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Phase I–II Study of Hypofractionated Simultaneous Integrated Boost With Tomotherapy for Prostate Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 2, pp. 392–398, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.08.038
CLINICAL INVESTIGATION
Prostate
PHASE I–II STUDY OF HYPOFRACTIONATED SIMULTANEOUS INTEGRATED BOOST WITH TOMOTHERAPY FOR PROSTATE CANCER NADIA DI MUZIO, M.D.,* CLAUDIO FIORINO, PH.D.,y CESARE COZZARINI, M.D.,* FILIPPO ALONGI, M.D.,* SARA BROGGI, PH.D.,y PAOLA MANGILI, PH.D.,y GIORGIO GUAZZONI, M.D.,z RICCARDO VALDAGNI, M.D.,x RICCARDO CALANDRINO, PH.D.,y AND FERRUCCIO FAZIO, M.D.*{k x
Departments of *Radiotherapy, y Medical Physics, and z Urology, Scientific Institute San Raffaele, Milan, Italy; Prostate Program—Scientific Direction, National Institute of Tumours, Milan, Italy; { Nuclear Medicine, Scientific Institute San Raffaele, Milan, Italy; and k IBFM-CNR, Milan, Italy Purpose: To report planning and acute toxicity data of the first 60 patients treated within a Phase I–II study with moderate hypofractionation by image-guided helical tomotherapy. Methods and Materials: Various clinical target volumes (CTVs) were defined: CTV1—pelvic nodes; CTV2—upper portion of seminal vesicles; CTV3—lower portion of SV; CTV4—prostate; overlap between planning target volume (PTV) 4 and rectum. Different doses to each PTV were simultaneously delivered in 28 fractions. For 31 low-risk patients: 56.0, 61.6, and 71.4 Gy for PTV2–4, respectively; for 20 intermediate-risk patients: 51.8, 61.6, 65.5, and 74.2 Gy for PTV1–4, respectively; for 9 high-risk patients: 51.8 and 65.5 Gy for PTV1–2 and 74.2 Gy for PTV3–4. For all patients, the dose to overlap was 65.5 Gy. Results: The mean fraction of rectum receiving more than 65 Gy (V65) and rectal Dmax were 10% and 70.8 Gy respectively. In cases of pelvic node irradiation, the intestinal cavity (outside PTV) receiving > 45 and 50 Gy was 86 and 12 cc, respectively. A homogeneous dose distribution within each PTV was guaranteed. Acute genitourinary toxicity according to RTOG scoring system was as follows: 21/60 (35%) Grade 1, 12/60 (20%) Grade 2, 2/60 (3%) Grade 3. Acute rectal toxicities were: 18/60 (30%) Grade 1. Twelve (20%) patients showed Grade 1 upper intestinal toxicity (uGI). No patients experienced $ Grade 2 acute rectal or uGI side effects. Conclusions: This study shows excellent results with regard to acute toxicity. Further research is necessary to assess definitive late toxicity and tumor control outcome. Ó 2009 Elsevier Inc. Tomotherapy, Prostate cancer, Simultaneous integrated boost, Hypofractionation, Acute toxicity.
INTRODUCTION
hypofractionated RT might be expected to yield better local control than conventional RT, making hypofractionation attractive because of the expected increase in the therapeutic ratio as well as the increase in logistical convenience for both patients and the radiation therapy department (7–10). However, the true a/b ratio is not yet well known and remains a source of considerable controversy (11). Geometric uncertainties have been recognized as an important issue in the treatment of prostate cancer (12–13). Moreover, by reducing the total number of fractions, the detrimental effect of setup error and organ motion may increase. If a lower prescription dose and hence fewer fractions are used, the percentage of total missed dose resulting from any single targeting error will be greater for hypofractionated treatments, and the biological impact of specific underdosing per fraction will be greater in a hypofractionated schedule compared with a conventional one. Image-guided radiation
External beam radiotherapy has an established role in the management of localized prostate cancer. However, biochemical control at 10 years is achieved in < 50% of patients with localized T1–T2 after treatment (1). Various strategies to improve treatment results have been suggested, including the addition of hormonal therapy and increased radiation dose to the primary tumor. Several studies have shown improved biochemical relapse-free survival with doses > 70 Gy (2–4). The use of conformal radiotherapy techniques has allowed dose escalation without significantly exacerbating acute and late treatment-related toxicity. Several recent investigations of the biologic behavior of prostate cancer showed that the a/b ratio of prostate cancer could be approximately 1.5– 3.0, lower than that for other cancers (5, 6). This indicates that the response of prostate cancer to radiation may be similar to that of tissues showing a late response. If this were so, Reprint requests to: Nadia Di Muzio, M.D., Radiotherapy Department, Scientific Institute San Raffaele, via Olgettina 60, 20132 Milan; Tel: (+39) 02-26437643; Fax: (+39) 02-26437639; E-mail: [email protected]
Conflict of interest: none. Received May 28, 2008, and in revised form Aug 7, 2008. Accepted for publication Aug 7, 2008. 392
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Table 1. Prescribed doses Low risk Dose/fr. Dose PTV1 (LN) PTV2 (SVc) PTV3 (SV1/3) PTV4 (P) Overlap
2 2.2 2.55 2.34
56 61.6 71.4 65.5
Intermediate risk Dose/fr.
Dose
1.85 2.2 2.34 2.65 2.34
51.8 61.6 65.5 74.2 65.5
High risk Dose/fr. Dose 1.85 2.34 2.65 2.65 2.34
51.8 65.5 74.2 74.2 65.5
Abbreviations: fr. = fraction; LN = pelvic lymph nodes; overlap = overlap between highest dose PTV and rectum; P = prostate; PTV = planning target volume; SVc = cranial portion of seminal vesicles; SV1/3 = proximal portion (one third) of seminal vesicles. The concomitantly delivered prescribed doses (Gy) for each target volume are shown according to the class risk.
therapy (IGRT) is able to minimize the deleterious effect of geometric uncertainties such that the delivered dose closely matches that of the planned radiation dose. The sharp dose gradients created with intensity-modulated helical tomotherapy (HTT) can conform the high-dose region to the planning target volume and limit the dose to the bladder, rectal wall, and femoral heads. Therefore, it should be possible to use a larger dose per fraction without increasing the risk of serious late injury to these tissues. The purpose of this study was to evaluate the incidence and severity of acute and early–late toxicity and side effects in patients with localized prostate cancer treated with a hypofractionated technique delivered by HTT (Hi ART 2, TomoTherapyÒ Hi-ArtÒ treatment system, TomoTherapy IncorporatedÒ, Madison, WI). METHODS AND MATERIALS Study design This was a single-institution, Phase I–II, open-label prospective clinical trial. The primary endpoint was the occurrence of any Grade 2 (G2) or more acute genitourinary (GU) or gastrointestinal (GI) toxicity within 3 months of RT, scored using the Radiation Therapy Oncology Group (RTOG) scoring system. Secondary endpoints were late GU and GI toxicity scored by means of the RTOG scoring system and biochemical-free survival defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) and the nadir+2 definition, or clinical failure defined as local, regional, or distant relapse.
