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Non-invasive stereotactic ablative boost in patients with locally advanced cervical cancer
  1. Shraddha Dalwadi1,
  2. Alfredo Echeverria1,
  3. Pavan Jhaveri1,
  4. Tung Bui1,
  5. Nabila Waheed2,
  6. Danny Tran3,
  7. Mark Bonnen4 and
  8. Michelle Ludwig1
  1. 1 Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas, USA
  2. 2 Department of Radiation Oncology, The Center for Cancer and Blood Disorders, Dallas, Texas, United States
  3. 3 Department of Radiation Oncology, Remote Dosimetry Services, Houston, Texas, USA
  4. 4 Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  1. Correspondence to Dr Michelle Ludwig, Baylor College of Medicine, Houston, TX 77030, USA; Michelle.Ludwig{at}bcm.edu

Abstract

Introduction The current literature is insufficient to guide care for patients with cervical cancer ineligible for brachytherapy. Stereotactic ablative radiotherapy boost is a clinical necessity for these patients, but highly debated among radiation oncologists.

Objective To report toxicity and survival outcomes in a large cohort of patients with locally advanced cervical cancer treated with a non-invasive stereotactic ablative radiotherapy boost instead of brachytherapy

Methods Patients with locally advanced cervical cancer were entered, between January 2008 and December 2018, who were recommended definitive intent external boost after pelvic radiotherapy to 45–50.4 Gy concurrent with weekly cisplatin and simultaneous/sequential nodal boost up to 55–66 Gy. Simulation CT was facilitated using radio-opaque fiducials, empty rectum, dedicated bladder filling, and whole body vaculoplastic immobilization. Kaplan-Meier survival estimates were used to report local/regional recurrences, distant metastases, cancer-specific survival, and overall survival.

Results A total of 25 patients were analyzed. Median follow-up was 25 months (range 6–54). Patients received stereotactic ablative radiotherapy due to refusal of brachytherapy (9/25, 36%), medical co-morbidities limiting implantation (9/25, 36%), or technical infeasibility (7/25, 28%). Typical fractionation was 24–30 Gy in 4–5 fractions (24/25, 96%). The most common long-term toxicity was grade 1–2 vaginal dryness, discomfort, stenosis, and/or dyspareunia (4/25, 16%). One patient had new post-treatment grade 4 fistula in an area of previous tumor erosion (1/25, 4%). Overall survival, cancer specific survival, loco-regional control, and distant control were 95.5%, 100%, 95.5%, and 89.1%, respectively, at 2 years.

Conclusion Further study of stereotactic ablative radiotherapy boost for cervical cancer is needed; a brachytherapy-similar approach portends clinical success with 95.5% overall survival and loco-regional control at 2 years.

  • cervical cancer
  • radiation
  • brachytherapy

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HIGHLIGHTS

  • Stereotactic ablative radiotherapy is an option for patients with cervical cancer ineligible for brachytherapy.

  • Brachytherapy-similar volumes and fractionation may be used with <5% grade 3 or higher toxicity.

  • Further studies are needed to determine the appropriate quality assurance metrics for cervical stereotactic ablative radiotherapy.

Introduction

Use of stereotactic ablative radiotherapy boost in place of brachytherapy for locally advanced cervical cancer is highly debated. Stereotactic ablative radiotherapy is an ultra-conformal form of external beam radiotherapy that uses strict immobilization and precise image guidance, allowing definitive doses to be delivered in five fractions or less.1 It was initially developed by translating the success of radiosurgery in managing intracranial metastases to corporal anatomy.2 Over the past decade, technological progress in the design and delivery of stereotactic ablative radiotherapy has led to its routine use as a curative option in select early-stage lung and low-risk and high-risk prostate cancer.3 This safe and non-invasive method has greatly improved access to care, particularly for patients with inoperable cancer with poor baseline performance status who were previously managed with palliative intent alone.4

In brief, successful disease ablation via stereotactic ablative radiotherapy is accomplished amid the following core competencies: (1) accurate target delineation using advanced diagnostic imaging and fusion; (2) meticulous intra-fraction and inter-fraction motion management using various techniques based on region of interest; (3) planning aims that prioritize dose conformality with rigorous quality assurance; and (4) precise image guidance with on-table CT.5 Doing so allows higher doses to be delivered in each treatment, shortening conventional treatment length from months to 1 or 2 weeks in some oncologic sites, such as lung and prostate. This approach also reduces necessary tumor margin, leading to less volume of normal tissue irradiated than with conventionally fractionated radiotherapy.

