The impact of brachytherapy boost for anal canal cancers in the era of de-escalation treatments

Brachytherapy. 2023 Jul-Aug;22(4):531-541. doi: 10.1016/j.brachy.2023.03.004. Epub 2023 May 6. PMID: 37150739.

Leonel Varela Cagetti M.D (1, A); Laurence Moureau-Zabotto M.D (2) ; Christophe Zemmour (3) ; Marjorie Ferré (4) ; Marc Giovaninni M.D (5) ; Flora Poizat  M.D (6) ; Bernard Lelong  M.D (7) ; Cecile De Chaisemartin M.D (7) ; Emmanuel Mitry  M.D (8) ; Marguerite Tyran (1)

Amira Zioueche-Mottet (9) ; Naji Salem (1); Agnès Tallet M.D (1)

A- Corresponding Author: Leonel Varela Cagetti, Department Of Radiation Oncology, Institut Paoli-Calmettes, Marseille, France. varelacagettil@ipc.unicancer.fr

1. Department of Radiation Oncology, Institut Paoli-Calmettes, Marseille, France
2. Department of Radiation Oncolgy, Centre de Radiothérapie du Pays d'Aix-en-Provence, France
3. Department of Clinical Research and Investigation, Biostatistics and Methodology Unit, Institut Paoli-Calmettes, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
4. Department of Medical Physics, Institut Paoli-Calmettes, Marseille, France
5. Oncology and Endoscopic Unit, Institut Paoli-Calmettes, Marseille, France
6. Department of Pathology,  Institut Paoli-Calmettes, Marseille, France
7. Department of  Digestive Surgical Oncology, Institut Paoli-Calmettes, Marseille, France
8. Department on Medical Oncology, Institut Paoli-Calmettes, Marseille, France
9. Centre of Radiation Oncology, French Red Cross, Toulon, France

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What was your motivation for initiating this study?

Anal cancer is an unusual disease, however, the incidence of carcinoma of the anal canal is rising (1). The majority of anal cancers are related to the presence of human papilloma virus (HPV) infection. There are different approaches to achieve cure with locoregional control and preservation of anal function. For small lesions, radiation therapy demonstrated excellent rates of local control and survival (2,3). In case of locally advanced stage, combination of radiotherapy and chemotherapy (CRT) [5- fluorouracil (5-FU) and mitomycin C (MMC)] is the current standard of care (4–7). Although this treatment is effective, 40% of survivors of anal cancer have gastrointestinal toxicities such as urgency and faecal incontinence with a negative impact on the quality of life (QOL). Locally advanced tumours are frequently associated with more faecal incontinence than surviving patients with smaller tumours (8). With the EBRT boost technique, the entire anal canal and sphincter are irradiated. The idea of our study was to evaluate survival outcomes, safety and the impact on gastrointestinal toxicity for patients treated with a high-dose-rate interstitial brachytherapy boost (HDR-ISBT) for SCC anal carcinoma in our institution. Furthermore, the dose to the non-tumoural sphincter delivered by HDR-ISBT was evaluated and correlated with gastrointestinal toxicity (faecal incontinence).

 

What were the main challenges during the work? 

This is a very special work. We know that the dose to the OAR delivered by brachytherapy is usually low due to the rapid fall of in dose, but we aimed to deal with the dose to the non-tumoural sphincter in depth, because the problem of faecal incontinence would be there. For that reason, the non-tumoural or contralateral sphincter was also delineated on CT images at the time of brachytherapy (anal canal wall + internal and external sphincters excluding the CTV).  Dose constraints for normal sphincter were: Dmean (Gy α/ β3) ≤10 Gy, D90 (Gy α/ β3) ≤5 Gy and D 2 cm3 (Gy α/ β3) ≤20 Gy.

What is the most important findings of your study?

We found that the dose to the normal sphincter of patients undergoing HDR-ISBT is negligible. As a consequence, chronic faecal incontinence grade 2 was present in 7.7% of patients, no fecal incontinence grade 3 was reported.

Furthermore, excellent rates of tumour control were acquired with a tumour dose up to 60 Gy (EQD2 α/ β10). Colostomy-free survival (CFS) at 5 years was 88% [79–94%], this is superior to the results of patients who underwent an EBRT boost reported in historical cohorts, even compared with the most modern series of ACC treated with IMRT technique (9).

 

What are the implications of this research?

Despite the retrospective character of this work, HDR-ISBT demonstrated that this technique is still a valuable modality boost to de-escalate the toxicity of treatments for ACC. Due to the low dose delivered to the normal sphincter, brachytherapy must be discussed in a multidisciplinary approach and proposed to patients to decrease long-term related treatment toxicities.

 

References

1-Eng C, Ciombor KK, Cho M, et al. Anal Cancer: Emerging Standards in a Rare Disease. J Clin Oncol. 2022 Aug 20;40(24):2774-2788

2-Badakhshi H, Budach V, Wust P, et al. Anal carcinoma: surgery does not influence prognosis when performed prior to concurrent radiochemotherapy. Anticancer Res 2013;33:4111–4115 .

3- Ortholan C, Ramaioli A, Peiffert D, et al. Anal canal carcinoma: early-stage tumors < or = 10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:479–485 .

4- Ajani J, Winter K, Gunderson L, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. A randomized controlled trial. JAMA 2008;299:1914–1921 .

5- UK Co-ordinating Committee on Cancer Research Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. Lancet 1996;348:1049–1054 .

6- Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997;15:2040–2049 .

7- Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996;14:2527–2539 .

8 -Bentzen A, Guren M, Vonen B, et al. Faecal incontinence after chemoradiotherapy in anal cancer survivors: Long-term results of a national cohort. Radiother Oncol 2013;108:55–60 .

9-Mitra D, Hong TS, Horick N, et al. Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dosepainted IMRT per RTOG 0529. Adv Radiat Oncol 2017;2:110–117.

           

          Leonel Varela Cagetti