Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC)

Urologic Oncology: Seminars and Original Investigations 30 (2012) 813– 820

Original article

Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC) Marianthi Panteliadou, M.D.a, Alexandra Giatromanolaki, M.D.b, Stavros Touloupidis, M.D.c, Evagelia Destouni, M.D.d, Pelagia G. Tsoutsou, M.D.a, Panagiotis Pantelis, M.D.d, Ioannis Abatzoglou, Ph.D.a, Kyriaki Sismanidou, M.Sc.a, Michael I. Koukourakis, M.D.a,* a

Department of Radiotherapy and Oncology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece b Department of Pathology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece c Department of Urology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece d Department of Radiotherapy and Oncology, Theagenion Cancer Hospital, Thessaloniki, Greece Received 15 June 2010; received in revised form 5 September 2010; accepted 7 September 2010

Abstract Introduction: Radiotherapy (RT) for bladder cancer is as an effective alternative of cystectomy. Although rapid cancer clonogen repopulation contributes to radio-resistance, accelerated RT schemes based on ⱕ2 Gy fractions have failed to improve results. We suggest that accelerated hypofractionation (HypoARC) may be more effective, as it targets both tumors with increased clonogenic activity and tumors with low radio-sensitivity. Patients and methods: Eighty-two bladder cancer patients were treated with concomitant-boost conformal RT (14 ⫻ 2.7 Gy to the pelvis and 15 ⫻ 3.4 Gy to the bladder, within 19 days). Patients received a daily dose of 0/500/750/1,000 mg of amifostine using a dose-individualization algorithm (15.8%, 8.5%, 19.5%, and 56.1% of patients respectively). Results: Early frequency grade 2–3, dysuria grade 1–2, diarrhea grade 2, and proctitis grade 2 appeared in 10.9%, 15.8%, 8.5%, and 13.4% of patients, respectively. The incidence of late sequelae was low (1.2% grade 2 frequency, 2.4% grade 2–3 dysuria, 2.4% grade 2–3 hematuria, 2.4% grade 2–3 incontinence). Patients receiving 1,000 mg of amifostine experienced significantly lower toxicities. The complete response rate, 3-year local control and disease specific survival rates were 86.6%, 56%, and 63%, respectively. Conclusions: HypoARC is linked with low early and late radiation toxicity, which is further reduced with the administration of high dose daily amifostine. The control and survival rates compare favorably with previously published data. © 2012 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Radiotherapy; Hypofractionation; Acceleration; Amifostine

1. Introduction Cystectomy is the standard approach for the treatment of invasive bladder cancer. However, radio-chemotherapy is as an effective alternative of cystectomy [1,2], often offered for older patients or patients inoperable for medical reasons. In a recent analysis of 458 patients with invasive bladder cancer treated with radical radiotherapy or cystectomy, there was no significant difference in the 10-year overall survival between the treatment groups (22% and 24%, re* Corresponding author. Tel.: ⫹0030-25510-74622; fax: ⫹0030-2551030349. E-mail address: [email protected] (M.I. Koukourakis). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2010.09.001

spectively), although for patient survival more than 2-years, the final outcome was marginally better in those treated with cystectomy [3]. The overall positive experience with radiotherapy for bladder cancer suggests that clinical research on novel radiotherapy techniques and/or combinations with novel chemotherapeutic and molecular targeting agents may eventually establish radiotherapy as a primary organ preservation treatment modality [4 –7]. Most studies performed use standard 1.8 –2 Gy daily fractionation, for a total dose of 64 –70 Gy over a period of 7 weeks. During this period, cancer clonogenic cells enter a phase of rapid tumor repopulation, which may counteract the efficacy of radiotherapy. Maciejewski and Majewski estimated that in order to compensate for such a cancer

