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Role of Principal Component Analysis in Predicting Toxicity in Prostate Cancer Patients Treated With Hypofractionated Intensity-Modulated Radiation Therapy
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, pp. e415–e421, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2011.01.024
CLINICAL INVESTIGATION
Prostate
ROLE OF PRINCIPAL COMPONENT ANALYSIS IN PREDICTING TOXICITY IN PROSTATE CANCER PATIENTS TREATED WITH HYPOFRACTIONATED INTENSITY-MODULATED RADIATION THERAPY DANNY VESPRINI, M.D.,*z MICHAEL SIA, M.D.,z GINA LOCKWOOD, M.MATH.,y DOUGLAS MOSELEY, PH.D.,z TARA ROSEWALL, M.SC.,z ANDREW BAYLEY, M.D.,z ROBERT BRISTOW, M.D., PH.D.,z PETER CHUNG, M.B.,z CYNTHIA MENARD, M.D.,z MICHAEL MILOSEVIC, M.D.,z PADRAIG WARDE, M.B.,z z AND CHARLES CATTON, M.D. *Department of Radiation Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada; yDepartment of Clinical Study Coordination and Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; and zRadiation Medicine Program, Princess Margaret Hospital, University Health Network, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada Purpose: To determine if principal component analysis (PCA) and standard parameters of rectal and bladder wall dose-volume histograms (DVHs) of prostate cancer patients treated with hypofractionated image-guided intensitymodulated radiotherapy (hypo-IMRT) can predict acute and late gastrointestinal (GI) toxicity. Methods and Materials: One hundred twenty-one patients underwent hypo-IMRT at 3 Gy/fraction, 5 days/week to either 60 Gy or 66 Gy, with daily online image guidance. Acute and late GI and genitourinary (GU) toxicity were recorded weekly during treatment and at each follow-up. All Radiation Therapy Oncology Group (RTOG) criteria toxicity scores were dichotomized as <2 and $2. Standard dosimetric parameters and the first five to six principal components (PCs) of bladder and rectal wall DVHs were tested for association with the dichotomized toxicity outcomes, using logistic regression. Results: Median follow-up of all patients was 47 months (60 Gy cohort= 52 months; 66 Gy cohort= 31 months). The incidence rates of $2 acute GI and GU toxicity were 14% and 29%, respectively, with no Grade $3 acute GU toxicity. Late GI and GU toxicity scores $2 were 16% and 15%, respectively. There was a significant difference in late GI toxicity $2 when comparing the 66 Gy to the 60 Gy cohort (38% vs. 8%, respectively, p = 0.0003). The first PC of the rectal DVH was associated with late GI toxicity (odds ratio [OR], 6.91; p < 0.001), though it was not significantly stronger than standard DVH parameters such as Dmax (OR, 6.9; p < 0.001) or percentage of the organ receiving a 50% dose (V50) (OR, 5.95; p = 0 .001). Conclusions: Hypofractionated treatment with 60 Gy in 3 Gy fractions is well tolerated. There is a steep dose response curve between 60 Gy and 66 Gy for RTOG Grade $2 GI effects with the dose constraints employed. Although PCA can predict late GI toxicity for patients treated with hypo-IMRT for prostate cancer, it provides no additional information over using more standard DVH parameters. Ó 2011 Elsevier Inc. Prostate cancer, Image-guided IMRT, Hypofractionation, Radiation toxicity, Principal component analysis.
INTRODUCTION
Data on radiotherapy (RT) dose response characteristics using clinical and experimental data suggest that prostate cancer has a low a/b value approximating 1.5, though this value remains under debate (5–7). A low a/b ratio implies an advantage to using larger fraction sizes with improved tumor control relative to total dose. If the a/b ratio of prostate is actually low, then it may be possible
Four randomized trials have shown improved biochemical relapse-free survival with radiation dose escalation of an additional 8 to 12 Gy for men with localized prostate cancer (1–4). This was achieved by extending standard 2 Gy/ fraction treatment courses using 3 dimensional conformal radiotherapy treatment techniques without image guidance.
Supplementary material for this article can be found at www.redjournal.org. Acknowledgment—The authors would like to thank Debbie Tsuji for clinical trials support and Lindsay Jacks for additional statistical support. Received July 21, 2010, and in revised form Jan 18, 2011. Accepted for publication Jan 18, 2011.
Reprint requests to: Dr. Charles Catton, M.D., Princess Margaret Hospital (UHN), 610 University Avenue, Toronto, ON M5G 2M9, Canada. Tel: (416) 946-2121; Fax: (416) 946-2111; E-mail: [email protected] Supported in part by funding from the Abbot Canadian Association of Radiation Oncologists Uro-Oncologic Radiation Awards competition. Conflict of interest: none. e415
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to provide effective radiation dose escalation with shorter radiation courses than are currently employed. The use of fewer hypofractionated treatments can potentially im-prove patient convenience and resource allocation. A potentially serious risk of adopting hypofractionation protocols is the increased risk from large doses per fraction on late normal tissue effects (8–10). This is clearly shown by the longterm results of hypofractionation on rectal cancer (11–13), where late damage to the rectum is seen many years after radiation. This risk may be mitigated by excluding normal tissues from the high-dose radiation volume as much as possible, and for prostate cancer, this includes the use of highly conformal treatment techniques such as intensity-modulated RT (IMRT) and optimization of the planning target volume (PTV) with Image-guided radiotherapy (IGRT). These techniques have been shown to be feasible and effective in phase II trials of hypofractionated RT and are presently being tested in a number of phase III trials (Medical Research Council/ Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer [MRC/CHHiP] [National Institutes of Health identifier: NCT00392535; David Dearnaley, Principal Investigator] (14), Ontario Clinical Oncology Group/ Prostate Fractionated Irradiation Trial (OCOG/PROFIT) [National Institutes of Health identifier: NCT00304759; Ch-arles Catton, Principal Investigator], and Radiation Therapy Oncology Group [RTOG] trial 0415 [National Institutes of Health identifier: NCT00331773; W. Robert Lee, Principal Investigator]). However, reliable information regarding normal tissue complications and its dependence on dose and volume need to be elucidated to continue safely with similar treatment protocols and to devise future hypofractionation protocols. The bladder and rectum are the dose-limiting organs for prostate cancer RT, with rectal bleeding requiring surgical intervention (RTOG Grades 3–4) being among the most severe of the complications encountered. Correlations between this late side effect and single points on the rectal dose-volume histograms (DVH) have been reported (15–24). The limitation to single-point analysis of DVH is that potentially critical dose volume information is lost that might best discriminate between treatment plans at high or low risk of complications. Principal component analysis (PCA) is a statistical tool that segregates DVHs with similar morphology, allowing the quantification of variability in DVH datasets. PCA provides the ability to compare common DVH characteristics to toxicity events without the loss of information that the use of simpler methods causes. PCA has been used to identify an association between reduced DVHs and the decreased risk of liver toxicity after partial liver irradiation, as well as the decreased risk of xerostomia after parotid gland irradiation (25). It has more recently been used to attempt to predict late toxicity to radiation in prostate cancer (20, 26, 27), though its application requires further analysis, especially with novel fractionation schemes. We previously reported early outcomes with hypofractionated RT in patients treated with 60 Gy in 20 fractions over 4 weeks. We now report the gastrointestinal (GI) and genitouri-
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nary (GU) toxicities observed with an extended study cohort and longer follow-up and determine if PCA or standard DVH parameters predict radiation-induced GI or GU toxicity. METHODS AND MATERIALS Study population The patient data set used consisted of 121 patients treated on a hypofractionation single- institution phase I–II open label prospective clinical trial (Table 1). Initial results for the first 92 patients treated to 60 Gy have been published previously (28). Toxicity analysis is presented for all patients. Corrupted archival tapes prevented radiation plan data retrieval for 19 patients. As a result, 102 patients were used in the DVH analysis and PCA.
