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Quality of Life After Whole Pelvic Versus Prostate-Only External Beam Radiotherapy for Prostate Cancer: A Matched-Pair Comparison
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 1, pp. 23–28, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.05.054
CLINICAL INVESTIGATION
Prostate
QUALITY OF LIFE AFTER WHOLE PELVIC VERSUS PROSTATE-ONLY EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER: A MATCHED-PAIR COMPARISON MICHAEL PINKAWA, M.D., PH.D., MARC D. PIROTH, M.D., RICHARD HOLY, M.D., KARIN FISCHEDICK, M.D., JENS KLOTZ, M.D., DALMA SZE´KELY-ORBA´N, M.D., AND MICHAEL J. EBLE, M.D., PH.D. Department of Radiotherapy, RWTH Aachen University, Aachen, Germany Purpose: Comparison of health-related quality of life after whole pelvic (WPRT) and prostate-only (PORT) external beam radiotherapy for prostate cancer. Methods and Materials: A group of 120 patients (60 in each group) was surveyed prospectively before radiation therapy (RT) (time A), at the last day of RT (time B), at a median time of 2 months (time C) and >1 year after RT (time D) using a validated questionnaire (Expanded Prostate Cancer Index Composite). All patients were treated with 1.8- to 2.0-Gy fractions up to 70.2 to 72.0 Gy with or without WPRT up to 45 to 46 Gy. Pairs were matched according to the following criteria: age ± 5years, planning target volume ± 10 cc (considering planning target volume without pelvic nodes for WPRT patients), urinary/bowel/sexual function score before RT ± 10, and use of antiandrogens. Results: With the exception of prognostic risk factors, both groups were well balanced with respect to baseline characteristics. No significant differences were found with regard to urinary and sexual score changes. Mean bladder function scores reached baseline levels in both patient subgroups after RT. However, bowel function scores decreased significantly more for patients after WPRT than in those receiving PORT at all times (p < 0.01, respectively). Significant differences were found for most items in the bowel domain in the acute phase. At time D, patients after WPRT reported rectal urgency (>once a day in 15% vs. 3%; p = 0.03), bloody stools ($half the time in 7% vs. 0%; p = 0.04) and frequent bowel movements (>two on a typical day in 32% vs. 7%; p < 0.01) more often than did patients after PORT. Conclusion: In comparison to PORT, WPRT (larger bladder and rectum volumes in medium dose levels, but similar volumes in high dose levels) was associated with decreased bowel quality of life in the acute and chronic phases after treatment but remained without adverse long-term urinary effects. Ó 2011 Elsevier Inc. Prostate cancer, Radiotherapy, Whole pelvic radiotherapy, Quality of life, Toxicity.
of the prostate only, a maximal tumor control rate of 94–95%, 75–80%, and 60–70% could be reached in case of 100% local control within the prostate, respectively. However, inasmuch as prospective randomized studies comparing WPRT to prostate-only radiotherapy (PORT) could not clearly demonstrate a consistent benefit regarding biochemically recurrence-free survival (3, 8, 9), the application of WPRT is still controversial. Similarly, a benefit could not be clearly shown for the combination of WPRT with temporary high-dose-rate or permanent lowdose-rate brachytherapy (10, 11). In every treatment decision process, the potential benefit needs to be weighed against the potential risk and toxicity. Traditionally, toxicity is assessed according to the RTOG (Radiation Therapy Oncology Group)/EORTC (European
INTRODUCTION Whole pelvic radiotherapy (WPRT) is used for the treatment of high-risk prostate cancer, either in cases of pathologically confirmed lymph node metastases or in cases of a certain risk of lymph node involvement (1–3). Currently available imaging modalities have a low sensitivity to detect affected nodes (4, 5), so that patients who are estimated to have an increased risk of lymph node involvement—usually above 15%—are considered for WPRT. The Roach formula, which incorporates prostate-specific antigen (PSA) is frequently applied to estimate this risk: 2/3 PSA + 10 (Gleason score-6) (6). In an extended pelvic lymphadenectomy, lymph node metastases will be detected in about 5–6%, 20–25%, and 30–40% of low-, intermediate-, and high-risk prostate cancer patients, respectively (7). Consequently, with the treatment Reprint requests to: Michael Pinkawa, M.D., Ph.D., Department of Radiotherapy, University Hospital Aachen, Pauwelsstr. 30, 52057 Aachen, Germany. Tel: (+49) 241-8035314; Fax: (+49) 241-8082543; E-mail: [email protected]
Presented at the European Society for Therapeutic Radiology and Oncology 2010 Annual Meeting, September 12–16, Barcelona, Spain Conflict of interest: none. Received April 1, 2010, and in revised form May 4, 2010. Accepted for publication May 5, 2010. 23
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Organisation of Research and Treatment of Cancer) grading system (9), occasionally also the LENT SOMA (Late Effects in Normal Tissues; Subjective, Objective, Management, Analytic scales) grading (8). Currently available results suggest a predominantly increased gastrointestinal toxicity in the acute and/or late phases after treatment for WPRT in comparison to PORT (8, 9, 12). Quality of life (QoL) studies concerning this comparison are scarce. The QoL questionnaires have the advantage of revealing all grades of toxicity from the patient’s perspective. Baseline problems can be taken into account accurately. Physician-acquired information has been shown to poorly correlate with data collected from patient self-assessment questionnaires (13). In this study, a matched-pair analysis was performed comparing QoL of patients after WPRT and PORT. METHODS AND MATERIALS This prospective study was based on consecutive patients who were treated for localized T1–3N0M0 prostatic carcinoma with three-dimensional conformal radiotherapy in the years 2003 to 2007. The treatment was based on a treatment planning