Study population Eligible patients had histologically confirmed adenocarcinoma of the prostate with clinical Stage T1b–c, T2a–c; N0, M0, age < 80 years, and Eastern Cooperative Oncology Group performance status 0–1. Previous or concomitant hormonal therapy for local disease was acceptable. The study was approved by the Institute S. Raffaele Ethics Committee, and written informed consent was required for participation. Pretreatment evaluation consisted of documented history and physical examination, including performance status and digital rectal examination. Serum prostate specific antigen (PSA) values and transrectal ultrasound-guided biopsy of the prostate were obtained within 12 months of enrolment. A negative bone scan before entry was required for all patients. Abdominal evaluation with ultrasound or CT/MRI scan was also required before radiation treatment.
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Exclusion criteria included a history of inflammatory bowel disease, previous malignancy within 5 years of prostate carcinoma diagnosis (except non melanomatous skin cancer), and prior pelvic radiotherapy. The participation of patients with anal-rectal fistula, previous abdominal surgery, serious diabetes, or serious hypertension was submitted to a collegial evaluation. In accordance with the National Comprehensive Cancer Network, three patient risk groups were identified: low risk (clinical Stage T1– T2, Gleason score # 6, PSA # 10); intermediate risk (clinical Stage T1–T2, Gleason score # 6, PSA > 10; clinical stage T1–T2, Gleason > 6, PSA # 10; or clinical stage T3, Gleason score < 6, PSA <10); and high risk (clinical stage T1–T3, Gleason score $ 7, PSA > 10). Patients were immobilized in the supine position with the same immobilization device for three-dimensional conformal radiotherapy (Comby-Fix). Specific instructions were given regarding daily preparation: comfortably full bladder (300 cc water 1 hour before treatment) and empty rectum. At initial simulation, patients were scanned in the treatment position (supine, arm on the chest). Axial images were obtained at 3-mm intervals through the pelvis (from L2 to 10 cm under the level of ischiatic lower bone margin). Permanent reference marks were placed on the skin at the time of the planning CT scan. The outlining of CTVs and organs at risk (OAR; bladder, femoral heads, rectum, intestinal cavity outside planning target volume [PTV], penile bulb) was performed according to International Commission on Radiation Units and Measurements 62. PTV was defined as CTV+8 mm margin, except in the cranial-caudal direction (10 mm); for pelvic lymph nodes 10mm in all directions except the portion close to bony structures where the margins were decreased to 5– 7 mm. At the interface between rectum and prostate PTV, an overlap volume was defined. The margins were similar to those applied in 3DCRT, with the exception of lymph nodes, where a wider margin was used for HTT to allow for potential miss due to the use of an megavoltage CT (MVCT) guide to track prostate movement. After contouring, images/contours were sent through DICOM export to the tomotherapy planning station for planning optimization. The randomized trial RTOG 9413 showed a benefit to long-term androgen deprivation and radiation therapy using WPRT (whole pelvic radiation therapy) and prostate boost approach in prostate patients with intermediate to high risk ($ 15% estimated from Roach’s equation) for pelvic node involvement (14, 15). On the basis of these results, the target was the prostate and seminal vesicles only in the low-risk cases; in intermediate- and high-risk patients, pelvic lymph nodes were also irradiated. In Table 1, the prescribed doses relative to the various target structures are reported for the different risk classes: PTV1 (pelvic lymph nodes [LN]), PTV2 (cranial portion of seminal vesicles [SVc]), PTV3 (proximal one third of seminal vesicles [SV1/3]), PTV4 (prostate [P]), and overlap between the highest dose PTV and rectum. Because the true value of a/b is not well known, our fractionation scheme was chosen to deliver a 2-Gy equivalent dose (EQD2) that was expected to be both efficacious and sufficiently safe for OAR for a/b ranging from 1.5 to 15.5 (11) (Table 2). Acute toxicity was recorded according to the RTOG scoring system. Follow-up appointments were scheduled every week during the treatment, at 4 and 12 weeks after the completion of treatment, every 4 months for the first year, and every 6 months subsequently.
Planning optimization HTT planning optimization is different from that of ‘‘conventional’’ IMRT inverse planning. Dose delivery is performed by translating the patient in a continuously rotating fan beam
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Table 2. Biologically 2-Gy equivalent doses (EQD2) Dose/ fraction Dose EQD2a/b1.5 EQD2a/b 3 EQD2a/b10 EQD2a/b15.5 1.85 2 2.2 2.34 2.55 2.65
51.8 56 61.6 65.5 71.4 74.2
49.6 56 65.1 71.9 82.6 88
50.2 56 64.1 70 79.3 83.8
51.1 56 62.6 67.4 74.7 78.2
51.4 56 62.3 66.8 73.6 77
The EQD2 for each dose/fraction applied in the protocol are shown for a range of a/b ratios, from 1.5 to 15.5. See Table 1 to link each value to the appropriate target volume. modulated by a binary multileaf collimator (MLC) (16). The inverse planning system seeks the best solution by changing the shape and the weight of a very large number of segments (typically thousands). Three main parameters can be set by the operator: field width, pitch, and modulation factor. Briefly, field width is the fixed field dimension in the cranial-caudal direction (to be chosen between 1, 2.5, and 5 cm); pitch is the ratio between the couch translation during one gantry rotation and the field width; the modulation factor is the ratio between maximum and average beam intensity. For most patients, a field dimension of 2.5 cm, a pitch of 0.3, and a modulation factor of 3.0–3.5 were used. Readers are referred to other published works (17, 18) to better interpret the meaning of these parameters and the methods of optimization. The irradiation times typically were in the range of 4–8 min. For all patients, the dose was prescribed as median dose to the smallest PTV (corresponding to the prostate). Concerning PTV1 (corresponding to LN), the goal was to deliver more than 98% of the prescribed dose to more than 95% of the volume while maintaining the highest possible dose homogeneity. Concerning the rectum, the dose in the overlap region between the rectum and the smallest PTV was always kept below an EQD2 of 70 Gy (a/b = 3) corresponding to 65.5 Gy in our 28-fraction schedule; outside the overlap, the planner attempted to reduce the dose as much as possible, starting from the fraction of rectum receiving ‘‘high’’ dose and then passing to intermediate-low doses. With this method, the resulting plan was expected largely to satisfy the dose constraints normally used for 3D-CRT. These values were derived from previous investigations (19–21) and scaled to take into account the nonconventional dose fractionation through the linear quadratic model (V65 < 25%; V55 < 45%; V45 < 60%). Concerning the bladder, a similar approach was followed but without any attempt to reduce the dose in the overlap between PTV1–4 and bladder. Femoral heads and femurs were set to receive a maximum dose below 50 Gy while reducing the fraction of organ receiving more than 35–40 Gy to a very low percentage. No hot spots (> 50 Gy) outside the PTV, excluding the first 1–2 cm surrounding it, were admitted. In cases that the bulb was drawn, the planner tried to reduce the dose as much as possible without reducing the coverage of the PTV on the most caudal slice. Concerning the intestinal cavity (IC) outside PTVs, the planner was asked to reduce the dose without compromising PTV coverage, starting from the fraction of IC receiving more than 40–50 Gy, and subsequently passing gradually to the fraction of IC receiving more than 20–30 Gy. Planning data of the first 60 consecutive patients were recovered (29 patients with pelvic node irradiation), including DVHs and dose statistics of PTVs, IC, rectum, bladder, femoral heads, and, where available, the bulbus of the penis.
