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Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine
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Original article
Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine Trimodalités pour le cancer de la vessie chez les personnes âgées : résection transurétrale, radiothérapie hypofractionée et gemcitabine H.A.H. Mohamed a , M.A. Salem b,∗ , M.S. Elnaggar c , A. Gabr d , A.M. Abdelrheem d a
Radiation Oncology Department, South Egypt Cancer Institute, Assiut University, Egypt Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt c Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt d Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Egypt b
a r t i c l e
i n f o
Article history: Received 11 May 2017 Received in revised form 20 September 2017 Accepted 21 September 2017 Keywords: Bladder cancer Hypofractionated radiotherapy Salvage cystectomy
a b s t r a c t Purpose. – A prospective phase II study carried out to evaluate hypofractionated radiotherapy with concurrent gemcitabine for bladder preservation in the elderly patient with bladder cancer. Patients and methods. – Thirty-one patients were enrolled, age ≥ 65 years, diagnosed with transitional cell carcinoma of the urinary bladder, after a maximum safe transurethral resection of a bladder tumour. They received 52.5 Gy in 20 fractions using 3D conformal radiotherapy with concurrent 100 mg/m2 gemcitabine weekly as a radiosensitizer. Results. – All patients completed their radiation therapy course, while seven patients received their chemotherapy irregularly due to grade 3 toxicities. Twenty-five patients (80.6%) achieved a complete response. At 2-years, overall survival was 94.4% and disease-free survival was 72.6%. T3 and residual after transurethral resection are factors that adversely affect disease-free survival. Conclusion. – Hypofractionated radiotherapy and gemcitabine as a radiosensitizer in elderly as organ preservation for transitional cell carcinoma bladder cancer have acceptable toxicity profile with good response rate and disease-free survival, keeping salvage cystectomy for persistence or recurrence of invasive cancer. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2018 Societ rights reserved.
r é s u m é Mots clés : Cancer de la vessie Radiothérapie hypofractionée Cystectomie de récupération
Objectifs de l’étude. – Il s’agit d’une étude prospective de phase II pour évaluer la radiothérapie hypofractionée avec gemcitabine concomitante pour la préservation de la vessie chez les personnes âgées atteintes de cancer de la vessie. Patients et méthodes. – Trente-et un-patients âgés de 65 ans et plus, atteints d’un carcinome transitionnel de la vessie de stade clinique T2 ou T3, N0, M0, après une résection transurétrale maximale, ont été inclus. Ils ont rec¸u une radiothérapie conformationnelle tridimensionnelle de 52,5 Gy en 20 fractions et 100 mg/m2 de gemcitabine par semaine en tant que radiosensibilisateur. Résultats. – Tous les patients ont terminé leur radiothérapie, tandis que sept patients ont rec¸u leur chimiothérapie irrégulièrement en raison d’une toxicité de grade 3. Vingt-cinq patients (80,6 %) ont obtenu une réponse complète. À 2 ans, la probabilité de survie globale était de 94,4 % et celle de survie sans maladie de 72,6 %. Le stade T3 et un résidu après la résection transurétrale étaient des facteurs affectant négativement la survie sans maladie.
∗ Corresponding author. South Egypt Cancer Institute, elmethaq street, Assiut P.C. 71111, Egypt. E-mail addresses: hamza [email protected] (H.A.H. Mohamed), [email protected] [email protected] (A. Gabr).
(M.A.
Salem),
maha [email protected]
(M.S.
Elnaggar),
https://doi.org/10.1016/j.canrad.2017.09.013 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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Conclusion. – La radiothérapie hypofractionnée pour le cancer de la vessie transtionnel chez les personnes âgées et la gemcitabine comme radiosensibilisateur, avec pour objectif la préservation de l’organe, a un profil de toxicité acceptable, avec des bons taux de réponse et de survie sans maladie, en gardant la cystectomie de sauvetage pour la persistance ou la récidive du cancer invasif. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
1. Introduction Bladder cancer is the second common cancer in Egyptian men (10.7%), in particularly in upper Egypt (12.60%), and it represents 21.1% age-adjusted rate in men [1]. The incidence of bladder cancer is increasing with age; patients’ ages 60 to 70 years represented 35.73%, while patients at least 70 years represents about 21.26% among Egyptian population with bladder cancer [2]. Only half of elderly patients with bladder cancer receive a radical treatment [3]. Radical cystectomy is not feasible for all elderly patients either because a patient is unfit for major surgery or refuses it; radiotherapy used for such patients. Chemotherapy, as a radiosensitizer, and radiotherapy achieved comparable to survival to cystectomy [4]. Hypofractionation is an attractive and convenient choice for elderly as it limits their travelling frequency and waiting time. Multiple studies used hypofractionated radiotherapy in elderly for palliation [5]; however, during the last decade hypofractionated schedules