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Combining concurrent radiotherapy and immunotherapy for synergistic effects in recurrent endometrial cancer – A case report

Highlights • Studies have shown that radiation enhances immunotherapy but no published studies exist for recurrent endometrial cancer.• Two patients, diagnosed with recurrent endometrial cancer, entered remission after concurrent radiation and immunotherapy.• Additional clinical trials are needed to determine the ideal timing and duration of combining radiation and immunotherapy.


Introduction
Uterine cancer is the second most common gynecological cancer affecting women globally. According to GLOBOCAN, there were 417,367 new cases and 97,370 deaths worldwide in 2020 (Global, 2021). According to the American Cancer Society, the average age at diagnosis in the US is 60. Despite the scientific strides that have been made in diagnosis and treatment, incidence (21.1 per 100, 000) rates in Northern America are the highest in the world and mortality rates (3.2 per 100,000) are the fourth highest globally (NCI, 2021).
The goal of this case report is to share the observed efficacy of the combined administration of radiotherapy and immunotherapy for the treatment of recurrent endometrial carcinomas. Multiple pre-clinical studies have demonstrated that radiotherapy enhances the effects of immunotherapy and other case reports have confirmed these findings (Formenti et al, 2018). However, there are no published studies regarding contemporaneous administration of radiation therapy and immunotherapy (Table 1). These two patient cases endorse the synergistic benefits of combined radiation therapy and immunotherapy followed by maintenance immunotherapy for managing relapsed endometrial carcinomas.

Case 1 narrative
A 58-year-old woman with a history of leiomyomas presented to the clinic with vaginal bleeding. She was diagnosed with FIGO Stage I Grade 1 endometrioid endometrial adenocarcinoma (limited to the polyp and endometrium) after undergoing total laparoscopic hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) with morcellation. The malignancy was limited to the polyp and endometrium. No nodal assessment was performed.
Two months later, she began to experience abdominal pain. Six months after diagnosis, a pelvic ultrasound and computed tomography (CT) scan revealed four enhancing masses at the lower abdominal wall  She was still asymptomatic at 12 months at follow-up incision site within the rectus abdominus and subcutaneous tissue. CTguided core biopsy confirmed estrogen (ER) and progesterone receptor (PR) positive metastatic adenocarcinoma. PET/CT scan confirmed multiple hypermetabolic anterior abdominal wall masses. They included a 2.4 × 2 cm mass on the left (L) lateral margin of the rectus muscle (SUV 22), a 2.3 × 1.7 cm right (R) rectus muscle mass (SUV 13), a 4.0 × 4.3 cm R rectus abdominis nodule (SUV 22), and a 1.9 × 1.3 cm sub-serosal mass adjacent to the rectosigmoid colon. She subsequently underwent debulking of the abdominal wall and rectosigmoid lesions followed by six cycles of carboplatin and paclitaxel with no evidence of recurrent disease upon treatment completion. Unfortunately, about three months later, she began experiencing intermittent left pelvic pain. CT of the abdomen and pelvis revealed a 1.3 × 1.2 R peri-psoas tumor and three subcutaneous masses at the level of the L anterior iliac spine measuring 1.0 × 0.9 cm, 2.5 × 1.3 cm and 1.0 × 0.9c.m. She was also referred for a Radiation Oncology consultation due to the recurrent stage IV disease at the L anterior abdominal wall and right peri-psoas adipose tissue.
She received 45 Gray (Gy) in 25 fractions to the pelvis, 56.7 Gy in 32 fractions to the L abdominal wall, and 54 Gy in 30 fractions to the R peripsoas tumor implant for one and a half months. The anterior L abdominal wall masses resolved.
Genetic testing revealed pathogenic mutations in CTNNB1 and PTEN genes and high microsatellite instability (MSI-H), the latter making her a potential candidate for immunotherapy.
Five months after the start of radiation therapy, she again developed a 3.2 × 1.3 cm lesion at the L anterior abdominal wall and biopsy was consistent with recurrent endometrial cancer. Of note, squamous metaplasia was noted in the biopsy sample. Following resection of the L abdominal wall nodule, she remained stable and in remission for another seven months (Fig. 1).
Subsequently, PET/CT revealed a large 7.1 × 2.4 cm FDG avid lesion (SUV 15.6) in the subcutaneous fat anterior to the L iliac wing, a new ER and PR -positive L anterior apex pulmonary mass measuring 4.3 × 3.1 cm (SUV 12.7) and a slightly enlarged 1.3 × 0.4 cm AP window lymph node without FDG avidity. A L lung core biopsy confirmed a CK7, PAX8, ER and PR positive necrotic adenocarcinoma of endometrioid origin.
Six months after combined radiotherapy (8 Gy × 2 to the lesion anterior to the L iliac wing) and pembrolizumab treatment, the patient had marked improvement. The L anterior apex lung mass shrunk from 4.3 × 3.1 cm (SUV 12.7) to 2.6 × 1.2 cm (SUV 2.0). The previously enlarged lymph node had resolved. Although the subcutaneous L iliac wing lesion had decreased slightly to 6.7 × 2.3 cm, its maximum uptake decreased markedly from 15.6 to 3.7 (Fig. 2 A-D).
Follow-up CT scans 21 months after the initiation of the combined immunotherapy and radiation course with subsequent pembrolizumab maintenance, confirmed no evidence of metastatic disease in the chest, abdomen, and pelvis.

