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PURPOSE: To compare the characteristics and outcomes of rectal cancer patients with local recurrence at a perianastomotic site (PA), a surgical field (SF) site, or in lateral lymph nodes (LLN). METHODS: A total of 114 consecutive patients who underwent surgery for recurrent, non-metastatic rectal cancer at a single comprehensive cancer center between 1997 and 2012 were grouped on the basis of radiographic assessment of type of recurrence: PA, 76 (67%) patients; SF, 25 (22%) patients; LLN, 13 (11%) patients. Demographic, clinical, and pathological features were compared between the three groups, as were disease-free survival (DFS) and overall survival (OS). RESULTS: Recurrence type was associated with positive circumferential margin in the primary resection (PA, 4 [6%]; SF, 4 [19%]; LLN, 3 [25%]; P = 0.027), prior neoadjuvant therapy for the primary tumor (PA, 57 [75%]; SF, 18 [72%]; LLN, 4 [31%]; P = 0.007) and location of the primary tumor in the upper rectum (PA, 33 [45%]; SF, 5 [23%]; LLN, 1 [8%]; P < 0.001). Patients with PA had longer median DFS (PA, 5.1 years; SF, 1.5 years; LLN, 1.2 years; P = 0.036). There was a non-significant trend toward longer OS and higher rates of R0 resection for PA. CONCLUSION: Type of recurrence after salvage surgery for locally recurrent rectal cancer is associated with longer DFS in patients with PA recurrence.

Background and Purpose Stereotactic body radiation therapy delivered using MR-guided radiotherapy (MRgRT) and automatic breathold gating has shown to improve overall survival for locally advanced pancreatic cancer (LAPC) patients. The goal of our study was to evaluate feasibility of treating LAPC patients using abdominal compression (AC) and impact of potential intrafraction motion on planned dose on a 1.5T MR-linac. Methods & Materials Ten LAPC patients were treated with MRgRT to 50 Gy in 5 fractions with daily online plan adaptation and AC. Three orthogonal plane cine MRI were acquired to assess stability of AC pressure in minimizing tumor motion. Three sets of T2w MR scans, pre-treatment (MRIpre), verification (MRIver) and post-treatment (MRIpost) MRI, were acquired for every fraction. A total of 150 MRIs and doses were evaluated. Impact of intrafraction organ motion was evaluated by propagating pre-treatment plan and structures to MRIver and MRIpost, editing contours and recalculating doses. Gross tumor volume (GTV) coverage and organs-at-risk (OARs) doses were evaluated on MRIver and MRIpost. Results Median total treatment time was 75.5 (49–132) minutes. Median tumor motion in AC for all fractions was 1.7 (0.7–7), 2.1 (0.6–6.3) and 4.1 (1.4–10.0) mm in anterior-posterior, left–right and superior-inferior direction. Median GTV V50Gy was 78.7%. Median D5cm3 stomach_duodenum was 24.2 (18.4–29.3) Gy on MRIver and 24.2 (18.3–30.5) Gy on MRIpost. Median D5cm3 small bowel was 24.3 (18.2–32.8) Gy on MRIver and 24.4 (16.0–33.6) Gy on MRIpost. Conclusion Dose-volume constraints for OARs were exceeded for some fractions on MRIver and MRIpost. Longer follow up is needed to see the dosimetric impact of intrafraction motion on gastrointestinal toxicity.

Background Increased risk of a second primary malignancy (SPM) before or after diagnosis of anal squamous cell carcinoma (ASCC) has been reported in a previous single‐institution study. We hypothesize that patients diagnosed with ASCC are at increased risk for developing SPMs before or after the diagnosis of ASCC. The primary objective of this study was to identify the diagnoses of cancer most likely to occur as SPMs before or after ASCC. Methods This work employs the Surveillance, Epidemiology, and End Results (SEER) Program registry data to conduct a US‐population‐based study of patients diagnosed with ASCC between 1975 and 2016. In patients diagnosed with ASCC, we evaluated the risk of SPMs and the risk of developing ASCC as an SPM after another cancer using standardized incidence ratios (SIR) for all SPMs by calculating the ratio of observed events in the ASCC cohort compared to expected (O/E) events in a matched reference cohort of the general population. Results A total of 7,594 patients with primary ASCC were included. Patients with ASCC were at increased risk of the diagnosis of an SPM (SIR = 1.45), particularly cancers of the lung, vulva, oropharynx, or colon. Patients with ASCC had an increased rate of previous malignancy (SIR = 1.23), especially Kaposi sarcoma or vulvar cancer. Overall elevated incidence of SPMs was unrelated to prior radiation treatment. Radiation treatment was associated with increased risk for SPMs in the female genital system but appeared protective against prostate cancer as SPMs. Conclusions Our findings support increased surveillance and screening for second malignancies in patients with these diagnoses, as patients with ASCC are often either survivors of a prior cancer diagnosis or are at increased risk of developing later malignancies., Survivors of anal squamous cell carcinoma are at increased risk for particular second malignancies and should be screened for these. Risk of second malignancies is sometimes related to radiation therapy, but radiation can also be protective against second cancers in some cases.

Background Proton beam radiation therapy (PBRT) has dosimetric advantages compared to photon radiation therapy for the treatment of major salivary gland tumors (MSGTs). Methods Patients with non-metastatic MSGTs treated at a single proton therapy center from October 2013 to October 2018 were retrospectively reviewed. Results Sixty-eight patients with MSGTs were included and the most common site and histology were the parotid gland (75.0%) and adenoid cystic carcinoma (22.1%), respectively. The 3-year rates of locoregional control, progression-free survival, and overall survival were 95.1% (95% CI: 89.9%-100.0%), 80.7% (70.2%-92.7%), and 96.1% (95% CI: 90.9%-100.0%), respectively. Conclusion In a large cohort of MSGTs treated with PBRT, the rates of locoregional control were high in short-term follow-up and treatment was well tolerated.

