Sexual organ-sparing with hydrogel spacer injections for rectal cancer radiotherapy: a feasibility pilot study

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Article

Reference

Sexual organ-sparing with hydrogel spacer injections for rectal cancer radiotherapy: a feasibility pilot study

ACHARD, Verane, et al.

Abstract

The aim of this pilot study was to investigate in two rectal cancer patients undergoing neoadjuvant chemo-radiotherapy (nCRT) the implant feasibility and dosimetric benefit in sexual organ-sparing of an injectable, absorbable, radiopaque hydrogel spacer.

ACHARD, Verane, et al . Sexual organ-sparing with hydrogel spacer injections for rectal cancer radiotherapy: a feasibility pilot study. British Journal of Radiology , 2021, vol. 94, no. 1120, p.

20200931

DOI : 10.1259/bjr.20200931 PMID : 33481641

Available at:

http://archive-ouverte.unige.ch/unige:154630

Disclaimer: layout of this document may differ from the published version.

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Cite this article as:

Achard V, Ris F, Rouzaud M, Puppa G, Buchs NC, De Perrot T, et al. Sexual organ- sparing with hydrogel spacer injections for rectal cancer radiotherapy: a feasibility pilot study. Br J Radiol 2021; 94: 20200931.

SHORT COMMUNICATION

Sexual organ- sparing with hydrogel spacer injections for rectal cancer radiotherapy: a feasibility pilot study

1VÉRANE ACHARD, MD, PhD, ^2,3FREDERIC RIS, MD, ¹MICHEL ROUZAUD, MSc, ⁴GIACOMO PUPPA, MD,

2,3NICOLAS C BUCHS, MD, ⁵THOMAS DE PERROT, MD, ⁶THIBAUD KOESSLER, MD, PhD, ¹CRISTINA PICARDI, MD and

1,2THOMAS ZILLI, MD

1Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland

2Faculty of Medicine, Geneva University, Geneva, Switzerland

3Department of Visceral Surgery, Geneva University Hospital, Geneva, Switzerland

4Department of Pathology, Geneva University Hospital, Geneva, Switzerland

5Department of Radiology, Geneva University Hospital, Geneva, Switzerland

6Department of Oncology, Geneva University Hospital, Geneva, Switzerland

Address correspondence to: Thomas Zilli E-mail: Thomas. Zilli@ hcuge. ch

INTRODUCTION

For advanced rectal tumors, neoadjuvant radiotherapy (RT) with or without concomitant chemotherapy followed by total mesorectal excision (TME) represents the standard of care treatment.¹

Despite its proven efficacy in reducing local relapse,¹ neoadjuvant chemo- RT (nCRT) has been associated with non- negligible side- effects, especially in terms of impaired sexual function. For females’ patients, pelvic RT is frequently associated with long- term complications such as vaginal stenosis (VS), vaginal dryness, and dyspareunia.^2,3 As for males, based on prostate cancer data, RT dose delivered to the penile bulb has been associated with an increased risk of developing erectile dysfunction (ED).⁴

In prostate cancer treatments, hydrogel spacers have been

volume.⁵ A randomized clinical trial has demonstrated in prostate cancer patients implanted with a spacer a better dosimetric profile for rectal and penile bulb sparing, a better quality of life for the bowel domains,⁶ and improved erectile function.⁷

Based on these assumptions, we aimed to investigate in rectal cancer patients undergoing nCRT the implant feasibility and dosimetric benefit in sexual organ- sparing of the injectable, absorbable, and radiopaque hydrogel spacer TraceIT^® (Augmenix – A subsidiary of Boston Scientific, MA, USA).

METHODS AND MATERIALS

In January 2017, two rectal cancer patients (one male and one female) were recruited in this prospective, single center,

Received:

01 August 2020 Accepted:

12 January 2021 Revised:

13 December 2020

Objectives: The aim of this pilot study was to investigate in two rectal cancer patients undergoing neoadjuvant chemoradiotherapy (nCRT) the implant feasibility and dosimetric benefit in sexual organ- sparing of an injectable, absorbable, radiopaque hydrogel spacer.

