Clinical trial NCT01272050: Radiation Therapy in Treating Patients With Relapsed Prostate Cancer After Surgery
Official title: Dose Intensified Salvage Radiotherapy in Biochemically Relapsed Prostate Cancer Without Macroscopic Disease. A Randomized Phase III Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: adenocarcinoma of the prostate
recurrent prostate cancer
stage IIA prostate cancer
stage IIB prostate cancer
stage III prostate cancer
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2011-01-07
Enrollment: 350
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known which radiation therapy regimen is more effective in treating patients with relapsed prostate cancer.

PURPOSE: This randomized phase III trial is studying the side effects of radiation therapy and comparing two radiation therapy regimens in treating patients with relapsed prostate cancer after surgery.

Detailed description: OBJECTIVES:

* To determine the tumor control in patients with biochemically relapsed prostate cancer without macroscopic disease treated with dose-intensive salvage radiotherapy.
* To determine the toxicity in these patients.
* To determine the quality of life of these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to Gleason score (≥ 8 vs 7 vs ≤ 6), pathological tumor classification (pT3b vs others), lymphadenectomy performed (yes \[pN0\] vs no \[cN0\]), persistent PSA after prostatectomy (detectable \[≥ 0.1 ng/mL\] vs undetectable \[\< 0.1 ng/mL\]), PSA at randomization (\> 0.5 ng/mL vs ≤ 0.5 ng/mL), participating center, and radiotherapy technique (3-dimensional conformal radiation therapy \[3D-CRT\] vs intensity-modulated radiation therapy \[IMRT\]/rotational techniques). Patient are randomized to 1 of 2 treatment arms.

* Arm A: Beginning at least 12 weeks after surgery, patients undergo radiotherapy\* once a day, 5 days a week, for 6.4 weeks for a total dose of 64 Gy (in 32 fractions of 2 Gy over 6.4 weeks).
* Arm B: Patients undergo radiotherapy\* once a day, 5 days a week, for 7 weeks for a total dose of 70 Gy (in 35 fractions of 2 Gy over 7 weeks).

NOTE: \*3-dimensional conformal radiation therapy, rotational techniques such as Tomotherapy®, Rapidarc®, or intensity-modulated arc technique and volumetric-modulated arc therapy are all eligible.

Patients complete quality-of-life questionnaires at baseline and at 3, 12, 24, 36, 48, and 60 months after completing study therapy.

After completion of study treatment, patients are followed every 6 months for 3 years and then every 12 months for up to 10 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of adenocarcinoma of the prostate

  * Lymph node negative disease

    * Stage pT2a-3b; R0-1; pN0 or cN0
* Undergone a radical prostatectomy ≥ 12 weeks prior to randomization
* PSA progression after prostatectomy defined as two consecutive rises with the second rising value \> 0.1 ng/mL OR three consecutive rises (the first value must be measured 4 weeks after radical prostatectomy)
* PSA ≤ 2 ng/mL at randomization

  * No persistent PSA \> 0.4 ng/mL, 4-20 weeks after radical prostatectomy
* No palpable prostatic fossa mass suggestive of recurrence, unless an ultrasound-guided biopsy is non-malignant
* No pre-salvage radiotherapy pelvic lymph node enlargement \> 1 cm in short axis diameter of the abdomen and pelvis (cN1) (unless the enlarged lymph node is sampled and negative)
* No evidence of macroscopic local recurrence or metastatic disease on pre-salvage radiotherapy MRI (with IV contrast) or multislice computed tomography (with IV and oral contrast) of the abdomen and pelvis assessed within 16 weeks prior to randomization
* No presence or history of bone metastases (bone scan must be performed in case of clinical suspicion \[e.g., bone pain\])
* Gleason score must be available

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Fertile patients must use effective contraception during and for 6 months after completion of study therapy
* Compliant and geographically proximal to allow for proper staging and follow-up
* No prior invasive malignancy, except non-melanomatous skin cancer or other malignancies with a documented disease-free survival of ≥ 5 years
* No bilateral hip prosthesis
* No severe or active co-morbidity likely to impact on the advisability of dose-intensive salvage radiotherapy, including any of the following:

