Consolidation whole abdomen irradiation following adjuvant carboplatin-paclitaxel based chemotherapy for advanced uterine epithelial cancer: feasibility, toxicity and outcomes

Endometrial cancer (EC) is the most common malignancy of the female genital tract in the United States with an estimated 47,100 new cases and 8,000 deaths in 2012 [1]. Most patients are diagnosed with early stage disease and have an excellent prognosis. However, for the <20% of patients presenting with extra-uterine disease (stages III and IV), the 5-year overall survival (OS) rates decrease dramatically and range from 30-89% to 0-20%, respectively [2‐5]. Optimal management for these patients remains undefined.

Gynecologic Oncology Group (GOG) protocol 122 prospectively randomized patients between chemotherapy and whole abdomen irradiation (WAI), and established the superiority of systemic chemotherapy [5]. As a consequence, WAI is generally no longer recommended in the postoperative treatment of patients with stage III or IV disease. However, recurrences were frequent in both treatment arms of GOG 122. More than half of the patients progressed or failed in the abdomen illustrating the need for further therapeutic improvements in this high-risk patient population.

A predilection for diffuse peritoneal spread is the rationale for the use of whole abdomen irradiation (WAI), which appeared to have provided therapeutic benefit in both retrospective and prospective studies including patients with proven peritoneal dissemination [5‐10]. It is logical to speculate that adding WAI following chemotherapy may result in superior survival outcomes by improving regional control. Recent studies have reported encouraging preliminary results of multimodal treatment, but have included few patients treated with WAI [11‐14].

We sought to review outcomes of WAI as part of multimodal post surgical treatment of women with abdomen-confined advanced EC at Massachusetts General Hospital (MGH).

Our data show that WAI as part of sequential multimodal based chemotherapy and radiotherapy is hematologically feasible and that acute toxicity is manageable in the context of contemporary supportive care. Tolerability was reflected in the fact that all patients completed radiotherapy treatment as planned, without toxicity-related interruptions and that no CTCAE grade 4 toxicities occurred during chemotherapy or WAI.

Systemic chemotherapy followed by WAI +/− whole pelvis boost, extended-field para-aortic boost and/or vaginal cuff High Dose Rate brachytherapy is an aggressive and potentially morbid treatment regimen. Historically, several studies have evaluated the toxicity of WAI as a consolidation treatment after chemotherapy in ovarian cancer. Myelosuppression was the cause of treatment delay in 9–36% and treatment could not be completed in 4–15% [15‐19].

However, little data exist regarding combinations of chemotherapy and WAI in EC. Two approaches were reported as being feasible without excessive acute toxicity: sequential doxorubicin-cisplatin chemotherapy followed by WAI and combined radiochemotherapy with weekly cisplatin and WAI with pelvic boost and optional para-aortic irradiation [20, 21]. However, a more intensive approach with radio-chemotherapy followed by systemic chemotherapy was considered not feasible due to prohibitive hematologic toxicity [22].

This is, to the best of our knowledge, the first report on feasibility of WAI after modern TP chemotherapy in endometrial cancer. A Canadian study reported on a similar treatment in ovarian cancer [15]. Overall, 34% of the 29 patients had either grade 3 or 4 acute gastrointestinal or hematologic toxicity. WAI was abandoned because of myelosuppression in 7% of patients, and toxicity-related breaks were required in 21% of patients. The results of this Canadian trial contrast with our results regarding toxicity and feasibility. This might be explained by differences in institutional practice in coping with acute toxicity under treatment. Our policy at MGH is not to interrupt radiotherapy treatment based on symptomatic side effects manageable with anti-emetics, anti-diarrheal agents and supportive I.V. hydration. Treatment is not interrupted unless absolute neutrophiles count falls below 900 cells per μL (microlitre) or platelets fall below 35,000 per μL of blood.

Late chronic radiation toxicity is a major concern for WAI, the most common reported being small bowel damage, occurring in approximately 10% of cases [19]. In the current study, there were 3 cases of small bowel obstruction, 2 of which required surgery (10%), and one case of sigmoid perforation, all in the context of tumor recurrence within the abdomen. Late hepatic toxicity (hepatic veno occlusive disease) is another rare but potential life-threatening complication following WAI [19, 20]. In the present study, no patient has developed veno-occlusive disease or liver necrosis. An elevation of liver enzymes following completion of treatment was observed in 50% of our cases, mostly transient and asymptomatic, with the exception of one grade 3 transient case. Still, the inherent risk of potential lethal liver toxicity emphasizes the necessity of careful liver dose limitation. At MGH, we routinely use blocking to keep the liver dose ≤22 Gy at 1.0 Gy/fraction and kidney dose ≤18 Gy. However, with ap/pa radiotherapy technique, using blocks comes at the cost of target coverage and results in underdosed areas within the upper abdomen. Intensity-modulated radiotherapy (IMRT) has been shown to render better coverage of the entire peritoneal cavity, including the liver capsule and the diaphragm while effectively sparing the liver parenchyma, kidneys, and some bone marrow [23, 24]. Future efficacy studies are likely to include this technical refinement.

We identified 20 patients treated over 11 years at MGH; this is fewer than 2 patients per year. Advanced EC is rare with few patients suitable for consolidation WAI and facilities offering WAI are even rarer. Our patients were selected because of a perceived high risk for intraperitoneal recurrence and the absence of known macroscopic residual tumor after chemotherapy. But despite clear methodological limitations of our study (small sample size, retrospective study, and modest duration of follow-up) our data shows a major and statistically significant difference in outcomes between stage III and IV and between EAC and SP. The importance of stage and histology is well documented in the literature [5‐7, 9, 12, 13]. Advanced stage EC is a heterogeneous group and the variety of therapeutic interventions in the literature - WAI alone, chemotherapy alone, multimodal treatment with or without WAI as part of the radiotherapy - makes comparisons difficult. Previous reports of treatment are summarized in Table 5.

In our study, despite the maximum effort given to the abdomen, the peritoneal cavity was still the most frequent site of initial failure, with 5/8 recurrences, 2 of which were associated with additional sites. There are areas of potential underdosage in the upper abdomen when using liver and kidney shielding. IMRT has the potential for more homogeneous target coverage and for conformal dose escalation and might decrease the intra-abdominal recurrence rate [23, 24]. However, this theoretical benefit has not yet been clinically proven.

The fact that 2 of 20 patients considered optimally debulked were found with FDG-avid residual disease on postoperative PET/CT using contrast enhanced diagnostic quality CT suggests a need for preoperative imaging in selected patients [25].

The curative potential of WAI as only postoperative adjuvant therapy has been proven for stage III and abdomen-confined IVB, especially for EAC [10]. However, the role of WAI in the era of polyagent chemotherapy treatment remains controversial [12‐14].

In summary, we demonstrate that in the contemporary era, WAI after carboplatin-paclitaxel based chemotherapy is feasible and safe with both manageable acute and late toxicities. This approach was associated with favorable outcomes in our patients with EAC, possibly attributable to radiotherapy benefit. Based on feasibility and manageable toxicity, it is our hypothesis that WAI coordinated with chemotherapy may warrant prospective investigation in this patient population. Given the challenges of accrual, an international study would be needed. Patients with SP histology did poorly and did not benefit from consolidative treatment as delivered in this study.