Methods: Two rectal cancer patients (one male and one female) underwent hydrogel implant between rectum and vagina/prostate before nCRT and curative surgery.

A CT scan was performed before and after injection and a comparative dosimetric study was performed testing a standard (45/50 Gy) and a dose escalated (46/55.2 Gy) schedule.

Results: In both patients, the spacer implant in the recto- prostatic or recto- vaginal space was feasible and

well tolerated. For the male, the dosimetric benefit with spacer was minimal for sexual organs. For the female however, doses delivered to the vagina were significantly reduced with spacer with a mean reduction of more than 5 Gy for both regimens.

Conclusions: For organ preservation protocols and selected sexually active female patients, use of hydrogel spacers can be considered to spare sexual organs from the high radiotherapy dose levels.

Advances in knowledge: For females with advanced rectal tumor, a spacer implant between the rectum and the vagina before nCRT is feasible and reduces doses delivered to the vagina.

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BJR Achard et al

Inclusion criteria were: age ≥18 years old; WHO performance status 0–1; locally advanced (T1-2 N + or T3 N0/N+) histo- logically proven rectal adenocarcinoma located in the middle or in the high rectum and candidates for preoperative RT or chemo- RT. Patients with tumors located in the lower rectum were eligible if the location of the tumor did not preclude the implant of the spacer.

Primary objective of the study was to evaluate the feasibility and safety of the TraceIT^® hydrogel implant in 10 patients (five males and five females) with rectal adenocarcinoma respecting the inclusion criteria of the study. The secondary objective was to evaluate the performance of TraceIT^® in reducing radiation exposure to sexual organs and to compare the dosimetric optimization with and without the implant for both a conven- tional external beam RT (EBRT) schedule and a dose escalated treatment. A stopping rule and evaluation of preliminary feasibility and potential dosimetric efficacy was introduced after the implant of the first two patients (one male and one female).

The study was approved by the local ethical committee (CER 2016–01268) and registered on Clinical. Trials. gov (NCT03258541).

Hydrogel implant

The procedure was performed via a transperineal approach under local anesthesia and ultrasound guidance. Implant was performed using an epidural anesthesia needle, by creating a hydrodissection in the recto- prostatic or recto- vaginal space with a saline solution mixed with lidocaine, and by injecting a maximum of 10 ml of TraceIT^® hydrogel.

Treatment

Two planning computed tomography (CT) scans in supine position were programmed before and 5 days after the implant of TraceIT^®. Patients were asked to have an empty rectum and a semi- filled bladder before the planning CT scans and every treatment session. Treatments volumes and organs at risk (OARs) were defined on both CTs (with or without spacer) according to the RTOG guidelines⁸ using a co- registration with the diagnostic MRI. The gross tumor volume (GTV) consisted of the macro- scopic rectal disease, including a 5 mm isotropic expansion to define the clinical target volume boost (CTV_2). The elective clinical target volume (CTV_1) included the whole mesorectum as described in Radiation Therapy Oncology Group (RTOG) guidelines.⁹ Planning target volumes (PTV_1 and PTV_2) were generated using a 5 mm isotropic expansion around the CTV_1 and CTV_2.

All patients were treated using a Volumetric Modulated Arc Therapy (VMAT) technique. A total dose of 45 Gy and 50 Gy in 25 fractions was prescribed to PTV_1 and PTV_2, respectively, using a simultaneous integrated boost (SIB) technique.

