A Study of Prostate and pelvIs Versus prOsTate Alone Treatment for Locally Advanced Prostate Cancer (PIVOTAL)

A Randomised Phase II Trial of Prostate and pelvIs Versus prOsTate Alone Treatment for Locally Advanced Prostate Cancer

Prostate cancer is the most common male cancer in the UK with 35,000 cases diagnosed annually. 35% of these are locally advanced disease. These patients have a high chance of pelvic lymph node involvement and have relatively poor prostate cancer survival rates of 22.5% at 10 years.

One of the standard treatments for these patients is radiotherapy to the prostate. PIVOTAL is a multi-centre phase II non-comparative randomised feasibility trial, in which patients with a high chance of pelvic lymph node involvement are randomised between prostate radiotherapy alone and prostate + pelvic radiotherapy.

Both groups will receive radiotherapy called Intensity Modulated Radiation Therapy (IMRT). This is a relatively new method of shaping radiotherapy treatment beams which allows the tumour to be treated more precisely, whilst avoiding more of the surrounding normal, healthy tissues (particularly the rectum, bladder and bowel). Using IMRT, it is possible to deliver higher doses of radiotherapy to the pelvis than with previous radiotherapy methods - this has been tested in a single hospital, single group setting and levels of side effects (toxicity) were acceptable.

PIVOTAL aims to find out whether toxicity levels at 18 weeks from the start of radiotherapy remain acceptable when treatment is given in multiple cancer centres across the UK. It is randomised to ensure unbiased collection of acute toxicity data and to provide information on patients' willingness to participate in a randomised study. Should the phase II study be successful, the investigators would develop a phase III trial to compare treatment effectiveness (disease control).

Patients who enter PIVOTAL will be followed up for two years from the start of radiotherapy and data relating to toxicity will be collected. They will also be asked to complete patient related symptoms questionnaires. Data related to disease recurrence will then be collected annually from patients' standard hospital visits.

Study Overview

• Status: Unknown
• Conditions: Prostate Cancer
• Intervention / Treatment: Radiation: Prostate alone IMRT; Radiation: Prostate and pelvis IMRT

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Queen Elizabeth
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
  • Cardiff, United Kingdom
    • Velindre Hospital
  • Ipswich, United Kingdom
    • Ipswich
  • Liverpool, United Kingdom
    • Clatterbridge Centre for Oncology
  • London, United Kingdom
    • Royal Marsden NHSFT
  • Newcastle, United Kingdom
    • Freeman Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Histologically confirmed, non-metastatic adenocarcinoma of the prostate, previously untreated (other than by neoadjuvant hormonal treatment)

2. National Collaborative Cancer Network locally advanced disease (T3b± or T4)43 or:

   • Estimated risk of pelvic lymph node involvement ≥30% * and either:

   • Gleason 9 or 10 or
   • Gleason 8 and one other high risk feature (T3± disease or PSA >20) or
   • Gleason 7 and 2 high risk features (T3± disease and PSA ≥30)
3. WHO performance status 0 or 1
4. Normal blood count (Hb > 11g/dl, WBC >4000/mm3, platelets >100,000/mm3)
5. LHRH analogue therapy for 6-9 months duration prior to proposed radiotherapy treatment and PSA < 4ng/ml prior to randomisation.
6. Age ≥ 18 years
7. Patients must be prepared to attend follow up. All patients participating in the Patient Reported Outcomes (PRO) Study must have adequate cognitive ability to complete the PRO questionnaires.

8. Written informed consent

   • T3a disease should be demonstrated convincingly, either clinically or by MRI. T3b disease (seminal vesicle involvement) must be convincingly demonstrated on MR.

