Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension

Background: It remains unclear whether patients with positive surgical margins or extracapsular extension benefit from adjuvant radiotherapy following radical prostatectomy. Objective: To compare the effectiveness and tolerability of adjuvant radiotherapy following radical prostatectomy. Design, setting, and participants: This was a randomised, open-label, parallel-group trial. A total of 250 patients were enrolled between April 2004 and October 2012 in eight Finnish hospitals, with pT2 with positive margins or pT3a, pN0, M0 cancer without seminal vesicle invasion. Intervention: A total of 126 patients received adjuvant radiotherapy at 66.6 Gy. Outcome measurements and statistical analysis: The primary endpoint was biochemical recurrence-free survival, which we analysed using the Kaplan-Meier method and Cox proportional hazard regression. Overall survival, cancer-specific survival, local recurrence, and adverse events were secondary endpoints. Results and limitations: The median follow-up time for patients who were alive when the follow-up ended was 9.3 yr in the adjuvant group and 8.6 yr in the observation group. The 10-yr survival for biochemical recurrence was 82% in the adjuvant group and 61% in the observation group (hazard ratio [HR] 0.26 [95% confidence interval {CI} 0.14-0.48], p <0.001), and for overall survival 92% and 87%, respectively (HR 0.69 [95% CI 0.29-1.60], p = 0.4). Two and four metastatic cancers occurred, respectively. Out of the 43 patients with biochemical recurrence in the observation group, 37 patients received salvage radiotherapy. In the adjuvant group, 56% experienced grade 3 adverse events, versus 40% in the observation group (p = 0.016). Only one grade 4 adverse event occurred (adjuvant group). A limitation of this study was the number of patients. Conclusions: Adjuvant radiotherapy following radical prostatectomy is generally well tolerated and prolongs biochemical recurrence-free survival compared with radical prostatectomy alone in patients with positive margins or extracapsular extension. Patient summary: Radiotherapy given immediately after prostate cancer surgery prolongs prostate-specific antigen progression-free survival, but causes more adverse events, when compared with surgery alone. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewe

Active treatment of prostate cancer

Prostate cancer is the second most common cancer worldwide and the most common cancer in Finland among men. While the prognosis of low-risk localised prostate cancer is excellent, a substantial proportion of prostate cancer patients experience disease progression after first-line treatment. This doctoral dissertation includes four studies that focused on active treatment options for prostate cancer patients with adverse pathologic features or risk factors associated with increased disease recurrence and/or mortality. Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in prostate cancer and resistance to radiotherapy in several solid tumours. In the first two non-randomised trials, the objective was to evaluate the safety and efficacy of 250 mg once daily gefitinib, an orally active EGFR inhibitor, in prostate cancer patients. In the first (phase I/II) trial, 42 patients with nonmetastatic prostate cancer received gefitinib in combination with radical radiotherapy as the first-line treatment. In the second (phase II) trial, 30 patients with biochemical recurrence following radical treatment received gefitinib monotherapy. The third study was a retrospective patient series of 46 patients with previously untreated metastatic prostate cancer—a diagnosis that continues to have poor overall survival. This study evaluated the safety and efficacy of multimodal treatment, including androgen deprivation and radical radiotherapy. In addition, the patients received various individually planned treatments. The fourth study was a multicentre trial that randomised 250 radical prostatectomy-treated patients into an adjuvant radiation (126 patients) or observation (124 patients) group. All patients had positive surgical margins or extracapsular extension, both of which have been associated with increased prostate cancer progression; however, it was unclear whether these patients benefit from adjuvant radiation after surgery. While most of the adverse events in the first study were mild to moderate, the toxicity of gefitinib in combination with radiation was unacceptable, considering that most patients had low-risk prostate cancer with a favourable prognosis even without any active treatments. In studies II–IV, the toxicity was acceptable. The efficacy of gefitinib in prostate cancer patients was modest, both in combination with radical radiotherapy and as a monotherapy. The multimodal treatment approach in metastatic prostate cancer was promising but requires further confirmation in randomised trials. Adjuvant radiotherapy following radical prostatectomy resulted in significant improvement in patients’ biochemical recurrence-free survival when compared to surgery alone. However, salvage radiation upon biochemical recurrence following surgery appeared equally effective in terms of overall survival. Prostate cancer patients with adverse pathologic features or risk factors form a heterogeneous group of patients with different prognoses. To balance the subjective experience of treatment toxicity and the treatment’s expected efficacy on survival, the patient must be adequately informed about the toxicity profiles of the treatments available as well as the risk for later disease progression. The aims of future research include more accurate risk-profiling for each prostate cancer patient, a better understanding of individual disease characteristics, and, thus, the identification of optimal treatments.Vaikka paikallisena todetun eturauhassyövän ennuste on nykyään erinomainen, huomattavalla osalla eturauhassyöpäpotilaista tauti uusiutuu parantavaksi tarkoitetusta hoidosta huolimatta. Tämä väitöskirja koostuu neljästä osatyöstä, jotka keskittyivät eturauhassyöpähoitoihin potilailla, joilla oli kohonnut riski syövän uusiutumiseen ja/tai syöpäkuolleisuuteen. Solukalvoilla esiintyvän epidermaalisen kasvutekijän reseptorin (EGFR) poikkeavan runsas esiintyminen on yhdistetty eturauhassyöpäpotilaiden huonoon ennusteeseen sekä sädehoidon huonoon tehoon monissa kiinteissä kasvaimissa. Gefitinibi on taas suun kautta otettava lääke, joka salpaa EGFR:n toimintaa. Tämän väitöskirjan kahdessa ensimmäisessä osatyössä tutkittiin gefitinibiä eturauhassyövän hoidossa. Ensimmäisessä tutkimuksessa gefitinibi annettiin yhdessä sädehoidon kanssa (42 potilasta) ja toisessa ainoana hoitona potilailla, joilla oli biokemiallisesti eli prostataspesifisen antigeenin (PSA) nousun perusteella todettu uusiutunut eturauhassyöpä (30 potilasta). Kolmannessa tutkimuksessa, jonka aineisto kerättiin potilastietokannasta hoitojen aloittamisen jälkeen, tarkasteltiin multimodaalihoidon turvallisuutta levinneessä eturauhassyövässä (46 potilasta). Hoitoon sisältyi antiandrogeeni-hoito ja sädehoito, joiden lisäksi potilaat saivat useita yksilöllisesti suunniteltuja kokeellisiakin hoitoja. Neljännessä osatyössä tutkittiin eturauhasen täydellisen poistoleikkauksen (radikaali prostatektomia) yhteydessä annettua liitännäissädehoitoa eturauhassyöpäpotilailla, joilla oli syöpäkudosta leikkauksessa poistetun eturauhasen pinnassa (positiivinen marginaali) tai syöpä oli levinnyt eturauhaskapselin läpi. Heillä oli siten suurentunut taudin uusiutumisriski verrattuna potilaisiin, joilla syöpäkudosta on vain eturauhaskapselin sisällä. Potilaat satunnaistettiin liitännäissädehoitoon (126 potilasta) tai seurantaan (124 potilasta). Gefitinibin ja sädehoidon yhdistelmän katsottiin aiheuttavan liikaa haittoja, kun taas tutkimuksissa II-IV annettujen hoitojen haittavaikutukset olivat hyväksyttäviä. Gefitinibin tehokkuus eturauhassyövän hoidossa oli vaatimaton kahdessa ensimmäisessä tutkimuksessa. Multimodaalihoito levinneessä eturauhassyövässä taas vaikutti lupaavalta, mutta tämän tuloksen vahvistamiseksi tarvitaan satunnaistettuja tutkimuksia. Liitännäissädehoitoa saaneilla potilailla esiintyi huomattavasti vähemmän eturauhassyövän biokemiallista uusiutumista kuin seurantaryhmän potilailla, mutta sillä ei ollut vaikutusta potilaiden elinaikaan. Tasapainottaakseen oman kokemuksensa hoidon haitoista ja hoidon odotettavissa olevasta vaikutuksesta elinaikaansa, eturauhassyöpäpotilaan on saatava riittävästi tietoa sekä saatavilla olevien hoitojen haittavaikutuksista että tautinsa etenemisriskistä. Tulevaisuuden tutkimustavoitteita ovat yksittäisen eturauhassyöpäpotilaan riskien tarkempi profilointi, eturauhassyövän yksilöllisten ominaisuuksien parempi ymmärtäminen ja siten optimaalisten hoitojen tunnistaminen

Editorial Comment : Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension

Non peer reviewe