Prostate adenocarcinoma definitive EBRT high-risk

• Intact prostate.

• High-risk prostate adenocarcinoma. See prostate adenocarcinoma risk category features table.

• N0 M0

• ECOG 0-2.

• Life expectancy >5 years.

Cautions

• Previous high dose radiation to the pelvis.

• Poor urinary and bowel function.

• Radiosensitising medications (e.g. methotrexate).

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Bilateral hip replacement.

• Non-rheumatoid collagen vascular disorders.

• Cardiac implantable electronic devices (CIEDs).

• Transurethral resection of the prostate (TURP).

Indications notes

• An alternative way to dose escalate is high dose rate (HDR) brachytherapy.
  • See ID 415 Prostate adenocarcinoma definitive brachytherapy HDR.

• If the patient has recently undergone a transurethral resection of the prostate (TURP) wait more than 3 months until urinary function has stabilised, before commencing radiation therapy.

• The use of a rectal spacer is optional.^r Caution where posterior extracapsular extension is present.

• Patients should be offered sexual counselling to manage potential late effects related to sexual function.

Androgen deprivation therapy (ADT)

• Androgen deprivation therapy is recommended for these patients. Risk factors should be considered in relation to individual co-morbidities.

Prostate only

 Prostate and elective pelvic lymph nodes

Prescription notes

• Elective nodal irradiation is optional in patients with intermediate and high-risk prostate cancer, based on assessment of risk factors. Although there is limited randomised evidence that treating the pelvic lymph nodes is superior to not treating nodes, a considerable proportion of randomised trials included nodal irradiation for patients with intermediate and high-risk prostate cancer.

• Consider isotoxic dose escalation to the GTV/dominant intraprostatic lesion (DIL) e.g. 67 Gy/20# or 82-95 Gy for conventionally fractionated prescriptions.^rr

• Dose prescriptions of 78 Gy EQD2, or slightly higher, to the prostate are favoured if they can be delivered safely using IGRT and/or IMRT/VMAT techniques and DVH constraints can be met.

• For patients where tolerability of treatment is a concern lower doses of 73.8-74 Gy EQD2, can be considered.

Prostate 

Elective nodal volumes

 Dominant intraprostatic lesion (DIL)

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume guides

• FROGG consensus guidelines for definitive EBRT in prostate adenocarcinoma.^r

• Radiographic and anatomic basis for prostate contouring errors and methods to improve prostate contouring accuracy.^r

• ESTRO ACROP consensus guidelines for localised prostate cancer.^r

• NRG oncology updated international consensus atlas on pelvic lymph node volumes for intact and post-operative prostate cancer.^r

OAR notes

• The reference committee strongly recommends that treating clinicians consider improving on these constraints based on departmental and patient-specific factors.

• When boosting DIL, prioritise OAR tolerance over DIL boost dose coverage.

• Refer to ID 3657 Prostate adenocarcinoma definitive EBRT prostate and pelvic lymph nodes for OAR constraints applicable to 25 fraction prostate and elective pelvic lymph node treatment.

Suggested OAR contouring atlases and guidelines

• RTOG  Pelvic normal tissue contouring guidelines for radiation therapy.^r

• ESTRO ACROP consensus guidelines of localised prostate cancer.^r

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Efficacy

Evidence suggests high-risk prostate cancer should be treated by multimodal therapy which may take the form of surgery, with or without radiation therapy (RT), and with or without androgen deprivation therapy (ADT), or dose-escalated RT with long-term ADT (RADAR).^rrr Recent results suggest further intensification of adjuvant therapy with the addition of systemic therapy, may further improve outcome for this group, but at the cost of greater toxicity.^rr Further trials and results are awaited to confirm the value of additional systemic agents.

Dose escalation

Dose­ escalated RT, using intensity modulated RT (IMRT) and daily image guided RT (IGRT), is the preferred RT treatment for high-risk prostate cancer. Dose escalation beyond 70 Gy has been evaluated in multiple studies, including:

• a meta-analysis of seven randomised controlled trials (RCTs) involving 2,812 patients by Viani et al.^r
• a comparative effectiveness study of five RCTs focused on high-risk patients (n = 13,538) by Kalbasi et al.^r
• a database analysis of 20,028 patients by Hall et al.^r
• a phase III trial conducted by Kuban et al.^r

Viani et al. found a significant reduction in the incidence of biochemical failure in patients with low, intermediate and high-risk localised prostate cancer, 24.8% with high dose RT versus 34.6% with conventional dose RT (p <0.0001).^r There was no difference in mortality and prostate cancer-specific mortality rates between high dose and conventional dose RT. On subgroup analysis, all subgroups showed a linear correlation between total dose of RT and biochemical failure. The analysis by Kalbasi et al. found dose escalated external beam RT (EBRT) (>75.6 Gy) was associated with improved overall survival for patients with high-risk prostate cancer (hazard ratio (HR) = 0.82, 95%  confidence interval (CI): 0.78-0.85, p <0.001) and for every incremental increase of approximately 2 Gy, there was a 6.3% reduction (95% CI:3.3-9.1%, p <0.001) in the hazard of death for high-risk patients.^r

© Int J Radiat Oncol Biol Physics 2009^r

Dominant intraprostatic lesion

It is now recognised that recurrence following prostate RT almost always occurs at the site of the dominant intraprostatic lesion (DIL), suggesting a potential role for dose-escalating the DIL to improve local control.^r This is further supported by the 10-year relapse pattern reported by Memorial Sloan Kettering Cancer Center (MSKCC).^r The key evidence supporting boosting the DIL comes from two trials: FLAME and DELINEATE.^rr

FLAME Trial^r

The FLAME trial was a randomised phase III trial involving 571 patients with intermediate (15%) and high-risk (84%) localised prostate cancer. Patients were randomised to receive either standard treatment: 77 Gy in 35 fractions (2.2 Gy per fraction) to the entire prostate (EQD2 81.1 Gy, α/β = 1.2), or standard treatment with a simultaneous integrated focal boost up to 95 Gy (2.7 Gy per fraction) (EQD2 115.8 Gy) targeting the macroscopic tumour visible on MRI. Elective regional lymph node irradiation was not performed.

Patients were planned using IMRT or VMAT techniques. DILs were contoured as gross tumour volumes (GTVs) using T2-weighted imaging (T2W), diffusion-weighted imaging (DWI), and dynamic contrast enhancement (DCE) MRI. There was no margin for clinical or planning target volume (PTV) for the boost. One or more GTVs could be contoured and treated. All patients had fiducials inserted for target verification during treatment.

The primary endpoint, 5-year biochemical disease-free survival (bDFS), was higher in the focal boost arm (92%) compared to the standard no-boost arm (85%). No differences were reported in prostate cancer-specific survival, overall survival, late toxicity, or health-related quality of life (HRQoL).

The Hypo-FLAME 3.0 trial (ClinicalTrials.gov ID NCT05705921 opens in a new tab or window) is currently underway, comparing whole prostate and DIL boost using an ultra hypofractionated schedule versus a moderately hypofractionated schedule.

DELINEATE Trial^r

The DELINEATE trial was a single centre phase II multi-cohort study involving 265 patients with intermediate (43%) and high-risk (57%) localised prostate cancer. Cohort A and C treated with a standard fractionation of 74 Gy in 37 fractions (2 Gy per fraction) to the prostate and seminal vesicles (PSV). Cohort C also received 60 Gy in 37 fractions to the pelvic lymph nodes. Both cohorts A and C included an integrated boost to 82 Gy (2.22 Gy per fraction) to the DIL. Cohort B patients were treated with a moderately hypofractionated technique of 60 Gy in 20 fractions (3 Gy per fraction) to the PSV and an integrated boost to 67 Gy (3.35 Gy per fraction) to the DIL.

Patients were planned with IMRT or VMAT techniques. DILs were identified using Prostate Imaging Reporting and Data System-1 (PI-RADS-1) criteria (score ≥3) and contoured as GTVs with T2W, DWI, and DCE MRI. A 2 mm margin was added for the PTV boost, excluding the urethra. Up to three DILs could be contoured and treated. Elective regional lymph node irradiation was not performed. All patients had fiducials inserted for target verification during treatment. The primary endpoint was late Radiation Therapy Oncology Group (RTOG) gastrointestinal toxicity at 1 year. Secondary endpoints were acute and late toxicity (clinician and patient reported) and freedom from biochemical/clinical failure at 5 years. The 1 year cumulative RTOG grade ≥2 gastrointestinal toxicity was 3.6% (Cohort A), 7.2% (Cohort B), and 8.4% (Cohort C). At 5 years, cumulative RTOG grade ≥2 gastrointestinal toxicity was: 12.8% (Cohort A), 14.6% (Cohort B)  and 20.7% (Cohort C). Cumulative RTOG grade ≥2 genitourinary toxicity at 5 years was: 12.9% (Cohort A) and 18.2% (Cohort B and C). The reported 5-year freedom from biochemical/clinical failure was: 98.2% (Cohort A), 96.7% (Cohort B) and 95.1% (Cohort C).

Androgen Deprivation Therapy (ADT)

The addition of ADT to RT has been shown to improve outcomes compared to radiation alone. Several recent studies have explored the question of ADT duration in the high-risk setting. There is growing evidence to support a duration of 18 months of ADT in combination with RT.

Bolla et al (EORTC 22991) randomised 819 patients with prostate cancer, intermediate-risk (75% of patients) and high-risk (25% of patients), to receive RT alone or RT plus ADT. Radiation doses were 70, 74 or 78 Gy, with ADT given during and following RT.^r After a median follow-up of 7.2 years, RT plus ADT improved biochemical progression-free survival compared to RT alone (HR = 0.53, 95% CI:0.42-0.67, p <0.001) irrespective of radiation doses. Clinical progression-free survival also showed statistically significant improvement, 88.7% for RT plus ADT, compared to 80.8% for RT alone (HR = 0.63, 95% CI:0.48-0.84, p = 0.001).

The use of ADT in combination with EBRT in patients with high-risk prostate cancer has been shown to improve prostate cancer-specific and overall survival in a number of key trials: SPCG7/SFUO3, Warde et al, TROG 96.10, RTOG 86.10, EORTC 22863, RTOG 85.31.^rrrrrr The 10-year outcomes of the EORTC 22863 trial showed significantly improved 10-year clinical disease-free survival, 10-year overall survival and 10-year prostate cancer mortality. High-risk patients (n = 415) were randomised to receive combined treatment (ADT during and 3 years following RT, n = 207) or RT alone (n = 208), with a median follow-up of 9.1 years.^r Overall survival was 58.1% for combined treatment, 39.8% for RT alone (HR = 0.6, 95% CI:0.45-0.80, p = 0.0004) and 10-year prostate cancer-specific mortality was 10.3% for combined treatment, versus 30.4% for RT alone  (HR = 0.38, 95%CI:0.24-0.60, p <0.0001). There was no significant difference in cardiovascular mortality between the treatment groups.

Fossa et al. reported on 10 and 15-year outcomes of the SPCG7/SFUO3 trial of 875 men (from Norway, Sweden and Denmark) with locally advanced disease, randomised to ADT alone (n = 439) versus ADT plus RT (n = 436).^r After a median of 7.6 years follow-up, the addition of ADT to RT more than halved the 10 and 15 year prostate cancer-specific mortality rates and substantially decreased overall mortality.

Warde et al. randomised 1,205 men with T3 or T4 prostate cancer to receive either ADT alone (n = 602) or ADT plus RT (n = 603), between 1995 and 2005​.^r With a median follow up of 6 years at time of analysis, 320 patients had died (175 in the ADT alone group and 145 in the ADT plus radiation group). The addition of ADT to radiation significantly improved overall survival at 7 years, 66% in the ADT alone group versus 74% in the ADT plus RT group (HR = 0.77, 95% CI:0.61-0.98, p = 0.033). The 7-year disease-specific deaths were 19% for ADT alone and 9% for ADT plus radiation (p = 0.001). A total of 346 patients developed progressive disease, 251 in the ADT alone group and 95 in the ADT plus radiation group.

© Lancet Oncol 2011^r

The Meta-Analysis of Randomised trials in Cancer of the Prostate (MARCAP) Consortium analysed 12 randomised trials involving 10,853 patients and evaluated the effect of ADT intensification in men with localised prostate cancer receiving RT, with a median follow-up of 11.4 years.^r The addition of ADT to radiation significantly improved metastasis-free survival and overall survival for both intermediate-risk and high-risk disease. The number-needed-to-treat (NNT) to prevent one distant metastasis event at 10 years was 18.0 (95% CI: 12.7–30.7) for intermediate-risk patients and 8.4 (95% CI: 6.0–13.8) for high-risk patients.

Duration of ADT

The optimal duration of ADT in the high-risk patient cohort has not been definitively determined. A number of phase III RCTs have been conducted to address the issue of timing. The key findings are listed below:

• EORTC 22961 – 970 men received EBRT plus 6 months of ADT and were randomised to observation (n = 483), or an additional 30 months of ADT(n = 487).^r At median follow-up of 6.4 years, the prolonged course of ADT was associated with a significant decrease in overall mortality compared to 6 months ADT, 5-year mortality 15.2% versus 19%, respectively (HR = 0.70, 95% CI:0.55-0.92). The 5-year cumulative prostate cancer-specific mortality was 3.2% for prolonged ADT versus 4.7% for short-term ADT.
• RTOG 92.02 - 10-year follow-up of 1,554 men with T2c-T4 prostate cancer, comparing radiation plus short-term ADT of 4 months to radiation plus long-term ADT of 24 months.^r RT plus long-term ADT, demonstrated a significant improvement in all endpoints, with the exception of overall survival:
  • Disease-free survival 13.2% versus 22.5%, p <0.0001.
  • Disease-specific survival 83.9% versus 88.7%, p = 0.0042.
  • Local progression 22.2% versus 12.3%, p <0.0001.
  • Distant metastasis 22.8% versus 14.8%, p <0.0001.
  • Biochemical failure 68.1% versus 51.9%, p <0.0001.
  • Overall survival 51.6% versus 53.9%, p = 0.36. On subgroup analysis of the Gleason score 8-10 group, long-term ADT showed an overall survival difference of 45.1% compared to 31.9% for short-term ADT, p = 0.0061.

The use of short-term neoadjuvant ADT (2-6 months) has been shown in some trials to provide improved benefit over RT alone in high-risk patients unable to tolerate long-term ADT.^rr

In a non-inferiority trial, Nabid et al. randomised 630 men with high-risk prostate cancer to receive either 18 or 36 months of ADT in combination with RT.^r At a median follow up of 9.4 years, 10-year overall survival was the same for both groups at 62%, with similar disease-specific survival of 92% and 91%, for 18 months and 36 months ADT, respectively.

The TROG 96.01 trial provides evidence that men with non-metastatic locally advanced cancers can be treated successfully with as little as 6 months neoadjuvant ADT before and during RT.^rThis trial randomised 818 men with T2b, T2c, T3 and T4 N0 M0 prostate cancer to receive RT alone, or 3 months of neoadjuvant ADT plus RT, or 6 months neoadjuvant ADT plus RT.^r At a median follow up of 10.6 years, compared with RT alone:

• 3 months of neoadjuvant ADT decreased the cumulative incidence of PSA progression (adjusted HR = 0.72, 95% CI:0.57-0.90, p = 0.003) and local progression (HR = 0.49, 95% CI:0.33-0.73, p = 0.0005), and improved event-free survival (HR = 0.63, 95% CI:0.52-0.77, p <0.0001).
• 6 months of neoadjuvant ADT further reduced PSA progression (HR = 0.57, 95% CI:0.46-0.72, p <0.0001) and local progression (HR = 0.45, 95% CI:0.30-0.66, p = 0.0001), and led to a greater improvement in event-free survival (HR = 0.51, 95% CI:0.42-0.61, p <0.0001). 
• 6 month neoadjuvant ADT decreased distant progression HR = (0.49, 95% CI:0.31-0.76, p = 0.001), prostate cancer-specific mortality (HR = 0.49, 95% CI:0.32-0.74, p = 0.0008), and all-cause mortality (HR = 0.63, 95% CI:0.48-0.83, p = 0.0008).

The TROG 03.04 RADAR trial randomised 1071 men with T2a (and Gleason score ≥7), or T2b-4 N0 M0 prostate cancer, to receive 6 months neoadjuvant ADT and RT with or without a further 12 months ADT.^r Two further treatment arms examined the addition of zoledronic acid to the 6 or 18 month ADT arms in a 2 by 2 factorial design. At a median follow-up of 10.4 years, 18 months of ADT was associated with a reduced prostate cancer-specific mortality of 9.7% compared to 13.3% with 6 months neoadjuvant ADT (absolute difference 3.7%, sub-hazard ratio = 0.70, 95% CI:0.3-7.1, adjusted p = 0.035).

© Lancet Oncol 2019^r 

The MARCAP meta-analysis demonstrated prolonging adjuvant ADT to at least 18 months was associated with further improvements in survival, with an NNT of 10.4 (95% CI: 7.6–16.4) for high-risk patients to avert one distant metastasis.^r However, neoadjuvant ADT did not show clear benefits and the authors concluded this should not be routinely recommended. The addition of ADT with RT and prolongation of the duration of ADT was associated with improvement in metastasis free survival across radiation therapy doses, risk groups, and patient ages. Future analyses will focus on optimising ADT duration and identifying genomic subsets that could benefit from shorter treatment.^r

The evidence appears to support a duration of 18 months of ADT, but the optimal duration for any individual patient requires careful consideration of a number of factors including disease related risk features and pre-existing medical co-morbidities. For further information related to ADT agents and toxicities refer to eviQ medical oncology for urogenital cancers.

Hypofractionation versus conventionally fractionated radiation therapy

The key evidence supporting hypofractionation is provided by a phase 3 multicentre international randomised non-inferiority trial (PROFIT) involving 1206 patients with intermediate-risk prostate cancer, receiving RT.^r PROFIT compared conventionally fractionated RT (78 Gy in 39 fractions; n = 598) with hypofractionated RT (60 Gy in 20 fractions; n = 608). The use of ADT was not permitted in this study. The primary end point was biochemical-clinical failure which was defined as the first occurrence of any of the following outcomes: PSA failure, hormonal intervention, clinical evidence of local or distant failure, or death from prostate cancer. After a median follow up of 6 years, the 5-year biochemical-clinical failure disease-free survival in both arms was 85% (95% CI:82-88%). The HR for the hypofractionated versus conventional arm was 0.96 (90% CI:0.77-1.20). The hypofractionated regimen was found to be non-inferior to the conventional regimen. In the hypofractionated arm, 10 deaths as a result of prostate cancer were observed, compared with 12 in the conventional arm (HR = 0.76, 95% CI:0.32-1.82). There was no significant difference for grade ≥3 late genitourinary or gastrointestinal toxicity. The hypofractionated arm observed significantly less late grade ≥2 gastrointestinal toxicity than the conventional arm.^r

Two other large, well powered, multicentre international non-inferiority randomised controlled trials, CHHiPP and RTOG 0415, have also reported non-inferior efficacy for hypofractionated regimens compared to conventional control arms.^rr

The CHHiP trial involved 3216 patients (73% with intermediate-risk prostate cancer and 15% with low-risk) randomly assigned to receive conventionally fractionated RT (74 Gy in 37 fractions) or one of two hypofractionated regimens (60 Gy in 20 fractions or 57 Gy in 19 fractions).^r Men with intermediate or high-risk disease also received 3-6 months of ADT before and during RT. Median follow-up was 62.4 months (IQR = 53.9-77.0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI:86.0-90.2%) in the conventional arm, 90.6% (95% CI:88.5-92.3%) in the hypofractionated 60 Gy arm, and 85.9% (95% CI:83.4-88.0%) in the hypofractionated 57 Gy arm. The hypofractionated 60 Gy regimen (n = 1074) was non-inferior to the conventional 74 Gy regimen (n = 1065) (HR = 0.84, 90% CI:0.68-1.03, pNI = 0.0018). Non-inferiority could not be claimed for the hypofractionated 57 Gy regimen (n = 1077) compared with conventional 74 Gy regimen (HR = 1.20, 90% CI:0.99-1.46, pNI = 0·48). Similar long-term side effects were observed between both the hypofractionated groups and the conventional group.^r

The RTOG 0415 study randomised 1115 patients with low-risk prostate cancer to receive conventionally fractionated RT (73.8 Gy in 41 fractions) (n = 542) or hypofractionated RT (70 Gy in 28 fractions) (n = 550).^r The use of ADT was not permitted in this study. After a median follow up of 5.8 years, the 5-year disease-free survival in the conventional arm was 85.3% (95% CI:81.9-88.1%) and 86.3% (95% CI:83.1-89.0%) in the hypofractionated arm. The HR for hypofractionated vs conventional fractionation was 0.85 (95% CI:0.64-1.14) with the hypofractionated regimen found to be non-inferior. There were no statistically significant differences in the early gastrointestinal and genitourinary toxicities; however, there was an increase in late grade 2-3 gastrointestinal and genitourinary toxicities observed in the hypofractionated arm (HR = 1.31-1.59).^r

The HYPRO trial showed non-superior disease control and a lack of non-inferiority for gastrointestinal and genitourinary toxicities of the hypofractionated regimen.^r HYPRO used a significantly higher biologically equivalent dose compared to other studies which potentially explains the increased toxicity.