Case 2 narrative
A 64-year-old female underwent robotic total laparoscopic hysterectomy (TLH) and bilateral salpingo-oophorectomy (BSO) to address vaginal bleeding. Pathologic analysis revealed FIGO stage 1A, grade 2 endometroid carcinoma, characterized by lymphovascular space invasion, a 5.6 cm tumor, and 48 percent myometrial invasion. Of seven lymph nodes submitted, none were positive for metastatic carcinoma. She was referred for adjuvant radiation therapy and received vaginal brachytherapy (30 Gy in 5 fractions prescribed to the vaginal surface) within two months of her surgery. Six months post radiation therapy (8 months post-surgery/at baseline), she developed persistent lower back pain and vaginal bleeding. An abdomen/pelvis CT scan revealed a pelvic mass while PET-CT confirmed multiple hypermetabolic lesions including within the previously treated vaginal cuff, consistent with metastatic disease. Additional lesions included a left pelvic sidewall mass measuring 2.2 × 1.8 cm (SUV 25.6), 2.5 × 2 cm (SUV 26.4) left vaginal cuff thickening, and a left perirectal fat nodule measuring 1.4 × 0.9 cm (SUV 19.8).
Biopsy of the left pelvic sidewall tumor revealed recurrent endometrial cancer and MSI-H status making her a candidate for immunotherapy.
She started taking megestrol acetate 40 mg and tamoxifen 20 mg twice a day with a mixed response on PET-CT three months later (11 months from baseline). Although the FDG avidity decreased within the L pelvic side wall, L vaginal cuff, L cul-de-sac and R pelvic sidewall nodules, there was a marked increase in the size and FDG avidity of multiple portal and L pelvic wall lymph nodes. For instance, a previously 1.2 × 0.9 cm (SUV 14.0) retrocrural lymph node increased to 2.3 × 1.7 cm (SUV 15.9), while the portocaval lymph node initially measuring 0.5 cm (SUV 6.1) increased to 1.1 × 1.0 cm (SUV 6.4).
A follow up CT scan two months later (13 months from baseline) continued to demonstrate a mixed response. The previously noted L vaginal cuff and R retrocrural metastases decreased slightly in size but the L pelvic side wall mass had grown to 3.21 × 2.13 cm and the portocaval lymph node mass to 2.82 × 2.1 cm, prompting consideration of concurrent immunotherapy and radiotherapy (Fig. 4 A and B).
The patient started pembrolizumab and radiotherapy concurrently (40 Gy in five fractions to the L pelvic wall and portal lymph nodes). A follow-up CT abdomen/pelvis scan two months after radiotherapy concluded (17 months from baseline) revealed partial response marked by the resolution of both the portocaval (Fig. 4C) and previously observed sub-centimeter right external iliac lymphadenopathy. Additionally, the right retrocrural lymph node shrank from 1.4 × 1.2 cm to 0.6 × 0.4 cm while the L pelvic sidewall lymph node decreased from 3.21 × 2.13 cm to 2.8 × 1.7 cm (Fig 4D). There were no new sites of abdominopelvic or pulmonary involvement.
The patient continued maintenance immunotherapy (Fig. 3). Follow up CT scans 24 and 29 months from baseline revealed a stable L pelvic sidewall and sub-centimeter R retrocrural lymph nodes and no new thoracic or abdominopelvic malignancies. She opted to stop treatment. CT of the abdomen and pelvis 34 months from baseline indicated a stable L pelvic sidewall lymph node measuring 3.0 × 1.3 cm with no other lymphadenopathy.

Case discussion
Endometrial cancer, also known as uterine cancer, is the most common gynecologic cancer (American College of Aobstetricians and Gynecologists (ACOG), 2019). Even though this malignancy is usually detected at an early stage, incidence and mortality rates have continued to rise in recent years, thereby necessitating the need for novel treatment modalities (American College of Aobstetricians and Gynecologists (ACOG), 2019). Currently, immunotherapy is approved for advanced endometrial cancer patients who have disease progression following prior systemic therapy. A systematic review of published literature failed to reveal any studies that concomitantly combined immunotherapy and radiotherapy (Mehnert et al., 2016;Hasumi et al., 2011;Genç et al., 2015;Altorki et al., 2021;Hatten et al., 2022 Mar 3). In the vignettes we presented, it is possible that immunotherapy alone may have eradicated the sites of local and distant disease. However, in other malignancies, concurrent administration of high-dose radiotherapy and immunotherapy has led to increased pathologic responses suggesting improved efficacy with simultaneous delivery of these treatment modalities (Altorki et al., 2021). Moreover, the first case may reflect the "abscopal effect" whereby the treatment of one site with radiotherapy generates robust immune-mediated response at untreated metastases distal to the site of radiotherapy (Hatten et al., 2022). Therefore, randomized controlled trials are necessary to probe the synergy of concomitant immunotherapy and radiotherapy in endometrial cancer cases. At present, NRG GY020 is the only trial, to our knowledge, testing the combination of radiotherapy and immunotherapy in early-stage endometrial cancer. Of note, both patients have had durable responses though one opted to stop maintenance treatment and the other continues to receive infusions to date. In future clinical trials, it will be key to determine the optimal duration of maintenance immunotherapy.

Conclusion
In summary, in this case report, we present two individuals with successful outcomes following the concurrent use of immunotherapy and radiotherapy for the treatment of metastatic endometrial cancer. These cases demonstrate the potential role of combination treatment in a broader population. However, due to the small sample size, additional clinical trials have to be conducted before this combination therapy is recommended for implementation on a widespread scale.
Patient Consent. The patients described in the manuscript have consented to the submission of the case report to the journal. No identifying information is included in this article.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This project was supported by the Ann and Weston Hicks Research Fund.