were used for radical treatment [6]. Hypofractionation with weekly radiosensitizer is effective and tolerated [5–8]. In elderly, the addition of chemotherapy to radiotherapy has been shown to improve 5-years locoregional control rates from 54% to 67% and 5-years survival from 35% to 48% [9]. Gemcitabine as a radiosensitizer in bladder cancer has been studied and found to be well tolerated and effective [10,11]. However, there is no prospective study evaluating gemcitabine concurrently with hypofractionated radiotherapy in elderly who are less likely to complete trimodalities treatment compared with younger patients [12]. Due to the lack of evidence, we conducted this work to study the toxicity and efficacy of hypofractionated radiotherapy and gemcitabine for bladder cancer, as a bladder conservative strategy. 2. Patients and methods This study recruited 31 patients between January 2011 to December 2016 and approved by our institutional ethics committee and informed consent. Our patients were unfit or refusing cystectomy. Patients were eligible if their age was at least 65 years, diagnosed with clinical stage T2 or T3, N0, M0 transitional cell carcinoma of the urinary bladder (pelvis MRI, pelvis–abdomen CT and chest x-ray) after maximum safe transurethral resection of a bladder tumour. Patient must have Eastern Cooperative Oncology Group (ECOG) performance score 2 or less, normal complete blood count, serum concentrations of creatinine 2.0 mg/dl or less, bilirubin 2 mg/dl or less, AST, and ALT 3 or less, upper limits of normal. Patients who had squamous cell carcinoma, earlier pelvic radiation therapy, systemic chemotherapy, intravesical chemotherapy or BCG were ineligible. 2.1. Treatment protocol Radiation started within 45 days after transurethral resection. Patient were planned to receive 52.5 Gy as total dose delivered in 20 fractions, five fractions per week, using 3D conformal radiotherapy. Patients received gemcitabine as a radiosensitizer at a
dose 100 mg/m2 weekly on Saturdays as a 30-minute infusion for 4 weeks, 2 to 4 h before radiation session. Simulation was done with the empty bladder in supine position. The clinical target volume included the bladder with additional 1.5 cm, the prostate and prostatic urethra (in men]. 2.2. Revaluation Acute toxicity was assessed during treatment and 6 weeks later according to Radiotherapy Oncology Group (RTOG) recommendations for genitourinary symptoms, while late toxicity was assessed and recorded every 3 months [13]. Quality of life assessements by NCCN-FACT FBlSI-18 questionnaire for bladder cancer patients were done as a baseline before treatment and 3 months after treatment. Patients underwent assessment of response 3 months after chemoradiation, radiologically by pelvis CT and/or MRI and cystoscopy at 3 months and 6 monthly thereafter. The radiological complete response was confirmed by biopsy and cytology. The presence of superficial recurrence were treated by intravesical chemotherapy. However, salvage cystectomy was indicated in cases of persistent invasive cancer, intractable urinary symptoms or incontinence. 2.3. Statistical methods Kaplan-Meier actuarial method from the time of diagnosis to the last follow-up was used to estimate disease-free survival and overall survival [14]. Log-rank test was used to compare survival rates. 3. Results This is prospective phase II; included 31 eligible patients with bladder cancer attending South Egypt Cancer Institute, Assiut University. Patients signed a consent from and the study was approved by the institute’s ethical committee. Patient’s characteristic are presented in Table 1. All patients completed their radiation therapy with supportive care, including painkillers (tramadol hydrochloride in eight patients) for cystitis during most of the course. Twenty-four patients received their chemotherapy regularly while three patients received three doses of gemcitabine, three patients two doses and a patient received chemotherapy only once, all of them due to grade 3 toxicity (Table 2). All patients were followed regularly according to schedule. Follow-up was considered from the onset of treatment. Patients tolerated the treatment protocol with a good quality of life (Table 3). A patient developed grade 3 late bladder toxicity and another patient rectal stenosis. Twenty-five patients (80.6%) achieved complete radiological and pathological response during first transurethral resection assessment after treatment. Five patients still had muscle invasive carcinoma and underwent cystectomy, however, the fourth patient had non-muscle invasive tumour subjected to repeated transurethral resection.
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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H.A.H. Mohamed et al. / Cancer/Radiothérapie xxx (2017) xxx–xxx Table 1 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: patient characteristics (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : caractéristique des patients. Age range Sex (n) Male Female ECOG performance score (n) 0 1 2 Tumour size (n) T2 T3 Grade (n) 1 2 3 Transurethral resection (n) Complete Incomplete Hydronephrosis (n) Present Absent Bilharziasis (n) Present Absent
65–82 years 30 1 0 21 10 17 14 0 13 18 15 16 13 18 21 10
ECOG : Easter Cooperative Oncology Group.