Radiation treatment planning The treatment technique has been previously described (28), and patients undergoing radical RT were treated with IMRT and daily online IGRT on implanted fiducial markers. Intrafractional prostate movement was mitigated though the use of a daily bowel and bladder protocol (29). Neoadjuvant or adjuvant androgen deprivation therapy was not routinely employed, although it was allowed. The clinical target volume (CTV) consisted of the entire prostate gland and base of the seminal vesicles. The prostatic apex was defined in reference to the apical fiducial marker based on ultrasonographic localization. The PTV was defined as the CTV with an additional 10-mm margin anteriorly, superiorly, inferiorly, and laterally. The posterior PTV margin was 7 mm posterior to the prostate gland. The treatment volume was constructed to include the PTV within the 95% isodose line. Femoral heads, bladder wall, and rectal wall were contoured throughout the treatment volume (18 mm from CTV as appropriate) in order to construct DVHs of the organs at risk. For both the bladder and rectum, inner and Table 1. Baseline characteristics of all patients versus patients used in the PCA All patients (n = 121) PCA patients (n = 102) Variable
No. of patients
Median age 71.5 T stage T1c 59 T2a 49 T2b 10 T2c 3 Gleason score 6 51 7 67 8–10 3 Median initial 7.15 (range, PSA (ng/ml) 0.68–25.38) Risk stratification* Low 31 Intermediate 82 High 8 Assigned Dose 60 Gy 92 66 Gy 29
% of total
No. of patients
% of total
71.0 49 40 8 2
48 43 8 3
47 42 8 3
42 55 2
45 54 3 7.13 (range, 0.68–25.38)
44 53 3
26 68 7
26 69 7
25 68 7
76 24
73 29
72 28
Abbreviation: PSA = prostate-specific antigen. * Canadian consensus guidelines. Lukka H. Prostate cancer: risk categories and role of hormones and radiotherapy. Can J Urol. 2002 Jun;9 Suppl 1:26-9.
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outer walls were separately delineated so that only the organ wall was used in radiation planning and DVH construction.
Radiation prescription The dose prescribed for the first 92 patients analyzed in this study was 60 Gy in 20 fractions over 4 weeks, as reported by Martin et al. (28). Given the acceptable acute and late toxicity experienced in this initial cohort, an additional 29 patients were treated with 66 Gy in 22 fractions over 4.5 weeks, using the same technique, treatment volumes, and fraction size but different dose constraints (Table 2). All doses were prescribed to CTV minimum, and the PTV was contained within the 95% isodose line. The class dose solutions for the organs at risk are shown in Table 2. Treatment plans that failed to meet dose constraints resulted in patients being treated off study protocol with image-guided RT using standard fractionation.
Toxicity scoring As we have described previously, all patients self-reported with the assistance of a radiation therapist on a weekly and prospective basis (30) acute GI or GU reactions and toxicity, using the RTOG toxicity criteria (31). Patients were seen in follow-up at 4 to 8 weeks following the completion of treatment, every 6 months to 5 years, and annually thereafter. At each follow-up visit, data were collected on late bowel and bladder toxicity, digital rectal examination was performed, and serum prostate-specific antigen (PSA) concentration was tested. Toxicity occurring within 90 days of the start of treatment was considered ‘‘acute.’’ For both acute and late toxicity, the maximum (i.e., worst) toxicity score experienced was used for analysis. Patients were classified as having experienced toxicity if they scored $Grade 2 using RTOG toxicity criteria.
Statistical considerations Acute and late toxicity rates were compared between the 60 Gy and 66 Gy cohorts, using the exact Cochran-Armitage trend test.
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When there were only two levels in the RTOG variable (i.e., only level 0–1 and 2), this test was equivalent to Fisher’s exact test. The following dosimetric parameters were extracted from the treatment plan rectal wall and bladder wall DVHs: maximum dose (Dmax; to a contiguous volume of 1 cm3); percent volume of rectal/bladder wall receiving $30 Gy (V30); percent volume of rectal/ bladder wall receiving $40 Gy (V40); and percent volume of rectal/bladder wall receiving $50 Gy (V50). These dosimetric parameters were individually examined using logistic regression to test whether they were related to the probability of having $Grade 2 RTOG toxicity. Table 3 shows the estimates of the normalized total dose equivalent in 2 Gy fractionsfor the doses described in this study.
Principal component analysis The PCA was performed as previously described (ref 27), and summarized in Supplementary material online in Appendix 1. The first five and six PCs for bladder and rectum were examined using logistic regression to test whether they were related to the probability of having >Grade 2 RTOG rectal or bladder toxicity. Analysis was done on the entire analyzable cohort (102 patients), as well as separately for each dose cohort (60 Gy, n = 73; 66 Gy, n = 29). The correlation between principal components (PCs) and DVH parameters was analyzed using Pearson correlation coefficients.
RESULTS Patient characteristics A total of 121 patients treated on protocol from September 2004 to December 2005 were analyzed in this study. Baseline characteristics for all patients are shown in Table 1. The median age at last follow-up was 71.5 years. The median follow-up for all patients at last follow-up was 47 months (range, 3.7–79 months; 31 months for the 66 Gy cohort, and 52 months for the 60 Gy cohort.
Table 2. Dose constraints Site PTV CTV Bladder wall/ rectal wall
Femoral heads
60 Gy constraint
66 Gy constraint
Max 63 Gy; min 57 Gy Max 63 Gy; min 60 Gy Max 61 Gy
Max 69.3 Gy; min 62.7 Gy Max 69.3 Gy; min 66 Gy Max 68 Gy
V40 <70% Only portions of BW/RW contained in PTV received $57 Gy
V60 <82% V50 <78%
Max 40 Gy
Acute toxicity The maximum acute GI and GU acute toxicities are shown for the whole group and for each fractionation schedule in Table 4. Overall, the treatment regimens were well tolerated, with only a single patient (<1%) experiencing an acute GI toxicity score of 3. Otherwise, 16 patients (13%) experienced an acute GI toxicity score of 2, and 35 patients (29%) experienced an acute GU toxicity score of 2. No acute GU toxicity Grade $3 was identified. There was no apparent difference in acute toxicities when comparing the 60 Gy cohort to the 66 Gy cohort (p $ 0.49), although given the relatively small Table 3. Equivalent doses using different a/b ratios
V40 <50% Only portion of BW/RW contained in PTV receives $62.7 Gy Max 45 Gy
Abbreviations: PTV = planning target volume; CTV = clinical target volume; BW = bladder wall; RW = rectal wall; V60, -50, -40 = percent volume that receives 60, 50, or 40 Gy; Max = maximum dose.
Equivalent dose in 2 Gy/fraction at the ratio shown Dose (in 3 Gy fractions) 66 Gy 60 Gy 50 Gy 40 Gy 30 Gy
a/b = 1.5
a/b = 3
a/b = 5
a/b = 10
85 77 64 51 39
79 72 60 48 36
75 69 57 46 34
72 69 54 43 33
Data shown are equivalent doses in 2 Gy/fraction using different a/b ratios, using the linear quadratic formula.
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Table 4. Maximum RTOG acute toxicity Patients (n = 121)
Dose 60 Gy (n = 92)
Dose 66 Gy (n = 29)
RTOG No. of % of No. of % of No. of % of p score patients total patients total patients total value* GI 0–1 2 3 4 GU 0–1 2 3 4
0.78 104 16 1 0
86 13 1 —
80 11 1 0
87 12 1 —
24 5 0 0
83 17 — —
86 35 0 0
71 29 — —
67 25 0 0
73 27 — —
19 10 0 0
66 34 — —
0.49
* Exact Cochran-Armitage trend test was used to compare Grade 4 toxicity between dose groups.
number of patients in the 66 Gy cohort (n = 29), we cannot exclude smaller differences in toxicity. Similar results were seen when restricting analysis to only the 102 patients used in the PCA (data not shown). Late toxicity The maximum late GI and GU and acute toxicities are shown for the whole group and for each fractionation schedule in Table 5 and Fig. 1. The most severe toxicities recorded were identified during follow-up, and toxicity continued to be collected after patients went on to salvage therapy. A total of 8 patients were treated with salvage androgen deprivation therapy, of which 3 patients experienced a late toxicity. Salvage therapy did not influence recorded late toxicity, in as much as all of these events occurred prior to salvage therapy being initiated. Three of the original 121 patients were lost to follow-up soon after treatment and were excluded from late toxicity analysis. A total of 18 patients (16%) experienced late GI toxicity score of $2 (only 2 patients had Grade 3, and 1 patient had Grade 4), Table 5. Maximum RTOG late toxicity All patients (n = 118)
Dose 60 Gy (n = 89)
Dose 66 Gy (n = 29)
RTOG No. of % of No. of % of No. of % of p score patients total patients total patients total value* GI 0–1 2 3 4 GU 0–1 2 3 4
0.0005 100 15 2 1
85 13 2 1
82 6 1 0
92 7 1 —
18 9 1 1
62 31 3 3
101 16 1 0
86 14 1 —
76 13 0 0
85 15 — —
25 3 1 0
86 10 3 —
0.78
* Exact Cochran-Armitage trend test was used to compare the four level toxicity versus dose group. For GI late toxicity, dichotomizing patients into RTOG score <2 versus $2, there was a highly significant increase in toxicity comparing the 66 Gy versus 60 Gy cohort (38% vs. 8%, respectively; p = 0.0003).
