1527ISSN 1473-7140© 2010 Expert Reviews Ltdwww.expert-reviews.com

Editorial

10.1586/ERA.10.138

Letter to the Editor

The need to revisit adjuvant and neoadjuvant radiotherapy in bladder cancerExpert Rev. Anticancer Ther. 10(10), 1527–1528 (2010)

Response to: Sandler HM, Mirhadi A. Current status of radiation therapy for bladder cancer. Expert Rev. Anticancer Ther. 10(6), 895–901 (2010).

I read with utmost interest the article by Sandler and Mirhadi entitled ‘Current status of radiation therapy for bladder cancer’ [1]. They extensively described the historical background of radiotherapy for bladder cancer and discussed the reasons that hindered its success in the past. The article clearly showed the current role of radiotherapy as a part of trimodality treat-ment to achieve a high level of survival with preservation of the physiological bladder. Trimodality treatment did not jeopardize the survival of these patients, as radical cyst ectomy (RC) remained a valid option for nonresponders and muscle- invasive local recurrences. They clearly showed that the value of radiotherapy was not elucidated in the past owing to the limita-tion in the radiotherapy techniques used. With the modern, advanced, safer and highly effective radiotherapy techniques, better results have been published that are comparable to the results of RC [2,3]. However, Sandler and Mirhadi restricted their review to radical radiotherapy with bladder preservation that was indicated in a selected group of patients; mainly T2–3a N0M0 [1]. They did not discuss the status of radiation oncology in the adjuvant or neoadjuvant settings to RC. These procedures are probably needed in more advanced stages (T3, T4a and those with pelvic nodal involvements). Although radical cystoprostatectomy with urinary diversion is indicated in such patients, their 5-year survival rates are generally dismal. For pT3, the 5-year survival rate ranged from 19 to 59%, while for pT4 the rate ranged from 9 to 49%. The pelvic nodal

involvement decreased the survival rate to 9–35% [4–7]. Some of these results were obtained with the addition of neoadjuvant or adjuvant radiotherapy and/or chemo-therapy not in randomized trials [5,7]. The causes of failure were mainly distant sys-temic metastasis or pelvic local recurrence. Local failure accounts for between 23 and 51% of failures depending upon the tumor stage, histopathological grade and pelvic nodal status [8–10]. The local recurrences after RC were under-reported in many publications because the findings of distant metastasis decreased the need for intensi-fied local follow-up when local recurrence was asymptomatic [8]. Some investigators never report local recurrence unless it is the sole site of relapse [6]. The considerable rate of local failure entailed the presence of residual micrometastasis in the pelvis, either at the site of the tumor bed or pelvic lymph nodes. Therefore, these microscopic residues need sterilization either through preoperative or postoperative radiotherapy (PORT), which represents a logical indica-tion, especially in locally advanced patients, to improve the treatment outcome.

Neoadjuvant (preoperative) radiotherapyMany retrospective studies have proved the benefit of preoperative radiotherapy in bladder cancer. There are only six prospective randomized reports address-ing this issue. Only one out of the six studies showed statistically significant survival improvement with preoperative radio therapy at 2 years [11]. Nevertheless, the benef icial effect of preoperative

Mohamed Saad ZaghloulChildren’s Cancer Hospital and National Cancer Institute, Cairo University, Cairo, Egypt mszagh@yahoo.com

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Expert Rev. Anticancer Ther. 10(10), (2010)1528

Letter to the Editor Zaghloul

radiotherapy was restricted to high-stage and/or high-grade tumors in the other studies. Furthermore, the meta-analysis of these six trials failed to prove its absolute beneficial effects [12]. The suggested reasons for these negative results were the inclu-sion of all tumor stages in the randomization, leading to dilution of its advantageous effect, and the lack of modern radiotherapy techniques at the time of the trials.

Adjuvant (postoperative) radiotherapyOnly one prospective randomized trial has addressed the value of PORT. This study included 236 patients and it proved the significant benefit of PORT in pT2b–pT4a tumor stages and all histological grades in urothelial cancer as well as squamous and adenocarcinoma [13]. PORT remained unpopular because of the fear of late gastrointestinal complications and sequelae. Modern techniques are currently used to ensure an adequately high dose is delivered to the target with much lower dose to the surrounding normal tissues, including gastrointestinal tissues.