computed tomography (CT) scan with the patient in a supine position with a slice thickness of 5 mm. Patients were asked to have a full bladder for the planning CT scan and each radiotherapy fraction. In all scans, prostate volume, planning target volume (PTV), bladder, and rectum were delineated by identifying the external contours. The rectum enclosed the region from the anal canal to the rectosigmoid flexure. For radiotherapy of pelvic nodes, all bowel loops excluding the rectum were additionally contoured. The integral dose (area under the curve) was defined as the relation of the area under the dose–volume histogram curve to the total area, multiplied by 100. Treatment plans were calculated using a four-field box technique with 15-MeV photons and a multileaf collimator for both WPRT and PORT. The PTV was required to be enclosed by the 90% isodose relative to the International Commission on Radiation Units and Measurements reference point (14). WPRT was designed to cover the distal common iliac, internal iliac, external iliac, obturator, and presecral lymph nodes, with the superior border at the L5–S1 interspace. The total dose in the reference point was 45.0 or 46.0Gy at 1.8- or 2.0-Gy daily fractions. The treatment continued with the same technique as the primary PORT. The clinical target volume included the prostate with seminal vesicles, with a margin of 1.5 cm in the anterior/lateral and 1 cm in the craniocaudal and dorsal directions for the PTV. The total dose to the prostate in the reference point was 70.2 or 72 Gy at 1.8- or 2.0-Gy daily fractions. Seminal vesicles were excluded after reaching a dose of 66.0 or 66.6 Gy. Patients after treatment of the prostate without seminal vesicles (15) were excluded from this evaluation. Patients were surveyed prospectively before (time A), at the last day (B), and at a median time of 2 months (range, 6 weeks to 6 months) after (C) and 16 months (range, 12–20 months) after (D) radiotherapy using a validated questionnaire, the Expanded Prostate Cancer Index Composite (EPIC) (16, 17). The questionnaire comprises 50 items concerning the urinary, bowel, sexual, and hormonal domains for function and bothersomeness. The multiitem scale scores were transformed linearly to a 0–100 scale, with higher scores representing better QoL. Bowel function was assessed in a greater detail, classifying questions in irritative, incontinence, and bleeding subscales (18).
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Only patients with questionnaire results from both time A and time D were included in the analysis, resulting in an initial group of 61 patients after WPRT and 223 patients after PORT. For each patient in the WPRT subgroup, a PORT patient was matched according to the following criteria: age 5years, PTV 10 cc (considering PTV without pelvic nodes for WPRT patients), urinary/bowel/sexual function score 10 before radiotherapy, and use of antiandrogens. A single patient after WPRT could not be matched because of extremely low pretreatment QoL scores in all domains, so that 60 patients after WPRT and 60 patients after PORT resulted for the final evaluation including 60/60 (time A), 45/46 (time B), 59/55 (time C), and 60/60 (time D) questionnaires after WPRT/PORT. The questionnaire was handed over to the patients personally by one of the physicians at times A, B, and C. The number of questionnaires was the lowest at the end of radiotherapy (time B) because this point in time was limited to a single day (last radiotherapy fraction), and there was no second opportunity to fill out a missed questionnaire. Patients presented in the department 6 to 10 weeks after the end of treatment. Missed questionnaires in the acute phase (time C) and questionnaires 1 to 2 years after radiotherapy (time D) were sent to the patients with a return envelope. If a questionnaire was not returned within 4 weeks, patients were contacted by telephone and were urged to complete it. The median time after treatment and the respective ranges for the questionnaires C and D were the same for patients after WPRT and PORT. Statistical analysis was performed using the SPSS 17.0 (SPSS, Chicago, Ill), software. The Wilcoxon’s matched-pairs test was applied to determine differences between the treatment groups and longitudinal changes in specific subgroups of patients. To explore statistical QoL score differences between different subgroups at a specific time, the Mann-Whitney U test was used. Contingency table analysis with the chi-square test was performed to compare treatment groups with respect to categoric variables. All p values reported are two-sided; p < 0.05 is considered significant.
RESULTS Baseline patient characteristics and treatmentplan–related data are presented in Table 1, showing a well-balanced distribution with regard to patient age, prostate volume, PTV prostate (i.e., PTV for the patients in the PORT group and for patients in the WPRT group after finishing whole pelvis irradiation), comorbidities, neoadjuvant hormonal therapy, and bladder/rectum volumes in the planning CT scans. Owing to the selection process of patients for WPRT, these patients significantly more often presented with prognostic risk factors (PSA >10 ng/mL, Gleason score >6, T stage >2a), and 90% (n = 54) could be classified as high-risk patients (more than one risk factor or PSA >20 ng/mL or Gleason score >7 or T stage $3). Dose–volume histograms for the bladder (Fig. 1) and rectum (Fig. 2) demonstrate differences predominantly for low and medium dose levels. As presented in Table 2, patients were well matched according to the baseline urinary, bowel, and sexual function scores. Additionally, no other baseline scores were found to be significantly different. The only domain with significant differences between WPRT and PORT was the bowel domain (Table 2). Significant changes at time D relative to baseline scores, with mean differences >5 points, were found only for the bowel function
Whole pelvic vs. prostate-only radiotherapy d M. PINKAWA et al.