3
Table 3 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: mean item scores for NCCN-FACT FBlSI-18 questionnaire for patient quality of life assessment. Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : scores moyens au questionnaire NCCN-FACT FBlSI-18 pour l’évaluation de la qualité de vie des patients. Questionnaire item Physical disease-related symptoms Pain Weight loss Trouble in urine control General weakness Dizziness Trouble in meeting family needs Appetite (For men only) Erection Good sleeping Emotional disease related symptoms Worry about the illness Sadness Treatment side effects Nausea Lack of energy Feeling ill Bowels control Bothering from treatment side effects Function and well-being Enjoying life Satisfaction with quality of life Total
Index score (mean ± SD) 2.9 3.1 2.6 3 3.1 3.5 3.1 3.6 3.1
± ± ± ± ± ± ± ± ±
08 0.6 0.9 0.7 0.6 0.8 0.7 0.8 0.8
2.1 ± 0.9 3.1 ± 0.7 2.1 3.2 3.1 3.4 3.2
± ± ± ± ±
0.6 0.9 0.8 1.5 0.8
1.2 ± 0.8 2 ± 1.1 51.4 ± 14.8
Mean of reverse items.
Table 2 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: acute toxicity (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : toxicité aiguë (n = 31). Toxicity Cystitis Grade 1–2 Grade 3 Proctitis Grade 1–2 Grade 3 Diarrhea Grade 1-2 Grade 2
Number of patients (%) 25 (80.6%) 6 (19.4%) 26 (83.9%) 5 (16.1%) 9 (29%) 1 (3.2%)
At 2-years median follow-up for all 31 patients, overall survival was 94.4% and disease-free survival 72.6% (Fig. 1). Among 25 patients who achieved complete response, four had local recurrence and underwent cystectomy, one patient had metastases and one patient devolved both local recurrence and distant metastasis. Cystectomy free survival was 64.2% (Fig. 2) as salvage cystectomy was performed in nine patients out of 31, five of them due to persistent invasive cancer, at the first assessment after chemoradiation and four patients developed local recurrence during follow-up with the intractable urinary symptom (severe burning pain and frequency). Residual tumour size and grade, after transurethral resection, and the presence of hydronephrosis are factors that adversely affected disease-free survival (Table 4). 4. Discussion We enrolled elderly patients because of increased median age of Egyptian patients with cancer bladder, from 47.4 years in the old series to 60.5 years mainly due to control of schistosomiasis [15]. We defined as elderly patients older than 65 years, as over
Fig. 1. Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: disease-free survival of all patients (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : survie sans maladie de tous les patients (n = 31).
60% of individuals aged 65 to 74 years have some disability and also because this age had been chosen by other authors [16,17]. Hypofractionation was a preferred option for elderly patients, especially when treated at overloaded radiation therapy centre, because it decreases waiting times and machine working time. Different hypofractionated radiotherapy protocols were used for palliative and radical treatment for cancer bladder and proved to be effective and safe. Patients received bladder only radiotherapy without attempts at elective pelvic nodal irradiation as it increased toxicity and did not affect rates of bladder preservation, disease-free survival or overall survival [13]. The maximum tolerated dose of gemcitabine was 150 mg/m2 and the recommended dose 100 mg/m2 when given weekly with radiation dose of 52.5 Gy in 20 fractions without any acute toxicity more than grade 1 and proven to be effective [18,19].
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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Fig. 2. Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: cystectomy free survival. Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : survie sans cystectomie.
Table 4 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: prognostic factors for 2-years disease-free survival (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : facteurs pronostiques pour la survie sans maladie à 2 ans (n = 31). Criteria Tumour stage T2 T3 Histological grade Grade 2 Grade 3 Transurethral resection adequacy Complete Incomplete Hydronephrosis Present Absent Bilharsis Present Absent
Disease-free survival rate (%)
P value 0.001
90.9 37 0.2065 82.4 29.2 0.0115 90.9 44.1 0.113 56.2 92.3 0.3176 61.4 88.9
Out of the thirty cases enrolled in our study, 25 (80.6%) had a complete response after chemoradiation, which is comparable to 72% complete response rate reported after analysis of 496 elderly patients from eight studies, or 88% for concurrent gemcitabine and hypofractionation in elderly patients [7,19]. Pos et al. reported 74% complete response after treating 50 patients with a total tumour dose 55 Gy in 20 fractions in 4 weeks similar to our results [20]. In a Japanese trial using extremely high concentration intraarterial chemotherapy selectively to the tumour, not to systemic circulation to decrease systemic adverse effects, authors reported prolonged complete response in over 90% (39 patients out of 43) without recurrence after a mean follow-up of 162 weeks, with 5and 12-year overall survival rates 92.7 and 69.5% (vs. 59.6 and 20.9% for cystectomy; P < 0.0092), respectively [21]. Acute toxicity was recorded in all patients with variable grades, while grade 3 toxicity that interfered with regularity of chemotherapy administration was reported in 22.6% of patients. This leads to the conclusion that elderly patients have a lower tolerance to chemotherapy as a radiosensitizer than young patients [12]. High grade of toxicity is usually reported among combined modalities for elderly patients, as James et al. reported one-third of grade 3/4 acute toxicity and 10% of patients had grade 3/4 late toxicity [9]. During follow-up most of the toxicity was controlled with a good quality of life score that was comparable to other studies using chemoradiation [22].