Evasion of immune recognition is a hallmark of cancer that facilitates tumorigenesis, maintenance, and progression. Systemic immune activation can incite tumor recognition and stimulate potent antitumor responses. While the concept of antitumor immunity is not new, there is renewed interest in tumor immunology given the clinical success of immune modulators in a wide range of cancer subtypes over the past decade. One particularly interesting, yet exceedingly rare phenomenon, is the abscopal response, characterized by a potent systemic antitumor response following localized tumor irradiation presumably attributed to reactivation of antitumor immunity.

Background Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. Methods We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. Results Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. Conclusions We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.

Purpose: Pelvic radiation therapy (RT) is standard of care for patients with locally advanced rectal cancer (LARC). Premature ovarian insufficiency (POI) in premenopausal women is a possible side effect. The purpose of our study was to evaluate factors associated with POI in women younger than 50 years, treated with pelvic RT for LARC, including those who underwent ovarian transposition (OT). Methods and Materials: We retrospectively reviewed the records of women younger than 50 years treated with pelvic RT for LARC at our institution between 2001 and 2019. Clinical and hormonal data were used to determine ovarian function. The ovaries and uterus were contoured and dose volume histograms were generated. Association of clinical and dosimetric factors with POI within 12 months of RT was evaluated using Wilcoxon-rank sum test and Fisher's exact test. Results: We identified 76 premenopausal women at time of RT with median age of 43 years (range, 20-49). Twenty-six women (34%) underwent OT. Neoadjuvant, concurrent, and adjuvant chemotherapy was administered in 56 (74%), 69 (91%), and 26 (34%) women, respectively. Median RT dose was 50 Gy/25 fractions. Among 75 women with 12 months of follow-up, 25% had preservation of ovarian function, all in the OT group. Ovarian function was preserved in 19 (76%) women who underwent OT. The median of ovarian mean dose was 1.7 Gy in the OT group versus 44.8 Gy in the non-OT group (P < .001). OT and age at RT were significantly associated with POI (P < .001). No patient with ovarian mean dose less than 1.36 Gy developed POI. Conclusions: OT was significantly associated with reduced risk of POI by enabling lower radiation doses to the ovaries. OT should be considered in young patients undergoing pelvic RT. Although there appears to be a significant association between ovarian mean dose and POI, larger studies are needed to find a dosimetric threshold. Our results suggest keeping the dose to the ovaries as low as reasonably achievable in patients who undergo OT and pelvic RT.

Purpose: To assess the effect of a combination of compressed sensing and SENSitivity Encoding (SENSE) acceleration techniques on radiation therapy magnetic resonance imaging (MRI) simulation workflows. Methods and Materials: Thirty-seven acquisitions were performed with both SENSE-only (SENSE) and combined compressed sensing and SENSE (CS) techniques in 24 patients receiving radiation therapy MRI simulation for a wide range of disease sites. The anatomic field of view prescription and image resolution were identical for both SENSE and CS acquisitions to ensure fair comparison. The acquisition time of all images was recorded to assess time savings. For each image pair, image quality, and ability to contour were assessed by 2 radiation oncologists. Aside from direct image pair comparisons, the feasibility of using CS to improve MRI simulation protocols by increasing image resolution, field of view, and reducing motion artifacts was also evaluated. Results: CS resulted in an average reduction of 27% in scan time with negligible changes in image quality and the ability to contour structures for RT treatment planning compared with SENSE. Physician scoring of image quality and ability to contour shows that while SENSE still has slightly better image quality compared with CS, this observed difference in image quality did not affect the ability to contour. In addition, the higher acceleration capability of CS enabled use of superior-inferior direction phase encoding in a sagittal 3-dimensional T2-weighted scan for substantially improved visibility of the prostatic urethra, which eliminated the need for a Foley catheter in most patients. Conclusions: The combination of compressed sensing and parallel imaging resulted in marked improvements in the MRI Simulation workflow. The scan time was reduced without significantly affecting image quality in the context of ability to contour. The acceleration capabilities allowed for increased image resolution under similar scanning times as well as significantly improved urethra visualization in prostate simulations.

BACKGROUND: More than 70% of patients with hepatocellular carcinoma (HCC) are not candidates for curative therapy or recur after curative-intent therapy. There is growing evidence on the use of ablative radiation therapy (RT) for liver tumors. We aimed to analyze outcomes of HCC patients treated with conventional versus ablative RT. METHODS: We retrospectively analyzed medical records of HCC patients treated with liver RT from 2001 to 2019. We defined ablative RT as biologically effective dose (BED) ≥80 Gy. RECIST 1.1 was used to define early responses at 3–6 months after RT, and local control (LC) at last follow-up (FU). Data was analyzed using Fisher exact test, Kaplan-Meier, cumulative incidence rates, Cox proportional hazards model and Fine-Gray competing risks. RESULTS: Forty-five patients were identified, of whom 14 (31.1%) received ablative RT using a stereotactic technique. With median FU of survivors of 10.1 months, 1-year cumulative incidence of LC was 91.7% for ablative and 75.2% for BED

Simple Summary Stereotactic ablative body radiotherapy (SABR) is an effective treatment for CRC liver metastases. Advanced radiation techniques are required to ensure safe and efficacious treatment. MR-guided radiotherapy is a new and evolving technology that can overcome many of the challenges of liver SABR. MR imaging before, during and after treatment delivery facilitates direct visualization of tumor target and adjacent normal healthy organs, real time MR imaging facilitates non-invasive tumor tracking and gating, and daily adaptive re-planning permits treatment plans to be adjusted for the anatomy of the day. MR-guided ablative radiation therapy is a promising radiation technology advance that can further facilitate safe tumor dose escalation of colorectal liver metastases. Abstract Technological advances have enabled well tolerated and effective radiation treatment for small liver metastases. Stereotactic ablative radiation therapy (SABR) refers to ablative dose delivery (>100 Gy BED) in five fractions or fewer. For larger tumors, the safe delivery of SABR can be challenging due to a more limited volume of healthy normal liver parenchyma and the proximity of the tumor to radiosensitive organs such as the stomach, duodenum, and large intestine. In addition to stereotactic treatment delivery, controlling respiratory motion, the use of image guidance, adaptive planning and increasing the number of radiation fractions are sometimes necessary for the safe delivery of SABR in these situations. Magnetic Resonance (MR) image-guided adaptive radiation therapy (MRgART) is a new and rapidly evolving treatment paradigm. MR imaging before, during and after treatment delivery facilitates direct visualization of both the tumor target and the adjacent normal healthy organs as well as potential intrafraction motion. Real time MR imaging facilitates non-invasive tumor tracking and treatment gating. While daily adaptive re-planning permits treatment plans to be adjusted based on the anatomy of the day. MRgART therapy is a promising radiation technology advance that can overcome many of the challenges of liver SABR and may facilitate the safe tumor dose escalation of colorectal liver metastases.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