In agreement with the QUANTEC guidelines¹⁰ dose constraints for the OARs were: bladder V50Gy ≤5%, V40Gy ≤35%, and V35Gy ≤50%; bowel bag V45Gy <195 ml; femoral heads V50Gy <5%; penile bulb mean dose <53 Gy; neurovascular bundles (NVB) mean dose <53 Gy. Mean dose received by the

vagina was planned as low as possible, ideally <35 Gy (<43 Gy acceptable variation).³ Treatments were planned in Eclipse^® with two 6X full VMAT arcs using a TrueBeam linear acceler- ator (Varian Medical System, Palo Alto, USA). The plan normal- ization was fixed such that the 95% isodose prescription line covered 98% of the PTVs.

In order to test the dosimetric advantage of the hydrogel spacer, two additional plans with and without the spacer were planned for each patient with a dose escalation schedule deliv- ering 46 Gy in 23 fractions of 2 Gy to the PTV_1 and 55.2 Gy in 2.4 Gy per fraction with a SIB technique to PTV_2 as reported in a published dose escalation protocol.¹¹ For patient #2, a fictive 4 cm GTV lesion was redefined at the level of the spacer (low- rectum, instead of at 12 cm from the anal verge) in order to maxi- mize the potential spring impact of the hydrogel.

All patients received a concomitant chemotherapy treatment with daily 825 mg m⁻² capecitabine during the whole treatment course. After an interval of 8–10 weeks after the end of the RT, patients underwent TME resection. Physical assessment including acute gastrointestinal, genitourinary, and sexual toxic- ities was performed using the CTACE v.4.0 grading scale at each follow- up visit.

RESULTS Patient #1

A 63- year- old female was diagnosed with T2N1M0 rectal adenocarcinoma at 2 cm from the anal verge. Six ml of TraceIT^® hydrogel were injected with no complications into the recto- vaginal space 10 days before the start of nCRT with a separation of 13 mm between the rectal wall and vagina (Figure 1). CRT was well tolerated with minimal toxicity (abdominal pain and pollakiuria of CTCAE v4.0 Grade 1). Abdominoperineal resection was performed 2 months later showing a ypT2 N1a (1/24) moderately differentiated adenocarcinoma resected with negative margins and no surgical related complications (tumor regression grading 4).¹² Adjuvant chemotherapy (capecitabine and oxaliplatin) was delivered from June to August 2017. In June 2020, the patient was in complete remission with no treatment related side- effects. At the last follow- up, the patient described a stable vaginal dryness of Grade 1 comparable to the baseline.

Patient #2

A 70- year- old male was presenting a rectal adenocarcinoma at 12 cm from the anal verge staged T3N2M0. He was implanted in the recto- prostatic space with 9 ml of TraceIT^® hydrogel 10 days before the start of nCRT (14 mm separation, Figure 2). The implant was well tolerated with no toxicity and only CTCAE v.4.0 Grade 1 abdominal spams and pollakiuria during the RT course.

No acute side effects were observed at the week four after RT follow- up. He underwent low anterior resection with mucosec- tomy and colo- anal anastomosis 10 weeks after the completion of CRT. The pathology report indicated a moderately differentiated adenocarcinoma classified ypT3b N1a (1/35) disease resected in negative margins. Anastomotic leakage occurred 2 days after the resection leading to a resection of the anastomosis and the creation of a terminal colostomy. On the histopathological analysis of the

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Figure 1. Axial and sagittal pelvic computed tomography views of patient #1 before (a, b) and after (c, d) the hydrogel spacer implant (GTV = gross tumor volume).

GTV

GTV GTV

GTV Vagina

Vagina

Vagina Vagina

Spacer

A

B

C

D

Figure 2. Axial and sagittal pelvic computed tomography views of patient #2 before (a, b) and after (c, d) the hydrogel spacer implant (GTV = gross tumor volume).

GTV

Bladder neck

GTV GTV

GTV

Bladder neck Bladder

neck

Spacer

A

B

C

D

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BJR Achard et al

specimen, a tumor regression of Grade 3 was observed with an important inflammatory reaction in the context of an arterioscle- rotic vasculopathy, with no relationship with the spacer implant.

