PURPOSE: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined. In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33–40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

Radiation therapy dose escalation using stereotactic body radiation therapy may significantly improve both local control (LC) and overall survival (OS) for patients with inoperable pancreas cancer. However, ablative dose cannot be routinely offered because of the risk of causing severe injury to adjacent normal organs. Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) represents a novel technique that may achieve safe delivery of ablative dose and improve long-term outcomes. We performed a single institution retrospective analysis of 35 consecutive pancreatic cancer patients treated with SMART in mid-inspiration breath hold on an MR-linear accelerator. Most had locally advanced disease (80%) and received induction chemotherapy (91.4%) for a median 3.9 months before stereotactic body radiation therapy. All were prescribed 5 fractions delivered in consecutive days to a median total dose of 50 Gy (BED₁₀ 100 Gy₁₀), typically with a 120% to 130% hotspot. Elective nodal irradiation was delivered to 20 (57.1%) patients. No patient had fiducial markers placed and all were treated with continuous intrafraction MR visualization and automatic beam triggering. With median follow-up of 10.3 months from SMART, acute (2.9%) and late (2.9%) grade 3 toxicities were uncommon. One-year LC, distant metastasis-free survival, progression-free survival, cause-specific survival, and OS were 87.8%, 63.1%, 52.4%, 77.6%, and 58.9%, respectively. To our knowledge, this is the first report of 5-fraction pancreas SMART delivered on an MR-linear accelerator. We observed minimal severe treatment-related toxicity and encouraging early LC. Prospective confirmation of feasibility and long-term clinical outcomes of dose intensified SMART is warranted.

Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose₁₀ [BED₁₀] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Background: Radiation therapy (RT) dose for inoperable pancreatic ductal adenocarcinoma (PDAC) has historically been non-ablative to avoid injuring gastrointestinal (GI) organs at risk (OARs). Accruing data suggest that dose escalation, in select patients, may significantly improve clinical outcomes. Early results of ablative stereotactic magnetic resonance image-guided adaptive radiation therapy (A-SMART) have been encouraging, although long-term outcomes are not well understood.Methods: A single institution retrospective analysis was performed of inoperable non-metastatic PDAC patients who received induction chemotherapy then 5-fraction A-SMART on a 0.35T-MR Linac from 2018-2021.Results: Sixty-two patients were evaluated with a median age of 66 years (range 35-91) and nearly all achieved Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (96.8%). Locally advanced disease was common (72.6%), otherwise borderline resectable (22.6%), or medically inoperable (4.8%). All received induction chemotherapy for a median 4.2 months (range, 0.2-13.3) most commonly FOLFIRINOX (n=43; 69.4%). Median prescribed dose was 50 Gy (range 40-50); median biologically effective dose (BED₁₀) was 100 Gy₁₀. The median local control (LC), progression-free survival (PFS), and overall survival (OS) from diagnosis were not reached, 20 months, and 23 months, respectively. Also, 2-year LC, PFS, and OS were 68.8%, 40.0%, and 45.5%, respectively. Acute and late grade 3+ toxicity rates were 4.8% and 4.8%, respectively.Conclusions: To our knowledge, this is the largest series of induction chemotherapy followed by ablative 5-fraction SMART delivered on an MR Linac for inoperable PDAC. The potential for this novel treatment strategy is to achieve long-term LC and OS, compared to chemotherapy alone, and warrants prospective evaluation.

Background: With an increasing number of proton centers capable of delivering pencil beam scanning (PBS), understanding the dosimetric differences in PBS compared to passively scattered proton therapy (PSPT) for pancreatic cancer is of interest. Methods: Optimized PBS plans were retrospectively generated for 11 patients with locally advanced pancreatic cancer previously treated with PSPT to 59.4 Gy on a prospective trial. The primary tumor was targeted without elective nodal coverage. The same treatment couch, target coverage and normal tissue dose objectives were used for all plans. A Wilcoxon t-test was performed to compare various dosimetric points between the two plans for each patient. Results: All target volume coverage goals were met in all PBS and passive scattering (PS) plans, except for the planning target volume (PTV) coverage goal (V100% >95%) which was not met in one PS plan (range, 81.8–98.9%). PBS was associated with a lower median relative dose (102.4% vs. 103.8%) to 10% of the PTV (P=0.001). PBS plans had a lower median duodenal V59.4 Gy (37.4% vs. 40.4%; P=0.014), lower small bowel median V59.4 Gy (0.11% vs. 0.37%; P=0.012), lower stomach median V59.4 Gy (0.01% vs. 0.1%; P=0.023), and lower median dose to 0.1 cc of the spinal cord {35.0 vs. 38.7 Gy [relative biological effectiveness (RBE)]; P=0.001}. Liver dose was higher in PBS plans for median V5 Gy (24.1% vs. 20.2%; P=0.032), V20 Gy (3.2% vs. 2.8%; P=0.010), and V25 Gy (2.6% vs. 2.2%; P=0.019). There was no difference in kidney dose between PBS and PS plans. Conclusions: Proton therapy for locally advanced pancreatic cancer using PBS was not clearly associated with clinically meaningful reductions in normal tissue dose compared to PS. Some statistically significant improvements in PTV coverage were achieved using PBS. PBS may offer improved conformality for the treatment of irregular targets, and further evaluation of PBS and PS incorporating elective nodal irradiation should be considered.