Adjuvant carboplatin and paclitaxel with “sandwich” method radiotherapy for stage III or IV endometrial cancer: long-term follow-up at a single-institution

Endometrial cancer is the most common gynecologic malignancy in North America. It is ranked 4^th among the highest solid tumors in Canadian women with around 8,000 new cases and 1,400 deaths each year in Canada [1]. With growing prevalence of endometrial cancer risk factors such as advancing age and obesity, there is increased focus on early detection and treatment [2]. Over 80% of patients present with early-stage disease, which can be cured with surgical resection alone. However, prognosis and survival continue to be poor among those with advanced disease, such as stage III and IV endometrial cancer [3].

Today, chemotherapy is the standard treatment for advanced disease. The Gynecology Oncology Group (GOG) has shown that both chemotherapy (GOG 107, 177) and whole abdominal radiation therapy (GOG 94) to be efficacious and tolerable in the treatment of advanced endometrial cancer [4, 5, 6, 7]. In Secord et al.’s [8] multi-institutional review, 3 treatment modalities were compared: 1) radiation therapy (RT) followed by chemotherapy, 2) chemotherapy followed by RT and 3) chemotherapy, followed by RT, followed by chemotherapy (“sandwich protocol”). The “sandwich protocol” showed significantly higher progression-free survival (PFS) and overall survival (OS) with lower risk of disease progression and patient mortality [8].

Furthermore, “sandwich method” showed better treatment tolerability, compared to other methods of chemoradiation. GOG 122 study reported a survival advantage with chemotherapy alone in advanced endometrial cancer. However, chemotherapy-alone treatment showed high toxicity rate and mortality rate [9]. In addition, giving all cycles of chemotherapy prior to radiotherapy increased the failure rate of radiotherapy due to combined toxicities and prolonged the period between surgery and radiation [10, 11, 12, 13].

In 2009, our group presented the results of a prospective cohort study examining the use of adjuvant carboplatin and paclitaxel interposed with involved field radiation for poor prognosis endometrial cancer [10]. The study had a median follow-up of 30 months (9–71 months) of 43 patients recruited between the years of 2002–2006. Twenty-one patients (49%) developed recurrence of disease at a median of 17 months (7–62 months). Median disease-free survival (DFS) was 50 months and median OS has not been reached. The 3-year DFS and OS rates were 53% and 68%, respectively. Five patients (12%) have experienced grade 3 chronic radiation toxicity and there were no grade 4 chronic toxicity. We concluded lower rates of local recurrence and favorable survival with the sandwich method for advanced endometrial cancer.

The primary aim of this current study includes to expand on our previous cohort to include patients who have been diagnosed with advanced endometrial cancer and completed adjuvant chemotherapy and radiotherapy in sandwich method up to the year of 2018. Primary objective includes analysis of OS and DFS among patients who underwent sandwich treatment method. Secondary objectives include assessment for vaginal, pelvic, and/or distant recurrence and evaluation of long-term treatment-related toxicities from the prospective and retrospective cohort.

This is a cohort study of adult women with advanced stage endometrial cancer enrolled at the London Regional Cancer Program, London, Ontario, Canada from 2002 to 2017. We retrospectively analyzed patients from 2007–2017 and added to the previous prospectively studied data from 2002–2006. The study was approved by the Health Sciences Research Ethics Board at the University of Western Ontario (REB#: 113218). Complete clinical data was abstracted by review of operative notes, both hospital and outpatient notes. Pathology reports were reviewed for histologic type, FIGO stage, tumor grade, number, location, status of lymph nodes, and other sites of metastasis. FIGO 1988 staging for endometrial carcinoma was used in this study, as part of the patient population data predate the 2009 staging version. Demographic information along with presenting symptoms, date of diagnosis, and date of surgery were also collected. Operative notes were reviewed for surgical staging and cytoreduction. Notes during and after chemotherapy and radiotherapy were reviewed for adverse events. Information regarding chemotherapy dose delays and/or dose modifications for each cycle and RT delays were reviewed. After therapy completion, follow up notes were reviewed for disease recurrence or progression, date and site of recurrence or progression, and date of last follow up appointment or date of de.

Advanced endometrial cancer was considered an incurable disease in the past. Historically, patients were given progestin (a form of progesterone) as systemic therapy post-operatively. Today, chemotherapy is the standard antineoplastic treatment option. The GOG has shown that both chemotherapy (GOG 107, 177) and whole abdominal RT (GOG 94) to be efficacious and tolerable in the treatment of advanced or recurrent endometrial cancer [4, 5, 6, 7]. Secord et al. [8] reported a multi-institutional review of varying adjuvant therapies used in advanced stage endometrial cancer. In their report, 3 modalities were examined and consisted of 1) RT followed by chemotherapy, 2) chemotherapy followed by RT and 3) chemotherapy, followed by RT, followed by chemotherapy (“sandwich protocol”). The 3-year PFS/OS was significantly higher in 3) 69%/88%, compared to 1) 52%/57%, and 2) 47%/54%. Furthermore, when compared to either chemotherapy or radiation alone, combined modalities resulted in significantly lower risk of disease progression and patient mortality [8]. The GOC study by Sutton et al. [14] reported that adjuvant whole abdominal irradiation reduced rate of pelvic recurrence. However, systemic chemotherapy reduces the risk of distant recurrence, but provides less local control. This supports the advantage of combining chemotherapy and radiotherapy [14].

