21st May 2017
I’ve been reading up a lot + getting the opinion of a number of cancer specialists (including a very highly trusted family doctor in Delhi, a relative in Mumbai who is a very highly experienced oncologist, a close oncologist specialist friend of my schoolmate in Gurgaon) and many other doctor friends (two of them through FTI) + friends. [My biopsy results are available here.]
Universally I’m being advised to undertake radical prostate surgery as soon as possible. One of them said I should do it this week!
This is quite a big deal. It means that I may need to cancel my plans to Switzerland and postpone my plans to India. It will amount to a significant loss of money + a severe disruption in plans to take SBP forward.
Even if I do manage to do the Switzerland trip (end June), I should probably return to Melbourne for surgery immediately after that and not spend any time in India, thereby disrupting the India leg of my trip (including national conference).
Mine appears to be borderline cancer (i.e. only has become aggressive relatively recently) and if I’m lucky it can be permanently eradicated through surgery. All doctors I’ve consulted want me not to delay.
1) An intermediate but potentially increasingly aggressive cancer
Prostate is a very slow growing cancer – on average.
“Prostate cancer may follow an aggressive course, similar to that of other cancers. However, many prostate cancers are indolent, and will have no impact on health, even without treatment. The natural history of prostate cancer diagnosed in the 1970s and 1980s has been well described. For example, Albertsen et al. (2005), reporting the long-term outcome of watchful waiting, found that the 15-year prostate cancer mortality for men with a Gleason score of 6 was 18–30%, while their 15-year risk of death from other causes was 25–59%.” [Source: Prostate cancer: diagnosis and treatment – by National Collaborating Centre for Cancer]
“Evidence comes from a randomised trial comparing radical prostatectomy and watchful waiting (Bill-Axelson et al. 2005; Steineck et al. 2002), in men with localised, well to moderately well differentiated prostate cancer [i.e. Gleason 6 or 7, I think]. Overall mortality, within 10 years of follow-up, was lower in men treated with prostatectomy than in those managed with watchful waiting: 27.0% versus 32.0% respectively (Bill-Axelson et al. 2005). Similarly, the rate of death from prostate cancer within 10 years of follow-up was lower in the prostatectomy group than in the watchful waiting group (9.6% vs. 14.9% respectively). Erectile dysfunction and urinary incontinence, however, were significantly more likely in the prostatectomy group (Steineck et al. 2002).” [Prostate cancer: diagnosis and treatment – by National Collaborating Centre for Cancer]
Statistically, it would appear that if I do nothing, my prospects could potentially be pretty much what they would have otherwise been (such as with surgery). At least for the first ten years [Source].
My worst tumours are Gleason 7 but it is 3+4, not 4+3. There is a huge difference between the two. (“For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers” [Source]).
The problem is that (a) a biopsy doesn’t pick up everything and (b) there is no guarantee that the tumour would not worsen rapidly (given grade 4 is an aggressive type of cancer).
There is no perineural invasion (meaning that no cancer cells were seen surrounding or tracking along a nerve fiber within the prostate). This suggests a lower chance of the cancer having spread outside the prostate. But by the same token, if I delay, this could change. Further, the biopsy has probably already spread some of the cancer cells around.
What tilted the decision was my relative from Mumbai (an oncologist) telling me that at a younger age (yes, I’m still “young” for such cancer!), the cancer tends to be more aggressive at a younger than at an older age. So really, waiting is not a good idea.
2) Active surveillance is not a good idea in this case
Over the course of ten years, there is virtually no difference in outcomes (death from prostate cancer) from any of the options. This is based on the results of on the largest randomised trials in history. [Source | journal article here]
FOR 10 YEARS, THERE IS NO REAL DIFFERENCE BETWEEN THE “TREATMENTS”
However, “treating the disease radically, when found, reduces the number of men who develop spread of prostate cancer”.
IT IS POSSIBLE THAT RADICAL OPTIONS WILL SHOW UP IN LONGER LIVE OVER A LONGER TIME FRAME.