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Image guidance: methods Daily MVCT image guidance was applied for all patients using the system integrated in the tomotherapy machine. A two-step matching strategy was followed: first, a fully automatic registration based on bony anatomy (bone matching [BM]) was carried out. After BM, the matching was adjusted by a physician through direct visualization (DV) of the prostate, quite consistently with a prostate center-of-mass shift. After the accomplishment of the matching procedures, the final correction was automatically applied for translations and roll angle rotation (axis of rotation: head-feet) and the patient was subsequently treated. For all patients, rectum emptying through daily enema before planning scan and each morning during therapy was prescribed to limit prostate motion and possible organ deformation. Data referred to 21 low-risk patients were recently reviewed (22). The results show that the combination of careful rectal emptying procedures and daily IGRT was able to reduce prostate motion dramatically: in approximately only 5% of the fractions, the motion of the prostate relative to bony anatomy was > 3 mm. As a consequence, the rigid correction applied by IGRT should be considered precise because of negligible impact of prostate deformation. The intrinsic uncertainty of our two-step matching strategy (BM+DV) was carefully investigated and found to be highly reliable (within 1 mm for BM and 3 mm for DV).
RESULTS Planning data In Fig. 1, a typical dose distribution of a low-risk patient is shown; in Fig. 2, the mean DVHs ( 1 SD) of rectum, bladder, femoral heads/femurs, and IC (only for intermediaterisk/high-risk patients) are shown. Rectal Dmean was 36.7 Gy (median value; range, 28.6–44.6 Gy); median values of V40, V50, and V65 were, respectively, 43.2% (range, 27.1%–60%), 32% (range, 15.9%–45 %), and 10.2% (range, 2%–19%), with maximum dose values between 68.7 and 74.7 Gy. The median value of bladder Dmean was 40.1 Gy (range, 31.7-–50.0 Gy) for ‘‘full’’ bladder patients (i.e., bladder volume > 300 mL), with median values of V40, V55, and V60, respectively, equals 47% (range, 31%–69%), 27% (range, 15%–42%), and 14% (range, 8%–22%). Dmax of femoral heads/femurs ranged between 22 and 52 Gy, with small values of V20 (range, 0.3%–40%); median value of V20 equals 54% (range, 34–92%) was estimated in case of nodes irradiation. Concerning IC in case of nodes irradiation, the median value of Dmean was 19.8 Gy (range, 18.8–20.8 Gy) and small fractions of IC receiving more than 40–45 Gy (see Fig. 2). Penile bulb Dmean was 30.5 Gy (median value). PTV coverage was more than satisfactory: median values of V95% for PTV1–4 ranged between 94% and 98%; Dmax of PTV4 was less than 76.5 and 78.5 Gy for low and intermediate-/high-risk patients, respectively. Good coverage of the overlap region (overlap between rectum and PTV4 for low and intermediate risk and PTV3-PTV4 for high risk) was also guaranteed: the median value of V95% was 99.7% (range, 96.5–100%) with maximum doses between 68 and 73 Gy.
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Fig. 1. Dose distribution and dose–volume histograms relative to planning target volumes (PTVs) (prostate, seminal vesicles, and overlap) and organs at risk (rectum, bladder, femoral [fem] heads, bulbus) for a low-risk patient.
Acute toxicity data Patients were enrolled starting in November 2005. At the time of the analysis (March 2008), 60 patients were available, having completed the treatment at least 3 months previously. Median follow-up was 13 months (range, 6–28 months). Median age of the group was 75 years (range, 60–79). T stage was as follows: 38 T1, 20 T2, and 2 T3 . Gleason scoring median value was 6, ranging from 2+2 to 5+5. Median initial PSA was 7 ng/mL with a range from 1.2 to 24.0 ng/mL. According to National Comprehensive Cancer Network class risk, 31 of 60 patients were considered low risk, 20 of 60 intermediate risk, and 9 of 60 high risk; pelvic LN were irradiated in 29 of 60 patients. Hormone therapy was prescribed when PSA was > 10, Gleason score was > 7 or in the presence of a prostate gland volume > 50 cc before treatment. Forty out 60 patients were selected for neoadjuvant or adjuvant hormone therapy (or both). The median duration of the treatment was 42 days (36–54 days). Acute GU toxicity was as follows: 25 of 60 (42%) Grade (G) 0, 21 of 60 (35%) G1, 12 of 60 (20%) G2, 2 of 60 (3%) G3. The median time to occurrence of GU toxicity (from the beginning of the treatment) was 28 days (range, 6–42). Acute rectal toxicities were reported as follows: 42 of 60 (70%) G0 and 18 of 60 (30%) G1, mainly proctitis. No patients experienced > G1 acute rectal side effects. Median time to G1 proctitis was 27 days (median value; range, 18–72 days). Twelve (20%) patients presented upper intestinal (uGI) toxicity with a median time to event of 28 days (6–41days), with 5 receiving pelvic irradiation. All were recorded as G1. The prescription dose (71.4 or 74.2 Gy) did not have any impact on acute toxicity. For the patients receiving 71.4 Gy
(n = 31), acute toxicity was seen in 8 of 31 and 5 of 31 G1 for proctitis and uGI, respectively; regarding GU, we registered 11 G1, 7 G2, and 1 G3 cases. For patients receiving 74.2 Gy (n = 29), acute toxicity was seen in 10 of 29 and 7 of 29 for proctitis and uGI, respectively; with regard to GU, we registered 10 G1, 5 G2, and 1 G3 cases. All patients presented biochemical control of disease according to the ASTRO definition of bNED, complete response at imaging and clinical evaluation at the last follow-up. DISCUSSION This report describes the first results regarding acute toxicity of 60 patients undergoing hypofractionated tomotherapy between November 2005 and March 2008. Tomotherapy was shown to be able to largely fulfill the constraints for the rectum: the volume of rectum receiving high doses was small, thanks in part to the safe dose prescription in the overlap between rectum and PTV (65.5 Gy, corresponding to a EQD2 for late toxicity of approximately 70 Gy); the rapid falloff of the dose outside PTV also permitted reduction of the dose bath to the rectum, thanks to the ‘‘as low as possible’’ optimization criteria followed during planning. The clinical results confirm that these efforts were effective in minimizing rectal acute toxicity: no patients experienced acute toxicity greater than G1. Our data compare favorably with most recent reports with similar fractionation schemes: Keiler et al. (23), in a series of 55 patients undergoing tomotherapy treatment with standard fractionation (79.2– 82.8 Gy in 44–46 fractions) reported GI acute toxicities of G1 in 64% and G2 in 25% of treated patients. Soete et al. (24), in
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Rectum
100 80
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60
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40 20 0
Femoral heads/femurs
100
%
%
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40 20
40
45
50
55
60
65
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75
0
80
20
25
30
35
40
Gy
Intestinal cavity outside PTV
700
55
60
65
70
80
500 400 300
%
cc
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Bladder
100
600
200
60 40 20
100 0
45
Gy
20
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30
35
40
45
50
55
60
65
70
Gy
0
40
45
50
55
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65
70
75
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Gy
Fig. 2. The mean dose–volume histograms ( 1 SD) for rectum, bladder, femoral heads/femurs and intestinal cavity (IC) outside planning target volumes (PTV) (expressed in cc) are shown. Concerning IC, only the data of intermediate-/highrisk patients (i.e., who underwent pelvic node irradiation) were considered.