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while 17 patients (15%) experienced a late GU toxicity score of $2 (of which only 1 patient had Grade 3). Although the number of late toxicity events is small, there was increased late GI toxicity scores of $2 in patient treated with the 66 Gy fractionation regimen (median follow-up, 31 months), as 11 patients (38%) treated with 66 Gy experienced $Grade 2 long-term toxicity, while only 7 patients (8%) of the 60 Gy cohort (median follow-up, 52 months) experienced $Grade 2 toxicity (p = 0.0003). The estimated late $2 Grade GI toxicity rate at 3 years for patients treated with 60 Gy was 7.1% (95% confidence interval [CI], 1.1–13.2) versus 40.6% (95% CI, 21.4–59.8) for patients treated with 66 Gy. There was no statistical difference in late GU toxicity between the groups (p = 0.8). When this analysis was applied to only those 102 patients used in the PCA, similar results were seen (data not shown). The cumulative incidence of maximum late toxicity in patients used for the PCA is displayed in Fig. 1. Principal components Corrupted archival tapes prevented data retrieval for 19 patients. Of these 19 patients, 3 and 4 patients had acute GI and GU toxicity scores of $2, respectively; 2 patients had late GI toxicity scores of 2; and no patients had late GU toxicity scores of $2. Therefore, 102 patients were used in the DVH and PCA. Baseline characteristics of these patients are included separately in Table 1. The median age at last follow-up for these patients was 71.0 years old. The median follow-up for all patients included in the PCA at last followup was 43 months (range, 3.7–78 months). Principal component analysis was completed for both the bladder and rectal wall data sets. The first PC (PC1) was associated with the largest variance in the data set, PC2 with the next largest, and so on. A value of 95% of the bladder wall variance was described by the first five PCs (the first PC representing 68%), while 91% of the rectal wall variance was described by the first six PCs (with the first PC accounting for 61%). PC1 was highly correlated to mean dose (the mean of the individual voxel doses that belong to that region of interest, i.e., bladder or rectum) and Dmax in both the GU and GI toxicity analyses (Pearson correlation coefficients: GU, r = 0.997, and r = 0.818; GI, r = 0.996, and r = 0.832, respectively; p < 0.0001 for all). Association of DVH with toxicity Prescribed dose, DVH variables, and PCs were examined using univariate logistic regression analysis to test whether they were related to the probability of experiencing toxicity (i.e., RTOG toxicity score of $2). Total dose was not associated with acute GI or GU toxicity (Table 6), though given the increased incidence of late GI toxicity reported above, receiving a prescribed dose of 66 Gy not unexpectedly predicted for late GI toxicity in the logistic regression analysis (odds ratio [OR], 8.31; 95% CI, 2.56–26.99; p = 0.0004) (Table 7). The standard DVH parameters used in this analysis are listed in Tables 6 and 7. There was a borderline association between V40, V50, and PC3 and acute GU toxicity (OR, 1.81; 95% CI, 2.16–0.56; p = 0.05, 0.04, and 0.06, respectively) (Table
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Fig. 1. Cumulative incidence of maximum late GU (A) and GI (B) toxicity in patients used for PCA (n = 102).
6), though none of the parameters predicted for acute GI (rectal wall) toxicity. In contrast, all of the standard DVH parameters examined were strongly associated with late GI toxicity, with ORs ranging from 3.71 and 6.90 (all p # 0.001) (Table 7). When logistic regression analysis was applied to the PCs of the rectal wall DVH, although the PC1 was also strongly associated with late GI toxicity (OR, 6.91; p < 0.001), this was not superior to Dmax, and although the OR estimate was higher than the other standard variables, their CIs overlapped. Comparison of these ORs for developing late GI toxicity is shown as a forest plot in Fig. 2. None of the standard DVH variables or any of the PCs predicted for late GU toxicity (Table 7). When independent analysis was separately performed for the 60 Gy and 66 Gy dose groups, the number of acute and late events were too low to provide enough statistical power to detect a significant association with any of the parameters and toxicity (data not shown). Table 6. Acute toxicity using univariate logistic regression of other parameters Rectal wall
DISCUSSION The role of hypofractionation for prostate cancer is unproven but remains a matter of clinical significance, given the published (32–34) and ongoing randomized clinical trials for the treatment of prostate cancer, MRC/CHHiP (NCT00392535; David Dearnaley, Principal Investigator) (14), OCOG/PROFIT (NCT00304759; Charles Catton, Principal Investigator), and RTOG 0415 (NCT00331773; W. Robert Lee, Principal Investigator). Our study demonstrates that 60 Gy delivered in 20 daily fractions over 4 weeks is well tolerated using our RT technique and dose constraints, although there is likely a steep dose response curve for late rectal toxicity when escalating dose from 60 Gy/20 fractions to 66 Gy/22 fractions. This potential clinical barrier is important given the different doses under clinical observation or being discussed for investigation.
Table 7. Late toxicity univariate logistic regression of other parameters
Bladder wall
Rectal wall
Variable
OR (95% CI)*
p value
OR (95% CI)
p value
Variable
OR (95% CI)*
Dose, 66 Gy Dmax V30 V40 V50 PC1 PC2 PC3 PC4 PC5 PC6
1.48 (0.45–4.87)y
0.52
1.30 (0.52–3.26)y
0.57
8.31(2.56–26.99)y
1.70 (0.58–4.99) 1.72 (0.83–3.43) 1.69 (0.83–3.44) 2.15 (0.83–5.57) 2.03 (0.81–5.10) 1.41 (0.61–3.27) 0.92 (0.53–1.59) 1.17 (0.64–2.14) 0.69 (90.42–1.15) 1.1 (0.73–1.59)
0.33 0.14 0.15 0.12 0.13 0.41 0.77 0.61 0.15 0.61
1.70 (0.74–3.92) 1.49 (0.87–2.59) 1.81 (1.02–3.32) 2.16 (1.06–4.76) 1.72 (0.88–3.44) 0.95 (0.78–1.16) 0.54 (0.53–0.99) 1.35 (0.78–2.48) 1.08 (0.72–1.69) –
0.21 0.15 0.05 0.04 0.12 0.63 0.06 0.31 0.71 –
Dose: 66 Gy Dmax V30 V40 V50 PC1 PC2 PC3 PC4 PC5 PC6
Abbreviations: PC1 = first principal component (PC2 = second principal component, etc.); Dmax = maximum dose; V30, -40, -50 = percent volume that receives 30, 40, or 50 Gy. * ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables. y Values based on a reference dose of 60 Gy.