  * History of inflammatory bowel disease
  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
  * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
  * Transmural myocardial infarction within the past 6 months
  * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of randomization
* No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or filling out quality-of-life questionnaires

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior pelvic radiotherapy
* No hormonal treatment or bilateral orchiectomy prior to or following prostatectomy
* At least 4 weeks since prior and no concurrent use of products known to affect PSA levels (e.g., PC Calm, PC Plus, PC SPES, finasteride, or fluconazole)
* At least 30 days since prior treatment in another clinical trial
* No other concurrent anticancer treatments, including luteinizing hormone-releasing hormone (LHRH) analogues, antiandrogens, orchiectomy, or chemotherapy
* No other concurrent investigational or experimental treatments or drugs

INCLUSION CRITERIA

* Patient must give written informed consent before randomization.
* Lymph node negative adenocarcinoma of the prostate treated with radical prostatectomy at least 12 weeks before randomization. Tumor stage pT2a-3b, R0-1, pN0 or cN0 according to the UICC TNM 2009 (see Appendix 1), Gleason score available.
* PSA progression after prostatectomy defined as two consecutive rises with the final PSA \> 0.1 ng/mL or three consecutive rises. The first value must be measured earliest 4 weeks after radical prostatectomy.
* PSA at randomization ≤ 2 ng/mL.
* WHO performance status 0-1 at randomization.
* Age at randomization between 18 and 75 years.
* Baseline QoL questionnaire (QLQ) has been completed.
* Patient agrees not to father a child during salvage RT and during 6 months thereafter.
* Patient compliance and geographic proximity allow proper staging and follow-up.
* The responsible pathologist has agreed to provide sample material for central pathological review (see Section 16) and tissue banking (only if patient gave informed consent) within the specified timelines.

EXCLUSION CRITERIA

* Persistent PSA 4-20 weeks after radical prostatectomy \> 0.4 ng/mL
* Palpable prostatic fossa mass suggestive of recurrence, unless an ultrasound guided biopsy is non-malignant.
* Pre-salvage RT pelvic lymph node enlargement \> 1 cm in short axis diameter of the abdomen and pelvis (cN1), unless the enlarged lymph node is sampled and negative, and/or evidence of macroscopic local recurrence or metastatic disease on pre-salvage RT MRI (magnetic resonance imaging; with i.v. contrast) or multislice computed tomography (CT; with i.v. and oral contrast) of the abdomen and pelvis assessed within 16 weeks prior to randomization.
* Presence or history of bone metastases. Bone scan must be performed in case of clinical suspicion (e.g. bone pain).
* Prior invasive malignancy, except non-melanomatous skin cancer or other malignancies with a documented disease-free survival for a minimum of 5 years.
* Hormonal treatment or bilateral orchiectomy prior to or following prostatectomy.
* Bilateral hip prosthesis.
* Prior pelvic radiotherapy.
* The use of products known to affect PSA levels within 4 weeks prior to start of trial treatment (e.g. PC Calm, PC Plus, PC SPES, finasteride, fluconazole).
* Severe or active co-morbidity likely to impact on the advisability of dose intensified salvage RT.
* Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent or filling out QoL questionnaires.
* Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to trial entry.