Our study reported 6.5% late toxicity, comparable to the rate reported by RTOG trials [23]. It appears that hypofractionation did not increase chronic toxicity, the same conclusion in a different study [24]. Modern radiation therapy technologies such intensitymodulated radiation therapy and helical tomotherapy decrease toxicity and increase therapeutic ratio, which is important for elderly patients [17]. Disease-free survival after 2 years was 72.6%, which is comparable to 67% reported after chemoradiotherapy with conventional fractionation [12,25]. Also, it is comparable to cystectomy in elderly patients as 2 years, recurrence-free, 73% [17]. Intra-arterial chemotherapy with radiation achieved higher disease-free survival and complete response in more than 90% patients without recurrence after 3 years’ follow-up, with 92.7% 5- year overall survival [21]. Complete transurethral resection should be recommended whenever it is safe, as residual lesions significantly and adversely affect survival. Salvage cystectomies are necessary in about 29% of cases, which is similar to other studies [26,27]. Hypofractionation cannot be considered the treatment of choice because ␣/ ratio of the bladder is 10 Gy, thus decreasing overall treatment times and larger fraction sizes have no potential therapeutic ratio advantages [28]. However, this concept changed with modern radiotherapy that decreases doses to organs at risk and late toxicity. Trials using modern radiation therapy such as intensity-modulated radiotherapy and helical tomotherapy have found further decreased toxiciy and enhanced therapeutic ratio [17]. Although our results are promising and offer a new option for elderly patients, they are interpreted cautiously because of the limited number of patients and we reported 2-years disease-free survival, as done in some phase II trial [29]; 5-years will be more informative with more patients included and a longer follow-up is encouraged. Hypofractionation with concurrent gemcitabine as radiosensitizer has an acceptable toxicity profile and tolerance, with good response rate and disease-free survival. Considering enhancing therapeutic ratio with new radiation therapy technologies and delivering higher doses of chemotherapy in the tumour rather than systemic drug administration should be investigated to treat elderly patients. Disclosure of interest The authors declare that they have no competing interest. References [1] Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol 2014;2014:437971. [2] Fedewa SA, Soliman AS, Ismail K, Hablas A, Seifeldin IA, Ramadan M, et al. Incidence analyses of bladder cancer in the Nile delta region of Egypt. Cancer Epidemiol 2009;33:176–81. [3] Gray PJ, Fedewa SA, Shipley WU, Efstathiou JA, Lin CC, Zietman AL, et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the united states: results from the national cancer data base. Eur Urol 2013;63:823–9. [4] Arcangeli G, Strigari L, Arcangeli S. Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: a systematic review of clinical trials. Crit Rev Oncol Hematol 2015;95:387–96. [5] McLaren DB, Morrey D, Mason MD. Hypofractionated radiotherapy for muscle invasive bladder cancer in the elderly. Radiother Oncol 1997;43:171–4. [6] Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086–94. [7] Turgeon G-A, Souhami L. Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer. Front Oncol 2014;4:206. [8] Chen RC, Shipley WU, Efstathiou JA, Zietman AL. Trimodality bladder preservation therapy for muscle-invasive bladder cancer. J Natl Compr Canc Netw 2013;11:952–60.
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[9] James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88. [10] Borut K, Lijana Z-K, Phase I. study of radiochemotherapy with gemcitabine in invasive bladder cancer. Radiother Oncol 2012;102:412–5. [11] Hussin M, Abbas H, Ahmed S, Abou M, Salem E. Gemcitabine versus cisplatin in concurrent radio chemotherapy for bladder preservation. Cancer Biol 2016;6:41–5. [12] Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, et al. Longterm outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014;32:3801–9. [13] 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 1995;31:1341–6. [14] Kaplan EL, Meier P. Nonparametric Estimation from incomplete observations. J Am Stat Assoc 2012;53:457–81. [15] Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, Nabil El-Bolkainy M. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Nat Cancer Inst 2007;19:158–62. [16] Shariat SF, Milowsky M, Droller MJ, et al. Bladder cancer in the elderly. Urol Oncol 2004;27:653–67. [17] Nguyen DP, Awamlh BAHAL, Charles Osterberg E, Chrystal J, Flynn T, Lee DJ, et al. Postoperative complications and short-term oncological outcomes of patients aged ≥ 80 years undergoing robot-assisted radical cystectomy. World J Urol 2015;33:1315–21. [18] Sangar VK, McBain CA, Lyons J, Ramani VAC, Logue JP, Wylie JP, et al. study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer. Int J Radiat Oncol Biol Phys 2005;61:420–5. [19] Choudhury A, Swindell R, Logue JP, Elliott PA, Livsey JE, Wise M, et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol 2011;29:733–8.