No additional treatment was performed and, on February 2020, the patient was disease- free with no major treatment related side- effects. From a urinary point of view, the patient was subjectively asymptomatic despite a decreased urinary flow rate requiring a treatment with alpha- blocker. As for sexual function, it remained unchanged during the follow- up.

Dosimetric study

For the two patients, the PTVs coverage sparing with or without spacer was comparable for the standard and the dose escalation

schedule, respectively (Table 1). Dose constraints to the OARs were respected for all plans (Table 1). For patient #1, the dose delivered to the vagina was significantly decreased using the spacer, with a Dmean reduction ranging from 5.7 to 5.3 Gy for the standard and the dose escalated regimen, respectively (Figure 3a). On the other hand, no clear benefit was observed for patient #2 with the spacer, except a 5.3 Gy Dmean difference to the bladder neck in the dose escalated protocol (Figure 3b).

DISCUSSION

Most data concerning rectal separation using hydrogel spacers have been published on prostate cancer. By separating the anterior rectal wall from the high- dose radiation region, spacers can Table 1. Comparative dosimetric results before and after spacer implant for the patient #1 and patient #2 with the standard and the dose escalated protocol

PTV/OARs

46/55.2 Gy 45/50 Gy

Before Spacer After Spacer Before Spacer After Spacer

Patient #1 PTV 2 D98% (Gy) 52.4 52.4 47.5 47.5

PTV 1 D98% (Gy) 43.8 43.7 42.8 42.8

Vagina Structure volume (cc) 32.7 31.1 32.7 31.1

Mean Dose (Gy) 44.6 39.3 41.4 35.7

Maximum Dose (Gy) 58.9 57.9 52.7 51.9

Bladder V 50 Gy (%) 0.1 0 0.2 0

V 40 Gy (%) 21.3 3.1 16.1 10.6

V 35 Gy (%) 35.5 9.2 30.7 22.6

Bowel bag V 45 Gy (cc) 209 144 175 93.5

Patient #2 PTV 2 D98% (Gy) 52.4 52.4 47.5 47.5

PTV 1 D98% (Gy) 43.8 43.8 42.8 42.7

Bladder Neck Structure volume (cc) 4.7 3.6 4.7 3.6

Mean Dose (Gy) 43.1 37.8 41.5 40.5

Maximum Dose (Gy) 45.5 43.7 43.9 44.2

Urethra Mean Dose (Gy) 44.7 43.3 42.7 41.6

Maximum Dose (Gy) 53.6 49.8 47.7 46.0

NVB Structure volume (cc) 4.8 4.6 4.8 4.6

Mean Dose (Gy) 47.9 48.0 45.2 44.6

Maximum Dose (Gy) 55.0 54.6 48.7 48.8

Prostate Structure volume (cc) 57.7 50 57.7 50

Mean Dose (Gy) 46.9 44.3 43.7 42.4

Maximum Dose (Gy) 55.1 54.9 49.1 48.9

Penile Bulb Structure volume (cc) 5.1 4 5.1 4

Mean Dose (Gy) 31.0 30.9 30.3 28.4

Maximum Dose (Gy) 45.4 45.9 43.4 42.0

Bladder V 50 Gy (%) 0 0 0 0

V 40 Gy (%) [td] 6.5 18.3 11.9

V 35 Gy (%) 47.4 29.0 41.4 33.6

Bowel bag V 45 Gy (cc) 23.7 15.1 0 0

NVB, Neuro vascular bundles; PTV, Planning target volume.

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minimize radiation- induced rectal toxicity and improve quality of life of prostate cancer patients.^6,7 In our study, we were, to the best of our knowledge, the first to test the implant feasibility and potential dosimetric benefit of a hydrogel spacer in rectal cancer patients who were candidates to a nCRT treatment.