Our data supports that treatment of advanced endometrial cancer with adjuvant chemoradiotherapy in sandwich method is feasible and efficacious, in the setting of a large population and long-term follow-up. The sandwich protocol had excellent local control, and encouraging DFS, and OS outcomes. The majority of our patients were able to receive all planned chemotherapy and radiation, allowing for optimal potential benefits of both treatments. Our results are consistent with the previous prospective cohort by Lupe et al. [10] This demonstrates reliability of the treatment protocol.

Subgroup analyses based on age group, nodal disease, and stage of disease, suggested that women above the age of 60 years were the only subgroup at a significantly higher risk of disease-free survival event or death. Histological subtype, location of positive nodes and stage (IIIa vs. higher stage) did not demonstrate a higher risk of recurrence or death.

Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone in patients with high-risk endometrial cancer have been reported in the PORTEC-3 trial. The longitudinal study investigated patients who received radiotherapy alone (48.6 Gy) in 1.8 Gy fractions 5 times a week or chemoradiotherapy (2 cycles concurrent cisplatin followed by 4 adjuvant cycles of carboplatin and paclitaxel). Significantly higher incidence of severe adverse events and reduced health-related quality of life were reported during and after treatment with adjuvant chemoradiotherapy compared to radiotherapy alone, but with rapid recovery. The final results show 5-year failure-free survival (FFS)/OS of 76.5%/81.4% and 69.1%/76.5% for combined chemoradiotherapy compared to radiotherapy alone, respectively. The study recommended chemoradiotherapy to maximize FFS while individually discussing benefits and risks to patients with advanced endometrial cancer [15, 16]. In addition, the PORTEC-3 study showed the 5-year OS and FFS for serous cancers at 71.4% and 59.7% respectively, for patients receiving chemoradiotherapy. Both were significantly higher than for patients who received radiotherapy alone (52.8% OS and 47.9% FFS). The investigators found benefit of the combination of chemotherapy and radiotherapy in high-intermediate risk patients, particularly those with p53 mutation/serous histology [16, 17]. These values were numerically higher than the outcomes in our experience where women, with serous histology, receiving sandwich chemoradiotherapy had 5-year OS and DFS of 56.0% and 48.6%, respectively, but it is noteworthy that all women in our study had at least stage IIIA disease, where PORTEC-3 included women with stage I and II disease as well.

In addition, GOG 258 was a randomized phase 3 clinical trial comparing 6 months of platinum based chemoradiotherapy to chemotherapy alone. Results suggested that the combined modality had lower rates of local/locoregional recurrence, while the chemotherapy alone group had lower rates for distant recurrence than the combined modality group. This may suggest that starting with chemotherapy lowers rates for distant recurrence [18]. While there is ongoing debate about the need of radiotherapy for locally advanced endometrial cancers, research shows that it improves local pelvic control.

In another retrospective observational cohort by Goodman et al., [19] results suggested that women who received chemotherapy followed by radiotherapy, experienced significantly longer 5-year OS than women who received radiotherapy before chemotherapy, chemotherapy alone, or radiotherapy alone. This might suggest that starting with systemic therapy rather than radiotherapy may improve survival outcomes. Using the chemoradiotherapy in sandwich protocol, may allow for better OS by starting with chemotherapy and also maintaining the benefit of local control from EBRT.

Consistently the sandwich group method reports a lower risk of high-grade acute drug toxicities compared to concurrent chemoradiotherapy followed by chemotherapy in cross-trial comparison, with acceptable rates of local disease control. Dose intensity and chemotherapy completion rates are also generally higher in the sandwich method than chemotherapy alone. There is a paucity of head-to-head comparison of these 2 modalities. A randomized clinical trial in North America has recent completed accrual (NCT02501954), and results are eagerly anticipated. In our original report by Lupe et al., [10] there were 31% acute grade 3 or 4 toxicities due to chemotherapy, 12% had acute grade 3 or 4 peripheral neuropathy, 5% had discontinued chemotherapy due to drug toxicity [11].

Our current analysis has limitations. This is a small retrospective study and we were not able to comment on long term drug toxicity due to the retrospective nature of the expansion cohort. We also did not have information on molecular subgroups of this cohort (p53abn, dMMR, NSMP, and POLEmut), as routine biomarker evaluation was not indicated during the period of treatment. It would be of interest to determine whether the sandwich protocol sequencing of treatment has a more favorable impact on certain subgroups.

In conclusion, we believe that using sandwich chemoradiotherapy as adjuvant therapy in patients with advanced endometrial cancer remains an effective and tolerable modality of treatment. The rates of complication and treatment delays appear favorable with the sandwich method with outcome measures consistent with contemporary reports for combined modality therapy in the adjuvant setting. These results support exploring future trials comparing the sandwich chemoradiotherapy method to concurrent chemoradiotherapy followed by chemotherapy to better evaluate OS, DFS, and acute and long-term toxicities.