36 patients (multi-institutional Phase II study) treated with hypofractionated IMRT(56 Gy in 16 fractions) reported a G2 GI acute toxicity of 36%. In a recent study, Junius et al. (25), in 38 men treated with hypofractionated IMRT (66 Gy in 2.64-Gy fractions) reported G1 and G2 GI acute toxicities in 47% and 16% of the patients (25). Our excellent results showing the absence of Grade 2 acute proctitis may be related to several factors. First, the improved dose distribution of tomotherapy plans allowed a reduced dose bath to the rectum, because the planner was careful to try to reduce the fraction of rectum receiving low and intermediate doses (between 20 and 50 Gy). Recent investigations report a clear correlation between the fraction of rectum receiving these levels of dose and acute rectal toxicity (26–28), suggesting that the rectum should be regarded as a parallel organ when considering moderate/severe acute toxicity. Our results are consistent with these findings. Second, daily positioning of the prostate with a < 3 mm accuracy 29 was achieved thanks to the daily MVCT check before treatment, in combination with our practice of prescribing rectal emptying before CT planning and before each fraction, as recently reported by Fiorino et al. (22). Concerning acute GU toxicity, our results (G1: 21/60; G2: 12/60; G3: 2/60) was comparable to those reported in many conventional fractionation series and in other hypofractionated trials. Kupelian et al. (30) reported incidences of 62%, 20%, and 1% for G1, G2, and G3, respectively. Martin et al. (31), after delivering 60 Gy in 20 fractions, reported 43% G1, 25% G2, and no G3 toxicity. The Fox Chase Cancer
Center reported 8% G3 acute GU toxicity in patients receiving 70.2 Gy in 26 fractions (32). Junius et al. (25) reported 26% G2 with no G3 in 38 patients treated with 66 Gy (2.65 Gy/fraction). Pollack et al. (32) reported higher figures of Grade 2 (40%) and 3 (8%) in the IMRT hypofractionated arm in their randomized trial, although the PTV margin was smaller. Slightly higher figures of acute G2 GU toxicity (44%) were also reported by Soete et al. (24) in a Phase II multi-institutional study (56 Gy in 16 fractions) with the delivery of a substantially higher daily dose. Keiler et al. (23) reported 22% Grade 2 and 4% Grade 3 in patients treated with HTT with standard fractionation. Because a large overlap between bladder/urethra and PTV is always present, a significant portion of the bladder receives the prescribed dose, whereas a good sparing of the bladder concerns the portion outside PTV. However, it appears clear that the relatively high daily dose in our trial (2.55–2.65 Gy) does not seem to be a limiting factor from the point of view of a potential increase of acute GU toxicity, in agreement with others using similar fractionation. Significantly, and in contrast to other reports, our results were obtained while irradiating pelvic nodes in approximately half of the patients, confirming the high efficiency of HTT in sparing the bladder in this situation. Our findings concerning the upper GI deserve some additional discussion. In our study, the intermediate and high-risk patients received 51.8 Gy in 28 fractions on pelvic lymph nodes (29/60 in current population). An excellent profile for upper GI acute toxicity was found with no patients reporting
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acute toxicity greater than G1; recently a number of articles have reported a dramatic reduction of acute upper GI and GU toxicity when using IMRT for treating pelvic nodes (33), and also with a concomitant boost approach (34). The results reported here are consistent with our preliminary report on our experience with pelvic node irradiation for prostate patients treated with radical, adjuvant, or salvage intent (35). Our results are achieved through HTT thanks to the dramatic reduction in the fraction of the intestinal cavity receiving a ‘‘high’’ dose. A recent review of the planning data of a large number of patients receiving pelvic nodes irradiation with 3D-CRT or conventional IMRT or HTT confirmed the ability of HTT to dramatically reduce the
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fraction of IC by between 30 and 50 Gy with a significant improvement also compared with conventional five-field IMRT (29). CONCLUSIONS In conclusion, this Phase I–II study demonstrates excellent results in terms of acute toxicity rates resulting from a hypofractionated regimen delivering 71.4–74.2 Gy in 28 fractions for localized prostate cancer. The tomotherapy planning and delivery system is able to create dose distributions highly tailored to the PTVs also in the actual contest of simultaneous integrated boost technique. Further follow-up is necessary to assess late toxicity and tumor control outcome.
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Radiation Therapy Oncology Group 9413. J Clin Oncol 2003; 21:1904–1911. Lawton CA, De Silvio M, Roach M, et al. An update of the Phase III trial comparing whole-pelvic (WP) to prostate-only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): Update analysis of RTOG94-13. Proceedings of 47th annual ASTRO Meeting. Denver, CO, October 16–20, 2005. p. 519. Mackie TR, Kapatoes J, Ruchala K, et al. Image guidance for precise conformal radiotherapy. Int J Radiat Oncol Biol Phys 2003;56:89–105. Grigorov G, Kron T, Wong E, et al. Optimization of helical tomotherapy treatment plans for prostate cancer. Phys Med Biol 2003;48:1933–1943. Shepard DM, Olivera GH, Reckwerdt PJ, et al. Iterative approaches to dose optimisation in tomotherapy. Phys Med Biol 2000;45:69–90. Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: Analysis of a large group of patients pooled from three institutions. Radiother Oncol 2002;64:1–12. Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose–volume constraints in high-dose conformal radiotherapy for localized prostate cancer. J Radiat Oncol Biol Phys 2003;57:953–962. Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3DCRT for localized prostate cancer: Preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys 2008;70:1130–1137. Fiorino C, Di Muzio N, Broggi S, et al. Evidence of limited motion of the prostate by careful emptying of the rectum as assessed by daily MVCT image-guidance with helical tomotherapy. Int J Radiat Oncol Biol Phys 2008;7:611–617. Keiler L, Dobbins D, Kulasekere R, et al. Tomotherapy for prostate adenocarcinoma: A report on acute toxicity. Radiother Oncol 2007;84:171–176. Soete G, Arcangeli S, De Meerleer G, et al. Phase II study of a four-week hypofractionated external beam radiotherapy regimen for prostate cancer: Report on acute toxicity. Radiother Oncol 2006;80:78–81. Junius S, Haustermans K, Bussels B, et al. Hypofractionated intensity modulated irradiation for localized prostate cancer, results from a Phase I/II feasibility study. Radiat Oncol 2007;2: 29. Vavassori V, Fiorino C, Rancati T, et al. Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D-CRT: Results of a prospective multicenter study. Int J Radiat Oncol Biol Phys 2007;66:1401–1410.