Adjuvant local & systemic radiochemotherapy A prospective controlled randomized trial was performed to test the tolerability and efficacy of adding adjuvant chemotherapy (gemcitabine and cisplatin) to PORT. A total of 142 high-risk bladder cancer patients were randomized. Preliminary results showed improvement in 2-year disease-free survival in the adju-vant radiochemotherapy group, although this did not reach sta-tistical significance [14]. Comparison of these two arms with a

third arm of adjuvant chemotherapy alone was performed in a randomized study of 198 patients at the National Cancer Institute (Cairo, Egypt). A better disease-free survival was reported for radio chemotherapy. Patients treated with adjuvant chemotherapy suffered from a higher percentage of locoregional failure [7].

It is worth noting that all preoperative and PORT trials were performed in the 1970s and 1980s. With the advancement in radiotherapy techniques using 3D conformal intensity- modulated radiotherapy and the volumetric verification techniques with image-guided and adaptive radiotherapy, one can deliver a max-imum radiation dose to the tumor and a minimal dose to the surrounding normal tissues. These techniques can minimize the immediate as well as late side effects. These also increase the dose to the target, leading to higher control rates.

Although the current status of radiation therapy for bladder cancer is mainly evident in the bladder-preserving radical setting, the same techniques that made the differences in the results can show similar improvements in the therapeutic ratio for pre- or postoperative settings [7].

Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References1 Sandler HM, Mirhadi A. Current status of

radiation therapy for bladder cancer. Expert Rev. Anticancer Ther. 10(6), 895–901 (2010).

2 Rodel C, Grabenbauer GG, Kuhn R et al. Combined modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J. Clin. Oncol. 20, 3061–3071 (2002).

3 Oh KS, Soto DE, Sandler HM et al. Combined modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: long-term results of a Phase I trial. Int. J. Radiat. Oncol. Biol. Phys. 74 (2), 511–517 (2009).

4 Dhar NB, Campbell SC, Zippe CD et al. Outcomes in patients with urothelial carcinoma of the bladder with limited pelvic lymph node dissection. BJU Int. 98(6), 1172–1175 (2006).

5 Stein S, Hochreiter W, Burkhard F et al. Radical cystectomy for bladder cancer today – a homogenous series without neoadjuvant therapy. J. Clin. Oncol. 21, 690–696 (2001).

6 Mederbacher S, Hochreiter W, Burkhard F et al. Radical cystectomy for bladder cancer today – a homogenous series without neoadjuvant therapy. J. Clin. Oncol. 21, 690–696 (2003).

7 Zaghloul MS. Adjuvant and neoadjuvant radiotherapy for bladder cancer: revisited. Future Oncol. 6(7), 1172–1191 (2010).

8 Greven KM, Spera JA, Solin LW. Local recurrence after cystectomy alone for bladder carcinoma. Cancer 69, 2767–2770 (1992).

9 Visser O, Nieuwenhuijzen JA, Horenblas S. Local recurrence after cystectomy and survival of patients with bladder cancer: a population based study in greater Amsterdam. J. Urol. 174, 97–102 (2005).

10 Hassan J, Cookson M, Smith J et al. Patterns of initial transitional cell recurrence in patients after cystectomy. J. Urol. 175, 2054–2057 (2007).

11 Awwad HK, Baki HA, El Bolkainy et al. Preoperative irradiation of T3 carcinoma in bilharzial bladder. Int. J. Rad. Oncol. Biol. Phys. 5, 787–794 (1979).

12 Huncharek M, Muscat J, Geschwind JF. Planned preoperative radiation therapy in muscle invasive bladder cancer. Results of metaanalysis. Anticancer Res. 18, 1931–1934 (1998).

13 Zaghloul MS, Awwad HK, Omar S et al. Postoperative radiotherapy of carcinoma in bilharzial bladder. Improved disease-free survival through improving local control. Int. J. Rad. Oncol. Biol. Phys. 22, 511–517 (1992).

14 Zaghloul MS, Khaled HM, Lotayef M, William H. Adjuvant chemoradiotherapy after radical cystectomy in advanced high risk bladder cancer patients: a prospective randomized trial. Presented at: ASCO 42nd Annual Meeting. Orlando, FL, USA, 2–6 June 2006 (Abstract 4545).

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