Christopher L. Hallemeier

Preoperative CA 19-9 level is an important prognostic factor in patients with pancreatic adenocarcinoma treated with surgical resection and adjuvant concurrent chemoradiotherapy.

ObjectivesTo evaluate preoperative CA 19-9 level as a prognostic factor in patients with resected adenocarcinoma of the pancreas. MethodsWe retrospectively reviewed the cases of consecutive patients with pancreatic adenocarcinoma who had CA 19-9 measured preoperatively and underwent potentially curative resection at Mayo Clinic from September 1995 to January 2005. Patients who died within 30 days of resection were excluded. ResultsSearch of our database identified 226 consecutive patients who met all the inclusion criteria. Adjuvant therapy was concurrent chemoradiotherapy (CCRT) in 122 patients, CCRT followed by chemotherapy in 23 patients, chemotherapy alone in 6 patients, and none in 69 patients. Median follow-up for surviving patients was 2.1 years. Median survival in all patients was 1.6 years. Patients with a high preoperative CA 19-9 level (defined as ≥180 U/mL) had a greater chance of having pathologic T3-T4 disease (P=0.03), positive lymph nodes (P=0.01), and histologic grade 3 or 4 (P=0.02). In multivariate analysis, a high preoperative CA 19-9 level (P=0.006) and R1-R2 margin status (P=0.03) were associated with decreased survival. Overall survival was increased for patients who received adjuvant CCRT (vs. those who did not; P=0.002) and for patients with high preoperative CA 19-9 level who received adjuvant CCRT (vs. those who did not; P<0.001). ConclusionsIn patients with resected adenocarcinoma of the pancreas, high preoperative CA 19-9 level was associated with adverse pathologic features and poorer survival. Adjuvant CCRT was associated with a significant survival benefit in patients with high preoperative CA 19-9 but not in those with low CA 19-9.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early‐stage non–small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single‐institution reports. The current multi‐institutional study reported outcomes evaluating the largest such population reported to date.

Outcomes in a Multi-institutional Cohort of Patients Treated With Intraoperative Radiation Therapy for Advanced or Recurrent Renal Cell Carcinoma

PURPOSE/OBJECTIVE(S) This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). METHODS AND MATERIALS Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. RESULTS IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. CONCLUSIONS We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma.

PURPOSE To report the outcomes in patients with recurrent or unresectable pilocytic astrocytoma (PA) treated with Gamma Knife stereotactic radiosurgery (SRS). METHODS AND MATERIALS Retrospective review of 18 patients (20 lesions) with biopsy-confirmed PA having SRS at our institution from 1992 through 2005. RESULTS The median patient age at SRS was 23 years (range, 4-56). Thirteen patients (72%) had undergone one or more previous surgical resections, and 10 (56%) had previously received external-beam radiation therapy (EBRT). The median SRS treatment volume was 9.1 cm(3) (range, 0.7-26.7). The median tumor margin dose was 15 Gy (range, 12-20). The median follow-up was 8.0 years (range, 0.5-15). Overall survival at 1, 5, and 10 years after SRS was 94%, 71%, and 71%, respectively. Tumor progression (local solid progression, n = 4; local solid progression + distant, n = 1; distant, n = 2; cyst development/progression, n = 4) was noted in 11 patients (61%). Progression-free survival at 1, 5, and 10 years was 65%, 41%, and 17%, respectively. Prior EBRT was associated with inferior overall survival (5-year risk, 100% vs. 50%, p = 0.03) and progression-free survival (5-year risk, 71% vs. 20%, p = 0.008). Nine of 11 patients with tumor-related symptoms improved after SRS. Symptomatic edema after SRS occurred in 8 patients (44%), which resolved with short-term corticosteroid therapy in the majority of those without early disease progression. CONCLUSIONS SRS has low permanent radiation-related morbidity and durable local tumor control, making it a meaningful treatment option for patients with recurrent or unresectable PA in whom surgery and/or EBRT has failed.

Long-term outcomes after maximal surgical resection and intraoperative electron radiotherapy for locoregionally recurrent or locoregionally advanced primary renal cell carcinoma.

PURPOSE To report outcomes of a multimodality therapy combining maximal surgical resection and intraoperative electron radiotherapy (IOERT) for patients with locoregionally (LR) recurrent renal cell carcinoma (RCC) after radical nephrectomy or LR advanced primary RCC. METHODS AND MATERIALS From 1989 through 2005, a total of 22 patients with LR recurrent (n = 19) or LR advanced primary (n = 3) RCC were treated with this multimodality approach. The median patient age was 63 years (range 46-78). Twenty-one patients (95%) received perioperative external beam radiotherapy (EBRT) with a median dose of 4,500 cGy (range, 4,140-5,500). Surgical resection was R0 (negative margins) in 5 patients (23%) and R1 (residual microscopic disease) in 17 patients (77%). The median IOERT dose delivered was 1,250 cGy (range, 1,000-2,000). Overall survival (OS) and disease-free survival (DFS) and relapse patterns were estimated using the Kaplan-Meier method. RESULTS The median follow-up for surviving patients was 9.9 years (range, 3.6-20 years). The OS and DFS at 1, 5, and 10 years were 91%, 40%, and 35% and 64%, 31%, and 31%, respectively. Central recurrence (within the IOERT field), LR relapse (tumor bed or regional lymph nodes), and distant metastases at 5 years were 9%, 27%, and 64%, respectively. Mortality within 30 days of surgery and IOERT was 0%. Five patients (23%) experienced acute or late National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) Version 4 Grade 3 to 5 toxicities. CONCLUSIONS In patients with LR recurrent or LR advanced primary RCC, a multimodality approach of perioperative EBRT, maximal surgical resection, and IOERT yielded encouraging results. This regimen warrants further investigation.

Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma.

BACKGROUND AND AIM Selected patients with unresectable perihilar cholangiocarcinoma can undergo neoadjuvant chemoradiotherapy followed by liver transplantation, which has been shown to improve survival. The aim of this study was to determine the feasibility and safety of endoscopic transpapillary insertion of nasobiliary tubes (NBTs) and brachytherapy catheters for high dose-rate (HDR) brachytherapy as part of this neoadjuvant chemoradiotherapy. PATIENTS AND METHODS Medical records of patients undergoing biliary brachytherapy for hilar cholangiocarcinoma at the Mayo Clinic, Rochester were reviewed. Patients were treated with curative intent using external beam radiotherapy (4500 cGy), chemotherapy (5-FU or capecitabine), and HDR brachytherapy (930 - 1600 cGy in one to four fractions delivered over 1 - 2 days) prior to planned liver transplantation. RESULTS Between 2009 and 2013, 40 patients underwent biliary HDR brachytherapy via endoscopically placed NBTs (8.5 - 10 Fr). Patients had a median age of 55 years (range 28 - 68); 25 patients (62.5 %) had primary sclerosing cholangitis. Prior to therapy, 29 patients (72.5 %) had plastic stents, two (5 %) had metal stents, and nine (22.5 %) had no stents. Bilateral NBTs were placed in five patients (12.5 %). NBT/brachytherapy catheter displacement was seen in eight patients (20 %) - five intraprocedure and three post-procedure. A radiotherapy error and NBT kinking each occurred once. Post-procedure adverse events included: cholangitis (n = 5; 12.5 %), severe abdominal pain (n = 3; 7.5 %), duodenopathy (n = 3; 7.5 %), gastropathy (n = 3; 7.5 %), and both duodenopathy and gastropathy (n = 2; 5 %). CONCLUSION HDR biliary brachytherapy administered via endoscopically placed NBTs and brachytherapy catheters is technically feasible and appears reasonably safe in selected patients with unresectable perihilar cholangiocarcinoma.

Multimodality therapy including salvage surgical resection and intraoperative radiotherapy for patients with squamous-cell carcinoma of the anus with residual or recurrent disease after primary chemoradiotherapy

BACKGROUND: For patients with residual or recurrent squamous-cell carcinoma of the anus after primary chemoradiotherapy, the standard treatment is surgical salvage. Patients with unresectable or borderline unresectable disease have poor outcomes, thus adjunctive treatments should be explored. OBJECTIVE: The aim of this study is to report outcomes for patients with residual/recurrent anal cancer treated with multimodality therapy including salvage surgical resection and intraoperative radiotherapy. DESIGN: This is an observational study. SETTINGS: This study was conducted at a tertiary referral center. PATIENTS: Thirty-two patients were treated between 1993 and 2012. Median age was 53 years (range, 34–87). Salvage treatment was performed for residual disease (n = 9), first recurrence (n = 17), or second recurrence (n =6) after primary chemoradiotherapy. INTERVENTIONS: Patients with recurrent disease received preoperative external beam reirradiation with concurrent chemotherapy. All patients underwent salvage surgical resection and intraoperative radiotherapy. Extent of surgical resection was R0 (negative margins, n = 16), R1 (microscopic residual, n = 13), or R2 (macroscopic residual, n = 3). The median intraoperative radiotherapy dose was 12.5 Gy. MAIN OUTCOME MEASURES: Treatment-related adverse events were classified according to the National Cancer Institute – Common Toxicity Criteria. Overall and disease-free survival were estimated by using the Kaplan-Meier technique. Central, local-regional, and distant failure were estimated by the use of the cumulative incidence method. RESULTS: Median length of hospital stay was 9 days. Mortality at 30 days after surgery and intraoperative radiotherapy was 0%. Fifteen patients (47%) experienced a total of 16 grade 3 treatment-related adverse events (wound complication (n = 6), bowel obstruction (n = 5), and ureteral obstruction (n = 3)). The 5-year estimates of overall and disease-free survival were 23% and 17%. The 5-year estimates of central, local-regional, and distant failure were 21%, 51%, and 40%. LIMITATIONS: This was a single-institution observational study with limited patient numbers. CONCLUSIONS: In this heavily pretreated, high-risk patient population, multimodality therapy including salvage surgery and intraoperative radiotherapy was associated with long-term survival in a small, but significant subset of patients.

Scanning proton beam therapy reduces normal tissue exposure in pelvic radiotherapy for anal cancer

An inter-comparison planning study between photon beam therapy (IMRT) and scanning proton beam therapy (SPBT) for squamous cell carcinoma of the anus (SCCA) is presented. SPBT plans offer significant reduction (>50%, P=0.008) in doses to small bowel, and bone marrow thereby offering the potential to reduce bowel and hemotoxicities.