of chromosomes by an enzyme, telomerase, that carries its own little RNA unit and was involved in one of the authors (Elizabeth Blackburn) of the story below winning a Nobel prize. As you get older, the length of your telomeres shortens, eventually giving rise to loss of important chromosomal information that can lead to cancer. In the journal club article, it was found that men who had shorter and more variable telomere length in their prostate cancer or the surrounding tissue, had a higher chance of developing metastases or dying from their disease. Of course this is bad news, and you might think there is nothing you can do about it. Not so fast….
Blackburn and her colleagues at UCSF have been studying men with prostate cancer to see if exercise and diet can influence telomere length. In a 2008 study, they found that peripheral blood cells had increased telomerase after 3 months of improved diet and exercise intervention. In their most recent study, they find that the continuation of the diet/exercise program results in actual increases in the telomere length in the peripheral blood cells. Since these are men with low risk prostate cancer who are being followed on a study with active surveillance, we will also be learning how such improved life style affects other genetic changes in serial biopsies of the cancers.
For now, the bet is that (as usual) you will benefit from increasing your exercise program, dropping red meat from your diet, and probably watching less football and doing more hiking this week with your family as you celebrate Thanksgiving. I’m just saying….
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One of the most common complaints my patients have is fatigue. There is little doubt that being de-androgenized leads to loss of muscle strength. But there are many other causes: aging, cancer, chemotherapy, anemia. Any/all of these have been studied in relationship to fatigue and fighting them can sometimes produce excellent results, most of which have been documented in various studies. Take anemia. Often I find that pca patients on hormonal therapy will drop their hemoglobin from the 14-16 normal range down to around 12. Transfusion at 12 seldom produces any difference in fatigue or exercise tolerance. However, it is important to recognize this phenomenon and not have your doctor go chasing vitamin deficiency (especially iron) unless there are other indications like a low red cell volume. You need T in order to maintain a healthy level of hemoglobin. No T, and PSA will go down, but so does the red cell count. Transfusion at hemoglobin below 10 is often helpful.
As for fatigue from inactivity or other causes, my thanks to Medscape for providing some interesting articles on which to blog. In this case, a recent article brought to our attention describes a small randomized trial of Qigong versus stretching in fighting fatigue and emotional problems in patients with prostate cancer. Qigong is described in wikipedia as being “a practice of aligning breath, movement, and awareness for exercise, healing, and meditation”. In the study, 40 fatigued prostate cancer survivors were randomized to stretching classes versus qigong classes, and the latter group had a lower dropout rate as well as greater improvement in a “fatigue and distress” questionnaire. Of course let’s remember that the class leaders probably had lots more suggestive language about “letting the good humors in and bad humors out” during all the breathing exercises than the stretching instructors. I would be pretty skeptical about such a study in general.
Nevertheless, I strongly recommend we all get off our butts and do more exercise. Patients who do so survive longer, have better stamina (else why would the NFL players have “2-a-days” during training season?), and can do more with their families. Although meta-analyses of exercise studies aren’t all that strong, they do indicate a real trend in better life for exercisers. “Current data suggest that incontinence, fitness, fatigue, body constitution, and also quality of life can be improved by clinical exercise in patients during and after prostate cancer.” Maybe you can even find an attractive Qigong instructor to encourage you!
Well, it’s that time again. I have started my itchy beard on behalf of men’s health. I urge you to support this research effort that started in Australia and is growing yearly. WE finally have a voice to match the Koman Race and pink shoelaces on NFL players!
This year I joined the Univesity of Colorado Cancer Center team. If you don’t want to grow your own or join our team, you can contribute to my scraggly growth here. It’s Movember and the time for change is now. As a part of Generation Moustache, I’ve committed my face to the cause and will be growing a moustache for the entire month of November to raise funds and awareness for men’s health.
I’d like you to support me as I fight the good fight. I’m restless for change and would love you to support my passion with a donation. You can donate to my moustache by:
1. Donating online at HTTP://MOBRO.CO/MICHAELGLODE
2. Writing a check to ‘Movember’, referencing my registration ID: 5798901 and mailing it to: Movember US, P.O. Box 1595, Culver City, CA 90232
Your donation will support world-class men’s health programs that combat prostate and testicular cancer.
These programs, directed by the Movember Foundation, are focused on awareness and education, living with and beyond cancer, and research to achieve our vision of an everlasting impact on the face of men’s health.
To find out more, visit the programs section of Movember’s website: HTTP://US.MOVEMBER.COM/PROGRAMS
Thanks for supporting Movember and helping me change the face of men’s health.