In the two patients included in the study, the implant was feasible and well tolerated with no impact on the surgical procedure, the postsurgical complication rate or the pathological outcome. On the other hand, the dosimetric study showed contrasting results, with no reduction for the males in the RT doses delivered to the sexual OARs after the injection of the spacer. Only a modest and probably clinically insignificant benefit was observed in the reduction of mean doses to the bladder neck, a structure potentially associated with a reduction in late urinary toxicity.¹³ On the contrary, for the female patient the injection of the hydrogel was associated with a significant decrease in the RT doses delivered to the vagina. By reducing the mean delivered dose to the vagina from 44.6 to 39.3 Gy for dose escalation, use of a spacer can potentially reduce the risk of developing a vs in female patients undergoing pelvic irradiation. Indeed, evaluating 65 females who underwent pelvic RT for rectal or anal cancer, Son et al found that a mean vaginal dose of 50.0 Gy was predictive of an increased risk to develop vs.³ When gEUD (a = 1) was <35 Gy and the mean vaginal dose was <43 Gy, the risk to develop a severe vs was significantly reduced.

Visualization of rectal tumors is often challenging and dose escalation protocols with focal boost to the GTV requires wide margins to take into account the inherent rectal motion.¹⁴ With

its radiopaque properties, the TraceIT^® spacer may be easily iden- tified on daily imaging cone beam CTs (CBCT) and can potentially be used as surrogate of the rectal tumor position during the whole treatment course. While an improvement in daily setup and treatment reproducibility is expected, reduction in interfrac- tional motion of the rectal tumor is probably less realistic.¹⁵ Our pilot study presents clear limitations that stem in the small sample size and in reporting limited results based on the feasibility of the spacer implant and of a comparative dosimetry analysis. Based on results obtained in this study, despite the dosimetric benefit observed in the reduction of the vaginal RT doses, it does not seem realistic to imagine a wider use of spacer in rectal cancer patients. Noteworthy, at the standard RT doses usually used in the neoadjuvant setting, the benefit in reducing vaginal toxicity is marginal and it should be weighted with the functional results of TME. Only for selected clinical scenarios like dose escalated protocols in the context of organ- sparing proce- dures for female and sexually active patients, use of spacer can be discussed in order to reduce vaginal doses and limit potential sexual toxicity on the long term. However, how the dosimetric improvement in reducing the dose to the vagina can translate in a real clinical benefit remains to be determined by larger studies with clearly defined clinical endpoints.

CONCLUSIONS

In our small pilot study, we were able to demonstrate the feasibility of a hydrogel spacer implant for rectal cancer patients undergoing nCRT. The implant was well tolerated and associated with a significant decrease in the mean doses delivered to Figure 3. Cumulative dose- volume histograms for the vagina (a) and the bladder neck (b) before (triangle) and after (square) hydrogel spacer injection in the dose escalated setting for patient #1 and patient #2, respectively.

Dose (Gy)

Volume (%)

Dose (Gy)

Volume (%)

A

B

VAGINA

BLADDER NECK

0 10 20 30 40 50

0 5 10 15 20 25 30 35 40 45

20 40 60 80 100

100 80 60 40 20 0

0

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BJR Achard et al

the vagina, while no benefit was observed in reduction of RT doses to male sexual organs. Further clinical applications of this procedure have to be prospectively evaluated, namely, for dose escalated RT protocols in sexually active female patients with low- rectal cancer candidates for organ preservation.

ACKNOWLEDGEMENTS

Ms Laurence Zulianello, PhD, Geneva University Hospital, Geneva, Switzerland.

CONFLICT OF INTEREST

TZ reports research grant from Augmenix Inc (Bedford, MA, US) for the study and Varian Medical Systems (Palo Alto, CA, US) outside the submitted work. Other authors report no conflict of interest.

FUNDING

This study was partially funded by a grant from the « Augmenix Inc (Bedford, MA, US) ». The granting bodies are not involved in data collection or analysis.

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