Many prostate cancers categorised as GS 7 progress very slowly and are in fact clinically insignificant. The slow progression rate of some GS 7 cancers can be illustrated by the PIVOT study. PIVOT included men diagnosed before the 2005 revision of the Gleason grading criteria, so up to half of GS 6 cancers in PIVOT would today be categorised as GS 7.4 Moreover, because they were diagnosed on standard transrectal biopsy, a third of those diagnosed with GS 6 cancer also had an undetected GS 7–10 cancer. The excellent prognosis of men with conservatively managed, localised “GS 6 cancer” reported in PIVOT (2·7% 12-year cancer-specific mortality) therefore also applies today to many men with GS 7 cancer. [Source: The drama of prostate cancer diagnostics – *Ola Bratt, Jonas Hugosson, Laurence Klotz, Vincent Gnanapragasam, Lancet Oncology March 2017]
FOR (T-stage ≤ T2a, Gleason score ≤ 6, and PSA level ≤ 10 ng/mL) PATIENTS:”patients who were surgically treated for their disease lived only 1·8 months longer than did those who received periodic biopsies and were regularly followed up. Although the benefits from immediate radical prostatectomy were small, “men on active surveillance benefited from an average of 6·4 more years of life free from treatment than those who were treated with surgery” 2·78% of men on active surveillance and 1·64% with surgery would die of the disease in 20 years, and those on active surveillance would have a signifi cantly longer treatment-free survival. Prostate Cancer Intervention versus Observation Trial (PIVOT) trial. In the randomised PIVOT trial, surgery did not reduce overall or prostate cancer related mortality or bone metastases in men with low risk disease compared with observation for 12 years. Surgery also resulted in treatment-related harms, including complications in 21·4% of men within 30 days after surgery, and increased number of men with erectile dysfunction and urinary incontinence. [Active surveillance beats surgery in low-risk prostate cancer, Published Online October 5, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70454-0]
But in my case the situation is not a clear low risk situation. In my case the Epstein criteria for insignificant prostate cancer (no more than one thirdof all cores positive, no more than half of any one core involved, and a PSA density <0.15) do not apply (noting that the Epstein criteria have been questioned in the literature because these tend to underestimate the seriousness of cancer).
- In my case 3+1+4+2+1+2 (12) out of 4+4+4+3+3+3 (21) biopsy cores were positive (excluding one section that may have had 2-3 cores but no figures were cited in the report. This means at best 12/23 which is GREATER THAN ONE THIRD.)
- Further two sections had coverage of 50 and 55 per cent.
An alternative criterion (used by a study by the Royal Marsden Hospital in London) requires 50 % or less of the biopsy samples positive for cancer – even this one is crossed in my case.
Accordingly, the risk of the cancer spreading outside the prostate is medium to high. And once it spreads, the cure will be harder.
“21% of men with low risk disease who underwent surveillance experienced progression (local symptoms or metastases), implying that harm was caused by undertreatment” [Diagnostic accuracy of multi-parametric MRI and transrectal ultrasound-guided biopsy in prostate cancer – in The Lancet, January 20, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30121-6
The only indisputable definition of such cancer is “cancer that is causing symptoms”. However, because symptomatic prostate cancers are too advanced for cure, attempts are made to predict the clinical significance of asymptomatic localised prostate cancers by their histology. These attempts are, however, thwarted by the fact that the predicted event typically occurs more than 10 years later (if ever). Patients and clinicians usually prefer to err on the safe side and not to miss the window of cure for a cancer that could later be lethal, so most men with localised prostate cancer are treated and left with permanent side-effects. [Source: The drama of prostate cancer diagnostics – *Ola Bratt, Jonas Hugosson, Laurence Klotz, Vincent Gnanapragasam, Lancet Oncology March 2017]
Additional reasons on this issue are provided at the end of this post.
3) Radiotherapy is not a bad option, but is has few further remedies if it fails
Radiation therapy has a slightly lower rate of longer term success than complete removal. The advantage is that it is far less invasive and has fewer side effects (initially). My quality of life will be initially better with radiation, but over the years, it is likely to worsen.
My oncologist relative from Mumbai told me that he would have recommended radiotherapy for me if I was 65 or over, but not in this case.
In his view, radiotherapy is also more suitable for the more aggressive forms of cancer, which have already spread. In my case there is potentially a small window of opportunity to excise the cancer permanently.
4) Radical surgery will have severe side effects but if it fails, radiotherapy can be used
Radical surgery is more severe but has a slightly better chance of eliminating the cancer if it is still localised within the prostate. Further, it if fails, then one has to undergo hormone therapy which I understand can be quite disastrous to one’s ability to function normally.
Side-effects: Surgery can cause incontinence and impotence, while radiotherapy can lead to problems with the bowel. [patients who had radical prostatectomy could experience a number of bothersome sexual difficulties, involving impairment of sexual desire, anejaculation, trouble with orgasm, and cosmetic alterations, such as penile shortening or shape alterations, potentially associated with a severe negative effect on the man’s selfperception of virility]
Very good comparison of side effects: https://www.cancer.dk/dyn/resources/File/file/1/5821/1475156802/ronald-chen_prostate-cancer-patient-reported-outcomes-what-do-we-know-and-what-is-still-unknown.pdf
Cancer can still recur if it has even slightly spread outside the prostate prior to the surgery. However, if it does come back, radiation becomes a “salvage” therapy and can be used to further extend life for a while.
