Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer.

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC. Statement of significance: This study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy.

Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I Interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy.

Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8 + T cells. This signature was dependent on radiation-induced increases of Type I interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

Radiation Therapy Exacerbates Tumor-Promoting Innervation and Nerve Signaling in Rectal Cancer.

PURPOSE: Many solid tumors present with perineural invasion (PNI), and innervation correlates with worsened prognosis. The effects that commonly administered therapies such as radiation therapy (RT) have on PNI status remain unknown. We investigated the contribution of RT on the nervous system and elucidated the implications that increased nerve signaling can have on tumor burden using our previously developed orthotopic murine model of rectal cancer (RC) and our targeted and clinically relevant short-course RT (SCRT) regimen. METHODS: Medical charts for patients with RC treated at the Wilmot Cancer Institute were obtained and PNI status was analyzed. Human data were accompanied by an orthotopic murine model of RC. Briefly, luciferase-expressing murine colon-38 (MC38-luc) tumor cells were injected orthotopically into the rectal wall of C57BL6 mice. Targeted SCRT (5 gray (Gy) per fraction for 5 consecutive fractions) was administered to the tumor. Intratumoral innervation was determined by immunohistochemistry (IHC), local norepinephrine (NE) concentration was quantified by enzyme-linked immunosorbent assay (ELISA), and ß2-adrenergic receptor (B2AR) expression was assessed by flow cytometry. Chronic NE signaling was mirrored by daily isoproterenol treatment, and the effect on tumor burden was determined by overall survival, presence of metastatic lesions, and tumor size. Isoproterenol signaling was inhibited by administration of propranolol. RESULTS: Human RC patients with PNI have decreased overall survival compared with patients without PNI. In our mouse model, SCRT induced the expression of genes involved in neurogenesis, increased local NE secretion, and upregulated B2AR expression. Treating mice with isoproterenol resulted in decreased overall survival, increased rate of metastasis, and reduced SCRT efficacy. Interestingly, the isoproterenol-induced decrease in SCRT efficacy could be abrogated by blocking the BAR through the use of propranolol, suggesting a direct role of BAR stimulation on impairing SCRT responses. CONCLUSIONS: Our results indicate that while SCRT is a valuable treatment, it is accompanied by adverse effects on the nervous system that may impede the efficacy of therapy and promote tumor burden. Therefore, we could speculate that therapies aimed at targeting this signaling cascade or impairing nerve growth in combination with SCRT may prove beneficial in future cancer treatment.

Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy.

PURPOSE: Orthotopic tumors more closely recapitulate human cancers than do ectopic models; however, precision targeting of such internal tumors for radiation therapy (RT) without inducing systemic toxicity remains a barrier. We developed an innovative murine orthotopic rectal tumor model where the insertion of clinical grade titanium fiducial clips on opposing sides of the rectal tumor allowed for targeted administration of short-course radiation therapy (SCRT). With this novel approach, clinically relevant RT regimens can be administered to orthotopic tumors to explore the biology and efficacy of radiation alone or as a combination therapy in a murine model that closely recapitulates human disease. METHODS AND MATERIALS: Murine Colon 38-luciferase tumor cells were injected into the rectal wall of syngeneic mice, and fiducial clips were applied to demarcate the tumor. An SCRT regimen consisting of 5 consecutive daily doses of 5 Gy delivered by an image-guided conformal small animal irradiator was administered 9 days after implantation. Tumor burden and survival were monitored along with histological and flow cytometric analyses on irradiated versus untreated tumors at various time points. RESULTS: SCRT administered to orthotopic rectal tumors resulted in a reduction in tumor burden and enhanced overall survival with no apparent signs of systemic toxicity. This treatment paradigm resulted in significant reductions in tumor cellularity and increases in fibrosis and hyaluronic acid production, recapitulating the SCRT-induced effects observed in human cancers. CONCLUSIONS: We have established a means to target murine orthotopic rectal tumors using fiducial markers with a fractionated and clinically relevant SCRT schedule that results in an RT response similar to what is observed in human rectal cancer. We also validated our model through examining various parameters associated with human cancer that are influenced by irradiation. This model can be used to further explore RT doses and scheduling, and to test combinatorial therapies.

Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy.

PURPOSE: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy. EXPERIMENTAL DESIGN: Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq). RESULTS: Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires. CONCLUSIONS: These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.

Oligoprogression in non-small cell lung cancer: a narrative review.