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[20] Pos FJ, van Tienhoven G, Hulshof MCCM, Koedooder K, González González D. Concomitant boost radiotherapy for muscle invasive bladder cancer. Radiother Oncol 2003;68:75–80. [21] Azuma H, Inamoto T, Ibuki N, Ubai T, Kotake Y, Takahara K, et al. Utility of the novel bladder preservation therapy, BOAI-CDDP-radiation (OMC-regimen), for elderly patients with invasive bladder cancer. Int J Oncol 2011;38:13–24. [22] El-Sayed I, El-Azab MAS, El-Gammal MA. Quality of life in bladder cancer patients treated with radical cystectomy and orthotopic bladder reconstruction versus bladder preservation protocol. J Cancer Sci Ther 2013;5. [23] Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, et al. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 2009;27:4055–61. [24] Duchesne GM, Bolger JJ, Griffiths GO, Trevor Roberts J, Graham JD, Hoskin PJ, et al. A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09. Int J Radiat Oncol Biol Phys 2000;47:379–88. [25] Abbas H, Aboziada MA, Abdalwanis ME, El-Gmal MA, Mokhtar A, Abo-Almagd MA, et al. Organ preservation in bilharzial bladder cancer in Egypt: single institutional experience. J Cancer Ther 2012;3:57–63. [26] Cooke PW, Dunn JA, Latief T, Bathers S, James ND, Wallace DM. Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer. Eur Urol 2000;38:279–86. [27] Peyromaure M, Slama J, Beuzeboc P, Ponvert D, Debré B, Zerbib M. Concurrent chemoradiotherapy for clinical stage T2 bladder cancer: report of a single institution. Urology 2004;63:73–7. [28] Kouloulias V, Tolia M, Kolliarakis N, Siatelis A, Kelekis N, Kouloulias V, et al. Evaluation of acute toxicity and symptoms palliation in a hypofractionated weekly schedule of external radiotherapy for elderly patients with muscular invasive bladder cancer. Int Braz J Urol 2013;39:77–82. [29] Hsieh C-H, Chung S-D, Chan P-H, Lai S-K, Chang H-C, Hsiao C-H, et al. Intensity modulated radiotherapy for elderly bladder cancer patients. Radiat Oncol 2011;6:75.
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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Disponible en ligne sur
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Original article
Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine Trimodalités pour le cancer de la vessie chez les personnes âgées : résection transurétrale, radiothérapie hypofractionée et gemcitabine H.A.H. Mohamed a , M.A. Salem b,∗ , M.S. Elnaggar c , A. Gabr d , A.M. Abdelrheem d a
Radiation Oncology Department, South Egypt Cancer Institute, Assiut University, Egypt Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt c Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt d Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Egypt b
a r t i c l e
i n f o
Article history: Received 11 May 2017 Received in revised form 20 September 2017 Accepted 21 September 2017 Keywords: Bladder cancer Hypofractionated radiotherapy Salvage cystectomy
a b s t r a c t Purpose. – A prospective phase II study carried out to evaluate hypofractionated radiotherapy with concurrent gemcitabine for bladder preservation in the elderly patient with bladder cancer. Patients and methods. – Thirty-one patients were enrolled, age ≥ 65 years, diagnosed with transitional cell carcinoma of the urinary bladder, after a maximum safe transurethral resection of a bladder tumour. They received 52.5 Gy in 20 fractions using 3D conformal radiotherapy with concurrent 100 mg/m2 gemcitabine weekly as a radiosensitizer. Results. – All patients completed their radiation therapy course, while seven patients received their chemotherapy irregularly due to grade 3 toxicities. Twenty-five patients (80.6%) achieved a complete response. At 2-years, overall survival was 94.4% and disease-free survival was 72.6%. T3 and residual after transurethral resection are factors that adversely affect disease-free survival. Conclusion. – Hypofractionated radiotherapy and gemcitabine as a radiosensitizer in elderly as organ preservation for transitional cell carcinoma bladder cancer have acceptable toxicity profile with good response rate and disease-free survival, keeping salvage cystectomy for persistence or recurrence of invasive cancer. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2018 Societ rights reserved.
r é s u m é Mots clés : Cancer de la vessie Radiothérapie hypofractionée Cystectomie de récupération
Objectifs de l’étude. – Il s’agit d’une étude prospective de phase II pour évaluer la radiothérapie hypofractionée avec gemcitabine concomitante pour la préservation de la vessie chez les personnes âgées atteintes de cancer de la vessie. Patients et méthodes. – Trente-et un-patients âgés de 65 ans et plus, atteints d’un carcinome transitionnel de la vessie de stade clinique T2 ou T3, N0, M0, après une résection transurétrale maximale, ont été inclus. Ils ont rec¸u une radiothérapie conformationnelle tridimensionnelle de 52,5 Gy en 20 fractions et 100 mg/m2 de gemcitabine par semaine en tant que radiosensibilisateur. Résultats. – Tous les patients ont terminé leur radiothérapie, tandis que sept patients ont rec¸u leur chimiothérapie irrégulièrement en raison d’une toxicité de grade 3. Vingt-cinq patients (80,6 %) ont obtenu une réponse complète. À 2 ans, la probabilité de survie globale était de 94,4 % et celle de survie sans maladie de 72,6 %. Le stade T3 et un résidu après la résection transurétrale étaient des facteurs affectant négativement la survie sans maladie.
∗ Corresponding author. South Egypt Cancer Institute, elmethaq street, Assiut P.C. 71111, Egypt. E-mail addresses: hamza [email protected] (H.A.H. Mohamed), [email protected] [email protected] (A. Gabr).
(M.A.