Purpose/Objective(s) This prospective multi-institutional study aimed to determine the safety and maximally tolerated dose of 3-fraction stereotactic body radiotherapy (SBRT) for locally advanced pancreatic cancer (LAPC). Materials/Methods Patients with localized, histologically confirmed pancreatic adenocarcinoma deemed unresectable on radiographic multidisciplinary review without distant progression following induction chemotherapy for at least 2 months were eligible. Patients received 3-fraction LINAC-based SBRT at 3 dose levels, 27Gy, 30Gy and 33Gy following a modified 3+3 design, allowing for enrollment of additional patients at the last dose level during the 90-day observation period, provided no dose-limiting toxicities (DLTs) were observed. DLTs were defined as ≥ Grade 3 treatment-related GI toxicity within 90 days of RT as scored by CTCAE v.4. The secondary endpoints were overall survival (OS), local progression-free and distant metastasis-free survival (LPFS and DMFS, respectively), treatment-related toxicity and quality of life. Results Between 3/2016 and 4/2019, 23 consecutive evaluable LAPC patients were enrolled at two academic hospitals (14 and 9 patients, respectively), including 8 patients at 27Gy, 8 patients at 30Gy and 7 patients at 33Gy. The median age was 67 years (range 52 - 79 years), 9 patients (39%) were male, all were stage III, 12 (52%) had a head/uncinate tumor location, with a median tumor size of 3.5cm (range, 1.0 - 6.4cm) and a median CA19-9 of 60U/mL (range, Conclusion For select LAPC patients, dose escalation to the target dose of 33Gy in 3 fractions resulted in no DLTs and disease outcomes comparable to conventional RT. These results warrant further exploration of hypofractionated SBRT schemes to maximize tumor control while enabling efficient integration of RT with systemic therapy for more expedient treatment options for these high-risk LAPC patients.

Purpose/objective(s) Liver metastases (LM) are associated with diminished anti-tumor immunity and response to immune checkpoint blockade (ICB). In preclinical models, liver-metastasis-directed radiotherapy (LRT) restores sensitivity to ICB; however, there is limited human data supporting this hypothesis. We therefore examined the outcomes of patients with LM treated with LRT and ICB. Materials/methods We reviewed the records of patients who received LRT and anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Patients were classified as receiving LRT before ICB, concurrently with the start of ICB (within 21 days), or as salvage during ICB (> 21 days after initiation). Outcome measures included time to failure of ICB (TTF) and overall survival, both defined from the initiation of ICB. For patients who received RT before or concurrently with ICB, outcomes were further stratified by presence of active LM at the time of ICB initiation. Patients who received LRT during ICB were excluded from comparative analyses to avoid potential immortal time bias. Results We identified 41 patients who received both ICB and LRT. 27 (66%) patients were male. The median age at LRT was 57 (26 - 80). Patients received a median of 2 lines of systemic therapy (0-4) before ICB. Tumor types included colorectal cancer (n = 20), non-small cell lung cancer (n = 10), anal squamous cell carcinoma (n = 5), melanoma (n = 4), and bladder cancer (n = 2). 16 patients were treated with LRT before ICB, 9 of whom recurred in the liver and had active LM at the start of ICB. 12 patients received LRT concurrently with ICB initiation, and 13 patients received salvage LRT during ICB. 95% (39/41) of patients had disease involving at least 2 organs at the time of ICB. Among the 28 patients treated with LRT before or concurrently with ICB, the presence of active, untreated LM (n = 21) at the time of the ICB initiation was associated with shorter TTF (HR 6.0, 95% CI 1.7 - 21.0, P = 0.005) and overall survival (HR 5.4, 95% CI 1.2 - 23.8, P = 0.025). The median TTF for patients with treated LM at ICB (n = 7) was 874 days (95% CI 111 - NR) vs. 78 days (95% CI 54 - 126) for patients with active LM (n = 21). Patients treated with LRT concurrently with the start of ICB (n = 12) did not have improved TTF compared to patients with active, untreated LM at the time of ICB who had prior LRT (n = 9) (P = 0.41). Among 13 patients treated with salvage RT during ICB, the median time to subsequent treatment failure was 101 days (95% CI 61 - NR). Conclusion This analysis suggests that patients with treated LM have improved TTF compared with patients with active LM at the time of ICB. This provides the first data in humans that treatment of LM may improve response to ICB and sheds light on the importance of LRT and ICB timing. Prospective studies to further investigate the use and timing of LRT and ICB are warranted.