Primary outcomes:
measure: Freedom from biochemical progression
timeFrame: from the day of trial randomization to the day of either first recorded biochemical progression, clinical progression or death due to clinical progression up to 10 years.
Secondary outcomes:
measure: Clinical progression-free survival
timeFrame: from the day of randomization to the day of the first record of either local or regional recurrence, distant recurrence, start of hormonal treatment, or death due to any cause up to 10 years.
measure: Time to hormonal treatment
timeFrame: time from trial randomization to start of hormonal treatment up to 10 years.
measure: Prostate cancer-specific survival
timeFrame: time from trial randomization to the date of death due to prostate cancer up to 10 years.
measure: Overall survival
timeFrame: time from trial randomization to the date of death from any cause up to 10 years.
measure: Acute and late gastrointestinal and genitourinary toxicity according to CTCAE v 4.0
timeFrame: occurring during treatment and up to 3 months after completion of treatment. Late toxicity is defined as occurring later than 3 months after end of treatment.
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Middelheim
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Ghent
country: Belgium
facility: St. Lukas Hospital Ghent
city: Aachen
country: Germany
facility: Universitaetsklinikum Aachen, Klinik für Strahlentherapie
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Dresden
country: Germany
facility: University Hospital and Medical Faculty Technical University of Dresden
city: Essen
country: Germany
facility: Universitaetsklinikum Essen, Klinik für Strahlentherapie
city: Homburg
country: Germany
facility: Universitätsklinikum Saarland
city: Munich
country: Germany
facility: Klinikum der LMU Muenchen
city: Munich
country: Germany
facility: Technische Universitaet Muenchen
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Rostock
country: Germany
facility: Klinik und Poliklinik fuer Strahlentherapie - Universitaetsklinikum Rostock
city: Tuebingen
country: Germany
facility: Universitaet Tuebingen
city: Wuerzburg
country: Germany
facility: Klinik fuer Strahlentherapie Universitaet Wuerzburg
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Biel
country: Switzerland
facility: Radio-Onkologiezentrum Biel-Seeland-Berner Jura AG
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: Münsterlingen
country: Switzerland
facility: Kantonsspital Muensterlingen
city: Sion
country: Switzerland
facility: Hopital de Sion
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: Radio-Onkologie Berner Oberland AG
city: Zurich
country: Switzerland
facility: Klinik Hirslanden
city: Zurich
country: Switzerland
facility: City Hospital Triemli
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: Charite University, Berlin, Germany
name: Pirus Ghadjar, MD
role: STUDY_CHAIR
affiliation: Bern University Hospital
name: Daniel M. Aebersold, Prof.
role: STUDY_CHAIR
affiliation: Bern University Hospital
name: George N. Thalmann, Prof.
role: STUDY_CHAIR
affiliation: Kantonsspital Graubünden
name: Daniel Zwahlen, PD Dr.
role: STUDY_CHAIR
References:
citation: Beck M, Sassowsky M, Schar S, Mathier E, Halter M, Zwahlen DR, Holscher T, Arnold W, Polat B, Hildebrandt G, Muller AC, Putora PM, Papachristofilou A, Hayoz S, Schar C, Li Q, Sumila M, Zaugg K, Guckenberger M, Ost P, Bosetti DG, Reuter C, Gomez S, Khanfir K, Aebersold DM, Ghadjar P, Pra AD. Adherence to Contouring and Treatment Planning Requirements Within a Multicentric Trial: Results of the Quality Assurance of the SAKK 09/10 trial. Int J Radiat Oncol Biol Phys. 2022 May 1;113(1):80-91. doi: 10.1016/j.ijrobp.2021.12.174. Epub 2022 Jan 3.
citation: Ghadjar P, Hayoz S, Bernhard J, Zwahlen DR, Holscher T, Gut P, Polat B, Hildebrandt G, Muller AC, Plasswilm L, Papachristofilou A, Schar C, Sumila M, Zaugg K, Guckenberger M, Ost P, Reuter C, Bosetti DG, Khanfir K, Gomez S, Wust P, Thalmann GN, Aebersold DM; Swiss Group for Clinical Cancer Research (SAKK). Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial. Eur Urol. 2021 Sep;80(3):306-315. doi: 10.1016/j.eururo.2021.05.033. Epub 2021 Jun 14.
citation: Ghadjar P, Hayoz S, Bernhard J, Zwahlen DR, Holscher T, Gut P, Guckenberger M, Hildebrandt G, Muller AC, Plasswilm L, Papachristofilou A, Stalder L, Biaggi-Rudolf C, Sumila M, Kranzbuhler H, Najafi Y, Ost P, Azinwi NC, Reuter C, Bodis S, Kaouthar K, Wust P, Thalmann GN, Aebersold DM. Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10. J Clin Oncol. 2015 Dec 10;33(35):4158-66. doi: 10.1200/JCO.2015.63.3529. Epub 2015 Nov 2.