Salem),
maha [email protected]
(M.S.
Elnaggar),
https://doi.org/10.1016/j.canrad.2017.09.013 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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Conclusion. – La radiothérapie hypofractionnée pour le cancer de la vessie transtionnel chez les personnes âgées et la gemcitabine comme radiosensibilisateur, avec pour objectif la préservation de l’organe, a un profil de toxicité acceptable, avec des bons taux de réponse et de survie sans maladie, en gardant la cystectomie de sauvetage pour la persistance ou la récidive du cancer invasif. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
1. Introduction Bladder cancer is the second common cancer in Egyptian men (10.7%), in particularly in upper Egypt (12.60%), and it represents 21.1% age-adjusted rate in men [1]. The incidence of bladder cancer is increasing with age; patients’ ages 60 to 70 years represented 35.73%, while patients at least 70 years represents about 21.26% among Egyptian population with bladder cancer [2]. Only half of elderly patients with bladder cancer receive a radical treatment [3]. Radical cystectomy is not feasible for all elderly patients either because a patient is unfit for major surgery or refuses it; radiotherapy used for such patients. Chemotherapy, as a radiosensitizer, and radiotherapy achieved comparable to survival to cystectomy [4]. Hypofractionation is an attractive and convenient choice for elderly as it limits their travelling frequency and waiting time. Multiple studies used hypofractionated radiotherapy in elderly for palliation [5]; however, during the last decade hypofractionated schedules were used for radical treatment [6]. Hypofractionation with weekly radiosensitizer is effective and tolerated [5–8]. In elderly, the addition of chemotherapy to radiotherapy has been shown to improve 5-years locoregional control rates from 54% to 67% and 5-years survival from 35% to 48% [9]. Gemcitabine as a radiosensitizer in bladder cancer has been studied and found to be well tolerated and effective [10,11]. However, there is no prospective study evaluating gemcitabine concurrently with hypofractionated radiotherapy in elderly who are less likely to complete trimodalities treatment compared with younger patients [12]. Due to the lack of evidence, we conducted this work to study the toxicity and efficacy of hypofractionated radiotherapy and gemcitabine for bladder cancer, as a bladder conservative strategy. 2. Patients and methods This study recruited 31 patients between January 2011 to December 2016 and approved by our institutional ethics committee and informed consent. Our patients were unfit or refusing cystectomy. Patients were eligible if their age was at least 65 years, diagnosed with clinical stage T2 or T3, N0, M0 transitional cell carcinoma of the urinary bladder (pelvis MRI, pelvis–abdomen CT and chest x-ray) after maximum safe transurethral resection of a bladder tumour. Patient must have Eastern Cooperative Oncology Group (ECOG) performance score 2 or less, normal complete blood count, serum concentrations of creatinine 2.0 mg/dl or less, bilirubin 2 mg/dl or less, AST, and ALT 3 or less, upper limits of normal. Patients who had squamous cell carcinoma, earlier pelvic radiation therapy, systemic chemotherapy, intravesical chemotherapy or BCG were ineligible. 2.1. Treatment protocol Radiation started within 45 days after transurethral resection. Patient were planned to receive 52.5 Gy as total dose delivered in 20 fractions, five fractions per week, using 3D conformal radiotherapy. Patients received gemcitabine as a radiosensitizer at a
dose 100 mg/m2 weekly on Saturdays as a 30-minute infusion for 4 weeks, 2 to 4 h before radiation session. Simulation was done with the empty bladder in supine position. The clinical target volume included the bladder with additional 1.5 cm, the prostate and prostatic urethra (in men]. 2.2. Revaluation Acute toxicity was assessed during treatment and 6 weeks later according to Radiotherapy Oncology Group (RTOG) recommendations for genitourinary symptoms, while late toxicity was assessed and recorded every 3 months [13]. Quality of life assessements by NCCN-FACT FBlSI-18 questionnaire for bladder cancer patients were done as a baseline before treatment and 3 months after treatment. Patients underwent assessment of response 3 months after chemoradiation, radiologically by pelvis CT and/or MRI and cystoscopy at 3 months and 6 monthly thereafter. The radiological complete response was confirmed by biopsy and cytology. The presence of superficial recurrence were treated by intravesical chemotherapy. However, salvage cystectomy was indicated in cases of persistent invasive cancer, intractable urinary symptoms or incontinence. 2.3. Statistical methods Kaplan-Meier actuarial method from the time of diagnosis to the last follow-up was used to estimate disease-free survival and overall survival [14]. Log-rank test was used to compare survival rates. 3. Results This is prospective phase II; included 31 eligible patients with bladder cancer attending South Egypt Cancer Institute, Assiut University. Patients signed a consent from and the study was approved by the institute’s ethical committee. Patient’s characteristic are presented in Table 1. All patients completed their radiation therapy with supportive care, including painkillers (tramadol hydrochloride in eight patients) for cystitis during most of the course. Twenty-four patients received their chemotherapy regularly while three patients received three doses of gemcitabine, three patients two doses and a patient received chemotherapy only once, all of them due to grade 3 toxicity (Table 2). All patients were followed regularly according to schedule. Follow-up was considered from the onset of treatment. Patients tolerated the treatment protocol with a good quality of life (Table 3). A patient developed grade 3 late bladder toxicity and another patient rectal stenosis. Twenty-five patients (80.6%) achieved complete radiological and pathological response during first transurethral resection assessment after treatment. Five patients still had muscle invasive carcinoma and underwent cystectomy, however, the fourth patient had non-muscle invasive tumour subjected to repeated transurethral resection.