6.90 (2.36–23.02) 4.33 (2.06–10.32) 3.71 (1.80–8.54) 5.95 (2.19–19.33) 6.91 (2.63–21.37) 1.04 (0.46–2.30) 0.82 (0.48–1.36) 0.89 (0.60–1.43) 1.3 (0.76–2.41) 1 (0.67–1.44)
Bladder wall p value
OR (95% CI) *
0.0004 0.739 (0.22–2.49)y <0.001 <0.001 <0.001 0.001 <0.001 0.92 0.45 0.56 0.37 0.98
1.33 (0.49–3.59) 1.24 (0.63–2.33) 1.23 (0.61–2.44) 1.35 (0.60–3.26) 1.29 (0.57–2.88) 0.74 (0.43–1.06) 1.02 (0.51–1.95) 1.64 (0.82–3.54) 0.96 (0.60–1.63) –
p value 0.62 0.57 0.52 0.55 0.49 0.54 0.26 0.96 0.18 0.88 –
Abbreviations: PC1= first principal component (PC2 = second principal component, etc.); Dmax = maximum dose; V30, -40, -50 = percent volume that receives 30, 40, or 50 Gy. * ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables. y Values based on reference 60 Gy.
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Fig. 2. Forest plot OR for developing late GI toxicity among the first PC and standard DVH parameters. ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables; PC1 = first PC; Dmax = maximum dose; V30, -40, -50= percent volume that receives 30, 40, and 50 Gy; CIs= confidence intervals.
Furthermore, the presence of a steep dose response curve for late rectal toxicity with large dose-per-fraction RT requires that the prescription method be taken into consideration when interpreting reported DVH dose constraints. In our protocol, all doses were prescribed to the CTV minimum, and the PTV was contained within the 95% isodose line. As a result, a significant portion of the CTVand PTV received up to 105% of prescribed dose. In other studies reporting lower rates of Grade 2 to 4 toxicity with a dose of 66 Gy/22 fractions, the dose was prescribed to the isocenter rather than to the CTV minimum. Rene et al. (35) reported 25% Grade 2 or 3 GI toxicity (they observed no Grade 4 or 5 toxicity) at a median follow-up of 51 months, compared to our observation of 38% Grade 2 to 4 GI toxicity at a median follow-up of 31 months. If a steep dose response curve exists in this dose range, such a difference in how treatment is prescribed may translate into very different toxicity outcomes, given that prescribing to a CTV minimum , as in our protocol, results in a larger volume of adjacent normal tissue being exposed to higher radiation doses than prescribing to the isocenter. Men treated with 60 Gy/20 fractions in our study had very acceptable levels of bladder and rectal toxicity, using the volumes and dose constraints outlined in Table 1. Our observation of 8% Grade 2 to 3 late GI and 15% Grade 2 late GU toxicity compares favorably with those seen in published high-dose RT randomized controlled trials (1–4, 36), where 18% to 43% late GI and 14% to 57% late GU toxicity rates have been reported. From our data, there appears to be no increase in late toxicity, using a 60 Gy hypofractionated regimen for localized prostate cancer. These findings need to be confirmed in ongoing randomized trials, and our results should encourage the ongoing support of these trials. The prediction of rectal toxicity from a given treatment plan is of importance for plan optimization and for the development of novel dose and fractionation regimens. The utility of PCA in predicting rectal toxicity is unclear and to our knowledge has only been examined in prostate cancer treated with standard fractionation. We previously
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reported that PCA was not useful in predicting late toxicity in men treated with standard fractionation (27), although the number of events in this study cohort was small. At least one other study was able to correlate rectal bleeding by using this statistical tool (20). The current study shows that traditional DVH parameters can predict Grade 2 or greater toxicity by using our hypofractionated IGRT technique and that the application of more sophisticated methods of DVH analysis like PCA did not contribute over these standard parameters. We found that PC1 was highly correlated to rectal toxicity, which is not surprising as it is also highly correlated to the Dmax. A possible weakness of this analysis is that given the relatively low number of late toxicity events, we grouped all patients together and analyzed DVH parameters and PCs regardless of dose. When the PCA was performed separately for both the 60 Gy and 66 Gy cohorts, none of the parameters analyzed achieved statistical significance, given the relatively low number of late events that each group experienced (data not shown). The standardization of treatment delivered between the cohorts minimized the amount of variation among patients treated on each dose level and would require many more patients to find statistically significant differences than the present number available for each dose level. Although there was no significant association of any of the parameters to toxicity in the PCA, when restricted to either subgroup we had insufficient patient numbers to determine whether assigned dose strongly affects the PCA analysis in the entire cohort. One of the drawbacks of PCA is that it is data setspecific and therefore not generalizable. Our conclusion that it does not provide superior prediction of radiation-induced toxicity to standard DVH criteria also supports more generalizable and less complicated forms of analysis. Of concern, a single patient who received 66 Gy developed late Grade 4 toxicity. This patient developed significant rectal bleeding 6 months posttreatment that was unresponsive to argon laser photocoagulation and eventually suffered a lifethreatening GI bleed. Colonoscopic visualization confirmed necrosis and perforation of the anterior rectal wall. He failed to improve with hyperbaric oxygen therapy, and a defunctioning colostomy was required. This patient experienced no significant acute toxicity, and there was no significant difference in his DVH parameters compared to those of the rest of the study cohort (data not shown). It is unclear why this patient experienced such a significant late effect from treatment, although we have abandoned the 66 Gy hypofractionated regimen as given in this study as an investigative treatment protocol. CONCLUSIONS Hypofractionated treatment of 60 Gy in 20 daily fractions is well tolerated, although there appears to be a steep dose response curve between 60 Gy and 66 Gy for RTOG Grade 2 or greater late GI effects with the dose constraints used in this study. Although PCA can segregate DVHs at increased risk for late GI toxicity for patients treated with hypofractionated image-guided IMRT for prostate cancer, it provides no additional value over using standard DVH parameters.
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REFERENCES 1. Al-Mamgani A, van Putten WL, Heemsbergen WD, et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72:980–988. 2. Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–487. 3. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:67–74. 4. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from proton radiation oncology group/American College of Radiology 95-09. J Clin Oncol 2010;28:1106–1111. 5. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095–1101. 6. Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. 7. Fowler JF. The radiobiology of prostate cancer including new aspects of fractionated radiotherapy. Acta Oncol 2005;44:265–276. 8. Brenner DJ. Fractionation and late rectal toxicity. Int J Radiat Oncol Biol Phys 2004;60:1013–1015. 9. Deore SM, Shrivastava SK, Supe SJ, et al. Alpha/beta value and importance of dose per fraction for the late rectal and rectosigmoid complications. Strahlenther Onkol 1993;169:521–526. 10. Steel GG. Basic clinical radiobiology. 3rd ed. New York: Arnold; 2002. 11. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997; 336:980–987. 12. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 1988;208:606–614. 13. Goldberg PA, Nicholls RJ, Porter NH, et al. Long-term results of a randomised trial of short-course low-dose adjuvant preoperative radiotherapy for rectal cancer: Reduction in local treatment failure. Eur J Cancer 1994;30A:1602–1606. 14. Khoo VS, Dearnaley DP. Question of dose, fractionation and technique: Ingredients for testing hypofractionation in prostate cancer—The CHHiP trial. Clin Oncol (R Coll Radiol) 2008;20: 12–14. 15. Benk VA, Adams JA, Shipley WU, et al. Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. Int J Radiat Oncol Biol Phys 1993;26:551–557. 16. Boersma LJ, van den Brink M, Bruce AM, et al. Estimation of the incidence of late bladder and rectum complications after high-dose (70-78 Gy) conformal radiotherapy for prostate cancer, using dose-volume histograms. Int J Radiat Oncol Biol Phys 1998;41:83–92. 17. Storey MR, Pollack A, Zagars G, et al. Complications from radiotherapy dose escalation in prostate cancer: Preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 2000;48:635–642. 18. Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 2001;49:685–698. 19. Rancati T, Fiorino C, Gagliardi G, et al. Fitting late rectal bleeding data using different NTCP models: Results from an Italian multi-centric study (AIROPROS0101). Radiother Oncol 2004;73:21–32.