Background and Objective: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and is the most common non-cutaneous cancer world-wide. In NSCLC, oligometastatic and oligoprogressive disease (OPD) have been recognized as separate entities within the realm of metastatic disease and are emerging concepts in the context of targeted systemic therapies. Our objectives are to discuss the current literature regarding the evolving definitions of OPD in the context of oligometastatic disease (OMD) for NSCLC. Further, to discuss current and future clinical trials that have shaped our local approach with stereotactic body radiation therapy (SBRT)/stereotactic ablative radiotherapy (SABR). Methods: Literature on OPD in NSCLC and local ablative therapy (LAT) including SBRT/SABR and stereotactic radiosurgery (SRS) was reviewed. Key Content and Findings: Oligoprogression is defined as limited (usually 3-5) metastatic areas progressing while on/off systemic therapy in the background of oligometastatic or polymetastatic disease. Prognosis in OPD with treatment (such as LAT and systemic therapy) may be more favorable. Outcomes for patients progressing on tyrosine kinase inhibitors (TKIs) with molecular mutations [such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)] who receive LAT are promising. Conclusions: Patients presenting with NSCLC metastasis with progression at a limited number of sites on/off a given line of systemic therapy may have favorable outcomes with aggressive LAT, which includes SBRT/SABR/SRS. Further studies need to be completed to further optimize treatment recommendations.

Coadministration of a Clinically Relevant Dexamethasone Dosage With Ablative Radiation Therapy Reduces Peripheral Lymphocytes But Does Not Alter In Vivo Intratumoral Lymphocyte Phenotype or Inhibit Efficacy of Radiation Therapy in a Murine Colorectal Tumor Model.

PURPOSE: Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse. METHODS AND MATERIALS: Intramuscularly implanted MC38 tumors were irradiated with 15 Gy after establishing for 7 days. Tumor bearing mice were administered dexamethasone using multiple schedules and doses. Peripheral lymphocyte reduction was monitored by complete blood count and intratumoral and tumor draining lymph node (tdLN) populations by flow cytometry. Effector phenotype and function of ex vivo stimulated tumor-infiltrating lymphocytes (TILs) and naïve splenocytes as well as in vivo TILs with or without dexamethasone were monitored by flow cytometry and ELISA. RESULTS: Long course high dose, short course high dose, and short course human equivalent dose dexamethasone reduced peripheral lymphocytes yet did not inhibit survival after irradiation. Short course high dose administration decreased TIL and tdLN lymphocyte activation as well as tdLN mass but did not affect TIL frequencies or change tdLN cell population composition. Dexamethasone inhibited effector function of ex vivo stimulated naïve splenocytes and TILs, but magnitude of IFN-γ secretion was consistently higher in TILs regardless of dexamethasone dose. In vivo analysis of TILs after irradiation and HE dexamethasone treatment showed that TILs had a similar effector phenotype compared with vehicle controls. CONCLUSIONS: Dexamethasone reduces blood and tdLN lymphocytes. Dexamethasone also suppresses TIL activation/effector function yet does not affect survival in irradiated MC38 tumor bearing mice, which depend on RT-induced immune responses for therapy efficacy. Additional study in human subjects is warranted.

Erratum: Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

[This corrects the article DOI: 10.3892/mco.2020.2196.].

Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive cancer that typically presents in the lung. The current case report describes a 56 year old male who presented to Strong Memorial Hospital with progressive dyspnea and was revealed to have a large anterior mediastinal tumor with metastases to axillary, hilar and mediastinal lymph nodes. Tumor marker results revealed an elevated plasma level of α-fetoprotein (AFP), which initially pointed towards a diagnosis of teratoma, but the tumor stained positive for neuroendocrine markers CD56, chromogranin, and synaptophysin on biopsy, consistent with LCNEC. AFP-positive tumor cells were identified, and no alternate cause for the elevated AFP was identified. The patient underwent genetic testing revealing the tumor to be ALK, ROS1, KRAS, BRAF and EGFR wild type. The patient received 6 cycles of chemotherapy with cisplatin (80 mg/m2) and etoposide (100 mg/m2) and then radiation with an initial minor response. The patients course was complicated by the development of superior vena cava syndrome requiring emergency stenting. The results of the current case suggest that AFP may be worthy of further exploration as a potential tumor marker in LCNEC.

Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis.

AIM: Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC). METHODS: From the Surveillance, Epidemiology and End Results registry, patients with pathologically confirmed T1-3N0 NSCLC were identified. Risks of brain metastases at time of initial diagnosis were analyzed. RESULTS: Patients selected to not undergo primary NSCLC resection had approximately tenfold greater incidence of brain metastases versus those who did. Younger age, adenocarcinoma histology, higher tumor stage and higher histologic grade were all significantly (p < 0.0001) associated with greater likelihood of presenting with brain metastases. CONCLUSION: Given the morbidity and mortality of brain metastases, routine brain screening after NSCLC diagnosis (particularly adenocarcinoma) may be justifiable, though more refined cost-benefit analyses are warranted.

Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment.

Over 80% of pancreatic ductal adenocarcinoma (PDA) patients are diagnosed with non-resectable late-stage disease that lacks effective neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) has shown promise as an emerging neoadjuvant approach for treating PDA, and here, we report that its combination with local interleukin-12 (IL-12) microsphere (MS) immunotherapy results in marked tumor reduction and cures in multiple preclinical mouse models of PDA. Our findings demonstrate an increase of intratumoral interferon gamma (IFNγ) production following SBRT/IL-12 MS administration that initiates suppressor cell reprogramming and a subsequent increase in CD8 T cell activation. Furthermore, SBRT/IL-12 MS therapy results in the generation of systemic tumor immunity that is capable of eliminating established liver metastases, providing a rationale for follow-up studies in advanced metastatic disease.

Stereotactic body radiotherapy in patients with multiple lung tumors: a focus on lung dosimetric constraints.

Introduction: Lung dosimetric constraints with stereotactic body/ablative radiotherapy (SBRT/SABR) for multiple lung lesions are not well-characterized in published literature. Classically, the lung is considered a 'parallel' organ, for which injury to functional subunits could result in partially compromised function of that organ/tissue. Therefore, with SBRT/SABR for >1 thoracic target (especially involving both lungs), lung dosimetry requires special consideration.Areas covered: Current cooperative group and multi-institutional studies of SBRT/SABR for oligometastases rely on lung constraints from expert opinion, including constraints of exposure (i.e., volume of lung receiving more than a threshold dose or mean lung dose) and/or critical volume (i.e. volume of lung receiving less than a threshold dose; also termed complementary volume). For radiation pneumonitis, which reflects inflammatory lung injury, it remains unclear which type of constraint is more predictive of toxicity risks.Expert opinion: With SBRT/SABR for multiple lung lesions, it is prudent to use both exposure and critical volume constraints. Treatment on alternate days (for radiation plans with separate treatment fields) or staging treatment may also lower lung toxicity risks. Further study on lung normal tissue complication probability in the setting of multiple lung targets is urgently needed, particularly analyses of critical volume metrics, which are relatively poorly studied.

Stereotactic Body Radiotherapy for Lung Metastases from Colorectal Cancer: Prognostic Factors for Disease Control and Survival.

OBJECTIVES: To evaluate disease control and survival after stereotactic body radiotherapy (SBRT) for lung metastases from colorectal cancer and to identify prognostic factors after treatment. METHODS: Patients with metastatic colorectal cancer to the lungs treated with SBRT from 2002 to 2013 were identified from a prospectively maintained database. Patients may have received prior systemic therapy, radiotherapy to nonthoracic sites and/or resection of thoracic and/or nonthoracic metastases. Endpoints were timed from end of SBRT and included overall survival (OS), progression-free survival, distant metastases-free survival, and local failure-free survival. Univariate and multivariate analysis using Cox proportional hazard modeling was used to identify prognostic factors. RESULTS: Sixty-five patients were identified. Before SBRT, 69.2% and 33.8% of patients received systemic therapy and lung-directed local therapy, respectively, for metastatic disease. At the time of SBRT, 64.6% had lung-only involvement. Median survivals were: OS of 20.3 months (95% confidence intervals [CI], 15.9-27.0 mo), progression-free survival of 5.7 months (95% CI, 3.2-7.0 mo), distant metastases-free survival of 5.8 months (95% CI, 3.2-7.6 mo), and local failure-free survival of 15.4 months (95% CI, 8.5-21.1 mo). Nearly all (98%) patients developed distant progression. Extra lung and liver involvement at the time of initial metastases (hazard ratios [HR] 2.10) and extra lung involvement at SBRT (HR 2.67) were the only independent predictors of OS. Net gross target volume of >14.1 mL (HR 2.49) was the only independent predictor of local failure-free survival. CONCLUSIONS: Reasonable survival and local control can be achieved with SBRT. We identified several prognostic factors testable in future prospective trials that may help improve patient selection.

SBRT for Hepatocellular Carcinoma: 8-Year Experience from a Regional Transplant Center.

