Outcomes and toxicity after salvage radiotherapy for vaginal relapse of endometrial cancer.

OBJECTIVES: Studies of salvage radiotherapy in locally recurrent endometrial cancer remain limited. The aim of this study was to evaluate the efficacy of salvage radiotherapy for vaginal relapse of endometrial cancer and to explore prognostic factors associated with outcomes. METHODS: We evaluated 30 patients treated with salvage external-beam radiotherapy and/or vaginal brachytherapy for vaginal relapses of endometrial cancer between 2009 and 2018. The inclusion criteria were: pathologically-confirmed recurrence; loco-regional relapse (in absence of distant metastases); and salvage treatment including external-beam radiotherapy and/or vaginal brachytherapy. Outcomes were evaluated via Kaplan-Meier, with the log-rank test employed to compare differences among various groups and identify prognostic factors. RESULTS: 30 patients developed vaginal recurrence at a median time of 20.6 months (range 2-219) post-hysterectomy. The most common site of recurrence was the vaginal apex (60%), followed by the distal vagina (10%). Salvage radiotherapy entailed combination external-beam radiotherapy and vaginal brachytherapy (n=24) or single modality treatment (n=6), along with concurrent chemotherapy in 20 cases. At a median follow-up of 4.4 years (range 0.1-130) post-radiotherapy, the 5 year rates of local control, regional control, metastasis-free interval, disease-free interval, and overall survival were 89%, 91.5%, 75.5%, 69%, and 83%, respectively. Factors associated with improved disease-free interval included: endometrioid histology (p=0.03), isolated vaginal relapse (p=0.003), late recurrence (>9 months) (p=0.007), and combined modality radiotherapy (p=0.001). The only factor associated with overall survival was isolated vaginal relapse (in the absence of other recurrent disease) (p=0.02). Regarding toxicity, 18% of patients experienced acute grade ≥3 events (most commonly gastrointestinal). The 5 year rates of rectal bleeding, small bowel obstruction, and pelvic fracture were 31%, 18%, and 13%, respectively. CONCLUSIONS: Salvage radiotherapy imparts excellent loco-regional control for vaginal relapses of endometrial cancer and should entail combination external-beam radiotherapy and vaginal brachytherapy. Patients should be closely monitored for late gastrointestinal toxicity following salvage radiotherapy.

PKM2 is not required for colon cancer initiated by APC loss.

BACKGROUND: Cancer cells express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2). PKM2 expression is not required for some cancers, and PKM2 loss can promote cancer progression; however, PKM2 has been reported to be essential in other tumor contexts, including a proposed non-metabolic role in ß-catenin nuclear translocation. PKM2 is expressed in colon cancers where loss of the Apc tumor suppressor results in ß-catenin nuclear translocation and aberrant activation of the canonical Wnt signaling pathway. Whether PKM2 is required in this colon cancer context has not been investigated. RESULTS: Colon tumorigenesis was induced in mice harboring conditional Apc and Pkm2 alleles, and tumor progression was monitored by serial colonoscopy. PKM2 deletion had no effect on overall survival, the number of mice that developed tumors, or the number of tumors that developed per animal. Immunohistochemical analysis demonstrated PKM2 expression in wild-type tumors and the expected loss of PKM2 expression in tumors from Pkm2 conditional mice. Loss of PKM2 resulted in pyruvate kinase M1 expression but had no effect on nuclear ß-catenin staining. These findings are consistent with tumor growth and activated Wnt signaling despite PKM2 loss in this model. We also found a large fraction of human colon cancers had very low or undetectable levels of PKM2 expression. CONCLUSIONS: PKM2 is not required for Apc-deficient colon cancer or for nuclear translocation of ß-catenin in Apc-null tumor cells. These findings suggest that PKM2 expression is not required for colon tumor formation or progression.