Purpose/objective(s) RT for rectal and anal cancer after prostate cancer RT is usually avoided due to fear of complications, and data on this topic is scarce. Our aim was to evaluate outcomes and toxicity associated with RT in this group of patients. Materials/methods We conducted a single institution retrospective study of patients treated with RT for rectal or anal cancer after prior prostate RT from 1/1/1995 - 8/1/2019. Acute and long-term toxicities were collected. Treatment plans were extracted to assess doses to organs at risk and target coverage. Wilcoxon rank sum test was used for correlation between dosimetry and toxicities. Estimated cumulative incidence was used for local progression. Results We identified 29 patients who received RT after prostate cancer RT, 19 with rectal cancer and 10 with anal cancer. None of those patients had metastatic disease. Prior prostate RT was delivered using low dose rate brachytherapy (LDR) in 15/29 patients with a median dose of 145 Gy (144-160), external beam RT (EBRT) in 10 patients with 79.2Gy/44 or 81Gy/45 fractions (fr), and EBRT + LDR in 4 patients with 50.4/28 + 80-110 Gy I-125 or Pd-103 LDR. RT for rectal cancer was delivered most commonly with 50.4Gy/28 fr or 1.5 Gy twice daily fractionation to 30-45 Gy (53% of patients). The most commonly used RT dose for anal cancer was 50Gy/25 fr. Brachytherapy was used in 6 (21%) patients: as a boost after EBRT in 2 patients with anal cancer and alone in 4 rectal cancer patients. Median interval between prostate and anorectal RT was 134 months (6-303). 68% and 80% of rectal and anal cancer patients got concurrent chemotherapy. Table 1 summarizes toxicities associated with anorectal re-RT. Two patients developed fistulas, one was urinary cutaneous after prostate LDR and 45Gy/25fr for rectal cancer, and the other recto vesicular after prostate LDR and 50Gy/25fr for anal cancer; both repaired by extensive surgery. Both patients had more than 10 years between the two RT courses. In 21 patients with available dosimetry, coverage was adequate with a GTV V100% of 98% for rectal cancer patients and 96% for anal cancer patients. There was no significant correlation between toxicities and dosimetric values probably due to the small sample size. The estimated 5-year local progression incidence for all patients was 22%: 11% for rectal cancer, and 4% for anal cancer patients. Conclusion RT of anorectal cancer after prior prostate cancer RT is feasible but poses a risk of fistulae. Further studies, possibly using proton therapy and/or rectal hydrogel spacers, are needed to further establish the feasibility of RT in this context, decrease toxicity, and improve outcomes.

Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Stereotactic ablative radiotherapy (SABR) commonly is used for small liver metastases. Modern conformal radiotherapy techniques, including 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy, enable the safe delivery of SABR to small liver volumes. For larger tumors, the safe delivery of SABR can be challenging due to a more limited volume of healthy normal liver parenchyma and the proximity of the tumor to radiosensitive organs, such as the stomach, duodenum, and large intestine. Controlling respiratory motion, the use of image guidance, and increasing the number of radiation fractions sometimes are necessary for the safe delivery of SABR in these situations.

Colorectal cancer is the third most common cancer in men and the second most common in women worldwide, and the incidence is increasing among younger patients. 30% of these malignancies arise in the rectum. Patients with rectal cancer have historically been managed with preoperative radiation, followed by radical surgery, and adjuvant chemotherapy, with permanent colostomies in up to 20% of patients. Beginning in the early 2000s, non-operative management (NOM) of rectal cancer emerged as a viable alternative to radical surgery in select patients. Efforts have been ongoing to optimize neoadjuvant therapy for rectal cancer, thereby increasing the number of patients potentially eligible to forgo radical surgery. Magnetic resonance guided radiotherapy (MRgRT) has recently emerged as a treatment modality capable of intensifying preoperative radiation therapy for rectal cancer patients. This technology may also predict which patients will achieve a complete response to preoperative therapy, thereby allowing for more appropriate selection of patients for NOM. The present work seeks to illustrate the potential role MRgRT could play in personalizing rectal cancer treatment thus expanding the role of NOM in rectal cancer.

The COVID-19 pandemic will consume significant health care resources. Given the concerns for rapidly increasing infection rates in the United States, impending staffing shortages, and the potential for resource reallocation, we rapidly reevaluated our rectal cancer practice policies during this public health emergency. Before the pandemic, we commonly used total neoadjuvant therapy with a strong preference for long-course chemoradiation. In the setting of the ongoing pandemic, we now mandate short-course radiation therapy (SCRT). Despite multiple randomized trials demonstrating no difference in locoregional recurrence, distant recurrence, or overall survival between SCRT and long-course chemoradiation, the adaptation of SCRT in the United States has been low given concerns for less tumor downstaging and increased toxicity. In the setting of the ongoing and likely prolonged COVID-19 pandemic, we feel that these concerns must be reevaluated, because SCRT presents a well-validated alternative that will allow us to meet the needs of a greater number of potentially curable patients at a time when resources are severely and acutely constrained.

Highlights • Median local recurrence free survival after repeat reirradiation was 9.1 months. • Grade 4 toxicities were reported in 21% of patients. • 61% of patients underwent subsequent therapies following repeat reirradiation. • Subsequent therapies following repeat reirradiation included surgery, chemotherapy and immunotherapy. • Repeat reirradiation is feasible and should be balanced against risk for toxicities., Purpose Recurrent head and neck cancers are associated with significant morbidity and mortality. Outcomes of multiple courses of radiation have not yet been described. Methods and Materials A single institution database was queried to retrospectively review treatment plans and select patients who underwent ≥ 3 courses of radiation to the head and neck region. Results Thirty-three patients were found to have ≥ 3 courses of radiation with overlapping fields. Median local recurrence free survival after last course of reirradiation was 9.1 months and median overall survival was 10 months. Grade 3 and above toxicities were reported in 15 patients (45%). Grade 4 and above toxicities were reported in seven patients (21%). There was no grade 5 toxicity. 20 patients (61%) underwent subsequent therapies following completion of repeat reirradiation. Conclusions Repeat reirradiation to the head and neck region is feasible and carries significant risks that are most appropriately managed with a multi-disciplinary team and must be balanced against the potential for local control and opportunities for emerging systemic therapies.