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repopulation, a median daily dose of 0.36 Gy is demanded [8]. Short radiotherapy schedules could eventually provide higher local control rates, although this has not been confirmed in the clinical practice [9 –11]. The size of daily radiotherapy fractions has not been thoroughly examined in bladder cancer. Tumors with low intrinsic radio-sensitivity or even hypoxic tumors, bearing shallow survival curve shoulders, are expected to be more sensitive to large radiotherapy fractions [12]. Although the high median ␣/␤ ratio of 10 Gy, reported in a recent radiobiological analysis of bladder carcinomas [13] questions the value of hypofractionation, high 5-year local control rates have been noted in the clinical practice [14,15]. The RTOG 95– 06 study, examining the combination of hypofractionation with chemotherapy, showed a 67% complete response rate and a 3-year survival of 83% [16]. Following an encouraging interim report [17], the current study provides mature results from a clinical trial combining hypofractionation and acceleration of radiotherapy, supported with individualized dose amifostine for cytoprotection, for bladder cancer. This scheme targets both tumors with intense clonogenic cell presence and tumors with low intrinsic and extrinsic radiosensitivity. The usage of amifostine at various dose levels (0 –1,000 mg) according to the individual tolerance (as previously reported [18]) allows the appraisal of the role of this cytoprotective agent in the prevention of early and late radiation toxicity, both expected to be increased following this aggressive radiotherapy schedule.

Table 1 Patient and disease characteristics No. pts. Mail/female Age (years) Median Range WHO PS Median Range T-stage* T1** T2 T3 T4 N-stge* N0 N1 Grade 2 3–4

82 78/4 75 53–88 0 0–1 10 33 34 5 75 7 10 72

* UICC stage based on histology report and CT/MRI imaging. ** Extensive presence of connective tissue invading bladder cancer unresponsive to transurethral resection and intravesical chemotherapy.

or refractory to transurethral resection and intravescical chemotherapy. Written informed consent was obtained from all patients. The study has been approved by the local ethics and scientific committees. 2.2. HypoARC details

2. Patients and methods From January 2003 to September 2009, 82 patients with invasive transitional cell bladder cancer have been recruited in the current prospective phase II study. The median follow-up of patients ranges from 2 to 63 months (median 21 months). The aims of the current phase II trial were: (1) to assess the early and late toxicity of a highly hypofractionated and accelerated radiotherapy scheme, (2) to assess the role of a previously established ‘dose individualizing algorithm’ of amifostine in the prevention of such toxicities, and (3) To assess the efficacy in terms of local control, disease free and disease specific overall survival. 2.1. Recruitment of patients The median performance status (WHO) of patients was 0 (range 0 –1). Patients previously treated with radiotherapy or pregnant women or patients with major heart, lung, liver, renal, psychiatric disease, or hematological malignancies were excluded from the protocol. Table 1 shows the patient and disease characteristics. Although most patients had muscle invading tumors, 10/82 had extensive presence of connective tissue invading lesions (T1-stage) unresponsive

Radiotherapy was given using an 18 MV linear accelerator (ELECTA) endowed with a multi-leaf collimator, after CT-simulation and conformal radiotherapy planning (Plato, Nucletron). A daily fraction of 2.7 Gy through four fields (box), directed to the pelvic area, was used to deliver a total of 14 fractions. These fields comprised the bladder, the prostatic urethra and the external iliac nodes up to the level of the common iliac ones (around the L1/S1 vertebra level). Using a concomitant boost technique, lateral fields confined to the whole bladder delivered an additional daily dose of 0.7 Gy, so that the daily dose to the bladder, through the 6 fields used, was 3.4 Gy for 14 fractions (days 1 to 18). An additional 3.4 Gy fraction was delivered to the whole bladder through the lateral booster fields, on day 19. For 10 T1-stage cases included in the study, a 4-field conformal technique, comprising the bladder alone was applied, using the same fractionation. For the radiobiological analysis of the above scheme, the normalized total dose (NTD) was calculated using the formula proposed by Maciejewski [8], NTD ⫽ D [(␣/␤ ⫹ d)/(␣/␤ ⫹ 2)], where ‘D’ is the total physical dose, ‘d’ the dose per fraction and ␣/␤ is the tissue specific ratio. The NTD corrected for overall treatment time was calculated using a previously proposed formula [17], NTD(T) ⫽ D [(␣/␤ ⫹ d)/(a/b ⫹ 2)] ⫹ ␭(Tc-To), where Tc is the number