Overall, there is a slightly higher overall chance of longer term survival with radical surgery + salvage radiation (if needed) than with only using radiation.
If I have this surgery, I might (at best) extend my life by a few years. Btw, death is still guaranteed!
I feel perfectly fit now but the stuff developing inside my body can potentially cause great harm in the future if left untreated. Even now there is no guarantee it has not spread. One can only try to fix it before things get worse.
So – now the question is merely going to be of picking the right surgeon/ hospital and working out the optimal way to deal with the costs.
Once the surgery date is fixed, I’ll let people know about any change in plans.
The good thing is that now that the decision has been taken, I can revert to focusing on SBP work.
I’ve got two choices – private insurance (which could speed up the surgery) or public system (which will take a few months, at most). Private “gap” costs could be significant, so I’ve got to trade off the costs/ benefits of the choices. That’ll be the next decision. Once I’ve decided and firmed up the date for surgery, my India etc. plans will be reviewed.
Further reasons why active surveillance is not a good option in my case.
PATTERN 3 IS NOT MESTASTIC
“Evidence exists that suggests the absence of invasive and metastatic behaviour in most prostate lesions. For example, when individual prostate lesions derived from one patient’s primary prostate cancer specimen were implanted into mice, only one lesion out of three showed characteristics of local invasion and eventually formed metastases” .. is strong evidence that exclusive Gleason pattern 3 prostate lesions are not a metastatic phenotype. [Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Hashim Uddin Ahmed, Manit Arya, Alex Freeman, Mark Emberton Lancet Oncology November 2012 ]
BUT PATTERN 4 IS PROBLEMATIC
The genes that were exclusively expressed in the pattern 4 tumours corresponded to those that are upregulated in embryonic, neuronal, and haemopoietic stem cells. Importantly, among these were EGF and EGFR. Overexpression of both of these genes is associated with independent cell proliferation and enhanced cell motility through several signal transduction mechanisms, including the MAPK, AKT, and RAS pathways. As well as the upregulation of EGFR, the investigators showed overexpression of MAP2K4 and the EGF-activated promigratory gene RALA, and downregulation of REPS2 (which negatively regulates EGFR via endocytosis), PHLPP, and PML (both of which inactivate the protein kinase phospho-AKT, which mediates growth-factor associated cell survival) in Gleason pattern 4 lesions. Amplification of HER2/neu, a member of the EGFR family, was almost exclusively confi ned to Gleason pattern 4 lesions rather than Gleason pattern 3 lesions. [Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Hashim Uddin Ahmed, Manit Arya, Alex Freeman, Mark Emberton Lancet Oncology November 2012 ]
We have some evidence that exclusive Gleason pattern 3 prostate lesions have this brake preserved and that high-grade cancers are more likely to have evolved a mechanism to overcome it. Tomlins and colleagues provided some of this evidence from their well designed experiments. They used radical prostatectomy specimens (101 micro dissected specimens from 44 individuals) to develop two phenotype tissue pools—one low-risk (exclusive Gleason pattern 3) and one high-risk (Gleason pattern 4 or higher). The high Gleason grade lesions showed decreased androgen signalling, similar to metastatic prostate cancer, which could reflect de-differentiation and account for the clinical association of the grade of the high-grade lesions with prognosis. This finding was also reported by Hendriksen and colleagues, who noted lower androgen signalling in high-grade Gleason pattern prostate cancer than in low-grade Gleason pattern lesions. The researchers suggested that localised prostate cancer cells become more aggressive by selectively down regulating androgen-responsive genes, which results in increased tumour cell replication and proliferation, dedifferentiation, or reduced apoptosis
The chemokine receptor CXCR4 is one of those elements that are upregulated in localised, highgrade Gleason pattern 4 lesions compared with Gleason pattern 3 lesions. This G-protein-coupled transmembrane receptor has a key role in the directional migration of cancer cells to specifi c metastatic sites in response to its ligand CXCL12. Additionally, CXCR4 upregulation has been associated with lymph node and bone metastasis in prostate cancer, possibly through activation of the RAS oncogene family member RAP1A, the expression of which is also upregulated in Gleason pattern 4 lesions relative to those containing only Gleason pattern 3. [Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Hashim Uddin Ahmed, Manit Arya, Alex Freeman, Mark Emberton Lancet Oncology November 2012 ]
In a study from Sweden of men with very small cancers who were treated with observation alone, death rates from prostate cancer remained very low (15 per 100,000 persons) for the first 15 years — but beyond that point, they skyrocketed (to 44 per 100,000 persons), and nearly all these men eventually died from prostate cancer. [Source]