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27. Peeters ST, Hoogeman MS, Heemsbergen WD, et al. Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61:1019–1034. 28. Valdagni R, Rancati T, Fiorino C, et al. Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3DCRT. Int J Radiat Oncol Biol Phys 2008; 71:1065–1073. 29. Fiorino C, Alongi F, Broggi S, et al. Physics aspects of prostate tomotherapy: Planning optimization and image-guidance issues. Acta Oncol 2008;47:1309–1316. 30. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland clinic experience. Int J Radiat Oncol Biol Phys 2007;68:1424–1430. 31. 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.
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32. 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. 33. Muren LP, Wasbø Helle SI, et al. Intensity-modulated radiotherapy of pelvic lymph nodes in locally advanced prostate cancer: Planning procedures and early experiences. Int J Radiat Oncol Biol Phys 2008;71:1034–1041. 34. Arcangeli S, Saracino B, Petrongari MG, et al. Analysis of toxicity in patients with high risk prostate cancer treated with intensity-modulated pelvic radiation therapy and simultaneous integrated dose escalation to prostate area. Radiother Oncol 2007;84:148–155. 35. Cozzarini C, Fiorno C, Di Muzio N, et al. Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer. Radiother Oncol 2007;84:164–170.
doi:10.1016/j.ijrobp.2008.08.038
CLINICAL INVESTIGATION
Prostate
PHASE I–II STUDY OF HYPOFRACTIONATED SIMULTANEOUS INTEGRATED BOOST WITH TOMOTHERAPY FOR PROSTATE CANCER NADIA DI MUZIO, M.D.,* CLAUDIO FIORINO, PH.D.,y CESARE COZZARINI, M.D.,* FILIPPO ALONGI, M.D.,* SARA BROGGI, PH.D.,y PAOLA MANGILI, PH.D.,y GIORGIO GUAZZONI, M.D.,z RICCARDO VALDAGNI, M.D.,x RICCARDO CALANDRINO, PH.D.,y AND FERRUCCIO FAZIO, M.D.*{k x
Departments of *Radiotherapy, y Medical Physics, and z Urology, Scientific Institute San Raffaele, Milan, Italy; Prostate Program—Scientific Direction, National Institute of Tumours, Milan, Italy; { Nuclear Medicine, Scientific Institute San Raffaele, Milan, Italy; and k IBFM-CNR, Milan, Italy Purpose: To report planning and acute toxicity data of the first 60 patients treated within a Phase I–II study with moderate hypofractionation by image-guided helical tomotherapy. Methods and Materials: Various clinical target volumes (CTVs) were defined: CTV1—pelvic nodes; CTV2—upper portion of seminal vesicles; CTV3—lower portion of SV; CTV4—prostate; overlap between planning target volume (PTV) 4 and rectum. Different doses to each PTV were simultaneously delivered in 28 fractions. For 31 low-risk patients: 56.0, 61.6, and 71.4 Gy for PTV2–4, respectively; for 20 intermediate-risk patients: 51.8, 61.6, 65.5, and 74.2 Gy for PTV1–4, respectively; for 9 high-risk patients: 51.8 and 65.5 Gy for PTV1–2 and 74.2 Gy for PTV3–4. For all patients, the dose to overlap was 65.5 Gy. Results: The mean fraction of rectum receiving more than 65 Gy (V65) and rectal Dmax were 10% and 70.8 Gy respectively. In cases of pelvic node irradiation, the intestinal cavity (outside PTV) receiving > 45 and 50 Gy was 86 and 12 cc, respectively. A homogeneous dose distribution within each PTV was guaranteed. Acute genitourinary toxicity according to RTOG scoring system was as follows: 21/60 (35%) Grade 1, 12/60 (20%) Grade 2, 2/60 (3%) Grade 3. Acute rectal toxicities were: 18/60 (30%) Grade 1. Twelve (20%) patients showed Grade 1 upper intestinal toxicity (uGI). No patients experienced $ Grade 2 acute rectal or uGI side effects. Conclusions: This study shows excellent results with regard to acute toxicity. Further research is necessary to assess definitive late toxicity and tumor control outcome. Ó 2009 Elsevier Inc. Tomotherapy, Prostate cancer, Simultaneous integrated boost, Hypofractionation, Acute toxicity.
INTRODUCTION
hypofractionated RT might be expected to yield better local control than conventional RT, making hypofractionation attractive because of the expected increase in the therapeutic ratio as well as the increase in logistical convenience for both patients and the radiation therapy department (7–10). However, the true a/b ratio is not yet well known and remains a source of considerable controversy (11). Geometric uncertainties have been recognized as an important issue in the treatment of prostate cancer (12–13). Moreover, by reducing the total number of fractions, the detrimental effect of setup error and organ motion may increase. If a lower prescription dose and hence fewer fractions are used, the percentage of total missed dose resulting from any single targeting error will be greater for hypofractionated treatments, and the biological impact of specific underdosing per fraction will be greater in a hypofractionated schedule compared with a conventional one. Image-guided radiation
External beam radiotherapy has an established role in the management of localized prostate cancer. However, biochemical control at 10 years is achieved in < 50% of patients with localized T1–T2 after treatment (1). Various strategies to improve treatment results have been suggested, including the addition of hormonal therapy and increased radiation dose to the primary tumor. Several studies have shown improved biochemical relapse-free survival with doses > 70 Gy (2–4). The use of conformal radiotherapy techniques has allowed dose escalation without significantly exacerbating acute and late treatment-related toxicity. Several recent investigations of the biologic behavior of prostate cancer showed that the a/b ratio of prostate cancer could be approximately 1.5– 3.0, lower than that for other cancers (5, 6). This indicates that the response of prostate cancer to radiation may be similar to that of tissues showing a late response. If this were so, Reprint requests to: Nadia Di Muzio, M.D., Radiotherapy Department, Scientific Institute San Raffaele, via Olgettina 60, 20132 Milan; Tel: (+39) 02-26437643; Fax: (+39) 02-26437639; E-mail: [email protected]
Conflict of interest: none. Received May 28, 2008, and in revised form Aug 7, 2008. Accepted for publication Aug 7, 2008. 392
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Table 1. Prescribed doses Low risk Dose/fr. Dose PTV1 (LN) PTV2 (SVc) PTV3 (SV1/3) PTV4 (P) Overlap
2 2.2 2.55 2.34
56 61.6 71.4 65.5
Intermediate risk Dose/fr.
