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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).

ABSTRACT: PURPOSE:To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers. METHODS AND MATERIALS:In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity. RESULTS:One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group. CONCLUSIONS:PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.

SUBMITTER: Dearnaley D

PROVIDER: S-EPMC6361768 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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).

Dearnaley David D Griffin Clare L CL Lewis Rebecca R Mayles Philip P Mayles Helen H Naismith Olivia F OF Harris Victoria V Scrase Christopher D CD Staffurth John J Syndikus Isabel I Zarkar Anjali A Ford Daniel R DR Rimmer Yvonne L YL Horan Gail G Khoo Vincent V Frew John J Venkitaraman Ramachandran R Hall Emma E

International journal of radiation oncology, biology, physics 20181206 3

<h4>Purpose</h4>To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.<h4>Methods and materials</h4>In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions ...[more]

PMID: 30528653

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Project description:Clinical trials evaluating the benefit of pelvic radiotherapy (PRT) in the radiotherapeutic management of patients with higher-risk prostate cancer have limited the superior field border to the S1/S2 or L5/S1 interspace. However, imaging and surgical series have demonstrated a high frequency of prostatic lymph node (LN) drainage beyond these landmarks.To determine the patterns of radiographically defined abdominopelvic LN failures and their potential implications for PRT field design.During 1992-2008, 2694 patients with localized prostate cancer were treated with prostate/seminal vesicle-only radiotherapy without PRT. Some 156 patients had their first failure within the abdominopelvic LNs, of whom 60 had isolated failures within the pelvic LNs.A radiologist reviewed all imaging and mapped each LN failure to a template consisting of 34 abdominopelvic LN stations.The median follow-up was 8.9 yr. Of patients who experienced first recurrence in the pelvic LNs (n=60), the common iliac station was involved in 55% (n=33) of patients, including 10% (n=6) who had isolated common iliac failures. Use of a PRT field superior border of L5/S1 would fully cover only 42% of the first recurrences among these patients. Extending the field to cover the common iliac stations would increase coverage to 93% of recurrences. The presence of T3/T4 disease and omission of androgen-deprivation therapy both independently conferred an approximate fivefold increase in the likelihood of having a common iliac LN failure. Use of imaging as a surrogate for LN involvement is the primary study limitation.Pelvic LN failures frequently occur superior to the commonly used L5/S1 landmark for PRT coverage, and use of ADT may be protective of more superior LN failures. The current RTOG 0924 trial is evaluating the benefit of PRT with extended superior coverage to L4/5 when possible, which, according to our data, should significantly improve the coverage of potential sites of failure.We looked at lymph node recurrence patterns after external beam radiotherapy of the prostate in men who did not have their lymph nodes treated. We found that there was a high incidence of pelvic lymph node recurrences above the internal and external iliac lymph node regions. Therefore, the current field recommendation for pelvic lymph nodes that stops at the superior border of the internal and external iliac vessels provides inadequate coverage of common sites of cancer recurrence, namely the common iliac lymph nodes.

Project description:BackgroundAbdominal/pelvic lymph node (LN) oligometastasis, a pattern of treatment failure, is observed occasionally, and radiotherapy may work as salvage therapy. The optimal prescription dose, however, is yet to be determined. This study assessed the efficacy of high-dose radiotherapy.MethodsThe medical records of 113 patients at 4 institutes were retrospectively analysed who had 1 to 5 abdominal/pelvic LN oligometastases and were treated with definitive radiotherapy between 2008 and 2018. The exclusion criteria included non-epithelial tumours, uncontrolled primary lesions, palliative intent, and re-irradiation. The prescription dose was evaluated by using the equivalent dose in 2 Gy fractions (EQD2). Patients receiving EQD2 ≥ 60 Gy were placed into the high-dose group, and the remaining others the low-dose group. Kaplan-Meier analyses were performed to evaluate overall survival (OS), local control (LC), and progression-free survival (PFS). Univariate log-rank and multivariate Cox proportional hazards model analyses were performed to explore predictive factors. Adverse events were compared between the high-dose and low-dose groups.ResultsThe primary tumour sites included the colorectum (n = 28), uterine cervix (n = 27), endometrium (n = 15), and ovaries (n = 10). The rate of 2-year OS was 63.1%, that of LC 59.7%, and that of PFS 19.4%. On multivariate analyses, OS were significantly associated with solitary oligometastasis (hazard ratio [HR]: 0.48, p = 0.02), LC with high-dose radiotherapy (HR: 0.93, p < 0.001), and PFS with long disease-free interval (HR: 0.59, p = 0.01). Whereas high-dose radiotherapy did not significantly improve 2-year OS in the entire cohort (74.8% in the high-dose vs. 52.7% in the low-dose; p = 0.08), it did in the subgroup of solitary oligometastasis (88.8% in the high-dose vs. 56.3% in the low-dose; p = 0.009). As for Late grade ≥ 3 adverse event, ileus was observed in 7 patients (6%) and gastrointestinal bleeding in 4 (4%). No significant association between the irradiation dose and adverse event incidence was found.ConclusionsAs salvage therapy, high-dose radiotherapy was recommendable for oligometastasis in the abdominal/pelvic LNs. For solitary oligometastasis, LC and OS were significantly better in the high-dose group.

