Reduction of PTV margins for elective pelvic lymph nodes in online adaptive radiotherapy of prostate cancer patients.

BACKGROUND: Cone beam CT (CBCT) based online adaptive radiotherapy (oART) is a new development in radiotherapy. With oART, the requirements for planning target volume (PTV) margins differ from standard therapy because motion occurs during a session. In this study, we aim to evaluate a margin reduction for locally advanced prostate patients treated with oART. MATERIAL AND METHODS: Intrafraction motion of the elective pelvic lymph nodes was evaluated by two radiation therapists (RTTs) for 150 fractions from 10 prostate patients treated with oART. PTV margins of 3, 4 and 5 mm where added to these lymph nodes for all patients. The seven first patients were treated with 5 mm PTV margin, while the last three patients were treated with 4 mm margin. After treatment, the RTTs reviewed the verification CBCTs and evaluated whether the various PTV margins would have covered the adapted clinical target volume, scoring each fraction as approved, inconclusive or rejected. Couch shifts corresponding to the rigid prostate match between the CBCTs were analyzed with respect to the RTT evaluation. RESULTS: The RTTs approved a 4 mm margin in 95% of the fractions, while 2% of the fractions were rejected. For a 3 mm margin, 57% of the fractions were approved, while 5% were rejected. The scoring from the two RTTs was consistent; e.g., for 3 mm, one RTT approved 58% of the fractions, while the other approved 55%. If the couch was moved less than 2 mm in any direction, 70% of the fractions were approved for a 3 mm margin, compared to 32% for shifts greater than 2 mm. CONCLUSION: It is safe to reduce the PTV margin from 5 to 4 mm for the elective pelvic lymph nodes for prostate patients treated with oART. Further margin reductions can be motivated for patients presenting little intrafraction motion.

Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years.

Importance: In cancer models, warfarin inhibits AXL receptor tyrosine kinase-dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort. Objective: To examine the association between warfarin use and cancer incidence. Design, Setting, and Participants: This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1 256 725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017. Exposures: Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled. Main Outcomes and Measures: Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012). Results: Of the 1 256 725 persons in the cohort, 607 350 (48.3%) were male, 649 375 (51.7%) were female, 132 687 (10.6%) had cancer, 92 942 (7.4%) were classified as warfarin users, and 1 163 783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex-adjusted incidence rate ratio (IRR) in all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) and in prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). There was no observed significant effect in colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In a subgroup analysis of patients with atrial fibrillation or atrial flutter, the IRR was lower in all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65) and in prevalent sites (lung, 0.39 [95% CI, 0.33-0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]; and colon, 0.71 [95% CI, 0.63-0.81]). Conclusions and Relevance: Warfarin use may have broad anticancer potential in a large, population-based cohort of persons older than 50 years. This finding could have important implications for the selection of medications for patients needing anticoagulation.

Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis.

Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.