Background: Differentiated thyroid cancer typically has an indolent clinical course but can cause significant morbidity by local progression. Oncologic surgical resection can be technically difficult due to the proximity to critical normal structures in the neck. Our objective was to review the safety, feasibility, and outcomes of definitive-intent intensity-modulated radiation therapy (IMRT) and to analyze whether patients receiving concurrent chemotherapy (CC-IMRT) had higher rates of disease control and survival over IMRT alone in patients with unresectable or gross residual disease (GRD).Methods: Eighty-eight patients with GRD or unresectable nonanaplastic, nonmedullary thyroid cancer treated with definitive-intent IMRT between 2000 and 2015 were identified. Local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses using cox regression were used to determine the impact of clinical conditions and treatment on LPFS, DMFS, and OS.Results: Of the 88 patients identified, 45 (51.1%) were treated CC-IMRT and 43 (48.9%) were treated with IMRT alone. All patients treated with CC-IMRT received weekly doxorubicin (10 mg/m(2)). The median followup among surviving patients was 40.3 months and 29.2 months for all patients. The LPFS at 4 years was 77.3%. Patients receiving CC-IMRT had higher LPFS compared with IMRT alone (CC-IMRT 85.8% vs. IMRT 68.8%, p = 0.036). The 4-year OS was 56.3% for all patients. Patients treated with CC-IMRT had higher OS compared to patients treated with IMRT alone (CC-IMRT 68.0% vs. IMRT 47.0%, p = 0.043). On multivariate analysis, receipt of concurrent chemotherapy was associated with a lower risk of death (HR 0.395, p = 0.019) and lower risk of local failure (HR 0.306, p = 0.042). Grade 3+ acute toxicities occurred in 23.9% of patients, the most frequent being dermatitis (18.2%) and mucositis (9.1%). 17.1% of patients required a percutaneous endoscopic gastrostomy (PEG) tube during or shortly after completion of RT, with 10.1% of patients needing a PEG more than 12 months after therapy. The rates of acute and late toxicities were not statistically higher in the CC-IMRT cohort, although trends towards higher toxicity in the CC-IMRT were present for dermatitis and PEG requirement.Conclusions: IMRT is a safe and effective means to achieve local control in patients with unresectable or incompletely resected nonanaplastic, nonmedullary thyroid cancer. Concurrent doxorubicin was not associated with worse toxicity and should be considered in these patients given its potential to improve local control and overall survival.

Purpose To evaluate the difference in prostate-specific antigen (PSA) recurrence–free, distant metastasis–free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). Methods and Materials During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post–radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). Results One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age ( P =.001), lower Gleason score ( P =.0003), and higher radiation therapy dose ( P =.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P =.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P =.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P =.04) on multivariate Cox analysis. Because all 50 prostate cancer–specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B ( P =.004). Conclusions Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis–free survival, overall survival, and cancer-specific survival outcomes.

Importance Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, setting, and participants This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main outcomes and measures Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and relevance In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

PURPOSE/OBJECTIVE(S) To report on our early experience of treating patients with pancreas ductal adenocarcinoma (PDAC) with ablative SBRT (50 Gy in 5 fractions) on the Elekta Unity MR-Linac. MATERIALS/METHODS Ten PDAC patients were treated with abdominal compression (AC) and daily online plan adaptation using Adapt-to-Shape (ATS) workflow. AC is the method of choice to reduce breathing motion since automatic breath-hold/gating or other motion management options are not yet available on Unity MR-Linac. Three tumors were located in the head of the pancreas and seven were in the body. Seven patients were considered inoperable per surgeon and six were node positive. Average GTV volume during simulation was 42.5 ± 24.8 cc. Three orthogonal plane cine MRI were acquired to assess AC belt pressure during MR simulation as well as during each treatment fraction to assess stability of AC in minimizing tumor motion. Three sets of 3D T2w MR scans, pre-treatment (MRIpre), verification (MRIver) and post-treatment (MRIpost) MRI, were acquired for online planning. To assess the dosimetric impact of intrafraction organ motion, a post-treatment quality assurance (QA) was performed before the next fraction by propagating pre-treatment plan and structures to both MRIver and MRIpost, editing the contours and recalculating dose. GTV coverage and selected organs-at-risk (OAR) dose constraints (e.g., < 33 Gy to 0.035 cc, < 25 Gy to 2 cc and < 25 Gy to 5cc volume) were evaluated on MRIver and MRIpost. RESULTS Median total treatment time was 75.5(49-132) minutes. Average contouring, planning, physics QA and beam-on time was 25.1 ± 11.9, 12.2 ± 6.0, 1.9 ± 1.5 and 14.1 ± 3.7 mins respectively. Average AP, LR and SI motion in FB and with compression was 0.3 ± 0.1, 0.6 ± 0.2 and 0.7 ± 0.2 and 0.2 ± 0.1, 0.2 ± 0.1, 0.4 ± 0.1 cm respectively, indicating that compression belt was effective in minimizing patient breathing motion. Average tumor motion in AC belt for all fractions was 0.2 ± 0.1, 0.2 ± 0.1 and 0.4 ± 0.2 cm in AP, LR and SI direction. Median GTV coverage was 78.7% of Rx dose for all fractions. Average GTV Dmax and GTV mean dose for all the fractions was 57.4 ± 0.7 and 51.2 ± 1.6 Gy respectively. Average 0.035 cc, D2cc and D5cc stomach dose was 34.4 ± 5.4, 26.7 ± 2.9 and 24.3 ± 2.1 Gy on MRIver and 35.3 ± 6.2, 27.0 ± 3.3 and 24.6 ± 2.5 Gy on MRIpost. Average 0.035 cc, D2cc and D5cc small bowel dose was 35.1 ± 6.3, 27.1 ± 3.6 and 24.4 ± 2.6 Gy on MRIver and 35.5 ± 6.5, 27.3 ± 3.9 and 24.6 ± 2.5 Gy on MRIpost. CONCLUSION MR-guided adaptive RT enables delivery of curative dose to pancreatic tumors by taking into account interfraction motion of gastrointestinal OARs in daily adaptive planning. To manage intrafraction motion in our current clinical workflow, the organ motion is assessed for first two fractions and conservative strategies (e.g., bigger PRV margins or change the directive to keep stomach 0.035 cc dose to < 30 Gy) are employed for later fractions. ATS workflow with AC and the post-treatment QA allow safe delivery of ablative radiation doses for selected cases of PDAC on Unity MR-Linac. AUTHOR DISCLOSURE N. Tyagi: Honoraria; Elekta. Travel Expenses; Elekta; ISMRM.J. Liang: None. S. Burleson: None. E. Subashi: None. P. Godoy Scripes: None. K.R. Tringale: None. P.B. Romesser: Travel Expenses; Elekta. M. Reyngold: None. C.H. Crane: Honoraria; Elekta. Travel Expenses; Elekta.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to individual patients. We established a biorepository of 32 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and theirex vivoresponses to clinically relevant chemotherapy and radiation treatment correlate well with responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive rectal cancer followed by metastasis to lung and liver. Importantly, engrafted tumors closely reflected the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based,in vitroplatform coupled with endoluminal propagation in animals.