Dose
1.85 2.2 2.34 2.65 2.34
51.8 61.6 65.5 74.2 65.5
High risk Dose/fr. Dose 1.85 2.34 2.65 2.65 2.34
51.8 65.5 74.2 74.2 65.5
Abbreviations: fr. = fraction; LN = pelvic lymph nodes; overlap = overlap between highest dose PTV and rectum; P = prostate; PTV = planning target volume; SVc = cranial portion of seminal vesicles; SV1/3 = proximal portion (one third) of seminal vesicles. The concomitantly delivered prescribed doses (Gy) for each target volume are shown according to the class risk.
therapy (IGRT) is able to minimize the deleterious effect of geometric uncertainties such that the delivered dose closely matches that of the planned radiation dose. The sharp dose gradients created with intensity-modulated helical tomotherapy (HTT) can conform the high-dose region to the planning target volume and limit the dose to the bladder, rectal wall, and femoral heads. Therefore, it should be possible to use a larger dose per fraction without increasing the risk of serious late injury to these tissues. The purpose of this study was to evaluate the incidence and severity of acute and early–late toxicity and side effects in patients with localized prostate cancer treated with a hypofractionated technique delivered by HTT (Hi ART 2, TomoTherapyÒ Hi-ArtÒ treatment system, TomoTherapy IncorporatedÒ, Madison, WI). METHODS AND MATERIALS Study design This was a single-institution, Phase I–II, open-label prospective clinical trial. The primary endpoint was the occurrence of any Grade 2 (G2) or more acute genitourinary (GU) or gastrointestinal (GI) toxicity within 3 months of RT, scored using the Radiation Therapy Oncology Group (RTOG) scoring system. Secondary endpoints were late GU and GI toxicity scored by means of the RTOG scoring system and biochemical-free survival defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) and the nadir+2 definition, or clinical failure defined as local, regional, or distant relapse.
Study population Eligible patients had histologically confirmed adenocarcinoma of the prostate with clinical Stage T1b–c, T2a–c; N0, M0, age < 80 years, and Eastern Cooperative Oncology Group performance status 0–1. Previous or concomitant hormonal therapy for local disease was acceptable. The study was approved by the Institute S. Raffaele Ethics Committee, and written informed consent was required for participation. Pretreatment evaluation consisted of documented history and physical examination, including performance status and digital rectal examination. Serum prostate specific antigen (PSA) values and transrectal ultrasound-guided biopsy of the prostate were obtained within 12 months of enrolment. A negative bone scan before entry was required for all patients. Abdominal evaluation with ultrasound or CT/MRI scan was also required before radiation treatment.
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Exclusion criteria included a history of inflammatory bowel disease, previous malignancy within 5 years of prostate carcinoma diagnosis (except non melanomatous skin cancer), and prior pelvic radiotherapy. The participation of patients with anal-rectal fistula, previous abdominal surgery, serious diabetes, or serious hypertension was submitted to a collegial evaluation. In accordance with the National Comprehensive Cancer Network, three patient risk groups were identified: low risk (clinical Stage T1– T2, Gleason score # 6, PSA # 10); intermediate risk (clinical Stage T1–T2, Gleason score # 6, PSA > 10; clinical stage T1–T2, Gleason > 6, PSA # 10; or clinical stage T3, Gleason score < 6, PSA <10); and high risk (clinical stage T1–T3, Gleason score $ 7, PSA > 10). Patients were immobilized in the supine position with the same immobilization device for three-dimensional conformal radiotherapy (Comby-Fix). Specific instructions were given regarding daily preparation: comfortably full bladder (300 cc water 1 hour before treatment) and empty rectum. At initial simulation, patients were scanned in the treatment position (supine, arm on the chest). Axial images were obtained at 3-mm intervals through the pelvis (from L2 to 10 cm under the level of ischiatic lower bone margin). Permanent reference marks were placed on the skin at the time of the planning CT scan. The outlining of CTVs and organs at risk (OAR; bladder, femoral heads, rectum, intestinal cavity outside planning target volume [PTV], penile bulb) was performed according to International Commission on Radiation Units and Measurements 62. PTV was defined as CTV+8 mm margin, except in the cranial-caudal direction (10 mm); for pelvic lymph nodes 10mm in all directions except the portion close to bony structures where the margins were decreased to 5– 7 mm. At the interface between rectum and prostate PTV, an overlap volume was defined. The margins were similar to those applied in 3DCRT, with the exception of lymph nodes, where a wider margin was used for HTT to allow for potential miss due to the use of an megavoltage CT (MVCT) guide to track prostate movement. After contouring, images/contours were sent through DICOM export to the tomotherapy planning station for planning optimization. The randomized trial RTOG 9413 showed a benefit to long-term androgen deprivation and radiation therapy using WPRT (whole pelvic radiation therapy) and prostate boost approach in prostate patients with intermediate to high risk ($ 15% estimated from Roach’s equation) for pelvic node involvement (14, 15). On the basis of these results, the target was the prostate and seminal vesicles only in the low-risk cases; in intermediate- and high-risk patients, pelvic lymph nodes were also irradiated. In Table 1, the prescribed doses relative to the various target structures are reported for the different risk classes: PTV1 (pelvic lymph nodes [LN]), PTV2 (cranial portion of seminal vesicles [SVc]), PTV3 (proximal one third of seminal vesicles [SV1/3]), PTV4 (prostate [P]), and overlap between the highest dose PTV and rectum. Because the true value of a/b is not well known, our fractionation scheme was chosen to deliver a 2-Gy equivalent dose (EQD2) that was expected to be both efficacious and sufficiently safe for OAR for a/b ranging from 1.5 to 15.5 (11) (Table 2). Acute toxicity was recorded according to the RTOG scoring system. Follow-up appointments were scheduled every week during the treatment, at 4 and 12 weeks after the completion of treatment, every 4 months for the first year, and every 6 months subsequently.