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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H.A.H. Mohamed et al. / Cancer/Radiothérapie xxx (2017) xxx–xxx Table 1 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: patient characteristics (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : caractéristique des patients. Age range Sex (n) Male Female ECOG performance score (n) 0 1 2 Tumour size (n) T2 T3 Grade (n) 1 2 3 Transurethral resection (n) Complete Incomplete Hydronephrosis (n) Present Absent Bilharziasis (n) Present Absent
65–82 years 30 1 0 21 10 17 14 0 13 18 15 16 13 18 21 10
ECOG : Easter Cooperative Oncology Group.
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Table 3 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: mean item scores for NCCN-FACT FBlSI-18 questionnaire for patient quality of life assessment. Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : scores moyens au questionnaire NCCN-FACT FBlSI-18 pour l’évaluation de la qualité de vie des patients. Questionnaire item Physical disease-related symptoms Pain Weight loss Trouble in urine control General weakness Dizziness Trouble in meeting family needs Appetite (For men only) Erection Good sleeping Emotional disease related symptoms Worry about the illness Sadness Treatment side effects Nausea Lack of energy Feeling ill Bowels control Bothering from treatment side effects Function and well-being Enjoying life Satisfaction with quality of life Total
Index score (mean ± SD) 2.9 3.1 2.6 3 3.1 3.5 3.1 3.6 3.1
± ± ± ± ± ± ± ± ±
08 0.6 0.9 0.7 0.6 0.8 0.7 0.8 0.8
2.1 ± 0.9 3.1 ± 0.7 2.1 3.2 3.1 3.4 3.2
± ± ± ± ±
0.6 0.9 0.8 1.5 0.8
1.2 ± 0.8 2 ± 1.1 51.4 ± 14.8
Mean of reverse items.
Table 2 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: acute toxicity (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : toxicité aiguë (n = 31). Toxicity Cystitis Grade 1–2 Grade 3 Proctitis Grade 1–2 Grade 3 Diarrhea Grade 1-2 Grade 2
Number of patients (%) 25 (80.6%) 6 (19.4%) 26 (83.9%) 5 (16.1%) 9 (29%) 1 (3.2%)
At 2-years median follow-up for all 31 patients, overall survival was 94.4% and disease-free survival 72.6% (Fig. 1). Among 25 patients who achieved complete response, four had local recurrence and underwent cystectomy, one patient had metastases and one patient devolved both local recurrence and distant metastasis. Cystectomy free survival was 64.2% (Fig. 2) as salvage cystectomy was performed in nine patients out of 31, five of them due to persistent invasive cancer, at the first assessment after chemoradiation and four patients developed local recurrence during follow-up with the intractable urinary symptom (severe burning pain and frequency). Residual tumour size and grade, after transurethral resection, and the presence of hydronephrosis are factors that adversely affected disease-free survival (Table 4). 4. Discussion We enrolled elderly patients because of increased median age of Egyptian patients with cancer bladder, from 47.4 years in the old series to 60.5 years mainly due to control of schistosomiasis [15]. We defined as elderly patients older than 65 years, as over
Fig. 1. Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: disease-free survival of all patients (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : survie sans maladie de tous les patients (n = 31).
60% of individuals aged 65 to 74 years have some disability and also because this age had been chosen by other authors [16,17]. Hypofractionation was a preferred option for elderly patients, especially when treated at overloaded radiation therapy centre, because it decreases waiting times and machine working time. Different hypofractionated radiotherapy protocols were used for palliative and radical treatment for cancer bladder and proved to be effective and safe. Patients received bladder only radiotherapy without attempts at elective pelvic nodal irradiation as it increased toxicity and did not affect rates of bladder preservation, disease-free survival or overall survival [13]. The maximum tolerated dose of gemcitabine was 150 mg/m2 and the recommended dose 100 mg/m2 when given weekly with radiation dose of 52.5 Gy in 20 fractions without any acute toxicity more than grade 1 and proven to be effective [18,19].
Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013
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Fig. 2. Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: cystectomy free survival. Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : survie sans cystectomie.