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Table 1. Demographic and treatment plan-related data Characteristic
WPRT (n = 60)
PORT (n = 60)
Patient age (y): median (range) Prostate volume (cc): median (range) PTV prostate (cc): median (range) PTV pelvis (cc): median (range) Three most frequent comorbidities Coronary heart disease Hypertension Diabetes % PSA #10 ng/mL % Gleason score #6 % T stage #2a % NHT Bladder volume (cc): median (range) Rectum volume (cc): median (range) AUC bladder (%): median (range) AUC rectum (%): median (range)
71 (56–81) 35 (15–114) 344 (197–506) 1,250 (665–2,293)
71 (56–82) 36 (12–98) 338 (164–539) —
23% 30% 8% 13%* 13%* 50%* 44% 192 (55–784) 113 (42–268) 66 (28–88)* 68 (48–83)*
27% 28% 12% 50%* 58%* 72%* 44% 175 (69–657) 95 (37–295) 45 (7–71)* 55 (27–78)*
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy; PTV = planning treatment volume; PSA = prostate-specific antigen; NHT = neoadjuvant hormonal therapy; AUC = area under the dose–volume histogram curve. * p < 0.01 for comparison between subgroups.
ences for urinary function were found neither for irritative symptoms nor for incontinence. There were no differences concerning the erectile function for WPRT in comparison to PORT. Rectal urgency and frequent bowel movements continued to be experienced by significantly more patients after WPRT even at time D, but a serious (occurring every day) incontinence was only rarely reported (a single patient vs. 2 patients after PORT vs. WPRT). In contrast to patients after PORT (0% at all points in time), a significant number of patients reported frequently occurring rectal bleeding after WPRT.
and bowel bother scores in the WPRT subgroup. With the exception of urinary bother, no significant differences were found in the urinary, sexual, and hormonal domains at time D in any of the subgroups. However, a difference of 4 points for the urinary bother score can be regarded as clinically insignificant. After larger changes in the acute phase during and at the end of treatment, scores nearly reached baseline levels at time C in these domains. Focussing on the irritative, incontinence, and bleeding subscores (Figs. 3–5), the greatest QoL changes in all subdomains at time B were well evident, again. Hardly any changes were found between the subscores at times C and D. The largest differences between the WPRT and PORT subgroups were also found at time B, with the most striking differences for the irritative subscores and the smallest for the bleeding subscores. Changes relative to baseline scores after WPRT in comparison to PORT differed significantly at all points in time. Selected symptoms are shown in Table 3, demonstrating a similar message as the actually calculated scores. Differ-
In this matched-pair comparison we demonstrated QoL differences between WPRT and PORT. External beam radiotherapy was associated with the largest urinary and bowel QoL in the acute phase at the end of treatment. However, differences between WPRT and PORT were found only in the bowel domain. These differences predominantly affected
Fig. 1. Dose–volume histogram for the bladder. WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Fig. 2. Dose–volume histogram for the rectum. WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
DISCUSSION
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Table 2. Function and bother scores (significant changes relative to baseline values at time A as bold numbers) Area Urinary function Urinary bother Bowel function Bowel bother Sexual function Sexual bother Hormonal function Hormonal bother
Treatment WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT
Time A: mean (quartiles) 94 (94;100;100) 92 (94;100;100) 86 (79;93;96) 84 (75;89;96) 95 (93;96;100) 94 (89;96;100) 96 (96;100;100) 94 (93;100;100) 22 (0;16;39) 24 (0;17;46) 51 (6;50;100) 61 (6;88;100) 84 (75;85;100) 82 (73;85;100) 89 (83;95;100) 86 (75;92;100)
Time B: mean (quartiles) 83 (74;90;100) 82 (69;85;96) 66 (46;70;82) 66 (49;68;87) 71* (58;73;88) 85* (78;87;96) 69* (46;79;89) 81* (62;89;100) 14 (0;3;27) 15 (0;3;35) 55 (13;69;100) 48 (0;28;100) 79 (70;80;95) 77 (70;80;95) 85 (75;88;100) 88 (75;88;100)
Time C: mean (quartiles)
Time D: mean (quartiles)
90 (84;100;100) 93 (94;95;100) 80 (61;89;96) 80 (71;82;96) 86* (75;93;96) 91* (89;99;100) 83 (74;96;100) 87 (82;96;100) 19 (0;8;36) 21 (0;18;35) 50 (0;56;94) 47 (0;31;100) 79 (70;80;95) 81 (70;85;100) 83 (78;92;100) 84 (72;92;100)
94 (94;100;100) 94 (94;97;100) 84 (75;91;96) 80 (66;86;96) 87* (81;93;96) 93* (89;93;100) 85 (75;96;100) 89 (86;96;100) 17 (0;11;30) 21 (0;13;35) 53 (14;59;72) 51 (0;50;100) 83 (75;88;100) 86 (79;90;100) 87 (79;88;100) 86 (82;92;100)
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy. * p < 0.05 for comparison between volume subgroups; quartiles = 25th, 50th, 75th percentiles.