Planning optimization HTT planning optimization is different from that of ‘‘conventional’’ IMRT inverse planning. Dose delivery is performed by translating the patient in a continuously rotating fan beam
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Table 2. Biologically 2-Gy equivalent doses (EQD2) Dose/ fraction Dose EQD2a/b1.5 EQD2a/b 3 EQD2a/b10 EQD2a/b15.5 1.85 2 2.2 2.34 2.55 2.65
51.8 56 61.6 65.5 71.4 74.2
49.6 56 65.1 71.9 82.6 88
50.2 56 64.1 70 79.3 83.8
51.1 56 62.6 67.4 74.7 78.2
51.4 56 62.3 66.8 73.6 77
The EQD2 for each dose/fraction applied in the protocol are shown for a range of a/b ratios, from 1.5 to 15.5. See Table 1 to link each value to the appropriate target volume. modulated by a binary multileaf collimator (MLC) (16). The inverse planning system seeks the best solution by changing the shape and the weight of a very large number of segments (typically thousands). Three main parameters can be set by the operator: field width, pitch, and modulation factor. Briefly, field width is the fixed field dimension in the cranial-caudal direction (to be chosen between 1, 2.5, and 5 cm); pitch is the ratio between the couch translation during one gantry rotation and the field width; the modulation factor is the ratio between maximum and average beam intensity. For most patients, a field dimension of 2.5 cm, a pitch of 0.3, and a modulation factor of 3.0–3.5 were used. Readers are referred to other published works (17, 18) to better interpret the meaning of these parameters and the methods of optimization. The irradiation times typically were in the range of 4–8 min. For all patients, the dose was prescribed as median dose to the smallest PTV (corresponding to the prostate). Concerning PTV1 (corresponding to LN), the goal was to deliver more than 98% of the prescribed dose to more than 95% of the volume while maintaining the highest possible dose homogeneity. Concerning the rectum, the dose in the overlap region between the rectum and the smallest PTV was always kept below an EQD2 of 70 Gy (a/b = 3) corresponding to 65.5 Gy in our 28-fraction schedule; outside the overlap, the planner attempted to reduce the dose as much as possible, starting from the fraction of rectum receiving ‘‘high’’ dose and then passing to intermediate-low doses. With this method, the resulting plan was expected largely to satisfy the dose constraints normally used for 3D-CRT. These values were derived from previous investigations (19–21) and scaled to take into account the nonconventional dose fractionation through the linear quadratic model (V65 < 25%; V55 < 45%; V45 < 60%). Concerning the bladder, a similar approach was followed but without any attempt to reduce the dose in the overlap between PTV1–4 and bladder. Femoral heads and femurs were set to receive a maximum dose below 50 Gy while reducing the fraction of organ receiving more than 35–40 Gy to a very low percentage. No hot spots (> 50 Gy) outside the PTV, excluding the first 1–2 cm surrounding it, were admitted. In cases that the bulb was drawn, the planner tried to reduce the dose as much as possible without reducing the coverage of the PTV on the most caudal slice. Concerning the intestinal cavity (IC) outside PTVs, the planner was asked to reduce the dose without compromising PTV coverage, starting from the fraction of IC receiving more than 40–50 Gy, and subsequently passing gradually to the fraction of IC receiving more than 20–30 Gy. Planning data of the first 60 consecutive patients were recovered (29 patients with pelvic node irradiation), including DVHs and dose statistics of PTVs, IC, rectum, bladder, femoral heads, and, where available, the bulbus of the penis.
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Image guidance: methods Daily MVCT image guidance was applied for all patients using the system integrated in the tomotherapy machine. A two-step matching strategy was followed: first, a fully automatic registration based on bony anatomy (bone matching [BM]) was carried out. After BM, the matching was adjusted by a physician through direct visualization (DV) of the prostate, quite consistently with a prostate center-of-mass shift. After the accomplishment of the matching procedures, the final correction was automatically applied for translations and roll angle rotation (axis of rotation: head-feet) and the patient was subsequently treated. For all patients, rectum emptying through daily enema before planning scan and each morning during therapy was prescribed to limit prostate motion and possible organ deformation. Data referred to 21 low-risk patients were recently reviewed (22). The results show that the combination of careful rectal emptying procedures and daily IGRT was able to reduce prostate motion dramatically: in approximately only 5% of the fractions, the motion of the prostate relative to bony anatomy was > 3 mm. As a consequence, the rigid correction applied by IGRT should be considered precise because of negligible impact of prostate deformation. The intrinsic uncertainty of our two-step matching strategy (BM+DV) was carefully investigated and found to be highly reliable (within 1 mm for BM and 3 mm for DV).
RESULTS Planning data In Fig. 1, a typical dose distribution of a low-risk patient is shown; in Fig. 2, the mean DVHs ( 1 SD) of rectum, bladder, femoral heads/femurs, and IC (only for intermediaterisk/high-risk patients) are shown. Rectal Dmean was 36.7 Gy (median value; range, 28.6–44.6 Gy); median values of V40, V50, and V65 were, respectively, 43.2% (range, 27.1%–60%), 32% (range, 15.9%–45 %), and 10.2% (range, 2%–19%), with maximum dose values between 68.7 and 74.7 Gy. The median value of bladder Dmean was 40.1 Gy (range, 31.7-–50.0 Gy) for ‘‘full’’ bladder patients (i.e., bladder volume > 300 mL), with median values of V40, V55, and V60, respectively, equals 47% (range, 31%–69%), 27% (range, 15%–42%), and 14% (range, 8%–22%). Dmax of femoral heads/femurs ranged between 22 and 52 Gy, with small values of V20 (range, 0.3%–40%); median value of V20 equals 54% (range, 34–92%) was estimated in case of nodes irradiation. Concerning IC in case of nodes irradiation, the median value of Dmean was 19.8 Gy (range, 18.8–20.8 Gy) and small fractions of IC receiving more than 40–45 Gy (see Fig. 2). Penile bulb Dmean was 30.5 Gy (median value). PTV coverage was more than satisfactory: median values of V95% for PTV1–4 ranged between 94% and 98%; Dmax of PTV4 was less than 76.5 and 78.5 Gy for low and intermediate-/high-risk patients, respectively. Good coverage of the overlap region (overlap between rectum and PTV4 for low and intermediate risk and PTV3-PTV4 for high risk) was also guaranteed: the median value of V95% was 99.7% (range, 96.5–100%) with maximum doses between 68 and 73 Gy.
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Fig. 1. Dose distribution and dose–volume histograms relative to planning target volumes (PTVs) (prostate, seminal vesicles, and overlap) and organs at risk (rectum, bladder, femoral [fem] heads, bulbus) for a low-risk patient.