20. Sohn M, Yan D, Liang J, et al. Incidence of late rectal bleeding in high-dose conformal radiotherapy of prostate cancer using equivalent uniform dose-based and dose-volume-based normal tissue complication probability models. Int J Radiat Oncol Biol Phys 2007;67:1066–1073. 21. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): Multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 2000;47:103–113. 22. Tucker SL, Cheung R, Dong L, et al. Dose-volume response analyses of late rectal bleeding after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:353–365. 23. Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:1297–1308. 24. Zapatero A, Garcia-Vicente F, Modolell I, et al. Impact of mean rectal dose on late rectal bleeding after conformal radiotherapy for prostate cancer: Dose-volume effect. Int J Radiat Oncol Biol Phys 2004;59:1343–1351. 25. Dawson LA, Biersack M, Lockwood G, et al. Use of principal component analysis to evaluate the partial organ tolerance of normal tissues to radiation. Int J Radiat Oncol Biol Phys 2005;62:829–837. 26. Bauer JD, Jackson A, Skwarchuk M, et al. Principal component, Varimax rotation and cost analysis of volume effects in rectal bleeding in patients treated with 3D-CRT for prostate cancer. Phys Med Biol 2006;51:5105–5123. 27. Skala M, Rosewall T, Dawson L, et al. Patient-assessed late toxicity rates and principal component analysis after imageguided radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:690–698. 28. Martin JM, Rosewall T, Bayley A, et al. Phase II trial of hypofractionated image-guided intensity-modulated radiotherapy for localized prostate adenocarcinoma. Int J Radiat Oncol Biol Phys 2007;69:1084–1089. 29. Nichol AM, Warde PR, Lockwood GA, et al. A cinematic magnetic resonance imaging study of milk of magnesia laxative and an antiflatulent diet to reduce intrafraction prostate motion. Int J Radiat Oncol Biol Phys 2010;77:1072–1078. 30. Rosewall T, Yan J, Bayley AJ, et al. Inter-professional variability in the assignment and recording of acute toxicity grade using the RTOG system during prostate radiotherapy. Radiother Oncol 2009;90:395–399. 31. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. 32. Lukka H, Hayter C, Julian JA, et al. Randomized trial comparing two fractionation schedules for patients with localized prostate cancer. J Clin Oncol 2005;23:6132–6138. 33. Pollack A, Hanlon AL, Horwitz EM, et al. Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial. Int J Radiat Oncol Biol Phys 2006;64:518–526. 34. Yeoh EE, Holloway RH, Fraser RJ, et al. Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: Updated results of a phase III randomized trial. Int J Radiat Oncol Biol Phys 2006;66:1072–1083. 35. Rene N, Faria S, Cury F, et al. Hypofractionated radiotherapy for favorable risk prostate cancer. Int J Radiat Oncol Biol Phys 2010;77:805–810. 36. Beckendorf V, Guerif S, Le Prise E, et al. The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate cancer: Feasibility and acute toxicity. Int J Radiat Oncol Biol Phys 2004;60: 1056–1065.
doi:10.1016/j.ijrobp.2011.01.024
CLINICAL INVESTIGATION
Prostate
ROLE OF PRINCIPAL COMPONENT ANALYSIS IN PREDICTING TOXICITY IN PROSTATE CANCER PATIENTS TREATED WITH HYPOFRACTIONATED INTENSITY-MODULATED RADIATION THERAPY DANNY VESPRINI, M.D.,*z MICHAEL SIA, M.D.,z GINA LOCKWOOD, M.MATH.,y DOUGLAS MOSELEY, PH.D.,z TARA ROSEWALL, M.SC.,z ANDREW BAYLEY, M.D.,z ROBERT BRISTOW, M.D., PH.D.,z PETER CHUNG, M.B.,z CYNTHIA MENARD, M.D.,z MICHAEL MILOSEVIC, M.D.,z PADRAIG WARDE, M.B.,z z AND CHARLES CATTON, M.D. *Department of Radiation Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada; yDepartment of Clinical Study Coordination and Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; and zRadiation Medicine Program, Princess Margaret Hospital, University Health Network, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada Purpose: To determine if principal component analysis (PCA) and standard parameters of rectal and bladder wall dose-volume histograms (DVHs) of prostate cancer patients treated with hypofractionated image-guided intensitymodulated radiotherapy (hypo-IMRT) can predict acute and late gastrointestinal (GI) toxicity. Methods and Materials: One hundred twenty-one patients underwent hypo-IMRT at 3 Gy/fraction, 5 days/week to either 60 Gy or 66 Gy, with daily online image guidance. Acute and late GI and genitourinary (GU) toxicity were recorded weekly during treatment and at each follow-up. All Radiation Therapy Oncology Group (RTOG) criteria toxicity scores were dichotomized as <2 and $2. Standard dosimetric parameters and the first five to six principal components (PCs) of bladder and rectal wall DVHs were tested for association with the dichotomized toxicity outcomes, using logistic regression. Results: Median follow-up of all patients was 47 months (60 Gy cohort= 52 months; 66 Gy cohort= 31 months). The incidence rates of $2 acute GI and GU toxicity were 14% and 29%, respectively, with no Grade $3 acute GU toxicity. Late GI and GU toxicity scores $2 were 16% and 15%, respectively. There was a significant difference in late GI toxicity $2 when comparing the 66 Gy to the 60 Gy cohort (38% vs. 8%, respectively, p = 0.0003). The first PC of the rectal DVH was associated with late GI toxicity (odds ratio [OR], 6.91; p < 0.001), though it was not significantly stronger than standard DVH parameters such as Dmax (OR, 6.9; p < 0.001) or percentage of the organ receiving a 50% dose (V50) (OR, 5.95; p = 0 .001). Conclusions: Hypofractionated treatment with 60 Gy in 3 Gy fractions is well tolerated. There is a steep dose response curve between 60 Gy and 66 Gy for RTOG Grade $2 GI effects with the dose constraints employed. Although PCA can predict late GI toxicity for patients treated with hypo-IMRT for prostate cancer, it provides no additional information over using more standard DVH parameters. Ó 2011 Elsevier Inc. Prostate cancer, Image-guided IMRT, Hypofractionation, Radiation toxicity, Principal component analysis.
INTRODUCTION
Data on radiotherapy (RT) dose response characteristics using clinical and experimental data suggest that prostate cancer has a low a/b value approximating 1.5, though this value remains under debate (5–7). A low a/b ratio implies an advantage to using larger fraction sizes with improved tumor control relative to total dose. If the a/b ratio of prostate is actually low, then it may be possible
Four randomized trials have shown improved biochemical relapse-free survival with radiation dose escalation of an additional 8 to 12 Gy for men with localized prostate cancer (1–4). This was achieved by extending standard 2 Gy/ fraction treatment courses using 3 dimensional conformal radiotherapy treatment techniques without image guidance.
Supplementary material for this article can be found at www.redjournal.org. Acknowledgment—The authors would like to thank Debbie Tsuji for clinical trials support and Lindsay Jacks for additional statistical support. Received July 21, 2010, and in revised form Jan 18, 2011. Accepted for publication Jan 18, 2011.