12065 Background: With a rising incidence of younger patients diagnosed with rectal cancer, the long-term toxicity of cancer-related therapy is becoming even more relevant. Risk of SPM is a known potential consequence of both chemotherapy (chemo) and radiation therapy (RT), yet the rate of SPM in patients with rectal cancer is still not defined. We sought to further investigate factors associated with and outcomes of SPM after RT for rectal cancer. Methods: Patients diagnosed with stage II-III rectal cancer treated with chemo and/or RT from 1995-2019 were included in a retrospective study. Patients treated with palliative intent and those who survived < 5 years from treatment were excluded. RT-associated SPM was defined as a cancer occurring ³5 years after RT completion. Cumulative incidence (CI) of SPM was analyzed using a landmark analysis at 5 years with death as a competing risk. For patients with CT simulation scans available, dosimetric analyses evaluated doses to the organs developing SPM. Kaplan Meier analysis was used to evaluate overall survival among patients who developed an SPM. Results: A total of 2,700 patients were included (RT = 978; chemo = 1722). Demographic characteristics were equivalent apart from age, which was higher in the RT group (61 vs 59 years, p < 0.001). Five (0.3%) chemo patients developed an SPM, all within 5-10 years after treatment for rectal cancer, vs 48 (4.9%) RT patients. The 8-year CI of developing an SPM in the RT group was 4% (95% CI 2.4-6.2) and increased to 17% at 15 years (95% CI 12.1-21.8) and 21% at 20 years (95% CI 14.8-27.7). Most (89%) RT patients had received chemotherapy (most commonly 5-FU or FOLFOX). The median time to SPM was 108 months (interquartile range [IQR], 84-140). After pelvic RT, the most common SPM histology was endometrial (38%), followed by prostate (31%), bladder (23%), sarcoma (4.2%), and other gynecologic cancers (4.2%). Seven patients had CT simulations for dosimetric analyses: median of maximum dose to the organ with SPM was 5301cGy (IQR, 4928-5427), median of mean dose was 4551 cGy (IQR, 4476-4751). None of the patients who developed endometrial cancer had Lynch syndrome. Median OS for patients with SPM after RT was 5.1 years with 5-yr OS of 58% (95% CI 43-77); 44 out of 48 patients needed at least one treatment modality for their SPM, and 8 received trimodality treatment [surgery, chemo and RT]. Conclusions: The CI of SPM increased from 4% at 8 years to 17% at 15 years and 21% at 20 years following pelvic RT for rectal cancer. Endometrial cancer was the most common SPM and survival following treatment of SPM was favorable. These data serve as a foundation for future prospective studies evaluating ways to reduce SPM such as proton therapy.

Importance Surgical resection has been considered the only curative option for patients with pancreatic cancer. Nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses to be given in patients with inoperable disease. Objective To determine the association of hypofractionated ablative radiation therapy (A-RT) with survival for patients with locally advanced pancreatic cancer (LAPC) treated with a novel radiation planning and delivery technique. Design, setting, and participants This cohort study included 119 consecutive patients treated with A-RT between June 2016 and February 2019 and enrolled in a prospectively maintained database. Patients were treated with a standardized technique within a large academic cancer center regional network. All patients with localized, unresectable, or medically inoperable pancreatic cancer with tumors of any size and less than 5 cm luminal abutment with the primary tumor were eligible. Interventions Ablative RT (98 Gy biologically effective dose) was delivered using standard equipment. Respiratory gating, soft tissue image guidance, and selective adaptive planning were used to address organ motion and limit the dose to surrounding luminal organs. Main outcomes and measures The primary outcome was overall survival (OS). Secondary outcomes included incidence of local progression and progression-free survival. Results Between 2016 and 2019, 119 patients (59 men, median age 67 years) received A-RT, including 99 with T3/T4 and 53 with node-positive disease, with a median carbohydrate antigen 19-9 (CA19-9) level greater than 167 U/mL. Most (116 [97.5%]) received induction chemotherapy for a median of 4 months (0.5-18.4). Median OS from diagnosis and A-RT were 26.8 and 18.4 months, respectively. Respective 12- and 24-month OS from A-RT were 74% (95% CI, 66%-83%) and 38% (95% CI, 27%-52%). Twelve- and 24-month cumulative incidence of locoregional failure were 17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, 21.6%-44.1%), respectively. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper gastrointestinal bleeding occurred in 10 patients (8%) with no grade 4 to 5 events. Conclusions and relevance This cohort study of patients with inoperable LAPC found that A-RT following multiagent induction therapy for LAPC was associated with durable locoregional tumor control and favorable survival. Prospective randomized trials in patients with LAPC are warranted.

140 Background: Online cancer patient and caregiver support groups have burgeoned in the recent years; many provide critical emotional support and experiential wisdom to newly diagnosed patients. We outline below our experience engaging patients in clinical trial design working with COLONTOWN, a 5000+ member, online colorectal cancer (CRC) patient and caregiver support and educational community. Effective trial design is a complicated and lengthy process that requires input from multiple sources. Complex trial design can be particularly challenging, where opinions are mixed and a clear path forward may not be visible. Informed patient perspectives from support groups can be invaluable in such situations. Methods: Principal Investigators (PIs) for the oligometastatic CRC ERASure trial and the Janus rectal cancer trial worked with the lead author, a patient who is the Scientific Director of COLONTOWN. An interactive survey strategy was adopted and followed to solicit group feedback. COLONTOWN members (n = 70-120) were enthusiastic to participate and share the logic behind poll choices, and their personal experiences. Poll participation led to additional scientific discussion and improved community engagement around the survey questions. Poll data and highlights of the discussion were collected and passed on to study PIs in a de-identified manner. Results: Feedback from COLONTOWN helped PIs gauge patient enthusiasm for trial concepts and provide patient perspective and clarity to controversial questions in study design. This was particularly useful where data to support more than one option was available and the guidance from the NCI Task Force or cooperative group was split. The perspective from COLONTOWN was invaluable and used alongside NCI Task Force and cooperative group feedback to make decisions to move the trial concept forward. Conclusions: Support groups such as COLONTOWN are a versatile, valuable, underutilized and available resource that can be used to tap into patient perspectives during any clinical trial design process. Ideally, when utilized early, structured patient input can provide unique insights to PIs developing clinical trial concepts that could eliminate barriers and shorten the inception part of trial design. Increased awareness and knowledge of trial design support provided by such cancer communities could facilitate the development of patient-friendly trials to promote better accrual.