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of days required for the delivery of the NTD using a conventionally fractionated scheme, To is the number of days required for the delivery of the current scheme, and ‘␭’ is the estimated daily dose consumed to compensate for rapid tumor repopulation. For cancer tissue an ␣/␤ ratio of 4 –10 Gy was considered. We also assumed a median ‘␭’ value of 0.4 – 0.8 Gy for cancer cells and of 0.2 Gy for normal tissues. Through the pelvic fields, a total physical dose of 37.8 Gy (equivalent to 42.2 Gy for ␣/␤⫽4 Gy) was delivered to the whole pelvis and lymph nodes (up to the lower boarder of the fifth lumbar vertebra). This dose was given within 18 days, thus with an acceleration of 11 days. The biological dose with time correction for normal tissues (␭ ⫽ 0.2 Gy) gives an equivalent of 44.4 Gy. For tumor spread to the nodes (␭ ⫽ 0.4 – 0.8 Gy), the time corrected dose is 46.6 –51 Gy. To the bladder, a total of 51 Gy of physical dose, equivalent to 62.9 Gy for ␣/␤ ⫽ 4 Gy, was delivered within 19 days (acceleration by 24 days). Assuming a ␭-value of 0.2 Gy for normal bladder, the time corrected dose to the bladder was 67.7 Gy. Assuming a tumor ␭-value of 0.4 Gy, the estimated time-corrected biological dose to the bladder tumor was 72 Gy (for a tumor ␣/␤ ⫽ 4 Gy) and 66 Gy (for a tumor ␣/␤ ⫽ 10 Gy).

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2.5. Treatment evaluation Complete blood cell count, serum urea, creatinine, and liver enzymes were assessed once every 2 weeks during the radio-chemotherapy therapy period. Radiation toxicity was monitored daily during radiotherapy, weekly for 1 month following the end of radiotherapy, monthly for 4 months, and 4-monthly thereafter. The NCI (National Cancer Institute) Common Toxicity Criteria Version 2 scale was used to assess chemotherapy and acute radiation toxicity [http://ctep.cancer.gov/protocoldevelopment/ electronic_applications/docs/ctcv20_4-30-992.pdf]. The LENT-SOMA toxicity scale was used to assess late radiation sequelae [19]. Response to treatment of measurable lesions was assessed with CT-scan and bladder endoscopy and performance of biopsies of any specious lesion, 2 and 4 months after treatment completion. CR was defined as complete disappearance of the intravescical lesion and normalization of the CT-scan. Residual tumor at cystoscopy 4 months after radiotherapy was considered as incomplete remission and failure of radiotherapy. Multi-agent chemotherapy was considered in these patients for palliation. 2.6. Chemotherapy

2.3. Radiotherapy delays Any grade 2 or higher toxicity (diarrhea, proctitis, or cystitis) was followed by the insertion of some days free of radiotherapy, supportive medication (loperamide, analgesics, or antibiotics when necessary) and treatment restarted once symptoms regressed to grade 1. 2.4. Amifostine administration Ondasetron 8 mg was administered per os, 30 – 60 min before amifostine injection. Amifostine 1,000 mg was diluted in 5 ml water for injection and was injected in two sites (usually at the right and left shoulder) [18]. The higher dose of amifostine (1,000 mg instead of 350 –500 mg used in other studies) applied was chosen to better protect tissues against the large fractions of radiotherapy. The dose of 1,000 mg was reached gradually (first day 500 mg, second day 750 mg, and third day 1,000 mg) using a previously reported algorithm [18]. The tolerance of amifostine was recorded daily using a proposed scoring system [18]. Fever/rash attributed to amifostine (or to any other drug) is followed by immediate interruption of amifostine. Using this algorithm, the optimal amifostine dose for each patient is established (ranging from 0 for patients who do not tolerate even low dose of amifostine up to 1,000 mg, a dose previously shown to be tolerated by about 60% of cancer patients), minimizing the amifostine side effects and giving 2- to 3-fold higher dose than the 250 –500 mg used in previous clinical trials [18].