the acute phase at the end of treatment. As a consequence of the patient selection for WPRT, baseline characteristics showed significant differences only regarding prognostic risk factors. It seems unlikely that worse prognostic risk factors might have an influence on the detected QoL differences. Differences in the urinary, sexual, and hormonal domains were not found. Generally low baseline sexual function scores have to be considered in this patient population because of the frequently given additional hormonal therapy (19) that was shown to be associated with a significant survival benefit for high-risk prostate cancer patients in randomized studies (2, 20). EPIC questionnaire measurements have the advantage of being most sensitive to changes in acute bowel toxicity in comparison to RTOG acute morbidity scoring criteria or proctoscopic toxicity scores
(21). According to data in the literature, mean QoL changes of below 5 points can be defined as clinically not significant, 5–10 as ‘‘little’’ changes, 10–20 as ‘‘moderate’’ changes, and >20 as ‘‘very much’’ changes (22). Applying these ranges for our data, in contrast to ‘‘little’’ bowel function changes after PORT at the end of treatment, ‘‘very much’’ changes after WPRT can be expected. After several weeks, ‘‘little’’ changes remained after WPRT. Bowel function recovered better after PORT, nearly reaching the baseline levels again. This difference remained at a similar level more than 1 year after treatment. Irritative changes (rectal urgency, frequency of bowel movements) were predominantly responsible for this difference in the acute and later phases. However, although frequent rectal bleeding concerned fewer than 10% of patients at any of the evaluated
Fig. 3. Mean bowel irritative scores. Cross-sectional comparison: significant difference between PORT and WPRT at times B (p < 0.01), C (p = 0.04), and D (p = 0.01). Longitudinal comparison relative to baseline values at time A: significant decrease after PORT only at time B (p < 0.01); significant decrease after WPRT at times B, C, and D (p < 0.01 for all comparisons). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Fig. 4. Mean bowel incontinence scores. Cross-sectional comparison: no significant differences between PORT and WPRT. Longitudinal comparison relative to baseline values at time A: no significant decrease after PORT; significant decrease after WPRT at times B (p < 0.01), C (p = 0.04), and D (p = 0.02). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Whole pelvic vs. prostate-only radiotherapy d M. PINKAWA et al.
Fig. 5. Mean bowel bleeding scores. Cross-sectional comparison: significant difference between PORT and WPRT only at time B (p = 0.03). Longitudinal comparison relative to baseline values at time A: no significant decrease after PORT; significant decrease after WPRT at times B (p < 0.01), C (p = 0.01), and D (p = 0.02). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
points in time, this symptom occurred only in the WPRT group in this analysis. A secondary evaluation of the RTOG 9413 compared WPRT with MPRT (‘‘mini-pelvis,’’ patients after PORT with a field size larger than 10 11cm2) and a smaller PORT (9). WPRT was shown to be associated with a significantly better biochemical control in comparison to MPRT or a smaller PORT. A significantly lower proportion of Grade 2 or higher acute and late genitourinary and gastrointestinal toxicities was found in the PORT subgroup in comparison with the MPRT and WPRT subgroups. Furthermore, late Grade 2 or higher gastrointestinal toxicities were significantly higher in the WPRT than in the MPRT subgroup. In contrast to these results, no differences in the urinary domain could be found in our study. A possible explanation
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could be better bladder filling in our patient group; a direct comparison is not possible because the bladder volume was not analyzed in the RTOG study. Prior publications have demonstrated a significant impact of bladder volume on urinary QoL changes (23, 24), so our patients were frequently and urgently instructed to come to treatment with a (comfortably) full bladder. Another explanation could be the application of three-dimensional conformal radiotherapy, which was not used in the RTOG 9413 study, resulting in a potentially better bladder sparing. Modern intensity-modulated radiation therapy techniques have the potential to spare the organs at risk even more efficiently (25) and to decrease QoL differences between PORT and WPRT. The GETUG-01 study did not find a benefit for WPRT in comparison to PORT considering progression-free survival (8). Neither was there a difference considering Grade 2 or higher acute (RTOG scale) or late (LENT SOMA scale) toxicities, with the exception of unexpectedly higher Grade 2 or higher acute urinary toxicity in the PORT arm. In the GETUG-01 trial, the treatment was performed with lower doses (<70 Gy for the majority of patients) and a lower volume (upper border at the S1–S2 interspace). Larger fractions ($2 Gy) were more frequently used in the PORT group and 1.8 Gy in the WPRT group, possibly explaining the increased acute urinary toxicity. It was the only currently available study with QoL assessment after WPRT in comparison to PORT, using the EORTC QLQ-C30 questionnaire, IPSS (International Prostatic Symptom Score) questionnaire, and SFI (Sexual Function Index) scales. No statistically detectable differences were observed between both arms. However, these questionnaires did not include any assessment of bowel QoL. Baseline QoL scores were not similar in both arms. This aspect was specifically respected in our evaluation.
Table 3. Selected symptoms Symptom Pain on urination $once a day Use of pads to control urinary leakage Very poor/no ability to have an erection Lack of energy $once a day Rectal urgency >once a day Uncontrolled leakage of stool >once a day Bloody stools $about half the time $Three bowel movements on a typical day Pain in the abdomen, pelvis, or rectum >once a week
Treatment WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT
Time A
Time B
Time C
Time D
3% 5% 4% 2% 49% 50% 16% 13% 2% 5% 0% 0% 0% 0% 8% 3% 2% 8%
34% 33% 7% 11% 67% 66% 29% 19% 52%* 13%* 12%y 2%y 9%y 0%y 34% 22% 31%y 13%y
9% 7% 9% 6% 56% 48% 21% 10% 17% 9% 7%y 0%y 3% 0% 24%y 9%y 12% 7%
0% 0% 5% 2% 57% 57% 13% 19% 15%y 3%y 3% 2% 7%y 0%y 32%* 7%* 15% 5%
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy. * p < 0.01. y p = 0.05 for comparison between volume subgroups.
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CONCLUSION In comparison to PORT, WPRT (larger bladder and rectum volumes in medium dose levels, but similar volumes in high dose levels) was associated with decreased bowel
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QoL in the short-term and long-term phases after treatment, but remained without adverse long-term urinary effects. No difference considering sexual function was found.