Reprint requests to: Dr. Charles Catton, M.D., Princess Margaret Hospital (UHN), 610 University Avenue, Toronto, ON M5G 2M9, Canada. Tel: (416) 946-2121; Fax: (416) 946-2111; E-mail: [email protected] Supported in part by funding from the Abbot Canadian Association of Radiation Oncologists Uro-Oncologic Radiation Awards competition. Conflict of interest: none. e415
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to provide effective radiation dose escalation with shorter radiation courses than are currently employed. The use of fewer hypofractionated treatments can potentially im-prove patient convenience and resource allocation. A potentially serious risk of adopting hypofractionation protocols is the increased risk from large doses per fraction on late normal tissue effects (8–10). This is clearly shown by the longterm results of hypofractionation on rectal cancer (11–13), where late damage to the rectum is seen many years after radiation. This risk may be mitigated by excluding normal tissues from the high-dose radiation volume as much as possible, and for prostate cancer, this includes the use of highly conformal treatment techniques such as intensity-modulated RT (IMRT) and optimization of the planning target volume (PTV) with Image-guided radiotherapy (IGRT). These techniques have been shown to be feasible and effective in phase II trials of hypofractionated RT and are presently being tested in a number of phase III trials (Medical Research Council/ Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer [MRC/CHHiP] [National Institutes of Health identifier: NCT00392535; David Dearnaley, Principal Investigator] (14), Ontario Clinical Oncology Group/ Prostate Fractionated Irradiation Trial (OCOG/PROFIT) [National Institutes of Health identifier: NCT00304759; Ch-arles Catton, Principal Investigator], and Radiation Therapy Oncology Group [RTOG] trial 0415 [National Institutes of Health identifier: NCT00331773; W. Robert Lee, Principal Investigator]). However, reliable information regarding normal tissue complications and its dependence on dose and volume need to be elucidated to continue safely with similar treatment protocols and to devise future hypofractionation protocols. The bladder and rectum are the dose-limiting organs for prostate cancer RT, with rectal bleeding requiring surgical intervention (RTOG Grades 3–4) being among the most severe of the complications encountered. Correlations between this late side effect and single points on the rectal dose-volume histograms (DVH) have been reported (15–24). The limitation to single-point analysis of DVH is that potentially critical dose volume information is lost that might best discriminate between treatment plans at high or low risk of complications. Principal component analysis (PCA) is a statistical tool that segregates DVHs with similar morphology, allowing the quantification of variability in DVH datasets. PCA provides the ability to compare common DVH characteristics to toxicity events without the loss of information that the use of simpler methods causes. PCA has been used to identify an association between reduced DVHs and the decreased risk of liver toxicity after partial liver irradiation, as well as the decreased risk of xerostomia after parotid gland irradiation (25). It has more recently been used to attempt to predict late toxicity to radiation in prostate cancer (20, 26, 27), though its application requires further analysis, especially with novel fractionation schemes. We previously reported early outcomes with hypofractionated RT in patients treated with 60 Gy in 20 fractions over 4 weeks. We now report the gastrointestinal (GI) and genitouri-
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nary (GU) toxicities observed with an extended study cohort and longer follow-up and determine if PCA or standard DVH parameters predict radiation-induced GI or GU toxicity. METHODS AND MATERIALS Study population The patient data set used consisted of 121 patients treated on a hypofractionation single- institution phase I–II open label prospective clinical trial (Table 1). Initial results for the first 92 patients treated to 60 Gy have been published previously (28). Toxicity analysis is presented for all patients. Corrupted archival tapes prevented radiation plan data retrieval for 19 patients. As a result, 102 patients were used in the DVH analysis and PCA.
Radiation treatment planning The treatment technique has been previously described (28), and patients undergoing radical RT were treated with IMRT and daily online IGRT on implanted fiducial markers. Intrafractional prostate movement was mitigated though the use of a daily bowel and bladder protocol (29). Neoadjuvant or adjuvant androgen deprivation therapy was not routinely employed, although it was allowed. The clinical target volume (CTV) consisted of the entire prostate gland and base of the seminal vesicles. The prostatic apex was defined in reference to the apical fiducial marker based on ultrasonographic localization. The PTV was defined as the CTV with an additional 10-mm margin anteriorly, superiorly, inferiorly, and laterally. The posterior PTV margin was 7 mm posterior to the prostate gland. The treatment volume was constructed to include the PTV within the 95% isodose line. Femoral heads, bladder wall, and rectal wall were contoured throughout the treatment volume (18 mm from CTV as appropriate) in order to construct DVHs of the organs at risk. For both the bladder and rectum, inner and Table 1. Baseline characteristics of all patients versus patients used in the PCA All patients (n = 121) PCA patients (n = 102) Variable
No. of patients
Median age 71.5 T stage T1c 59 T2a 49 T2b 10 T2c 3 Gleason score 6 51 7 67 8–10 3 Median initial 7.15 (range, PSA (ng/ml) 0.68–25.38) Risk stratification* Low 31 Intermediate 82 High 8 Assigned Dose 60 Gy 92 66 Gy 29
% of total
No. of patients
% of total
71.0 49 40 8 2
48 43 8 3
47 42 8 3
42 55 2
45 54 3 7.13 (range, 0.68–25.38)
44 53 3
26 68 7
26 69 7
25 68 7
76 24
73 29
72 28
Abbreviation: PSA = prostate-specific antigen. * Canadian consensus guidelines. Lukka H. Prostate cancer: risk categories and role of hormones and radiotherapy. Can J Urol. 2002 Jun;9 Suppl 1:26-9.
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outer walls were separately delineated so that only the organ wall was used in radiation planning and DVH construction.
Radiation prescription The dose prescribed for the first 92 patients analyzed in this study was 60 Gy in 20 fractions over 4 weeks, as reported by Martin et al. (28). Given the acceptable acute and late toxicity experienced in this initial cohort, an additional 29 patients were treated with 66 Gy in 22 fractions over 4.5 weeks, using the same technique, treatment volumes, and fraction size but different dose constraints (Table 2). All doses were prescribed to CTV minimum, and the PTV was contained within the 95% isodose line. The class dose solutions for the organs at risk are shown in Table 2. Treatment plans that failed to meet dose constraints resulted in patients being treated off study protocol with image-guided RT using standard fractionation.
Toxicity scoring As we have described previously, all patients self-reported with the assistance of a radiation therapist on a weekly and prospective basis (30) acute GI or GU reactions and toxicity, using the RTOG toxicity criteria (31). Patients were seen in follow-up at 4 to 8 weeks following the completion of treatment, every 6 months to 5 years, and annually thereafter. At each follow-up visit, data were collected on late bowel and bladder toxicity, digital rectal examination was performed, and serum prostate-specific antigen (PSA) concentration was tested. Toxicity occurring within 90 days of the start of treatment was considered ‘‘acute.’’ For both acute and late toxicity, the maximum (i.e., worst) toxicity score experienced was used for analysis. Patients were classified as having experienced toxicity if they scored $Grade 2 using RTOG toxicity criteria.
Statistical considerations Acute and late toxicity rates were compared between the 60 Gy and 66 Gy cohorts, using the exact Cochran-Armitage trend test.
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When there were only two levels in the RTOG variable (i.e., only level 0–1 and 2), this test was equivalent to Fisher’s exact test. The following dosimetric parameters were extracted from the treatment plan rectal wall and bladder wall DVHs: maximum dose (Dmax; to a contiguous volume of 1 cm3); percent volume of rectal/bladder wall receiving $30 Gy (V30); percent volume of rectal/ bladder wall receiving $40 Gy (V40); and percent volume of rectal/bladder wall receiving $50 Gy (V50). These dosimetric parameters were individually examined using logistic regression to test whether they were related to the probability of having $Grade 2 RTOG toxicity. Table 3 shows the estimates of the normalized total dose equivalent in 2 Gy fractionsfor the doses described in this study.
Principal component analysis The PCA was performed as previously described (ref 27), and summarized in Supplementary material online in Appendix 1. The first five and six PCs for bladder and rectum were examined using logistic regression to test whether they were related to the probability of having >Grade 2 RTOG rectal or bladder toxicity. Analysis was done on the entire analyzable cohort (102 patients), as well as separately for each dose cohort (60 Gy, n = 73; 66 Gy, n = 29). The correlation between principal components (PCs) and DVH parameters was analyzed using Pearson correlation coefficients.
RESULTS Patient characteristics A total of 121 patients treated on protocol from September 2004 to December 2005 were analyzed in this study. Baseline characteristics for all patients are shown in Table 1. The median age at last follow-up was 71.5 years. The median follow-up for all patients at last follow-up was 47 months (range, 3.7–79 months; 31 months for the 66 Gy cohort, and 52 months for the 60 Gy cohort.