Liposomal doxorubicin (Caelyx) 20 mg/m2 every 2 weeks was administered in 41/82 patients, for a total of 3 cycles concurrently with radiation. The impact of chemotherapy on the efficacy and toxicity of HypoARC has been previously analyzed [20]. Chemotherapy administration was not randomized. The expected benefits and side effects were explained at the first consultation of the patient and they were freely left to decide whether they wished or not to receive this adjunctive therapy. Analysis showed that chemotherapy was more frequently accepted by younger patients (median age 70.2 years vs. 75.5 years, P ⫽ 0.001), but there was no other difference between patients accepting or declining chemotherapy. 2.7. Statistical analysis The statistical analysis and graph presentation of survival curves was performed using the GraphPad Prism ver. 5.00 and the GraphPad Instat packages (San Diego, CA). The Fisher’s exact test was used to compare categorical variables, as appropriate. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to determine statistical differences between life tables. Patient and treatment-related variables were analyzed in a multivariate stepwise logistic regression model to determine which ones contain independently significant information. P values ⬍ 0.05 were considered to be statistically significant.

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Table 2 Early pelvic toxicity assessed with the NCI (National Cancer Institute) common toxicity criteria in patients treated with HypoARC

mg; 13/82 (15.9%) patients interrupted amifostine due to intolerable nausea and/or fatigue. At these individualized dose levels, patients experienced only grade 0/1 asthenia or nausea. Local erythema grade 2 at the site of injection appeared in 3/38 (7.9%) patients. Six out of 69 patients (8.7%) interrupted amifostine after the fifth to eleventh injection due to fever/rash. This symptom was not related to the dose level (1/7 vs. 2/16 vs. 3/46 at 500, 750, and 1,000 mg respectively; P ⫽ 0.65). Amifostine was immediately interrupted. No case with necrolytic skin syndrome was recorded.

HypoARC No. pts. 82 (%) Frequency 0. None 1. up to 2⫻ normal 2. ⬎2⫻ normal but ⬍hourly 3. ⬎hourly, demand catheter Dysuria 0. None 1. Mild 2. Relieved with analgesics 3. Persistent, demand catheter Bladder infection 0. None 1. Responsive to antibiotics 2. Demand i.v. therapy Proctitis 0. None 1. Mild rectal discomfort 2. Requires medication 3. Pads, parenteral support, transfusion 4. Necrosis, life threatening bleeding, colostomy Diarrhea 0. ⬍4 stools 1. 4–6 stools 2. ⬎7 stools, incontinence 3. Hospitalization, collapse Dermatitis 0. None 1. Faint erythema/dry desquamation 2. Brisk erythema/patchy moist desquamation 3. Confluent moist desquamation 4. Skin necrosis

42 (51.3) 31 (37.8) 7 (8.5) 2 (2.4) 69 (84.2) 12 (14.6) 1 (1.2) 0 (0)

3.2. Early radiation toxicity Table 2 reports the early toxicities. Patients receiving HypoARC had low grade 2–3 frequency (10.9%), and grade 1–2 dysuria (15.8%). Bladder infection was observed in 3.7% of patients. Grade 2 diarrhea was noted in 8.5% of patients. Proctitis grade 1–2 appeared in 39% of patients. Severe grade 3 proctitis appeared in 1.2% of patients. Skin/ perineal toxicity was negligible.

79 (96.3) 3 (3.7) 0 (0) 49 (59.8) 21 (25.6) 11 (13.4) 1 (1.2) 0 (0)

3.3. Overall treatment time

57 (69.5) 18 (22.0) 7 (8.5) 0 (0)

3. Results

All 82 cases recruited in the HypoARC trial accomplished therapy. Early toxicities (see the Methods section), however, resulted in delays in some patients; 52/82 (63.4%) patients accomplished therapy within 19 days (no delays), 14/82 (17%) within 21–26 days (less than 1 week treatment protraction), and 16/82 (19.6%) within 29 –34 days (more than 1 week treatment protraction). Even in this case, the overall treatment time was reduced by at least 2 weeks compared with patients receiving standard fractionation.

