Due to the absence of randomized data clearly showing a superiority of one treatment option over the others in terms of classical survival endpoints, patients diagnosed with High-Risk Prostate Cancer (HRPCa) are currently basing their choice mostly on individual reasons and personal motivations.
Also the fear for side effects and for quality of life (QoL) deterioration after treatment, have been consistently shown to affect treatment choice. A significant number of papers have been published comparing toxicities and QoL impact of the different management options available for PCa: some of them, but not all, have carefully compared the incidence of side effects during and after treatment also took into account the base-line patient profile in an attempt to derive the actual and net impact of surgery or radiotherapy (RT).
Interestingly, almost all of these papers are devoted to localized disease where the comparison is largely among “single therapies” arms as virtually all patients are treated with a single modality and where association of modalities (RT + Androgen Deprivation Therapy, ADT, or radical prostatectomy, RP, followed by RT or brachytherapy, BT, + RT…) are extremely unusual because generally never recommended for the optimal management of these stages of the disease. Radical prostatectomy alone is thus compared to brachytherapy alone and/or external beam radiotherapy (EBRT) alone.
In the HRPCa setting, on the contrary, this is rarely the case and multimodality approaches are quite often needed following international Guidelines based on randomized evidence (as it is the case for RT) or adopted for the majority of patients due to the post-op findings or the late evolution of the disease (as it is the case for upfront surgery). Patients and their families, but also professionals responsible for treatment counselling for patients diagnosed with HRPCa are thus left in a real absence of contemporary, validated, comparative data on toxicities and their impact on QoL for this particular subset of patients.
The side effects profiles for the available options in the management of the PCa localized disease are well defined and compared in several non-randomized studies. Generally speaking the long term impact of RP, EBRT and brachytherapy (BT) on QoL is, in all series, negligible while erectile dysfunction appears more frequently after surgery as compared to EBRT or BT (especially in the first two to three years after treatment) and gastro-intestinal side effects are more common after EBRT.
Radiotherapy plus ADT
The knowledge that for patients having HRPCa the adjunction of (long-term) ADT to RT yields better survival results as compared to RT alone comes basically from old randomized clinical trial (RCT) launched in the late 1980s by the EORTC (22861) and the RTOG (92-02). At that time, only treatment-related, physician-reported toxicity were described without detailed information about their impact on patientperceived QoL; furthermore only the most classical toxicity (genito-urinary, GU, and gastro-intestinal, GI) were reported with little, if any, consideration for the persistence of erectile dysfunction once ADT was stopped.
Even more recent RCT, confirming the merit of the combination of RT with ADT versus ADT alone for HRPCa patients (SPCG-7, INT-94.0110), only concentrated the toxicity report on GU and GI toxicity, with virtually no data on sexual QoL. All together the bottom line of these randomized evidences is straightforward: RT+ADT is not more toxic as compared to RT alone or to ADT alone at least in terms of GU and GI toxicity. On the other hand, it is out of question that adding ADT to RT will translate in a long-lasting erectile dysfunction.
Furthermore, it is noteworthy that any evidence exists about an increase likelihood of any toxicity when RT is employed for patients with HRPCa as compared to patients having low-risk PCa while mono-institutional surgical series clearly suggest that an increased risk of urinary incontinence and erectile dysfunction is associated with RP for HRPCa patients versus surgery for low-risk ones (Suardi, 2012).
Radiotherapy after radical prostatectomy
When RP is adopted as initial treatment option for HRPCa, mature series emanating from centres of surgical excellence, clearly indicates that at least 75 to 80 % of patients will need some form of (early) adjuvant treatment (RT and/or ADT) or of (late) salvage ones. This means the added toxicity of both treatments (RP plus RT and eventually ADT) should be considered when counselling HRPCa patients for a surgical approach. In this respect, RCT of post-op immediate RT versus observation have not shown an increase risk of developing GU nor GI toxicity but mono-institutional series are less reassuring and seem to suggest that adding RT to RP may impact on the time- to-continence recovery both after nerve-sparing and non-nervesparing surgery (Suardi, 2014).
Radiotherapy- less toxic than radical prostatectomy for HRPCa?
The global picture of the toxicity profile for the different treatment options available for HRPCa is difficult to derive from the published literature and it is thus impossible to give a clear answer to this question. Most of the existing comparative data apply to the low-risk scenario where the vast majority of patients are managed with a single treatment modality. This is rarely the case for the HRPCa group of patients for whom RT is invariably supplemented with (long-term) ADT with a clear detrimental impact on the sexual domain, but no clear evidence of a worst GU and GI toxicity profile as compared to RT alone.
On the contrary, for 75 to 80 % of patients undergoing RP as first treatment for HRPCa, the need for subsequent adjuvant/salvage RT/ADT will exacerbate both GU toxicity (= incontinence) and erectile dysfunction. When discussing the different treatment options for their HRPCa, patients should be fully informed about the toxicity profiles associated with their choice, taking into account the whole “package” of potential treatments needed to maximise the chance of controlling the disease.
HRPCa patients represent a highly heterogeneous group. For the vast majority of these patients, the association of irradiation and (long-term) ADT will remain mandatory. In the spectrum of HRPCa we cannot exclude that a selected subgroup of patients (those with local low burden of disease, cT3a or initial cT3b, Gleason score 7 and PSA < 20 ng/ml for ex) may benefit from a dose escalation into the prostate with short-term (six months) of ADT thus reducing the likelihood of combined RT-ADT side effects.
Furthermore, data are accumulating on the possible toxic effect of ADT in terms of cardiac deaths especially for patients with an initial greater burden of comorbidities. These considerations need to be addressed in the everyday clinical practice by radiotherapists treating HRPCa suggesting that clinicians will need to personalize decision to use ADT as adjunct to RT balancing the proven benefits against the known side effects of ADT but also the potential cardiovascular harms.
One of the challenges for the radiotherapy community in the near future when managing HRPCa patients will certainly be to better stratify patients to better adapt the duration of ADT based on the characteristics of the disease, but also on the comorbidities profile of every single patient.
Dr. Alberto Bossi. Dept. of Radiation Oncology, Gustave Roussy, Villejuif (FR).
Sunday, 22 March
07.30-10.55: Plenary Session 2, Prostate Cancer
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