Despite incorporation into National Comprehensive Cancer Network guidelines for multiple disease sites, little progress has been made in investigating stereotactic ablative radiotherapy for gynecologic malignancies, largely due to the established safety and success of brachytherapy in accomplishing the same goals. Nonetheless, patients who cannot undergo brachytherapy due to complex medical co-morbidities, technical reasons, or refusal have no current standard of care to guide practice. Dosimetric feasibility of brachytherapy-similar stereotactic ablative radiotherapy has been described in the literature.6 Furthermore, population-based data suggest that the use of brachytherapy is declining and use of external boost techniques is rising.7 One propensity matched National Cancer Database study showed similar results between stereotactic ablative radiotherapy and brachytherapy, with inferior results seen when conventionally fractionated techniques were employed.8 Unfortunately, this dataset does not provide further information on safety and tolerability of stereotactic ablative radiotherapy compared with brachytherapy. Additionally, the hazard ratios for intensity-modulated radiotherapy and stereotactic ablative radiotherapy overlap, probably due to the small size of the stereotactic ablative radiotherapy group. The use of gynecologic stereotactic ablative radiotherapy in place of brachytherapy requires further scrutiny.

We report the largest cervical cancer stereotactic ablative radiotherapy cohort to date and the first to integrate both a high-risk clinical target volume (encompassing residual disease and whole cervix) and an intermediate-risk clinical target volume (encompassing initial disease), similar to the method used in brachytherapy boost.

Methods

Patient Selection

Between January 2008 and December 2018, 25 women with locally advanced cervical cancer were managed at the Baylor College of Medicine with pelvic radiation to 45–50.4 Gy concurrent with weekly cisplatin. A simultaneous and sequential nodal boost up to 55–66 Gy was permitted for positron emission tomography-avid nodal disease. All patients underwent pre-operative clearance with anesthesia, discussion at a departmental brachytherapy peer review, and personalized comprehensive informed consent in order to receive brachytherapy but were deemed ineligible for the standard of care. Both intra-cavitary and interstitial brachytherapy techniques were considered and offered, if appropriate, to all patients. If not possible and the patient was a candidate for stereotactic ablative radiotherapy, special attention was given to the poorly studied risks associated with cervical stereotactic ablative radiotherapy, which were hypothesized to include pain, bleeding, sub-optimal tumor control, infection, or trauma to nearby structures with severity ranging up to death. Definitive intent management was agreed on at a multidisciplinary tumor board.

Three radio-opaque fiducials were placed in clinic anterior and lateral to the cervix or residual cervical mass after pelvic chemoradiation. Patients then underwent repeat CT simulation with empty rectum accomplished with medical bowel preparation. A Foley catheter was used for dedicated bladder filling to 100–300 mL. A whole body vaculoplastic immobilization device with vest attachment was used for reproducible motion management. High-risk clinical target volume and intermediate-risk clinical target volume were contoured according to EMBRACE II guidelines for brachytherapy, aided by manual co-registration with T1 post-contrast MRI from both pre- and post-external beam image sets. Specifically, intermediate-risk clinical target volume was defined as pre-treatment volume of disease, and high-risk clinical target volume was defined as post-pelvic chemoradiotherapy volume of disease evident on physical examination and imaging.9 A 2–3 mm planning margin was added. Bladder, rectum, sigmoid, small bowel, bone marrow, and femoral heads were identified as organs at risk. Cumulative dose calculations were tabulated in biologically effective dose in terms of 2 Gy per fraction equivalents.10 Treatment was delivered every other day using a hexapod-capable linear accelerator in three to five fractions. Physician and physicist were present for patient set up, image approval, and treatment without any discernible delay between on-table cone-beam CT and beam on. A typical plan is shown in Figure 1. EMBRACE II guidelines were used for organ-at-risk constraints and target goals.

Figure 1

Typical stereotactic ablative radiotherapy plan in locally advanced cervical cancer. (A) Sagittal view, (B) coronal view.