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doi:10.1016/j.ijrobp.2010.05.054
CLINICAL INVESTIGATION
Prostate
QUALITY OF LIFE AFTER WHOLE PELVIC VERSUS PROSTATE-ONLY EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER: A MATCHED-PAIR COMPARISON MICHAEL PINKAWA, M.D., PH.D., MARC D. PIROTH, M.D., RICHARD HOLY, M.D., KARIN FISCHEDICK, M.D., JENS KLOTZ, M.D., DALMA SZE´KELY-ORBA´N, M.D., AND MICHAEL J. EBLE, M.D., PH.D. Department of Radiotherapy, RWTH Aachen University, Aachen, Germany Purpose: Comparison of health-related quality of life after whole pelvic (WPRT) and prostate-only (PORT) external beam radiotherapy for prostate cancer. Methods and Materials: A group of 120 patients (60 in each group) was surveyed prospectively before radiation therapy (RT) (time A), at the last day of RT (time B), at a median time of 2 months (time C) and >1 year after RT (time D) using a validated questionnaire (Expanded Prostate Cancer Index Composite). All patients were treated with 1.8- to 2.0-Gy fractions up to 70.2 to 72.0 Gy with or without WPRT up to 45 to 46 Gy. Pairs were matched according to the following criteria: age ± 5years, planning target volume ± 10 cc (considering planning target volume without pelvic nodes for WPRT patients), urinary/bowel/sexual function score before RT ± 10, and use of antiandrogens. Results: With the exception of prognostic risk factors, both groups were well balanced with respect to baseline characteristics. No significant differences were found with regard to urinary and sexual score changes. Mean bladder function scores reached baseline levels in both patient subgroups after RT. However, bowel function scores decreased significantly more for patients after WPRT than in those receiving PORT at all times (p < 0.01, respectively). Significant differences were found for most items in the bowel domain in the acute phase. At time D, patients after WPRT reported rectal urgency (>once a day in 15% vs. 3%; p = 0.03), bloody stools ($half the time in 7% vs. 0%; p = 0.04) and frequent bowel movements (>two on a typical day in 32% vs. 7%; p < 0.01) more often than did patients after PORT. Conclusion: In comparison to PORT, WPRT (larger bladder and rectum volumes in medium dose levels, but similar volumes in high dose levels) was associated with decreased bowel quality of life in the acute and chronic phases after treatment but remained without adverse long-term urinary effects. Ó 2011 Elsevier Inc. Prostate cancer, Radiotherapy, Whole pelvic radiotherapy, Quality of life, Toxicity.
of the prostate only, a maximal tumor control rate of 94–95%, 75–80%, and 60–70% could be reached in case of 100% local control within the prostate, respectively. However, inasmuch as prospective randomized studies comparing WPRT to prostate-only radiotherapy (PORT) could not clearly demonstrate a consistent benefit regarding biochemically recurrence-free survival (3, 8, 9), the application of WPRT is still controversial. Similarly, a benefit could not be clearly shown for the combination of WPRT with temporary high-dose-rate or permanent lowdose-rate brachytherapy (10, 11). In every treatment decision process, the potential benefit needs to be weighed against the potential risk and toxicity. Traditionally, toxicity is assessed according to the RTOG (Radiation Therapy Oncology Group)/EORTC (European
INTRODUCTION Whole pelvic radiotherapy (WPRT) is used for the treatment of high-risk prostate cancer, either in cases of pathologically confirmed lymph node metastases or in cases of a certain risk of lymph node involvement (1–3). Currently available imaging modalities have a low sensitivity to detect affected nodes (4, 5), so that patients who are estimated to have an increased risk of lymph node involvement—usually above 15%—are considered for WPRT. The Roach formula, which incorporates prostate-specific antigen (PSA) is frequently applied to estimate this risk: 2/3 PSA + 10 (Gleason score-6) (6). In an extended pelvic lymphadenectomy, lymph node metastases will be detected in about 5–6%, 20–25%, and 30–40% of low-, intermediate-, and high-risk prostate cancer patients, respectively (7). Consequently, with the treatment Reprint requests to: Michael Pinkawa, M.D., Ph.D., Department of Radiotherapy, University Hospital Aachen, Pauwelsstr. 30, 52057 Aachen, Germany. Tel: (+49) 241-8035314; Fax: (+49) 241-8082543; E-mail: [email protected]
Presented at the European Society for Therapeutic Radiology and Oncology 2010 Annual Meeting, September 12–16, Barcelona, Spain Conflict of interest: none. Received April 1, 2010, and in revised form May 4, 2010. Accepted for publication May 5, 2010. 23
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Organisation of Research and Treatment of Cancer) grading system (9), occasionally also the LENT SOMA (Late Effects in Normal Tissues; Subjective, Objective, Management, Analytic scales) grading (8). Currently available results suggest a predominantly increased gastrointestinal toxicity in the acute and/or late phases after treatment for WPRT in comparison to PORT (8, 9, 12). Quality of life (QoL) studies concerning this comparison are scarce. The QoL questionnaires have the advantage of revealing all grades of toxicity from the patient’s perspective. Baseline problems can be taken into account accurately. Physician-acquired information has been shown to poorly correlate with data collected from patient self-assessment questionnaires (13). In this study, a matched-pair analysis was performed comparing QoL of patients after WPRT and PORT. METHODS AND MATERIALS This prospective study was based on consecutive patients who were treated for localized T1–3N0M0 prostatic carcinoma with three-dimensional conformal radiotherapy in the years 2003 to 2007. The treatment was based on a treatment planning computed tomography (CT) scan with the patient in a supine position with a slice thickness of 5 mm. Patients