Summary Objectives Patients treated with definitive chemoradiation for oropharyngeal squamous cell carcinoma (OPC) experience excellent outcomes but treatment toxicities remain significant. The adoption of intensity modulated radiation therapy (IMRT) reduced morbidity by allowing targeting of at risk areas while sparing uninvolved regions. We explored whether level V lymphatics (LVN) can be omitted from elective volumes in OPC. Materials and methods This analysis included 408 patients treated for stage III/IV OPC with IMRT at our institution. For 295 (72.3%) patients, bilateral LVN were covered, while LVN were omitted in 113 (27.7%). Nodal staging was N2a or greater in 324 patients (79.4%). All but one received concurrent chemotherapy. Actuarial regional recurrence was calculated using the KM method with the event of interest defined as any regional recurrence; all others were censored. Univariate and multivariate analyses were performed on variables significantly associated with both the inclusion of elective LVN and regional recurrence. Results After a median follow-up of 63.6 months (range, 1.3–125 months), there were no level V failures in either group. The 2-year cumulative rate of regional failure (RF) was 4.5% (95% CI = 2.9–6.6) in the overall cohort, 2.2% (95% CI = 0.1–5.9) in the LVN untreated group, and 5.4% (95% CI = 3.4–8.1) in the LVN treated group. After adjusting for Stage and tobacco status, there was no significant difference between the two groups in RF (HR = 1.75 95% CI = (0.61–5.07), p = 0.30). Conclusion LVN can be safely omitted from the clinical target volume in locally advanced OPC without gross LVN involvement.

As proton beam radiation therapy (PBRT) may allow greater normal tissue sparing when compared with intensity-modulated radiation therapy (IMRT), we compared the dosimetry and treatment-related toxicities between patients treated to the ipsilateral head and neck with either PBRT or IMRT.Between 01/2011 and 03/2014, 41 consecutive patients underwent ipsilateral irradiation for major salivary gland cancer or cutaneous squamous cell carcinoma. The availability of PBRT, during this period, resulted in an immediate shift in practice from IMRT to PBRT, without any change in target delineation. Acute toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.Twenty-three (56.1%) patients were treated with IMRT and 18 (43.9%) with PBRT. The groups were balanced in terms of baseline, treatment, and target volume characteristics. IMRT plans had a greater median maximum brainstem (29.7 Gy vs. 0.62 Gy (RBE), ​P0.001), maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), ​P0.001), mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), ​P0.001), mean contralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P0.001), and mean contralateral submandibular (4.1 Gy vs. 0.0 Gy (RBE), ​P0.001) dose when compared to PBRT plans. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia (5.6% vs. 65.2%, P0.001), mucositis (16.7% vs. 52.2%, P=0.019), and nausea (11.1% vs. 56.5%, P=0.003).The unique properties of PBRT allow greater normal tissue sparing without sacrificing target coverage when irradiating the ipsilateral head and neck. This dosimetric advantage seemingly translates into lower rates of acute treatment-related toxicity.

We provide a comprehensive analysis of anatomical patterns of recurrence following external beam radiotherapy in patients with localized prostate cancer.This retrospective analysis included 2,694 patients with localized prostate cancer who received definitive, dose escalated external beam radiotherapy from 1991 to 2008. First recurrence sites were defined as initial sites of clinically detected recurrence and any subsequent clinically detected recurrence within 3 months. Anatomical recurrence patterns were classified as local (prostate/seminal vesicles only), lymphotropic (lymph nodes only) and osteotropic (bones only) in patients with disease confined only to these respective sites for at least 2 years from the initial clinically detected recurrence.Prostate was the most common first recurrence site in the low, intermediate and high risk groups with an 8-year cumulative incidence of 3.5%, 9.8% and 14.6%, respectively. The 8-year risk of isolated pelvic lymph node relapse as the first recurrence site was 0%, 1.0% and 3.3%, respectively. In the 474 patients with clinically detected recurrence the most common first recurrence site was local in 55.3%, bone in 33.5%, pelvic lymph nodes in 21.3% and abdominal lymph nodes in 9.1%. Patients showed unique relapse distributions, including a pattern that was local in 41.6%, lymphotropic in 9.7%, osteotropic in 20.3% and multiorgan/visceral in 28.5%. Anatomical recurrence pattern was the strongest predictor of prostate cancer specific mortality on multivariate analysis of patients with clinically detected recurrence.The most common first recurrence site after dose escalated external beam radiotherapy for prostate cancer is in the prostate and seminal vesicles in all risk groups. In contrast, patients treated without elective pelvic lymph node irradiation are at relatively low risk for isolated pelvic lymph node relapse. Recurrence patterns revealed a tropism for specific anatomical distributions with divergent prognoses, suggesting underlying biological differences among tumors.