Post-Treatment Protocol

All gynecologic patients receiving stereotactic ablative radiotherapy were seen at 4 weeks after completion of treatment to assess residual toxicity. The subsequent follow-up protocol at our radiation oncology clinic is at 3-month intervals after completion of treatment, with focused history and physical examination, including vaginal speculum examination for at least 2 years. Biopsy and imaging were performed only if clinically indicated (such as a suspicious mass seen on the cervix 9 months after treatment). After 2 years, primary management is shifted to our gynecologic oncology team, with surveillance clinical visits, and with radiation oncology generally spaced 6 months apart for up to 5 years after completing treatment.

Data were collected by manual retrospective chart review. Demographic data, acute side effects, and chronic toxicity were recorded. Local and regional recurrence were defined as any in-field, pelvic, or para-aortic disease discovered after definitive chemoradiation. Kaplan-Meier survival curves were used to analyze recurrence and survival outcomes. JMP-14 was used for statistical accuracy.

Results

Patient Characteristics

A total of 25 patients were included in the analysis (Table 1). The median age was 55 years (range 39 to 72) and median follow-up in our cohort was 25 months (range 6–54). Most patients had squamous histology (24/25, 96%) and International Federation of Gynecology and Obstetrics (FIGO 2018) stage distribution was varied (I: 2/25, 8%; II: 11/25, 44%; III: 3/25, 12%; IVA: 9/25, 36%; no IVB patients). Patients were recommended stereotactic ablative radiotherapy due to refusal of brachytherapy (9/25, 36%), complex medical co-morbidities and/or inability to obtain anesthesia clearance (9/25, 36%), or technical infeasibility (7/25, 28%). Stereotactic ablative radiotherapy fractionation was generally 24–30 Gy in four to five fractions (24/25, 96%). Two patients were treated for locoregionally recurrent disease (one after surgical management and the other after definitive chemoradiation).

Table 1

Patient characteristics

Long-term toxicity present after 6 months is summarized in Table 2. The most common toxicity, experienced in 4 (16%) patients, was grade 1–2 vaginal dryness/discomfort with or without stenosis and dyspareunia. Three patients (12%) had fistula to adjacent structures: one asymptomatic vesicovaginal fistula pre-dating treatment, one grade 2 vesicovaginal fistula causing recurrent urinary tract infections pre-dating treatment, and one new post-treatment grade 4 suspected venovaginal fistula. The grade 4 suspected venovaginal fistula was diagnosed clinically in a stage IVA patient with initial disease involving adjacent organs and vasculature who presented 8 months after treatment with refractory vaginal bleeding. One patient experienced grade 2 radiation proctitis and one experienced grade 2 cystitis.

Table 2

Observed physician-reported, long-term toxicity with cervical stereotactic ablative radiotherapy

Clinical endpoints are summarized in Figure 2 and Table 3. Two-year actuarial overall survival was 95.5% and cancer-specific survival was 100%. In this cohort, one stage IV patient died due to sepsis at 8 months after treatment and one stage I patient died of cardiac arrest at 28 months after treatment. Both were probably unrelated to their oncologic treatment according to chart review and discussion with gynecologic oncology and managing radiation oncologist. All other patients were alive at last follow-up and no patients had died due to malignancy. Locoregional control was 95.5% and distant control was 89.1% at 2 years. Only one stage IVA patient exhibited local recurrence along the anterior vagina 8 months after treatment. Two patients had distant metastases—one with initially stage III disease at 4 months after treatment and the other with initially stage I disease at 18 months after treatment. These patients were managed by gynecologic oncology without subsequent local consolidative therapy to metastatic lesions.

Figure 2

Kaplan-Meier curves for survival and disease control outcomes. Overall survival, cancer-specific survival, loco-regional control, and distant control were 95.5%, 100%, 95.5%, and 89.1%, respectively, in this cohort receiving gynecologic stereotactic ablative radiotherapy with short-term follow-up.