Table 2. Dose constraints Site PTV CTV Bladder wall/ rectal wall
Femoral heads
60 Gy constraint
66 Gy constraint
Max 63 Gy; min 57 Gy Max 63 Gy; min 60 Gy Max 61 Gy
Max 69.3 Gy; min 62.7 Gy Max 69.3 Gy; min 66 Gy Max 68 Gy
V40 <70% Only portions of BW/RW contained in PTV received $57 Gy
V60 <82% V50 <78%
Max 40 Gy
Acute toxicity The maximum acute GI and GU acute toxicities are shown for the whole group and for each fractionation schedule in Table 4. Overall, the treatment regimens were well tolerated, with only a single patient (<1%) experiencing an acute GI toxicity score of 3. Otherwise, 16 patients (13%) experienced an acute GI toxicity score of 2, and 35 patients (29%) experienced an acute GU toxicity score of 2. No acute GU toxicity Grade $3 was identified. There was no apparent difference in acute toxicities when comparing the 60 Gy cohort to the 66 Gy cohort (p $ 0.49), although given the relatively small Table 3. Equivalent doses using different a/b ratios
V40 <50% Only portion of BW/RW contained in PTV receives $62.7 Gy Max 45 Gy
Abbreviations: PTV = planning target volume; CTV = clinical target volume; BW = bladder wall; RW = rectal wall; V60, -50, -40 = percent volume that receives 60, 50, or 40 Gy; Max = maximum dose.
Equivalent dose in 2 Gy/fraction at the ratio shown Dose (in 3 Gy fractions) 66 Gy 60 Gy 50 Gy 40 Gy 30 Gy
a/b = 1.5
a/b = 3
a/b = 5
a/b = 10
85 77 64 51 39
79 72 60 48 36
75 69 57 46 34
72 69 54 43 33
Data shown are equivalent doses in 2 Gy/fraction using different a/b ratios, using the linear quadratic formula.
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Table 4. Maximum RTOG acute toxicity Patients (n = 121)
Dose 60 Gy (n = 92)
Dose 66 Gy (n = 29)
RTOG No. of % of No. of % of No. of % of p score patients total patients total patients total value* GI 0–1 2 3 4 GU 0–1 2 3 4
0.78 104 16 1 0
86 13 1 —
80 11 1 0
87 12 1 —
24 5 0 0
83 17 — —
86 35 0 0
71 29 — —
67 25 0 0
73 27 — —
19 10 0 0
66 34 — —
0.49
* Exact Cochran-Armitage trend test was used to compare Grade 4 toxicity between dose groups.
number of patients in the 66 Gy cohort (n = 29), we cannot exclude smaller differences in toxicity. Similar results were seen when restricting analysis to only the 102 patients used in the PCA (data not shown). Late toxicity The maximum late GI and GU and acute toxicities are shown for the whole group and for each fractionation schedule in Table 5 and Fig. 1. The most severe toxicities recorded were identified during follow-up, and toxicity continued to be collected after patients went on to salvage therapy. A total of 8 patients were treated with salvage androgen deprivation therapy, of which 3 patients experienced a late toxicity. Salvage therapy did not influence recorded late toxicity, in as much as all of these events occurred prior to salvage therapy being initiated. Three of the original 121 patients were lost to follow-up soon after treatment and were excluded from late toxicity analysis. A total of 18 patients (16%) experienced late GI toxicity score of $2 (only 2 patients had Grade 3, and 1 patient had Grade 4), Table 5. Maximum RTOG late toxicity All patients (n = 118)
Dose 60 Gy (n = 89)
Dose 66 Gy (n = 29)
RTOG No. of % of No. of % of No. of % of p score patients total patients total patients total value* GI 0–1 2 3 4 GU 0–1 2 3 4
0.0005 100 15 2 1
85 13 2 1
82 6 1 0
92 7 1 —
18 9 1 1
62 31 3 3
101 16 1 0
86 14 1 —
76 13 0 0
85 15 — —
25 3 1 0
86 10 3 —
0.78
* Exact Cochran-Armitage trend test was used to compare the four level toxicity versus dose group. For GI late toxicity, dichotomizing patients into RTOG score <2 versus $2, there was a highly significant increase in toxicity comparing the 66 Gy versus 60 Gy cohort (38% vs. 8%, respectively; p = 0.0003).
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while 17 patients (15%) experienced a late GU toxicity score of $2 (of which only 1 patient had Grade 3). Although the number of late toxicity events is small, there was increased late GI toxicity scores of $2 in patient treated with the 66 Gy fractionation regimen (median follow-up, 31 months), as 11 patients (38%) treated with 66 Gy experienced $Grade 2 long-term toxicity, while only 7 patients (8%) of the 60 Gy cohort (median follow-up, 52 months) experienced $Grade 2 toxicity (p = 0.0003). The estimated late $2 Grade GI toxicity rate at 3 years for patients treated with 60 Gy was 7.1% (95% confidence interval [CI], 1.1–13.2) versus 40.6% (95% CI, 21.4–59.8) for patients treated with 66 Gy. There was no statistical difference in late GU toxicity between the groups (p = 0.8). When this analysis was applied to only those 102 patients used in the PCA, similar results were seen (data not shown). The cumulative incidence of maximum late toxicity in patients used for the PCA is displayed in Fig. 1. Principal components Corrupted archival tapes prevented data retrieval for 19 patients. Of these 19 patients, 3 and 4 patients had acute GI and GU toxicity scores of $2, respectively; 2 patients had late GI toxicity scores of 2; and no patients had late GU toxicity scores of $2. Therefore, 102 patients were used in the DVH and PCA. Baseline characteristics of these patients are included separately in Table 1. The median age at last follow-up for these patients was 71.0 years old. The median follow-up for all patients included in the PCA at last followup was 43 months (range, 3.7–78 months). Principal component analysis was completed for both the bladder and rectal wall data sets. The first PC (PC1) was associated with the largest variance in the data set, PC2 with the next largest, and so on. A value of 95% of the bladder wall variance was described by the first five PCs (the first PC representing 68%), while 91% of the rectal wall variance was described by the first six PCs (with the first PC accounting for 61%). PC1 was highly correlated to mean dose (the mean of the individual voxel doses that belong to that region of interest, i.e., bladder or rectum) and Dmax in both the GU and GI toxicity analyses (Pearson correlation coefficients: GU, r = 0.997, and r = 0.818; GI, r = 0.996, and r = 0.832, respectively; p < 0.0001 for all). Association of DVH with toxicity Prescribed dose, DVH variables, and PCs were examined using univariate logistic regression analysis to test whether they were related to the probability of experiencing toxicity (i.e., RTOG toxicity score of $2). Total dose was not associated with acute GI or GU toxicity (Table 6), though given the increased incidence of late GI toxicity reported above, receiving a prescribed dose of 66 Gy not unexpectedly predicted for late GI toxicity in the logistic regression analysis (odds ratio [OR], 8.31; 95% CI, 2.56–26.99; p = 0.0004) (Table 7). The standard DVH parameters used in this analysis are listed in Tables 6 and 7. There was a borderline association between V40, V50, and PC3 and acute GU toxicity (OR, 1.81; 95% CI, 2.16–0.56; p = 0.05, 0.04, and 0.06, respectively) (Table
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Fig. 1. Cumulative incidence of maximum late GU (A) and GI (B) toxicity in patients used for PCA (n = 102).
6), though none of the parameters predicted for acute GI (rectal wall) toxicity. In contrast, all of the standard DVH parameters examined were strongly associated with late GI toxicity, with ORs ranging from 3.71 and 6.90 (all p # 0.001) (Table 7). When logistic regression analysis was applied to the PCs of the rectal wall DVH, although the PC1 was also strongly associated with late GI toxicity (OR, 6.91; p < 0.001), this was not superior to Dmax, and although the OR estimate was higher than the other standard variables, their CIs overlapped. Comparison of these ORs for developing late GI toxicity is shown as a forest plot in Fig. 2. None of the standard DVH variables or any of the PCs predicted for late GU toxicity (Table 7). When independent analysis was separately performed for the 60 Gy and 66 Gy dose groups, the number of acute and late events were too low to provide enough statistical power to detect a significant association with any of the parameters and toxicity (data not shown). Table 6. Acute toxicity using univariate logistic regression of other parameters Rectal wall
DISCUSSION The role of hypofractionation for prostate cancer is unproven but remains a matter of clinical significance, given the published (32–34) and ongoing randomized clinical trials for the treatment of prostate cancer, MRC/CHHiP (NCT00392535; David Dearnaley, Principal Investigator) (14), OCOG/PROFIT (NCT00304759; Charles Catton, Principal Investigator), and RTOG 0415 (NCT00331773; W. Robert Lee, Principal Investigator). Our study demonstrates that 60 Gy delivered in 20 daily fractions over 4 weeks is well tolerated using our RT technique and dose constraints, although there is likely a steep dose response curve for late rectal toxicity when escalating dose from 60 Gy/20 fractions to 66 Gy/22 fractions. This potential clinical barrier is important given the different doses under clinical observation or being discussed for investigation.