were asked to have a full bladder for the planning CT scan and each radiotherapy fraction. In all scans, prostate volume, planning target volume (PTV), bladder, and rectum were delineated by identifying the external contours. The rectum enclosed the region from the anal canal to the rectosigmoid flexure. For radiotherapy of pelvic nodes, all bowel loops excluding the rectum were additionally contoured. The integral dose (area under the curve) was defined as the relation of the area under the dose–volume histogram curve to the total area, multiplied by 100. Treatment plans were calculated using a four-field box technique with 15-MeV photons and a multileaf collimator for both WPRT and PORT. The PTV was required to be enclosed by the 90% isodose relative to the International Commission on Radiation Units and Measurements reference point (14). WPRT was designed to cover the distal common iliac, internal iliac, external iliac, obturator, and presecral lymph nodes, with the superior border at the L5–S1 interspace. The total dose in the reference point was 45.0 or 46.0Gy at 1.8- or 2.0-Gy daily fractions. The treatment continued with the same technique as the primary PORT. The clinical target volume included the prostate with seminal vesicles, with a margin of 1.5 cm in the anterior/lateral and 1 cm in the craniocaudal and dorsal directions for the PTV. The total dose to the prostate in the reference point was 70.2 or 72 Gy at 1.8- or 2.0-Gy daily fractions. Seminal vesicles were excluded after reaching a dose of 66.0 or 66.6 Gy. Patients after treatment of the prostate without seminal vesicles (15) were excluded from this evaluation. Patients were surveyed prospectively before (time A), at the last day (B), and at a median time of 2 months (range, 6 weeks to 6 months) after (C) and 16 months (range, 12–20 months) after (D) radiotherapy using a validated questionnaire, the Expanded Prostate Cancer Index Composite (EPIC) (16, 17). The questionnaire comprises 50 items concerning the urinary, bowel, sexual, and hormonal domains for function and bothersomeness. The multiitem scale scores were transformed linearly to a 0–100 scale, with higher scores representing better QoL. Bowel function was assessed in a greater detail, classifying questions in irritative, incontinence, and bleeding subscales (18).
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Only patients with questionnaire results from both time A and time D were included in the analysis, resulting in an initial group of 61 patients after WPRT and 223 patients after PORT. For each patient in the WPRT subgroup, a PORT patient was matched according to the following criteria: age 5years, PTV 10 cc (considering PTV without pelvic nodes for WPRT patients), urinary/bowel/sexual function score 10 before radiotherapy, and use of antiandrogens. A single patient after WPRT could not be matched because of extremely low pretreatment QoL scores in all domains, so that 60 patients after WPRT and 60 patients after PORT resulted for the final evaluation including 60/60 (time A), 45/46 (time B), 59/55 (time C), and 60/60 (time D) questionnaires after WPRT/PORT. The questionnaire was handed over to the patients personally by one of the physicians at times A, B, and C. The number of questionnaires was the lowest at the end of radiotherapy (time B) because this point in time was limited to a single day (last radiotherapy fraction), and there was no second opportunity to fill out a missed questionnaire. Patients presented in the department 6 to 10 weeks after the end of treatment. Missed questionnaires in the acute phase (time C) and questionnaires 1 to 2 years after radiotherapy (time D) were sent to the patients with a return envelope. If a questionnaire was not returned within 4 weeks, patients were contacted by telephone and were urged to complete it. The median time after treatment and the respective ranges for the questionnaires C and D were the same for patients after WPRT and PORT. Statistical analysis was performed using the SPSS 17.0 (SPSS, Chicago, Ill), software. The Wilcoxon’s matched-pairs test was applied to determine differences between the treatment groups and longitudinal changes in specific subgroups of patients. To explore statistical QoL score differences between different subgroups at a specific time, the Mann-Whitney U test was used. Contingency table analysis with the chi-square test was performed to compare treatment groups with respect to categoric variables. All p values reported are two-sided; p < 0.05 is considered significant.
RESULTS Baseline patient characteristics and treatmentplan–related data are presented in Table 1, showing a well-balanced distribution with regard to patient age, prostate volume, PTV prostate (i.e., PTV for the patients in the PORT group and for patients in the WPRT group after finishing whole pelvis irradiation), comorbidities, neoadjuvant hormonal therapy, and bladder/rectum volumes in the planning CT scans. Owing to the selection process of patients for WPRT, these patients significantly more often presented with prognostic risk factors (PSA >10 ng/mL, Gleason score >6, T stage >2a), and 90% (n = 54) could be classified as high-risk patients (more than one risk factor or PSA >20 ng/mL or Gleason score >7 or T stage $3). Dose–volume histograms for the bladder (Fig. 1) and rectum (Fig. 2) demonstrate differences predominantly for low and medium dose levels. As presented in Table 2, patients were well matched according to the baseline urinary, bowel, and sexual function scores. Additionally, no other baseline scores were found to be significantly different. The only domain with significant differences between WPRT and PORT was the bowel domain (Table 2). Significant changes at time D relative to baseline scores, with mean differences >5 points, were found only for the bowel function
Whole pelvic vs. prostate-only radiotherapy d M. PINKAWA et al.