PURPOSE: The study aimed to evaluate stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) in patients not eligible for liver transplant (LT). METHODS: We retrospectively identified transplant-ineligible HCC patients treated with SBRT to the liver between 2004 and 2013. Our primary endpoint was overall survival (OS). We also report treatment toxicities using CTCAE 3.0, radiographic response, and patterns of failure. RESULTS: We identified 93 patients with median age at SBRT of 65.8 years. Forty-six percent were classified as Child-Pugh B or C and 85% had an Eastern Cooperative Oncology Group performance status of 1-2. After SBRT, 86% of patients experienced no or mild treatment-related adverse events. Only 8% of patients experienced grade 3 and 2% of patients experienced grade 4 adverse events. Overall radiographic response was complete in 1.2%, partial in 35.4%, stable in 43.9%, and progressive disease in 19.5%. Median OS was 8.8 months with 1-, 2-, and 3-year OS rates of 38.0, 29.8 and 21.2%, respectively. The Cancer of the Liver Italian Program (CLIP) score was found to strongly correlate with survival. Median OS for patients with CLIP scores of 0, 1, 2, and 3 was 21.1, 8.5, 5.1, and 7.1 months, respectively (p = 0.003). CONCLUSION: Our series demonstrates that SBRT is generally safe for HCC patients, even those with advanced liver failure. Although survival is generally poor, we were able to identify a group of patients with good liver function and early tumor stage who can achieve median OS of close to 2 years with SBRT.

Comparison of outcomes between SBRT, yttrium-90 radioembolization, transarterial chemoembolization, and radiofrequency ablation as bridge to transplant for hepatocellular carcinoma.

PURPOSE: To evaluate and compare outcome of stereotactic body radiation therapy (SBRT), yttrium-90 radioembolization, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE) as bridge to liver transplant (LT) in patients with hepatocellular carcinoma. METHODS AND MATERIALS: We retrospectively reviewed patients treated at our institution with SBRT, TACE, RFA, or yttrium-90 as bridge to LT between 2006 and 2013. We analyzed radiologic and pathologic response and rate of failure after bridge therapy. Toxicities were reported using Common Terminology Criteria for Adverse Events, 4.0. Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival after LT. RESULTS: Sixty patients with a median age 57.5 years (range, 44-70) met inclusion criteria. Thirty-one patients (50.7%) had hepatitis C cirrhosis, 14 (23%) alcoholic cirrhosis, and 8 (13%) nonalcoholic steatohepatitis cirrhosis. Patients received a total of 79 bridge therapies: SBRT (n = 24), TACE (n = 37), RFA (n = 9), and Y90 (n = 9). Complete response (CR) was 25% for TACE, 8.6% for SBRT, 22% for RFA, and 33% for Y90. Grade 3 or 4 acute toxicity occurred following TACE (n = 4) and RFA (n = 2). Transplant occurred at a median of 7.4 months after bridge therapy. Pathological response among 57 patients was 100% necrosis (n = 23, 40%), >50% necrosis (n = 20, 35%), <50% necrosis (n = 9, 16%), and no necrosis (n = 5, 9%). Pathologic complete response was as follows: SBRT (28.5%), TACE (41%), RFA (60%), Y90 (75%), and multiple modalities (33%). At a median follow-up of 35 months, 7 patients had recurrence after LT. DFS was 85.8% and overall survival was 79% at 5 years. CONCLUSION: All bridge therapies demonstrated good pathological response and DFS after LT. SBRT and Y90 demonstrated significantly less grade ≥3 acute toxicity. Choice of optimal modality depends on tumor size, pretreatment bilirubin level, Child-Pugh status, and patient preference. Such a decision is best made at a multidisciplinary tumor board as is done at our institution.

Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: implications for radiation therapy planning.

BACKGROUND AND PURPOSE: This study seeks to: (a) quantify radiologic-pathologic discrepancy for pancreatic adenocarcinoma by comparing tumor size on conventional computed tomography (C-CT) and 3-dimensional CT (3D-CT) to corresponding pathologic specimens; and (b) to identify clinico-pathologic characteristics predictive of radiologic-pathologic discrepancy to assist radiotherapy planning. MATERIALS AND METHODS: Sixty-three patients with pancreatic adenocarcinoma and preoperative C-CT and volume-rendered 3D-CT imaging within 6 weeks of resection were identified. Maximum tumor diameter (MTD) was measured on pathology, C-CT, and 3D-CT and compared for each patient as well as among different clinico-pathologic subgroups. RESULTS: There was a trend toward C-CT underestimation of MTD compared to final pathology (p=0.08), but no significant difference between 3D-CT MTD and pathology (p=0.54). Pathologic tumor size was significantly underestimated by C-CT in patients with larger pathologic tumor size (>3.0 cm, p=0.0001), smaller tumor size on C-CT (<3.0 cm, p=0.003), higher CA19-9 (>90 U/mL, p=0.008), and location in the pancreatic head (p=0.015). A model for predicting pathologic MTD using C-CT MTD and CA19-9 level was generated. CONCLUSIONS: 3D-CT may allow for more accurate contouring of pancreatic tumors than C-CT. Patients with the above clinico-pathologic characteristics may require expanded margins relative to tumor size estimates on C-CT during radiotherapy planning.

Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer.

Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.