Table 7. Late toxicity univariate logistic regression of other parameters
Bladder wall
Rectal wall
Variable
OR (95% CI)*
p value
OR (95% CI)
p value
Variable
OR (95% CI)*
Dose, 66 Gy Dmax V30 V40 V50 PC1 PC2 PC3 PC4 PC5 PC6
1.48 (0.45–4.87)y
0.52
1.30 (0.52–3.26)y
0.57
8.31(2.56–26.99)y
1.70 (0.58–4.99) 1.72 (0.83–3.43) 1.69 (0.83–3.44) 2.15 (0.83–5.57) 2.03 (0.81–5.10) 1.41 (0.61–3.27) 0.92 (0.53–1.59) 1.17 (0.64–2.14) 0.69 (90.42–1.15) 1.1 (0.73–1.59)
0.33 0.14 0.15 0.12 0.13 0.41 0.77 0.61 0.15 0.61
1.70 (0.74–3.92) 1.49 (0.87–2.59) 1.81 (1.02–3.32) 2.16 (1.06–4.76) 1.72 (0.88–3.44) 0.95 (0.78–1.16) 0.54 (0.53–0.99) 1.35 (0.78–2.48) 1.08 (0.72–1.69) –
0.21 0.15 0.05 0.04 0.12 0.63 0.06 0.31 0.71 –
Dose: 66 Gy Dmax V30 V40 V50 PC1 PC2 PC3 PC4 PC5 PC6
Abbreviations: PC1 = first principal component (PC2 = second principal component, etc.); Dmax = maximum dose; V30, -40, -50 = percent volume that receives 30, 40, or 50 Gy. * ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables. y Values based on a reference dose of 60 Gy.
6.90 (2.36–23.02) 4.33 (2.06–10.32) 3.71 (1.80–8.54) 5.95 (2.19–19.33) 6.91 (2.63–21.37) 1.04 (0.46–2.30) 0.82 (0.48–1.36) 0.89 (0.60–1.43) 1.3 (0.76–2.41) 1 (0.67–1.44)
Bladder wall p value
OR (95% CI) *
0.0004 0.739 (0.22–2.49)y <0.001 <0.001 <0.001 0.001 <0.001 0.92 0.45 0.56 0.37 0.98
1.33 (0.49–3.59) 1.24 (0.63–2.33) 1.23 (0.61–2.44) 1.35 (0.60–3.26) 1.29 (0.57–2.88) 0.74 (0.43–1.06) 1.02 (0.51–1.95) 1.64 (0.82–3.54) 0.96 (0.60–1.63) –
p value 0.62 0.57 0.52 0.55 0.49 0.54 0.26 0.96 0.18 0.88 –
Abbreviations: PC1= first principal component (PC2 = second principal component, etc.); Dmax = maximum dose; V30, -40, -50 = percent volume that receives 30, 40, or 50 Gy. * ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables. y Values based on reference 60 Gy.
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Fig. 2. Forest plot OR for developing late GI toxicity among the first PC and standard DVH parameters. ORs are expressed as a change equal to the interquartile range of each variable to allow comparison of ORs between variables; PC1 = first PC; Dmax = maximum dose; V30, -40, -50= percent volume that receives 30, 40, and 50 Gy; CIs= confidence intervals.
Furthermore, the presence of a steep dose response curve for late rectal toxicity with large dose-per-fraction RT requires that the prescription method be taken into consideration when interpreting reported DVH dose constraints. In our protocol, all doses were prescribed to the CTV minimum, and the PTV was contained within the 95% isodose line. As a result, a significant portion of the CTVand PTV received up to 105% of prescribed dose. In other studies reporting lower rates of Grade 2 to 4 toxicity with a dose of 66 Gy/22 fractions, the dose was prescribed to the isocenter rather than to the CTV minimum. Rene et al. (35) reported 25% Grade 2 or 3 GI toxicity (they observed no Grade 4 or 5 toxicity) at a median follow-up of 51 months, compared to our observation of 38% Grade 2 to 4 GI toxicity at a median follow-up of 31 months. If a steep dose response curve exists in this dose range, such a difference in how treatment is prescribed may translate into very different toxicity outcomes, given that prescribing to a CTV minimum , as in our protocol, results in a larger volume of adjacent normal tissue being exposed to higher radiation doses than prescribing to the isocenter. Men treated with 60 Gy/20 fractions in our study had very acceptable levels of bladder and rectal toxicity, using the volumes and dose constraints outlined in Table 1. Our observation of 8% Grade 2 to 3 late GI and 15% Grade 2 late GU toxicity compares favorably with those seen in published high-dose RT randomized controlled trials (1–4, 36), where 18% to 43% late GI and 14% to 57% late GU toxicity rates have been reported. From our data, there appears to be no increase in late toxicity, using a 60 Gy hypofractionated regimen for localized prostate cancer. These findings need to be confirmed in ongoing randomized trials, and our results should encourage the ongoing support of these trials. The prediction of rectal toxicity from a given treatment plan is of importance for plan optimization and for the development of novel dose and fractionation regimens. The utility of PCA in predicting rectal toxicity is unclear and to our knowledge has only been examined in prostate cancer treated with standard fractionation. We previously
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reported that PCA was not useful in predicting late toxicity in men treated with standard fractionation (27), although the number of events in this study cohort was small. At least one other study was able to correlate rectal bleeding by using this statistical tool (20). The current study shows that traditional DVH parameters can predict Grade 2 or greater toxicity by using our hypofractionated IGRT technique and that the application of more sophisticated methods of DVH analysis like PCA did not contribute over these standard parameters. We found that PC1 was highly correlated to rectal toxicity, which is not surprising as it is also highly correlated to the Dmax. A possible weakness of this analysis is that given the relatively low number of late toxicity events, we grouped all patients together and analyzed DVH parameters and PCs regardless of dose. When the PCA was performed separately for both the 60 Gy and 66 Gy cohorts, none of the parameters analyzed achieved statistical significance, given the relatively low number of late events that each group experienced (data not shown). The standardization of treatment delivered between the cohorts minimized the amount of variation among patients treated on each dose level and would require many more patients to find statistically significant differences than the present number available for each dose level. Although there was no significant association of any of the parameters to toxicity in the PCA, when restricted to either subgroup we had insufficient patient numbers to determine whether assigned dose strongly affects the PCA analysis in the entire cohort. One of the drawbacks of PCA is that it is data setspecific and therefore not generalizable. Our conclusion that it does not provide superior prediction of radiation-induced toxicity to standard DVH criteria also supports more generalizable and less complicated forms of analysis. Of concern, a single patient who received 66 Gy developed late Grade 4 toxicity. This patient developed significant rectal bleeding 6 months posttreatment that was unresponsive to argon laser photocoagulation and eventually suffered a lifethreatening GI bleed. Colonoscopic visualization confirmed necrosis and perforation of the anterior rectal wall. He failed to improve with hyperbaric oxygen therapy, and a defunctioning colostomy was required. This patient experienced no significant acute toxicity, and there was no significant difference in his DVH parameters compared to those of the rest of the study cohort (data not shown). It is unclear why this patient experienced such a significant late effect from treatment, although we have abandoned the 66 Gy hypofractionated regimen as given in this study as an investigative treatment protocol. CONCLUSIONS Hypofractionated treatment of 60 Gy in 20 daily fractions is well tolerated, although there appears to be a steep dose response curve between 60 Gy and 66 Gy for RTOG Grade 2 or greater late GI effects with the dose constraints used in this study. Although PCA can segregate DVHs at increased risk for late GI toxicity for patients treated with hypofractionated image-guided IMRT for prostate cancer, it provides no additional value over using standard DVH parameters.
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