Background: KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, poor drug delivery, immunosuppression, and de novo resistance to chemo- and immunotherapies. Recently, we demonstrated that a combination of MEK and CDK4/6 inhibitors can potently suppress PDAC tumor cell proliferation through induction of RB-mediated senescence and trigger a senescence-associated secretory phenotype (SASP) capable of remodeling the tumor microenvironment (TME) (Ruscetti et al., Science 2018). Here, we set out to explore how senescence induction could remodel the PDAC TME and alter the treatment landscape of this disease. Methods: The Pdx1-Cre;LSL-KRASG12D;Trp53fl/wt (KPC) genetically engineered mouse model (GEMM) of PDAC, as well as immunocompetent C57BL/6 mice transplanted with PDAC organoids derived from this model, were treated for 2 weeks with the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib. Induction of senescence was determined by SA-β-gal staining, and secretion of SASP factors was determined by qPCR and cytokine array. The impact on vascularization and vascular function, as well as the immune system, was determined by immunohistochemistry and flow cytometry analysis. shRNAs targeting the p65 subunit of NF-KB were used to assess the effect of SASP knockdown on treatment responses, and high doses of a VEGFR2 blocking antibody were used to assess the effects of inhibiting neovascularization on these SASP-dependent phenotypes. Trametinib and palbociclib treatment was combined with the chemotherapeutic agent gemcitabine or PD-1 checkpoint blockade immunotherapy to study the impact on tumor responses and long-term survival of PDAC tumor-bearing animals. Results: We find that therapy-induced senescence following trametinib and palbociclib treatment produces a SASP rich in proangiogenic factors, culminating in increased vascular density and perfusion in hypovascular PDAC tumors. This SASP-dependent vascular remodeling leads to enhanced drug uptake of the chemotherapeutic agent gemcitabine, and combining our senescence-inducing therapy with gemcitabine drives tumor regressions and prolonged survival in gemcitabine-refractory PDAC GEMMs and PDXs. In addition, increased antigen presentation and SASP-mediated vascular remodeling upon treatment mediates CD8+ T cell accumulation and activation within the PDAC TME, sensitizing these tumors to PD-1 checkpoint blockade. Conclusions: These results demonstrate that therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies in PDAC through SASP-dependent, non-cell autonomous effects on the tumor vasculature and immune system. This abstract is also being presented as Poster A46. Citation Format: Marcus Ruscetti, John P. Morris, IV, Riccardo Mezzadra, James Russell, Josef Leibold, Paul B. Romesser, Janelle Simon, Amanda Kulick, Yu-jui Ho, Myles Fennell, Jinyang Li, Robert J. Norgard, John E. Wilkinson, Direna Alonso-Curbelo, Ramya Sridharan, Xiang Li, Daniel Heller, Elisa de Stanchina, Ben Z. Stanger, Charles J. Sherr, Scott W. Lowe. Senescence induction triggers vascular remodeling and new vulnerabilities to chemo- and immunotherapy in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR01.

OBJECTIVES: Occult primary non-small cell lung cancer (OP-NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation, with little known about how outcomes compare to typical Stage III NSCLC. We reviewed our experience treating OP-SCLC with definitive radiotherapy and compared outcomes to a contemporary cohort of stage III NSCLC patients. MATERIALS AND METHODS: We reviewed 605 patients with stage III NSCLC staged with PET-CT and treated with definitive radiotherapy between 1998 and 2013. Overall survival, intrathoracic control, and freedom from distant metastasis were computed using Kaplan-Meier method and logrank comparison. Cox hazard ratios were used to perform univariate and multivariate analyses. RESULTS: Twenty-one patients were identified with OP-NSCLC (3.5%). Patients with OP-NSCLC, as compared to known primary NSCLC, had significantly better 5-year rates of intrathoracic control (83.5% vs. 24.2%, P

Small molecules spark NK cell responseImmunotherapy is a powerful treatment for certain cancers. Yet for those patients that do not respond, simultaneous strategies that mobilize the immune system and directly target malignant cells may be more effective. Ruscettiet al.report that combining two clinically approved cancer drugs promoted immune surveillance and killing of KRAS-mutant lung tumors in mice (see the Perspective by Cornen and Vivier). The two small molecules—a mitogen-activated protein kinase inhibitor and a cyclin-dependent kinase 4/6 inhibitor—induced natural killer (NK) cell recruitment and elimination of senescent lung cancer cells, which did not occur when either agent was used alone.Science, this issue p.1416; see also p.1355

Background The purpose of this study was to evaluate how gross tumor volume (GTV) affects treatment outcome among different race/ethnic groups in patients with head and neck cancer receiving definitive radiotherapy (RT). Methods Ninety-one patients with head and neck cancer were treated to a median RT dose of 69.96 Gy in 33 fractions. The patient's self-reported race/ethnicity, primary tumor, and nodal GTV were obtained. Two-year actuarial local, nodal, and distant control, and overall and disease-free survival were calculated. Results The patients were categorized as white (n = 43) or non-white (n = 48), which included 29 African Americans, 11 Hispanics, 5 Asians, and 3 others. The mean primary GTV was 21.0 cc and 39.9 cc for whites and non-whites, respectively (p = .011). White patients reported improved overall survival of 85.4% compared to non-whites (65.8%; p = .006). Improvements in local and nodal control and disease-free survival rates were also observed. Conclusion White patients demonstrated improved treatment outcomes compared with non-whites, which may be reflective of tumor volume. © 2014 Wiley Periodicals, Inc. Head Neck, 2015

The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting.We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT.This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients.All patients received EBRT at doses of 75.6-86.4 Gy.The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer-specific mortality (PCSM).From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions.Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF.In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.

Salivary gland malignancies are uncommon, representing 1–6% of head and neck malignancies and 0.3% of all cancers (55% occur in parotid gland, 30% in submandibular gland, 10–15% in the sublingual and minor salivary glands). The majority of salivary gland tumors are primarily managed surgically followed by radiation ± chemotherapy. Indications for postoperative radiation include intermediate-/high-grade tumor, close/positive margins, lymph node metastases, and lymphovascular invasion as well as T3/T4 tumors or recurrent disease in some circumstances. The role of postoperative chemoradiation for high-risk salivary tumors is currently the subject of the ongoing RTOG 10-08 trial (NCT01220583). Unresectable cases are often managed with radiation therapy, preferably with concurrent systemic therapy.

BACKGROUND Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT). METHODS During 1991–2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (