Rochelle J. Botten

Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Carcinoma: Final Results of Phase III Randomized Trial

PURPOSE To evaluate the long-term efficacy and toxicity of a hypofractionated (55 Gy in 20 fractions within 4 weeks) vs. a conventionally fractionated (64 Gy in 32 fractions within 6.5 weeks) dose schedule for radiotherapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS A total of 217 patients were randomized to either the hypofractionated (n=108) or the conventional (n=109) dose schedule. Most patients (n=156) underwent RT planning and RT using a two-dimensional computed tomography method. Efficacy using the clinical, radiologic, and prostate-specific antigen data in each patient was evaluated before RT and at predetermined intervals after RT until death. Gastrointestinal and genitourinary toxicity using the modified Late Effect in Normal Tissue-Subjective Objective Management Analytic (LENT-SOMA) scales was also evaluated before and at intervals after RT to 60 months. RESULTS The whole group has now been followed for a median of 90 months (range, 3-138). Of the 217 patients, 85 developed biochemical relapse (nadir prostate-specific antigen level+2 μg/L), 36 in the hypofractionated and 49 in the conventional group. The biochemical relapse-free, but not overall, survival at 90 months was significantly better with the hypofractionated (53%) than with the conventional (34%) schedule. Gastrointestinal and genitourinary toxicity persisted 60 months after RT and did not differ between the two dose schedules. Multivariate analyses revealed that the conventional schedule was of independent prognostic significance, not only for biochemical failure, but also for an increased risk of worse genitourinary symptoms at 4 years. CONCLUSIONS A therapeutic advantage of the hypofractionated compared with the conventional dose schedule for RT of prostate cancer was evident at 90 months in the present study.

Evidence for efficacy without increased toxicity of hypofractionated radiotherapy for prostate carcinoma: early results of a Phase III randomized trial.

PURPOSE We performed a randomized trial to compare the GI and urogenital toxicity of radiotherapy (RT) for localized (confined to the organ), early-stage (T1-T2N0M0, TNM classification) carcinoma of the prostate, using a conventional (64 Gy in 32 fractions within 6.5 weeks) vs. a hypofractionated (55 Gy in 20 fractions within 4 weeks) schedule and to determine the efficacy of the respective treatment schedules. METHODS AND MATERIALS This report is based on an interim analysis of the first 120 consecutive patients in this Phase III trial after a median follow-up of 43.5 months (range 23-62). RT planning was based on two-dimensional CT data, and the treatment was delivered using a three- or four-field 6-23-MV photon technique. GI and urogenital toxicity (symptom questionnaires incorporating the subjective elements of the late effects of normal tissues-subjective, objective, management, analytic classification of late effects and the European Organization for Research and Treatment of Cancer sexual function questionnaire) were evaluated before RT and 1 month, 1 year, and 2 years after RT completion. The efficacy of RT was assessed clinically (digital rectal examination and radiologic imaging) and biochemically (prostate-specific antigen assay) at baseline, and every 3 months for 2 years after RT and every 6 months subsequently. RESULTS RT, whether conventional or hypofractionated, resulted in an increase in all six symptom categories used to characterize GI toxicity and in four of five symptom categories used to document urinary morbidity 1 month after therapy completion. Sexual dysfunction (based on limited data), which existed in more than one-third of patients before RT, also increased to just more than one-half of patients 1 month after RT. The increase in urinary toxicity after RT was not sustained (diurnal urinary frequency had decreased significantly at 2 years). In contrast, all six symptom categories of GI toxicity remained increased 1 year after RT. Four of the six GI symptom categories (rectal pain, mucous discharge, urgency of defecation, and rectal bleeding) were still increased at 2 years compared with baseline. Except for a slightly greater percentage of patients experiencing mild rectal bleeding at 2 years among those who received hypofractionated RT, no differences were noted in toxicity between the conventional and hypofractionated RT schedule. The mean prostate-specific antigen level was 14.0 +/- 1.0 ng/mL at baseline and declined to a nadir of 1.3 +/- 0.2 ng/mL at a median of 16.8 months (range 0.8-28.3) after RT completion. However, it then rose in 17 patients (8 in the hypofractionated and 9 in the conventional treatment group). Only 8 of these 17 patients were found to have signs of clinical relapse (5 local, 1 regional lymph node, and 2 systemic [bony metastases]) after histopathologic and radiologic reassessment). The remaining 9 patients had biochemical relapse only (defined as three consecutive rises in prostate-specific antigen after nadir). The 4-year biochemical relapse-free survival rate was 85.8% for all patients and did not differ significantly between the two radiation dose schedules (86.2% for the hypofractionated and 85.5% for the conventional fractionation group). CONCLUSION RT for prostate carcinoma, using a three- or four-field 6-23-MV photon technique without posterior shielding of the lateral fields, is an underestimated cause of persistent GI morbidity. The incidence of clinically significant GI and urogenital toxicity after conventional and hypofractionated RT appears to be similar. Hypofractionated RT for carcinoma of the prostate seems just as effective as conventional RT after a median follow-up approaching 4 years.

Chronic effects of therapeutic irradiation for localized prostatic carcinoma on anorectal function.

PURPOSE To evaluate prospectively the prevalence and pathophysiology of anorectal dysfunction following radiation therapy (RTH) for localized carcinoma of the prostate. METHODS AND MATERIALS The following parameters of anorectal function were evaluated in each of 35 patients (aged 55-82 years) with localized prostatic carcinoma treated with RTH either to a dose of 55 Gy/20 fractions/4 weeks (18 patients) or 64 Gy/32 fractions/6.5 weeks (17 patients), before RTH and 4-6 weeks and at a mean (+/- SD) of 1.4 (+/- 0.2) years after its completion: (1) anorectal symptoms (questionnaire), (2) anorectal pressures at rest and in response to voluntary squeeze and increases in intra-abdominal pressure (multiport anorectal manometry), (3) rectal sensation (balloon distension) and (4) anal sphincteric morphology (endoanal ultrasound). RESULTS All but 1 patient completed three series of measurements. RTH had no effect on anal sphincteric morphology. The increase in frequency of defecation and fecal urgency and incontinence scores previously reported in the patients 4-6 weeks after RTH were sustained 1 year later (p < 0.001, p < 0.001, and p < 0.05, cf. baseline, respectively). At this time, 56% (19 of 34), 50% (17 of 34) and 26% (9 of 34) of the patients had increased frequency of defecation, fecal urgency, and incontinence, respectively. Decreases in anal sphincteric pressures at rest and in response to voluntary squeeze recorded in the patients 4-6 weeks after RTH were not sustained 1 year later but the volumes of rectal distension associated with perception of the stimulus and desire to defecate were lower compared with baseline volumes (p < 0.01 and p < 0.05, respectively), reflecting heightened rectal sensitivity in the patients. There was no difference in measurements between the two radiation dose regimens. Univariate logistical regression analysis was performed on patients who had experienced increased symptom scores or decreases in recorded motor and sensory manometric parameters at 1 year, cf. baseline. The predictor variables used included individual patient tumor and treatment characteristics as well as individual patient symptom scores and parameters of anorectal motor and sensory function at baseline and 4-6 weeks after RTH. The results of the univariate logistical regression analysis showed that (1) frequency of defecation at 4-6 weeks and (2) rectal volumes at baseline both for (a) perception (p < 0.001) and (b) desire to defecate (p < 0.001), predicted significantly for the patients who had symptoms and signs of anorectal dysfunction at 1 year. Individual patient tumor and treatment-related variables tested, in contrast, had no predictive significance. CONCLUSIONS Anorectal symptoms following RTH for prostatic carcinoma are common and persist at least until 1 year after its completion and are associated with objective evidence of heightened rectal sensitivity.

Acute effects of therapeutic irradiation for prostatic carcinoma on anorectal function

Aim—The incidence of anorectal symptoms after radiotherapy (RTH) for localised pelvic malignant disease is unclear. In addition, the effects of pelvic irradiation on both anorectal motility and sensory function are poorly defined. A prospective study was therefore performed on 35 patients (55–82 years of age) with localised prostatic carcinoma before and four to six weeks after RTH to assess its effects on anorectal function. Methods—Anorectal symptoms were assessed by questionnaire. Anorectal pressures at rest and in response to voluntary squeeze, rectal distension, and increases in intra-abdominal pressure were evaluated with perfused sleeve side hole manometry. Rectal sensation was tested during graded balloon distension. Rectal compliance was calculated by the pressure-volume relation obtained during the testing of rectal sensation. Ultrasound was used to determine anal sphincter structure and integrity. Results—RTH had no effect on anal sphincter morphology. The frequency of defecation increased after RTH (7 (3–21) v 10 (3–56) bowel actions a week; p<0.01). After RTH, 16 patients had faecal urgency and eight faecal incontinence, compared with five and one respectively before RTH (p<0.01 for each). Basal and squeeze sleeve recorded pressures were reduced after RTH (54 (3)v 49 (3) mm Hg (p<0.05) and 111 (8)v 102 (8) mm Hg (p<0.01), before and after RTH respectively; means (SEM)). Rectal compliance was reduced after RTH (1.2 v 1.4 mm Hg/ml, p<0.05). After RTH, threshold volumes for perception of rectal distension were lower in the 16 patients who either experienced faecal urgency for the first time (13 patients) or reported worsening of this symptom (three patients) compared with the remaining patients (34 (4)v 48 (5) ml respectively, p<0.05). Conclusion—Faecal incontinence (23%) is a common problem four to six weeks after RTH for prostatic carcinoma and is associated with minor reductions in anal sphincter pressures. The high prevalence of faecal urgency in patients after RTH may be related to alterations in rectal perception of stool.

Anorectal Dysfunction Increases with Time Following Radiation Therapy for Carcinoma of the Prostate

OBJECTIVES:To characterize the prevalence and pathophysiology of anorectal dysfunction up to 2 yr following radiation therapy (RT) for localized carcinoma of the prostate.METHODS:Thirty-eight patients, median age 68 (range 60–82) yr with localized prostate carcinoma randomly assigned to one of two radiation dose schedules, underwent evaluation of the following variables of anorectal function before RT, as well as 4–6 wk and 1 and 2 yr after its completion: (1) symptoms, (2) anorectal motility, (3) anorectal sensory function, and (4) anal sphincteric morphology.RESULTS:There was a persistent increase in anorectal symptoms after RT. At 2 yr, bowel frequency, urgency, and fecal incontinence were increased in 50%, 47%, and 26% of patients, respectively. After RT, there were progressive reductions of (1) basal anal pressures, (2) anal pressures in response to squeeze and increased intra-abdominal pressure, (3) rectal compliance, and (4) rectal volumes associated with sensory perception and the desire to defecate. The thickness of the external anal sphincter increased with time after RT. No difference was observed between the patients in the two radiation dose schedules.CONCLUSIONS:Anorectal dysfunction following RT for prostate carcinoma is an underestimated cause of morbidity, which progresses with time. The prevalence and pathophysiology of anorectal dysfunction is similar after treatment with two commonly used radiation dose schedules.

Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitus

Aims  To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus.

Anorectal Function After Three- Versus Two-Dimensional Radiation Therapy for Carcinoma of the Prostate

PURPOSE To compare the effects of (three-dimensional) 3D vs. two-dimensional (2D) radiation therapy (RT) for carcinoma of the prostate on the prevalence and pathophysiology of anorectal dysfunction. METHODS AND MATERIALS Anorectal symptoms, motility, sensory function, and anal sphincter morphology were evaluated before and up to 2 years after randomly assigned hypofractionated vs. conventionally fractionated RT in 67 patients (median age, 69 years; range, 54-82 years) with localized prostate carcinoma, using either a 3D (n = 29) or 2D (n = 38) treatment technique. RESULTS Anorectal symptoms increased 4 to 6 weeks after RT and persisted in both patient groups. At 2 years, abnormalities included increased stool frequency (55% vs. 53%, p = NS), urgency of defecation (72% vs. 47%, p < 0.05), fecal incontinence (28% vs. 26%, p = NS), and rectal bleeding (38% and 42%, p = NS). Anorectal motility and sensory function deteriorated after RT in both groups with reductions in basal anal pressures, anal pressures in response to squeeze, rectal compliance, and rectal volumes associated with the desire to defecate. External but not internal sphincter thickness changed in the treatment groups although in different directions. However no differences in motility or sensory function were detected between the groups. Baseline anorectal motility but not treatment technique and the hypofracionated schedule were of independent prognostic significance for anorectal motor dysfunction and rectal bleeding respectively at 2 years. CONCLUSION The prevalence and pathophysiology of anorectal dysfunction 2 years after RT for prostate carcinoma was largely independent of the treatment techniques used in this study.

Pathophysiology and Natural History of Anorectal Sequelae Following Radiation Therapy for Carcinoma of the Prostate

PURPOSE To characterize the prevalence, pathophysiology, and natural history of chronic radiation proctitis 5 years following radiation therapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS Studies were performed in 34 patients (median age 68 years; range 54-79) previously randomly assigned to either 64 Gy in 32 fractions over 6.4 weeks or 55 Gy in 20 fractions over 4 weeks RT schedule using 2- and later 3-dimensional treatment technique for localized prostate carcinoma. Each patient underwent evaluations of (1) gastrointestinal (GI) symptoms (Modified Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales including effect on activities of daily living [ADLs]); (2) anorectal motor and sensory function (manometry and graded balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before RT, at 1 month, and annually for 5 years after its completion. RESULTS Total GI symptom scores increased after RT and remained above baseline levels at 5 years and were associated with reductions in (1) basal anal pressures, (2) responses to squeeze and increased intra-abdominal pressure, (3) rectal compliance and (4) rectal volumes of sensory perception. Anal sphincter morphology was unchanged. At 5 years, 44% and 21% of patients reported urgency of defecation and rectal bleeding, respectively, and 48% impairment of ADLs. GI symptom scores and parameters of anorectal function and anal sphincter morphology did not differ between the 2 RT schedules or treatment techniques. CONCLUSIONS Five years after RT for prostate carcinoma, anorectal symptoms continue to have a significant impact on ADLs of almost 50% of patients. These symptoms are associated with anorectal dysfunction independent of the RT schedules or treatment techniques reported here.

Argon Plasma Coagulation Therapy Versus Topical Formalin for Intractable Rectal Bleeding and Anorectal Dysfunction After Radiation Therapy for Prostate Carcinoma

PURPOSE To evaluate and compare the effect of argon plasma coagulation (APC) and topical formalin for intractable rectal bleeding and anorectal dysfunction associated with chronic radiation proctitis. METHODS AND MATERIALS Thirty men (median age, 72 years; range, 49-87 years) with intractable rectal bleeding (defined as ≥1× per week and/or requiring blood transfusions) after radiation therapy for prostate carcinoma were randomized to treatment with APC (n=17) or topical formalin (n=13). Each patient underwent evaluations of (1) anorectal symptoms (validated questionnaires, including modified Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic and visual analogue scales for rectal bleeding); (2) anorectal motor and sensory function (manometry and graded rectal balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before and after the treatment endpoint (defined as reduction in rectal bleeding to 1× per month or better, reduction in visual analogue scales to ≤25 mm, and no longer needing blood transfusions). RESULTS The treatment endpoint was achieved in 94% of the APC group and 100% of the topical formalin group after a median (range) of 2 (1-5) sessions of either treatment. After a follow-up duration of 111 (29-170) months, only 1 patient in each group needed further treatment. Reductions in rectal compliance and volumes of sensory perception occurred after APC, but no effect on anorectal symptoms other than rectal bleeding was observed. There were no differences between APC and topical formalin for anorectal symptoms and function, nor for anal sphincteric morphology. CONCLUSIONS Argon plasma coagulation and topical formalin had comparable efficacy in the durable control of rectal bleeding associated with chronic radiation proctitis but had no beneficial effect on anorectal dysfunction.

Disturbed Colonic Motility Contributes to Anorectal Symptoms and Dysfunction After Radiotherapy for Carcinoma of the Prostate

PURPOSE To evaluate the role of colonic motility in the pathogenesis of anorectal symptoms and dysfunction after radiotherapy (RT) for carcinoma of the prostate. PATIENTS AND METHODS Thirty-eight patients, median age 71 (range, 50-81) years with localized prostate carcinoma randomized to one of two radiation dose schedules underwent colonic transit scintigraphy and assessment of anorectal symptoms (questionnaire), anorectal function (manometry), and anal sphincteric morphology (endoanal ultrasound) before and at 1 month and 1 year after RT. RESULTS Whole and distal colonic transit increased 1 month after RT, with faster distal colonic transit only persisting at 1 year. Frequency and urgency of defecation, fecal incontinence, and rectal bleeding increased 1 month after RT and persisted at 1 year. Basal anal pressures remained unchanged, but progressive reductions occurred in anal squeeze pressures and responses to increased intra-abdominal pressure. Rectal compliance decreased progressively in the patients, although no changes in anorectal sensory function ensued. Radiotherapy had no effect on the morphology of the internal and external anal sphincters. Distal colonic retention was weakly related to rectal compliance at 1 month, but both faster colonic transit and reduced rectal compliance were more frequent with increased fecal urgency. At 1 year, a weak inverse relationship existed between colonic half-clearance time and frequency of defecation, although both faster whole-colonic transit and reduced rectal compliance occurred more often with increased stool frequency. CONCLUSION Colonic dysmotility contributes to anorectal dysfunction after RT for carcinoma of the prostate. This has implications for improving the management of anorectal radiation sequelae.