3.1. Amifostine dose and tolerance

3.4. Amifostine dose and early toxicities

Using the dose individualization algorithm, 46/82 (56.1%) patents received a daily dose of 1,000 mg of amifostine, 16/82 (19.5%) 750 mg, and 7/82 (8.5%) 500

Table 3 shows the early toxicities according to the amifostine dose. Amifostine significantly reduced dysuria (P ⫽ 0.01), and this effect was more prominent in the highest

78 (95.1) 2 (2.4) 2 (2.4) 0 (0) 0 (0)

Table 3 Early radiation toxicity and amifostine dose Amifostine dose

A. 0 (13 pts.) B. 500 (7 pts.) C. 750 (16 pts.) D. 1,000 (46 pts.) P value

* A/B vs. C/D. ** 〈 vs. B/C/D. *** A vs. D.

Dysuria

Frequency

0

1

8 6 14 41

4 1 2 5

2 1 0 0 0 0.04* 0.01** 0.01***

3

0

1

0 0 0 0

4 4 8 26

6 2 8 15

Proctitis 2 2 1 0 4 0.13* 0.11** 0.10***

Diarrhea

3

0

1

1 0 0 1

6 4 7 32

3 3 5 10

2 4 0 3 4 0.56* 0.31** 0.06***

3

0

1

0 0 1 0

8 4 7 32

2 3 5 10

2 3 0 3 4 0.23* 0.11** 0.17***

3 0 0 1 0

M. Panteliadou et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) 813– 820 Table 4 Overall treatment time and radiotherapy delays Amifostine dose

A. 0 (13 pts.) B. 500 (7 pts.) C. 750 (16 pts.) D. 1,000 (46 pts.) P value

Accomplishment of RT 19 days

22–26 days

2–33 days

5 (38.5%) 3 (42.8%) 10 (62.5%) 34 (73.9%)

3 (23.0%) 2 (28.6%) 1 (6.2%) 8 (17.4%) 0.05* 0.11** 0.01***

5 (38.5%) 2 (28.6%) 5 (31.3%) 4 (8.7%)

* A/B vs. C/D. ** 〈 vs. B/C/D. *** A vs. D.

(1,000 mg) dose level (P ⫽ 0.01). Although frequency was reduced in patients receiving amifostine, the difference did not reach significance. A marginal significance was reached for proctitis at the highest amifostine dose level (P ⫽ 0.06). No significant difference was noted in the incidence of diarrhea. Radiotherapy delay due to early toxicities is an important marker of the severity of such toxicities and of the time demanded for their regression. High amifostine dose (750 –1,000 mg) significantly prevented treatment delays (P ⫽ 0.05) Table 4. However, the best protection was offered by the highest amifostine dose level of 1,000 mg (P ⫽ 0.01). 3.5. Late radiation toxicity Within a median follow-up of 19 months, patients treated with HypoARC showed a low incidence of severe late sequelae compared to standard RT. Overall, the grade 2–3 toxicities were lower than 2.5% (Table 5). Patients treated with HypoARC who did not receive amifostine had significantly worse frequency (P ⫽ 0.04). No significant difference was noted for dysuria and for rectal toxicity. 3.6. Response to radiotherapy Following HypoARC the complete response (CR) rate was 86.6%. This was higher in the T1 stage (100%) and dropped gradually to 90.9% in the T2 stage and to 79.5% in the T3– 4 stage (P ⬎ 0.18). The dose of amifostine did not affect the CR rates (0 mg: 10/13, 500 mg: 6/7, 750 mg: 13/16, and 1,000 mg: 42/46; P ⫽ 0.50). 3.7. Local control Following HypoARC the 1-, 2-, and 3-year local relapse free survival (LRFS) rate was 73%, 63%, and 56%, respectively. There was no effect of T-stage (Fig. 1A) or of radiotherapy delays (Fig. 1B) on LRFS. Although the 3-year

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LRFS was better in patients who received 1,000 mg of amifostine, the difference was not significant (Fig. 1C; P ⬎ 0.18). In multivariate analysis, none of the examined variables was an independent prognostic parameter of local disease progression (data not shown). 3.8. Disease specific overall survival Following HypoARC the 1-, 2-, and 3-year disease specific overall survival (OS) was 82%, 71%, and 63%, respectively. There was no effect of T-stage (Fig. 2A), of radiotherapy delays (Fig. 2B), and of amifostine dose (Fig. 2C) on OS. In multivariate analysis, none of the examined vari-