Table 4 Prospective phase II study evaluating hypofractionated radiotherapy with concurrent gemcitabine for bladder cancer in the elderly patient: prognostic factors for 2-years disease-free survival (n = 31). Étude prospective de phase II évaluant la radiothérapie hypofractionée avec gemcitabine concomitante pour cancer de la vessie chez les personnes âgées : facteurs pronostiques pour la survie sans maladie à 2 ans (n = 31). Criteria Tumour stage T2 T3 Histological grade Grade 2 Grade 3 Transurethral resection adequacy Complete Incomplete Hydronephrosis Present Absent Bilharsis Present Absent
Disease-free survival rate (%)
P value 0.001
90.9 37 0.2065 82.4 29.2 0.0115 90.9 44.1 0.113 56.2 92.3 0.3176 61.4 88.9
Out of the thirty cases enrolled in our study, 25 (80.6%) had a complete response after chemoradiation, which is comparable to 72% complete response rate reported after analysis of 496 elderly patients from eight studies, or 88% for concurrent gemcitabine and hypofractionation in elderly patients [7,19]. Pos et al. reported 74% complete response after treating 50 patients with a total tumour dose 55 Gy in 20 fractions in 4 weeks similar to our results [20]. In a Japanese trial using extremely high concentration intraarterial chemotherapy selectively to the tumour, not to systemic circulation to decrease systemic adverse effects, authors reported prolonged complete response in over 90% (39 patients out of 43) without recurrence after a mean follow-up of 162 weeks, with 5and 12-year overall survival rates 92.7 and 69.5% (vs. 59.6 and 20.9% for cystectomy; P < 0.0092), respectively [21]. Acute toxicity was recorded in all patients with variable grades, while grade 3 toxicity that interfered with regularity of chemotherapy administration was reported in 22.6% of patients. This leads to the conclusion that elderly patients have a lower tolerance to chemotherapy as a radiosensitizer than young patients [12]. High grade of toxicity is usually reported among combined modalities for elderly patients, as James et al. reported one-third of grade 3/4 acute toxicity and 10% of patients had grade 3/4 late toxicity [9]. During follow-up most of the toxicity was controlled with a good quality of life score that was comparable to other studies using chemoradiation [22].
Our study reported 6.5% late toxicity, comparable to the rate reported by RTOG trials [23]. It appears that hypofractionation did not increase chronic toxicity, the same conclusion in a different study [24]. Modern radiation therapy technologies such intensitymodulated radiation therapy and helical tomotherapy decrease toxicity and increase therapeutic ratio, which is important for elderly patients [17]. Disease-free survival after 2 years was 72.6%, which is comparable to 67% reported after chemoradiotherapy with conventional fractionation [12,25]. Also, it is comparable to cystectomy in elderly patients as 2 years, recurrence-free, 73% [17]. Intra-arterial chemotherapy with radiation achieved higher disease-free survival and complete response in more than 90% patients without recurrence after 3 years’ follow-up, with 92.7% 5- year overall survival [21]. Complete transurethral resection should be recommended whenever it is safe, as residual lesions significantly and adversely affect survival. Salvage cystectomies are necessary in about 29% of cases, which is similar to other studies [26,27]. Hypofractionation cannot be considered the treatment of choice because ␣/ ratio of the bladder is 10 Gy, thus decreasing overall treatment times and larger fraction sizes have no potential therapeutic ratio advantages [28]. However, this concept changed with modern radiotherapy that decreases doses to organs at risk and late toxicity. Trials using modern radiation therapy such as intensity-modulated radiotherapy and helical tomotherapy have found further decreased toxiciy and enhanced therapeutic ratio [17]. Although our results are promising and offer a new option for elderly patients, they are interpreted cautiously because of the limited number of patients and we reported 2-years disease-free survival, as done in some phase II trial [29]; 5-years will be more informative with more patients included and a longer follow-up is encouraged. Hypofractionation with concurrent gemcitabine as radiosensitizer has an acceptable toxicity profile and tolerance, with good response rate and disease-free survival. Considering enhancing therapeutic ratio with new radiation therapy technologies and delivering higher doses of chemotherapy in the tumour rather than systemic drug administration should be investigated to treat elderly patients. Disclosure of interest The authors declare that they have no competing interest. References [1] Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol 2014;2014:437971. [2] Fedewa SA, Soliman AS, Ismail K, Hablas A, Seifeldin IA, Ramadan M, et al. Incidence analyses of bladder cancer in the Nile delta region of Egypt. Cancer Epidemiol 2009;33:176–81. [3] Gray PJ, Fedewa SA, Shipley WU, Efstathiou JA, Lin CC, Zietman AL, et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the united states: results from the national cancer data base. Eur Urol 2013;63:823–9. [4] Arcangeli G, Strigari L, Arcangeli S. Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: a systematic review of clinical trials. Crit Rev Oncol Hematol 2015;95:387–96. [5] McLaren DB, Morrey D, Mason MD. Hypofractionated radiotherapy for muscle invasive bladder cancer in the elderly. Radiother Oncol 1997;43:171–4. [6] Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086–94. [7] Turgeon G-A, Souhami L. Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer. Front Oncol 2014;4:206. [8] Chen RC, Shipley WU, Efstathiou JA, Zietman AL. Trimodality bladder preservation therapy for muscle-invasive bladder cancer. J Natl Compr Canc Netw 2013;11:952–60.
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Please cite this article in press as: Mohamed HAH, et al. Trimodalities for bladder cancer in elderly: Transurethral resection, hypofractionated radiotherapy and gemcitabine. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.013