Acute toxicity data Patients were enrolled starting in November 2005. At the time of the analysis (March 2008), 60 patients were available, having completed the treatment at least 3 months previously. Median follow-up was 13 months (range, 6–28 months). Median age of the group was 75 years (range, 60–79). T stage was as follows: 38 T1, 20 T2, and 2 T3 . Gleason scoring median value was 6, ranging from 2+2 to 5+5. Median initial PSA was 7 ng/mL with a range from 1.2 to 24.0 ng/mL. According to National Comprehensive Cancer Network class risk, 31 of 60 patients were considered low risk, 20 of 60 intermediate risk, and 9 of 60 high risk; pelvic LN were irradiated in 29 of 60 patients. Hormone therapy was prescribed when PSA was > 10, Gleason score was > 7 or in the presence of a prostate gland volume > 50 cc before treatment. Forty out 60 patients were selected for neoadjuvant or adjuvant hormone therapy (or both). The median duration of the treatment was 42 days (36–54 days). Acute GU toxicity was as follows: 25 of 60 (42%) Grade (G) 0, 21 of 60 (35%) G1, 12 of 60 (20%) G2, 2 of 60 (3%) G3. The median time to occurrence of GU toxicity (from the beginning of the treatment) was 28 days (range, 6–42). Acute rectal toxicities were reported as follows: 42 of 60 (70%) G0 and 18 of 60 (30%) G1, mainly proctitis. No patients experienced > G1 acute rectal side effects. Median time to G1 proctitis was 27 days (median value; range, 18–72 days). Twelve (20%) patients presented upper intestinal (uGI) toxicity with a median time to event of 28 days (6–41days), with 5 receiving pelvic irradiation. All were recorded as G1. The prescription dose (71.4 or 74.2 Gy) did not have any impact on acute toxicity. For the patients receiving 71.4 Gy
(n = 31), acute toxicity was seen in 8 of 31 and 5 of 31 G1 for proctitis and uGI, respectively; regarding GU, we registered 11 G1, 7 G2, and 1 G3 cases. For patients receiving 74.2 Gy (n = 29), acute toxicity was seen in 10 of 29 and 7 of 29 for proctitis and uGI, respectively; with regard to GU, we registered 10 G1, 5 G2, and 1 G3 cases. All patients presented biochemical control of disease according to the ASTRO definition of bNED, complete response at imaging and clinical evaluation at the last follow-up. DISCUSSION This report describes the first results regarding acute toxicity of 60 patients undergoing hypofractionated tomotherapy between November 2005 and March 2008. Tomotherapy was shown to be able to largely fulfill the constraints for the rectum: the volume of rectum receiving high doses was small, thanks in part to the safe dose prescription in the overlap between rectum and PTV (65.5 Gy, corresponding to a EQD2 for late toxicity of approximately 70 Gy); the rapid falloff of the dose outside PTV also permitted reduction of the dose bath to the rectum, thanks to the ‘‘as low as possible’’ optimization criteria followed during planning. The clinical results confirm that these efforts were effective in minimizing rectal acute toxicity: no patients experienced acute toxicity greater than G1. Our data compare favorably with most recent reports with similar fractionation schemes: Keiler et al. (23), in a series of 55 patients undergoing tomotherapy treatment with standard fractionation (79.2– 82.8 Gy in 44–46 fractions) reported GI acute toxicities of G1 in 64% and G2 in 25% of treated patients. Soete et al. (24), in
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Rectum
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Intestinal cavity outside PTV
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Fig. 2. The mean dose–volume histograms ( 1 SD) for rectum, bladder, femoral heads/femurs and intestinal cavity (IC) outside planning target volumes (PTV) (expressed in cc) are shown. Concerning IC, only the data of intermediate-/highrisk patients (i.e., who underwent pelvic node irradiation) were considered.
36 patients (multi-institutional Phase II study) treated with hypofractionated IMRT(56 Gy in 16 fractions) reported a G2 GI acute toxicity of 36%. In a recent study, Junius et al. (25), in 38 men treated with hypofractionated IMRT (66 Gy in 2.64-Gy fractions) reported G1 and G2 GI acute toxicities in 47% and 16% of the patients (25). Our excellent results showing the absence of Grade 2 acute proctitis may be related to several factors. First, the improved dose distribution of tomotherapy plans allowed a reduced dose bath to the rectum, because the planner was careful to try to reduce the fraction of rectum receiving low and intermediate doses (between 20 and 50 Gy). Recent investigations report a clear correlation between the fraction of rectum receiving these levels of dose and acute rectal toxicity (26–28), suggesting that the rectum should be regarded as a parallel organ when considering moderate/severe acute toxicity. Our results are consistent with these findings. Second, daily positioning of the prostate with a < 3 mm accuracy 29 was achieved thanks to the daily MVCT check before treatment, in combination with our practice of prescribing rectal emptying before CT planning and before each fraction, as recently reported by Fiorino et al. (22). Concerning acute GU toxicity, our results (G1: 21/60; G2: 12/60; G3: 2/60) was comparable to those reported in many conventional fractionation series and in other hypofractionated trials. Kupelian et al. (30) reported incidences of 62%, 20%, and 1% for G1, G2, and G3, respectively. Martin et al. (31), after delivering 60 Gy in 20 fractions, reported 43% G1, 25% G2, and no G3 toxicity. The Fox Chase Cancer
Center reported 8% G3 acute GU toxicity in patients receiving 70.2 Gy in 26 fractions (32). Junius et al. (25) reported 26% G2 with no G3 in 38 patients treated with 66 Gy (2.65 Gy/fraction). Pollack et al. (32) reported higher figures of Grade 2 (40%) and 3 (8%) in the IMRT hypofractionated arm in their randomized trial, although the PTV margin was smaller. Slightly higher figures of acute G2 GU toxicity (44%) were also reported by Soete et al. (24) in a Phase II multi-institutional study (56 Gy in 16 fractions) with the delivery of a substantially higher daily dose. Keiler et al. (23) reported 22% Grade 2 and 4% Grade 3 in patients treated with HTT with standard fractionation. Because a large overlap between bladder/urethra and PTV is always present, a significant portion of the bladder receives the prescribed dose, whereas a good sparing of the bladder concerns the portion outside PTV. However, it appears clear that the relatively high daily dose in our trial (2.55–2.65 Gy) does not seem to be a limiting factor from the point of view of a potential increase of acute GU toxicity, in agreement with others using similar fractionation. Significantly, and in contrast to other reports, our results were obtained while irradiating pelvic nodes in approximately half of the patients, confirming the high efficiency of HTT in sparing the bladder in this situation. Our findings concerning the upper GI deserve some additional discussion. In our study, the intermediate and high-risk patients received 51.8 Gy in 28 fractions on pelvic lymph nodes (29/60 in current population). An excellent profile for upper GI acute toxicity was found with no patients reporting
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acute toxicity greater than G1; recently a number of articles have reported a dramatic reduction of acute upper GI and GU toxicity when using IMRT for treating pelvic nodes (33), and also with a concomitant boost approach (34). The results reported here are consistent with our preliminary report on our experience with pelvic node irradiation for prostate patients treated with radical, adjuvant, or salvage intent (35). Our results are achieved through HTT thanks to the dramatic reduction in the fraction of the intestinal cavity receiving a ‘‘high’’ dose. A recent review of the planning data of a large number of patients receiving pelvic nodes irradiation with 3D-CRT or conventional IMRT or HTT confirmed the ability of HTT to dramatically reduce the
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fraction of IC by between 30 and 50 Gy with a significant improvement also compared with conventional five-field IMRT (29). CONCLUSIONS In conclusion, this Phase I–II study demonstrates excellent results in terms of acute toxicity rates resulting from a hypofractionated regimen delivering 71.4–74.2 Gy in 28 fractions for localized prostate cancer. The tomotherapy planning and delivery system is able to create dose distributions highly tailored to the PTVs also in the actual contest of simultaneous integrated boost technique. Further follow-up is necessary to assess late toxicity and tumor control outcome.
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