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Table 1. Demographic and treatment plan-related data Characteristic
WPRT (n = 60)
PORT (n = 60)
Patient age (y): median (range) Prostate volume (cc): median (range) PTV prostate (cc): median (range) PTV pelvis (cc): median (range) Three most frequent comorbidities Coronary heart disease Hypertension Diabetes % PSA #10 ng/mL % Gleason score #6 % T stage #2a % NHT Bladder volume (cc): median (range) Rectum volume (cc): median (range) AUC bladder (%): median (range) AUC rectum (%): median (range)
71 (56–81) 35 (15–114) 344 (197–506) 1,250 (665–2,293)
71 (56–82) 36 (12–98) 338 (164–539) —
23% 30% 8% 13%* 13%* 50%* 44% 192 (55–784) 113 (42–268) 66 (28–88)* 68 (48–83)*
27% 28% 12% 50%* 58%* 72%* 44% 175 (69–657) 95 (37–295) 45 (7–71)* 55 (27–78)*
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy; PTV = planning treatment volume; PSA = prostate-specific antigen; NHT = neoadjuvant hormonal therapy; AUC = area under the dose–volume histogram curve. * p < 0.01 for comparison between subgroups.
ences for urinary function were found neither for irritative symptoms nor for incontinence. There were no differences concerning the erectile function for WPRT in comparison to PORT. Rectal urgency and frequent bowel movements continued to be experienced by significantly more patients after WPRT even at time D, but a serious (occurring every day) incontinence was only rarely reported (a single patient vs. 2 patients after PORT vs. WPRT). In contrast to patients after PORT (0% at all points in time), a significant number of patients reported frequently occurring rectal bleeding after WPRT.
and bowel bother scores in the WPRT subgroup. With the exception of urinary bother, no significant differences were found in the urinary, sexual, and hormonal domains at time D in any of the subgroups. However, a difference of 4 points for the urinary bother score can be regarded as clinically insignificant. After larger changes in the acute phase during and at the end of treatment, scores nearly reached baseline levels at time C in these domains. Focussing on the irritative, incontinence, and bleeding subscores (Figs. 3–5), the greatest QoL changes in all subdomains at time B were well evident, again. Hardly any changes were found between the subscores at times C and D. The largest differences between the WPRT and PORT subgroups were also found at time B, with the most striking differences for the irritative subscores and the smallest for the bleeding subscores. Changes relative to baseline scores after WPRT in comparison to PORT differed significantly at all points in time. Selected symptoms are shown in Table 3, demonstrating a similar message as the actually calculated scores. Differ-
In this matched-pair comparison we demonstrated QoL differences between WPRT and PORT. External beam radiotherapy was associated with the largest urinary and bowel QoL in the acute phase at the end of treatment. However, differences between WPRT and PORT were found only in the bowel domain. These differences predominantly affected
Fig. 1. Dose–volume histogram for the bladder. WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Fig. 2. Dose–volume histogram for the rectum. WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
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Table 2. Function and bother scores (significant changes relative to baseline values at time A as bold numbers) Area Urinary function Urinary bother Bowel function Bowel bother Sexual function Sexual bother Hormonal function Hormonal bother
Treatment WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT
Time A: mean (quartiles) 94 (94;100;100) 92 (94;100;100) 86 (79;93;96) 84 (75;89;96) 95 (93;96;100) 94 (89;96;100) 96 (96;100;100) 94 (93;100;100) 22 (0;16;39) 24 (0;17;46) 51 (6;50;100) 61 (6;88;100) 84 (75;85;100) 82 (73;85;100) 89 (83;95;100) 86 (75;92;100)
Time B: mean (quartiles) 83 (74;90;100) 82 (69;85;96) 66 (46;70;82) 66 (49;68;87) 71* (58;73;88) 85* (78;87;96) 69* (46;79;89) 81* (62;89;100) 14 (0;3;27) 15 (0;3;35) 55 (13;69;100) 48 (0;28;100) 79 (70;80;95) 77 (70;80;95) 85 (75;88;100) 88 (75;88;100)
Time C: mean (quartiles)
Time D: mean (quartiles)
90 (84;100;100) 93 (94;95;100) 80 (61;89;96) 80 (71;82;96) 86* (75;93;96) 91* (89;99;100) 83 (74;96;100) 87 (82;96;100) 19 (0;8;36) 21 (0;18;35) 50 (0;56;94) 47 (0;31;100) 79 (70;80;95) 81 (70;85;100) 83 (78;92;100) 84 (72;92;100)
94 (94;100;100) 94 (94;97;100) 84 (75;91;96) 80 (66;86;96) 87* (81;93;96) 93* (89;93;100) 85 (75;96;100) 89 (86;96;100) 17 (0;11;30) 21 (0;13;35) 53 (14;59;72) 51 (0;50;100) 83 (75;88;100) 86 (79;90;100) 87 (79;88;100) 86 (82;92;100)
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy. * p < 0.05 for comparison between volume subgroups; quartiles = 25th, 50th, 75th percentiles.