Table 5 Late pelvic radiation toxicity, assessed LENT-SOMA scale, in patients treated with HypoARC HypoARC No. pts 82 (%) Frequency 0. None 1. ⬍4 hourly 2. Every 2–3 hours 3. Every 1–2 hours 4. Catheter, surgical intervention Dysuria 0. None 1. Mild 2. Tolerable 3. Intense 4. Catheter, surgical intervention Hematuria 0. None 1. Microscopic 2. Macroscopic, Hb drop ⬍10% 3. Continuous, Hb drop 10%–20% 4. Persistent, Hb drop ⬎20% Bladder Incontinence 0. None 1. Less than weekly 2. Less than daily 3. Pads 4. Permanent catheter Diarrhea 0. No 1. ⬍4 stools 2. 4–8 stools 3. ⬎8 stools, incontinence 4. Hospitalization, colostomy Rectal bleeding 0. None 1. Microscopic 2. Occasional 3. Daily 4. Colostomy Tenesmus 0. None 1. Occasional 2. Frequent 3. Permanent 4. Colostomy

71 (86.6) 10 (12.2) 1 (1.2) 0 (0.0) 0 (0.0) 75 (91.2) 5 (6.1) 1 (1.2) 1 (1.2) 0 (0.0) 80 (97.6) Not assessed 1 (1.2) 1 (1.2) 0 (0.0) 79 (96.4) 1 (1.2) 1 (1.2) 1 (1.2) 0 (0.0) 81 (98.8) 1 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) 82 (100) Not assessed 0 (0.0) 0 (0.0) 0 (0.0) 80 (97.5) 2 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

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4. Discussion During the past 20 years, the clinical value of altered fractionation has been under intense investigation. Hyperfractionated techniques have shown important benefit in patients with head-neck cancer [21]. Hypofractionation seems to be effective in the treatment of tumors with relatively low radiobiological ␣/␤-ratio, such as prostate and breast cancer [22,23]. On the other hand, acceleration of the radiotherapy schedule has shown improved efficacy in the treatment of head-neck and lung cancer [21,24]. In bladder cancer, hyperfractionated and accelerated techniques have failed to show a clear superiority over standard fractionation. A retrospective analysis on 480 patients did not confirm an impact of the overall treatment time on the efficacy of radiotherapy [9]. Moonen et al. noted

Fig. 1. Local relapse free survival of patients according to (A) T-stage, (B) radiotherapy delays and, (C) dose of amifostine.

ables was an independent prognostic parameter (data not shown). 3.9. The addition of liposomal doxorubicin The effect of liposomal doxorubicin on the efficacy of HypoARC in terms of local control and overall survival has been reported in a recent study [20]. Briefly, liposomal doxorubicin did not affect the toxicity of radiotherapy, had no significant impact on tumor control, but significantly improved the overall survival. The 3-year survival rate was 72.1% in patients receiving LDox vs. 58.7% in patients who were treated wit radiotherapy alone [20]. In multivariate analysis, however, none of the available parameters was an independent prognostic variable of death events.

Fig. 2. Disease specific overall survival of patients according to (A) T-stage, (B) radiotherapy delays and, (C) dose of amifostine.