Table 3

Tabulation of clinical outcomes up to 2 years

Discussion

Patients at our institution who were unable to receive standard-of-care brachytherapy underwent an external boost to definitive dosing using a novel technique, stereotactic ablative radiation therapy. Despite extremely conservative clinical and physics quality assurance metrics, overall survival, cancer-specific survival, loco-regional control, and distant control were 95.5%, 100%, 95.5%, and 89.1%, respectively, at 2 years. Still, the use of an external boost in place of brachytherapy for definitive-intent cervical cancer is highly debated.

While brachytherapy remains the unequivocal standard of care in locally advanced cervical cancer, many requisites limit its use. Brachytherapy in locally advanced cervical cancer is an invasive procedure, often necessitating anesthesia for at least initial applicator placement and not uncommonly for each subsequent treatment if poorly tolerated. Studies suggest that the procedure can be associated with residual symptoms similar to those experienced in post-traumatic stress disorder.11 12 Lastly, informed consent for brachytherapy may be declined by the patient. Some patients are amenable to brachytherapy after careful counseling and informed consent with detail of the potential risks of stereotactic ablative radiotherapy, but not all patients agree to standard of care and therefore require an external boost. Gynecologic stereotactic ablative radiotherapy has the ability to bypass many of the involved procedures and risks associated with brachytherapy, although with a separate risk profile of its own still to be established in prospective studies.

Few retrospective patient series report the use of stereotactic ablative radiotherapy in cervical cancer despite national data showing its community use. Haas et al treated six patients to a MRI-evident gross tumor, obtaining 100% local control at 14 months and no grade 3 or higher toxicity.13 Mamitz et al reported 11 patients receiving stereotactic ablative radiotherapy to residual disease and the cervix with 78% local control at 6 months and no significant acute toxicity.14 Kubicek et al describe four patients treated to gross disease and the cervix with 25% grade 3 or higher toxicity and 64% local control at 4 months.15 Lastly, Hsieh et al document nine patients who were treated to the gross disease only, 11% grade 3 or higher toxicity and 78% local control at 3 years.16

The only published phase II study investigating stereotactic ablative radiotherapy boost for patients with cervical cancer ineligible for brachytherapy closed early at 15 patients due to 26.7% significant rectal toxicity.17 This University of Texas at Southwestern study is the highest level of data investigating cervical stereotactic ablative radiotherapy with close patient follow-up and centralized institutional review board-supervised approach. While the early closing of this trial due to gastrointestinal toxicity is concerning, patients in this trial had an extremely high median rectal 2 cc max dose of 90.6 Gy 2 Gy per fraction equivalents.17 For reference, we limit our rectal 2 cc max dose to 75 Gy 2 Gy per fraction equivalents at our institution, based on the brachytherapy literature. The results of another phase II study with 55 patients is pending publication, with interim results suggesting favorable toxicity profile and quality of life outcomes.18 Five-year local control in this trial was reported as 92.3%.18 Notably, both these studies involve stereotactic ablative radiotherapy to the residual disease and/or cervix without inclusion of an intermediate-risk volume as is standard at our institution.

In high-dose rate brachytherapy, Nag et al have established a formula for determining cumulative dose calculations in terms of 2 Gy per fraction equivalents.10 The translation of 2 Gy per fraction equivalents to hypofractionation schema is not well understood, even in sites such as lung and prostate where stereotactic ablative radiotherapy is now routinely used.19 20 This is perhaps the main limitation in the translation of stereotactic ablative radiotherapy to gynecologic malignancy, with a high level of disagreement among radiation oncologists due to concern about gastrointestinal toxicity and the availability of brachytherapy alternatives. Mitigation of this risk involves continuing to develop and validate cumulative dose calculations representative of biologic dose delivered to normal and tumorous tissue. Our technique is to use brachytherapy-similar dose fractionation (dose schedules as recommended by the American Brachytherapy Society) and cumulative dose calculation by physics without any dose-dampening modification, providing an extremely conservative measure of dose to normal tissue. We attribute this approach to our success in limiting gastrointestinal toxicity in comparison with other historical series.

Conclusion

We report favorable outcomes with the use of brachytherapy-similar stereotactic ablative radiotherapy when brachytherapy is not possible for locally advanced cervical cancer. Future studies should establish optimal volumes, fractionation, and cumulative dose calculation with this emerging technology.

References

Footnotes

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  • Contributors All authors contributed to this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. No comparative or complex analyses were performed in this small series.