     • Risk of pelvic lymph node involvement = (Gleason score - 6) x 10 + 2/3 PSA

Exclusion criteria:

1. Prior pelvic radiotherapy
2. Prior major pelvic surgery (e.g. colectomy, colostomy, cystectomy, prostatectomy)*
3. Radiologically suspicious (short axis diameter ≥1.0cm unless biopsied and negative) or pathologically confirmed lymph node involvement
4. Life expectancy < 5 years
5. Castrate resistant prostate cancer (rising PSA after LHRHa and anti-androgen)
6. Previous active malignancy within the last 5 years other than basal cell carcinoma
7. Co-morbid conditions likely to impact on the decision to treat with radiotherapy (e.g. previous inflammatory bowel disease, previous colo-rectal surgery, significant bladder instability or urinary incontinence)

8. Bilateral hip prosthesis or fixation which would interfere with standard radiation beam configuration

   • Patients who have undergone minor pelvic surgery will be eligible (eg appendicectomy, trans urethral resection of prostate (TURP), exploratory laparoscopy, haemorrhoidectomy, inguinal/femoral hernia repair)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prostate Alone IMRT; Participants will receive standard prostate Intensity Modulated Radiotherapy (IMRT) of 74Gy in 37 fractions delivered over 7.5 weeks.	Radiation: Prostate alone IMRT; Participants will receive standard prostate IMRT of 74Gy in 37 fractions delivered over 7.5 weeks.
Experimental: Prostate & Pelvis IMRT; Participants will receive prostate and pelvis IMRT with a dose of 74Gy in 37 fractions delivered over 7.5 weeks to the prostate and 60Gy in 37 fractions delivered over 7.5weeks to the pelvis.	Radiation: Prostate and pelvis IMRT; Participants will receive prostate and pelvis IMRT with a dose of 74Gy in 37 fractions delivered over 7.5 weeks to the prostate and 60Gy in 37 fractions delivered over 7.5weeks to the pelvis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute lower GI RTOG toxicity at week 18 of follow-up.	Proportion of patients with acute GI RTOG grade ≥2 toxicity at week 18 from start of radiotherapy calculated as the number of patients with grade ≥2 toxicity at week 18 over the number of evaluable at week 18.	18 weeks post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to deliver 60Gy in 37 fractions to the pelvis using the varying radiotherapy planning techniques and delivery systems at the participating centres.		2 yr
Late (1 and 2 year) toxicity	Measured using RTOG toxicity scale and CTCAE	2 yr
Patient Reported Outcomes	Participants are requested to complete questionnaires to record the impact of the treatments on bowel and bladder function.	2 yr
Biochemical progression free survival		10 yr
Time to local progression		10 yr
Time to distant metastases		10 yr
Overall survival		10 yr

Collaborators and Investigators

• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: Cancer Research UK
• Investigators: Principal Investigator: Prof. David Dearnaley, Institute of Cancer Research/RMHNHSFT

Publications and helpful links

General Publications

• Harris VA, Staffurth J, Naismith O, Esmail A, Gulliford S, Khoo V, Lewis R, Littler J, McNair H, Sadoyze A, Scrase C, Sohaib A, Syndikus I, Zarkar A, Hall E, Dearnaley D; PIVOTAL Trialists. Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015 Jul 15;92(4):874-83. doi: 10.1016/j.ijrobp.2015.03.021. Epub 2015 Mar 30.
• Dearnaley D, Griffin CL, Lewis R, Mayles P, Mayles H, Naismith OF, Harris V, Scrase CD, Staffurth J, Syndikus I, Zarkar A, Ford DR, Rimmer YL, Horan G, Khoo V, Frew J, Venkitaraman R, Hall E. Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL). Int J Radiat Oncol Biol Phys. 2019 Mar 1;103(3):605-617. doi: 10.1016/j.ijrobp.2018.10.003. Epub 2018 Dec 6.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: October 26, 2011
• First Submitted That Met QC Criteria: September 11, 2012
• First Posted (Estimate): September 14, 2012

Study Record Updates

• Last Update Posted (Actual): January 4, 2019
• Last Update Submitted That Met QC Criteria: January 2, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: ICR-CTSU/2010/10025; CRUK/10/022 (Other Grant/Funding Number: CRUK); ISRCTN48709247 (Registry Identifier: ISRCTN)