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a marginal impact of the overall treatment time on local control [10]. In a randomized study by Horwich et al., the usage of accelerated radiotherapy (1.8Gy twice-a-day) did not improve of radiation efficacy in bladder cancer patients [11]. The clinical experience on accelerated hypofractionation in bladder cancer is limited. An RTOG study [16] showed a 66% 3-year LRFS in 34 cases analyzed, while the study by Cowan et al. [25] reported a 40%– 60% 5-year local relapsefree survival, using a partial bladder irradiation technique. The current HypoARC study, by recruiting 82 cases, is the largest reported up to now in the field. 4.1. Toxicities from HypoARC vs. amifostine Despite the aggressiveness of the HypoARC regimen, early radiation toxicity from pelvic tissues was low. The administration of amifostine during HypoARC may account for this finding [26]. The protective effect was higher at the 1,000 mg dose level suggesting a dose-dependent cytoprotective efficacy, compatible with experimental data [27]. Such high amifostine dose levels seemed also to protect against proctitis and diarrhea. The delays of HypoARC due to early toxicities were significantly reduced by amifostine. Regarding the late radiation sequelae, HypoARC was proven to be a safe regimen. Again, the administration of amifostine significantly reduced the incidence of frequency in patients receiving HypoARC. 4.2. Local control and survival Tumor complete response was documented in 86.6% of patients undergoing HypoARC, and the 3-year local relapse-free survival reached 56%. This result is similar to the one reported by Pos et al. where a 55% 3-year local progression free survival was recorded following an accelerated and slightly hypofractionated regimen (2.7 Gy per fraction) [28]. The 3-year overall survival was 63%. The RTOG-97-06 reported a 3-year local control and overall survival of 73% and 61%, respectively, following a twice daily accelerated radio-chemotherapy scheme [29]. A randomized trial from the Royal Marsden, UK, reported a 3-year overall survival rate of 54% for patients undergoing accelerated (1.8 –2 Gy twice daily), and 47% for those treated with standard radiotherapy [11]. It seems that bladder cancer has increased sensitivity to large radiotherapy fractions when acceleration is applied. It may be that HypoARC, by targeting both tumors with high clonogen content and with low radio-sensitivity, treats effectively a large percentage of bladed cancer cases that cannot be adequately treated by simply accelerating the overall treatment time. The addition of amifostine, in contrast to worries regarding eventual interference with the antitumor effect of radiotherapy by protecting cancer cells [30], showed, on the contrary, a trend towards improved radiotherapy efficacy. This benefit, however, cannot be attributed to the reduced

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overall treatment time. As even patients who experience the most protracted delays accomplished HypoARC within 5 weeks, it may be that the benefit from acceleration is already achievable by a 2-week acceleration time. The eventual control benefit from amifostine should be sought on indirect reasons, such as an anti-angiogenic effect or immune protection and stimulatory activity of amifostine [31,32]. 4.3. A comment on treatment economics We attempted to estimate the cost of HypoARC in comparison to the one of standard radiotherapy. The total number of 500 mg vials of amifostine demanded for HypoARC was 30 (2 vials ⫻ 15 fractions), which is similar to the number of vials that would be demanded in conventionally fractionated regimens (1 vial ⫻ 30 –35 fractions). We took into account: (1) the Greek regulations for charging radiotherapy to insurance organizations, (2) the median cost for transportation to our department by car, (3) the lost of working days for patients younger than 65 years old and, (4) the cost of amifostine. The total cost was estimated to 4.400 Euro for HypoARC and 3.200 Euro for standard radiotherapy. This difference should be balanced against the convenience of HypoARC in terms of patients’ reduced travel discomfort and in terms of faster turnover of patients in the radiotherapy waiting lists. Moreover, the reduced late toxicities noted in patients receiving high amifostine dose are a gain that should not be considered strictly in economical terms, as there is no effective therapy for such complications. 4.5. Limitations of the study The current study is a prospective phase II study and lacks appropriate control groups that are necessary to assess inferiority or superiority, in terms of toxicity, local control, and survival over the standard conventionally fractionated radiotherapy. The low early and late toxicity noted and the high complete response rates obtained are certainly encouraging and justify further testing in properly designed randomized trials. The benefits from amifostine, although clear and dose-dependent, should also be confirmed in randomized trials. It is important to exclude that a biological background related to amifostine intolerance does not also increase the radiation susceptibility, which could be a source of bias. The usage of liposomal doxorubicin, a nonconventional drug for radio-chemotherapy combination, showed good systemic tolerance compared with that expected from conventional cisplatin regimens, but testing in randomized trials is imperative.

5. Conclusions The accelerated administration of large radiotherapy fractions in patients with bladder cancer is linked with low early and late radiation toxicity, which is further reduced by

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high dose amifostine. The efficacy in terms of complete responses, local control, and disease-specific survival compares favorably with previously published data. The reduced by 4 weeks overall treatment time is convenient for patients residing away from radiotherapy departments, and also convenient for busy radiotherapy departments. It is stressed that this study, although prospective, is not randomized either for the usage of amifostine or of liposomal doxorubicin, so that the current evidence needs confirmation in larger randomized trials, including also cohorts treated with conventional cisplatin-based chemo-radiotherapy.

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