Further review articles and guidelines have been published.^rrrrAll recommend moderate hypofractionation as a treatment option for select, well-informed patients. Although a caveat has been expressed regarding uncertainty of longer term outcomes, recently published data from randomised control trials with longer follow-up suggest the findings reported at 5-6 years do not change significantly at 8-9 years.^rrr

Prostate cancer risk category

Some caution should be given to the application of hypofractionated regimens in different risk settings. PROFIT enrolled intermediate risk patients only, RTOG 0415 cautions not to extrapolate results beyond the setting of low-risk prostate disease, and CHHiP enrolled patients with low, intermediate and high-risk disease, however, patients were predominantly in the intermediate-risk category.^rrr

IMRT and IGRT

PROFIT was the only trial to mandate IGRT for all patients, and the vast majority of the men in PROFIT received IMRT rather than 3DCRT.^r

Elective pelvic lymph node irradiation

Two RCTs demonstrated equivalent progression-free survival (PFS) with the addition of elective pelvic lymph node irradiation. RTOG 9413, a 2 × 2 factorial study, stratified 1,274 intermediate and high-risk prostate cancer patients (>15% risk of pelvic lymph node involvement) based on hormonal sequencing and radiation field. Patients were randomised to neoadjuvant hormonal therapy (NHT) and whole pelvis radiotherapy (WPRT); NHT and prostate only RT; WPRT and adjuvant hormonal therapy (AHT); or prostate only RT and AHT. After a median follow-up of 8.8 years (14.8 years for living patients), no significant PFS difference was seen between NHT + WPRT and prostate only RT + AHT.^r Similarly, GETUG-01 randomised 446 patients to either pelvic node + prostate or prostate-only radiation, showing no significant 10-year overall or event-free survival difference.^r

A more recent trial, POP-RT, randomised 224 high-risk prostate cancer patients (>20% pelvic lymph node risk) to prostate-only RT or prostate and pelvic node RT (68 Gy/25 fractions for prostate, with or without 50 Gy/25 fractions for nodes).^r POP-RT demonstrated a disease-free survival benefit with pelvic node RT (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P.002), differing from previous trials by using dose-escalated, moderately hypofractionated regimens and PSMA-PET in 80% of patients. Although gastrointestinal side effects were similar, POP-RT revealed a higher rate of genitourinary grade 2+ late toxicity with pelvic lymph node RT (20.0% vs 8.9%; P = .02).^r

When pelvic lymph nodes are included, several trials have explored simultaneous treatment with 44 Gy in 20 fractions to the pelvic nodes. The first study, with a median follow-up of 70 months, showed excellent pelvic control, with distant metastasis as the primary mode of failure.^r

Faria et al. 2020 reported long-term outcomes of a prospective phase I/II study of 105 patients with localised high-risk prostate cancer that were treated with 60 Gy/20 fractions (4 weeks) to the prostate and 44 Gy to the pelvic nodes.^r With a median follow-up of 74 months, they demonstrated that this regimen was effective, feasible, and well-tolerated, with low rates of late gastrointestinal and genitourinary toxicities.

Results from the PIVOTALboost^r and RTOG 0924 opens in a new tab or window trials are still awaited to clarify the role of pelvic nodal RT. The ongoing PEARLS trial opens in a new tab or window is currently recruiting patients, delivering 44 Gy in 20 fractions to uninvolved nodes with a boost of 51 Gy to involved nodes.^r

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below:

• CHHiP found no difference between the hypofractionated versus conventional treatment arms for patient-reported 2 and 5 year frequency or cumulative incidence of late bowel, bladder or sexual toxicities.^r
• Both the PROFIT and CHHiP trials reported an increased rate of early gastrointestinal grade ≥2 toxicity in the hypofractionated arm compared to the conventionally fractionated arm.^rr
• Late gastrointestinal grade ≥2 toxicity was reported as similar in both treatment arms in the CHHiP trial.^r The PROFIT trial reported reduced rates in the hypofractionated arm.^r
• Arcangeli et al. provides the longest follow-up and shows equivalent late toxicity rates between hypofractionated and conventionally fractionated radiation therapy.^r
• In a sub group analysis by Pollack et al. 2013, poor urinary function at baseline in the hypofractionated arm was associated with higher rate of late genitourinary grade ≥2 toxicity, although longer term follow-up showed no difference in patient reported QoL based on initial IPSS and fractionation schedule.^rr