Project description:IntroductionExtended pelvic lymph node dissection (ePLND) in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) is a widely used procedure. However, little is known about anatomical site-specific yields and subsequent metastatic patterns in these patients.Patients and methodsData on a consecutive series of 1107 patients undergoing RARP at our centre between 2004 and 2018 were analysed. In men undergoing LN dissection, the internal, external and obturator nodes were removed and sent in separately. We performed an analysis of LN yields in total and for each anatomical zone, patterns of LN metastases and complications. Oncological outcome in pN+ disease was assessed including postoperative PSA persistence and survival.ResultsA total of 823 ePLNDs were performed in the investigated cohort resulting in 98 men being diagnosed as pN+ (8.9%). The median (IQR) LN yield was 19 (14-25), 10 (7-13) on the right and 9 (6-12) on the left side (P < 0.001). A median of six (4-8) LNs were retrieved from the external, three (1-6) from the internal iliac artery, and eight (6-12) from the obturator fossa. More men had metastatic LNs on the right side compared to the left (41 vs. 19). Symptomatic lymphoceles occurred exclusively in the ePLND group (2.3% vs. 0%, p = 0.04). Postoperatively, 47 (47.9%) of men with pN+ reached a PSA of < 0.1μg/ml. There was no association between a certain pN+ region and postoperative PSA persistence or BCRFS. The estimated cancer specific survival rate at 5 years was 98.5% for pN+ disease.ConclusionRobot-assisted laparoscopic ePLND with a high LN yield and low complication rate is feasible. However, we observed an imbalance in more removed and positive LNs on the right side compared to the left. A high rate of postoperative PSA persistence and early recurrence in pN+ patients might indicate a possibly limited therapeutical value of the procedure in already spread disease. Yet, these men demonstrated an excellent survival.

Project description:Purpose To assess acute gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and pelvic lymph nodes for prostate cancer. Materials and Methods A prospective study (ClinicalTrials.gov: NCT02874014), evaluating moderately hypofractionated IMPT for high-risk or unfavorable intermediate-risk prostate cancer, accrued a target sample size of 56 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 6750 and 4500 centigray radiobiologic equivalent (cGyRBE), respectively, in 25 daily fractions. All received androgen-deprivation therapy. Acute GI and GU toxicities were prospectively assessed from 7 GI and 9 GU categories of the Common Terminology Criteria for Adverse Events (version 4), at baseline, weekly during radiotherapy, and 3-month after radiotherapy. Fisher exact tests were used for comparisons of categorical data. Results Median age was 75 years. Median follow-up was 25 months. Fifty-five patients were available for acute toxicity assessment. Sixty-two percent and 2%, respectively, experienced acute grade 1 and 2 GI toxicity. Grade 2 GI toxicity was proctitis. Sixty-five percent and 35%, respectively, had acute grade 1 and 2 GU toxicity. The 3 most frequent grade 2 GU toxicities were urinary frequency, urgency, and obstructive symptoms. None had acute grade ≥ 3 GI or GU toxicity. The presence of baseline GI and GU symptoms was associated with a greater likelihood of experiencing acute GI and GU toxicity, respectively. Of 45 patients with baseline GU symptoms, 44% experienced acute grade 2 GU toxicity, compared with only 10% among 10 with no baseline GU symptoms (P = 0.07). Although acute grade 1 and 2 GI and GU toxicities were common during radiotherapy, most resolved at 3 months after radiotherapy. Conclusion A moderately hypofractionated IMPT targeting the prostate/seminal vesicles and regional pelvic lymph nodes was well tolerated with no acute grade ≥ 3 GI or GU toxicity. Patients with baseline GU symptoms had a higher rate of acute grade 2 GU toxicity.

Dataset Information

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).

Publications

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).

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