the acute phase at the end of treatment. As a consequence of the patient selection for WPRT, baseline characteristics showed significant differences only regarding prognostic risk factors. It seems unlikely that worse prognostic risk factors might have an influence on the detected QoL differences. Differences in the urinary, sexual, and hormonal domains were not found. Generally low baseline sexual function scores have to be considered in this patient population because of the frequently given additional hormonal therapy (19) that was shown to be associated with a significant survival benefit for high-risk prostate cancer patients in randomized studies (2, 20). EPIC questionnaire measurements have the advantage of being most sensitive to changes in acute bowel toxicity in comparison to RTOG acute morbidity scoring criteria or proctoscopic toxicity scores
(21). According to data in the literature, mean QoL changes of below 5 points can be defined as clinically not significant, 5–10 as ‘‘little’’ changes, 10–20 as ‘‘moderate’’ changes, and >20 as ‘‘very much’’ changes (22). Applying these ranges for our data, in contrast to ‘‘little’’ bowel function changes after PORT at the end of treatment, ‘‘very much’’ changes after WPRT can be expected. After several weeks, ‘‘little’’ changes remained after WPRT. Bowel function recovered better after PORT, nearly reaching the baseline levels again. This difference remained at a similar level more than 1 year after treatment. Irritative changes (rectal urgency, frequency of bowel movements) were predominantly responsible for this difference in the acute and later phases. However, although frequent rectal bleeding concerned fewer than 10% of patients at any of the evaluated
Fig. 3. Mean bowel irritative scores. Cross-sectional comparison: significant difference between PORT and WPRT at times B (p < 0.01), C (p = 0.04), and D (p = 0.01). Longitudinal comparison relative to baseline values at time A: significant decrease after PORT only at time B (p < 0.01); significant decrease after WPRT at times B, C, and D (p < 0.01 for all comparisons). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Fig. 4. Mean bowel incontinence scores. Cross-sectional comparison: no significant differences between PORT and WPRT. Longitudinal comparison relative to baseline values at time A: no significant decrease after PORT; significant decrease after WPRT at times B (p < 0.01), C (p = 0.04), and D (p = 0.02). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
Whole pelvic vs. prostate-only radiotherapy d M. PINKAWA et al.
Fig. 5. Mean bowel bleeding scores. Cross-sectional comparison: significant difference between PORT and WPRT only at time B (p = 0.03). Longitudinal comparison relative to baseline values at time A: no significant decrease after PORT; significant decrease after WPRT at times B (p < 0.01), C (p = 0.01), and D (p = 0.02). WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy.
points in time, this symptom occurred only in the WPRT group in this analysis. A secondary evaluation of the RTOG 9413 compared WPRT with MPRT (‘‘mini-pelvis,’’ patients after PORT with a field size larger than 10 11cm2) and a smaller PORT (9). WPRT was shown to be associated with a significantly better biochemical control in comparison to MPRT or a smaller PORT. A significantly lower proportion of Grade 2 or higher acute and late genitourinary and gastrointestinal toxicities was found in the PORT subgroup in comparison with the MPRT and WPRT subgroups. Furthermore, late Grade 2 or higher gastrointestinal toxicities were significantly higher in the WPRT than in the MPRT subgroup. In contrast to these results, no differences in the urinary domain could be found in our study. A possible explanation
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could be better bladder filling in our patient group; a direct comparison is not possible because the bladder volume was not analyzed in the RTOG study. Prior publications have demonstrated a significant impact of bladder volume on urinary QoL changes (23, 24), so our patients were frequently and urgently instructed to come to treatment with a (comfortably) full bladder. Another explanation could be the application of three-dimensional conformal radiotherapy, which was not used in the RTOG 9413 study, resulting in a potentially better bladder sparing. Modern intensity-modulated radiation therapy techniques have the potential to spare the organs at risk even more efficiently (25) and to decrease QoL differences between PORT and WPRT. The GETUG-01 study did not find a benefit for WPRT in comparison to PORT considering progression-free survival (8). Neither was there a difference considering Grade 2 or higher acute (RTOG scale) or late (LENT SOMA scale) toxicities, with the exception of unexpectedly higher Grade 2 or higher acute urinary toxicity in the PORT arm. In the GETUG-01 trial, the treatment was performed with lower doses (<70 Gy for the majority of patients) and a lower volume (upper border at the S1–S2 interspace). Larger fractions ($2 Gy) were more frequently used in the PORT group and 1.8 Gy in the WPRT group, possibly explaining the increased acute urinary toxicity. It was the only currently available study with QoL assessment after WPRT in comparison to PORT, using the EORTC QLQ-C30 questionnaire, IPSS (International Prostatic Symptom Score) questionnaire, and SFI (Sexual Function Index) scales. No statistically detectable differences were observed between both arms. However, these questionnaires did not include any assessment of bowel QoL. Baseline QoL scores were not similar in both arms. This aspect was specifically respected in our evaluation.
Table 3. Selected symptoms Symptom Pain on urination $once a day Use of pads to control urinary leakage Very poor/no ability to have an erection Lack of energy $once a day Rectal urgency >once a day Uncontrolled leakage of stool >once a day Bloody stools $about half the time $Three bowel movements on a typical day Pain in the abdomen, pelvis, or rectum >once a week
Treatment WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT WPRT PORT
Time A
Time B
Time C
Time D
3% 5% 4% 2% 49% 50% 16% 13% 2% 5% 0% 0% 0% 0% 8% 3% 2% 8%
34% 33% 7% 11% 67% 66% 29% 19% 52%* 13%* 12%y 2%y 9%y 0%y 34% 22% 31%y 13%y
9% 7% 9% 6% 56% 48% 21% 10% 17% 9% 7%y 0%y 3% 0% 24%y 9%y 12% 7%
0% 0% 5% 2% 57% 57% 13% 19% 15%y 3%y 3% 2% 7%y 0%y 32%* 7%* 15% 5%
Abbreviations: WPRT = whole pelvic radiation therapy; PORT = prostate-only radiation therapy. * p < 0.01. y p = 0.05 for comparison between volume subgroups.
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CONCLUSION In comparison to PORT, WPRT (larger bladder and rectum volumes in medium dose levels, but similar volumes in high dose levels) was associated with decreased bowel
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QoL in the short-term and long-term phases after treatment, but remained without adverse long-term urinary effects. No difference considering sexual function was found.
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