Clinical Oncology

An Update to Changing Patterns of Anal Carcinoma in the United States Objectives: Approximately 8,300 new cases of anal carcinoma will be diagnosed in the United States in 2019. Anal squamous cell carcinoma (SCC) accounts for about 70% of all anal cancers. As cancer prevention and treatments have evolved over time, medical management of human immunodeficiency virus has improved, and sexual behaviors have changed, anal carcinoma incidence rates (IRs) may have also changed. Methods: The 9 oldest Surveillance, Epidemiology, and End Results registries were used to identify and determine IR of carcinoma in situ (CIS) and invasive SCC for 9757 patients below 65 years diagnosed with anal SCC/CIS from 1973 to 2014. Joinpoint regression models identified time points at which incidence trends changed. Results: The incidence of CIS decreased since 2010 (age-adjusted IR annual percent change [APC]: −5.65, 95% CI: −10.0 to −1.1), especially for men (APC: −8.30, 95% CI: −12.6 to −3.8). In contrast, the incidence of SCC increased since 2007 (APC: 2.59, 95% CI: 0.1-5.2). During 2010-2014, men were more likely to present with CIS (incidence rate ratio [IRR]: 3.234, 95% CI: 3.000-3.489) but less likely to present with localized (IRR: 0.827, 95% CI: 0.754-0.906), regional (IRR: 0.603, 95% CI: 0.537-0.676), and distant SCC (IRR: 0.751, 95% CI: 0.615-0.915) compared with women. Conclusions: The previously observed rise in anal SCC/CIS incidence slowed in 2010, largely due to a decline in CIS rates. Patients were more likely to present with CIS than SCC at any stage. Future studies are necessary to determine if this decline in CIS precedes a decline in invasive SCC.

CA 19-9 Response: A Surrogate to Predict Survival in Patients With Metastatic Pancreatic Adenocarcinoma Objective: The objective of this study was to determine the features of carbohydrate antigen (CA) 19-9 decline that correlates best with survival benefit in patients with metastatic pancreatic cancer. Methods: This is a retrospective study of 225 patients with metastatic pancreatic cancer receiving first-line therapy. Analysis was performed by the Kaplan-Meier method and Cox-proportional hazards ratios. CA 19-9 decline was grouped into quartiles within different CA 19-9 baseline groups. Time to nadir and CA 19-9 decline at month-2 (M2) of therapy were evaluated for patients with a baseline level ≥1000 U/mL. Results: No significant trend in survival was observed across baseline CA 19-9 levels. The greatest survival benefit was seen with a ≥75% decline to nadir. Among those with a ≥75% decline and baseline ≥1000 U/mL, 43 of 57 patients had a >50% decline at M2 of therapy and additional survival benefit was observed with a slower decline to nadir. Small sample sizes limited analysis of other baseline groups. CA 19-9 decline at M2 was not predictive. Conclusions: In patients with a CA 19-9 ≥1000 U/mL, serial CA 19-9 levels may be considered as a surrogate for serial imaging to evaluate treatment response, with a ≥75% decline indicating the greatest survival benefit. Survival was improved further in the setting of a slower decline to nadir with the highest benefit seen in patients with a nadir occurring at 4 months or longer.

Real-world Outcomes Among Patients Treated With Gemcitabine-based Therapy Post-FOLFIRINOX Failure in Advanced Pancreatic Cancer Objectives: Limited evidence exists for chemotherapy selection in advanced pancreatic cancer (APC) after first-line FOLFIRINOX. Second-line gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded in the Canadian provinces of Alberta (AB) and Manitoba (MB), but not in British Columbia (BC). We compared population-based outcomes by region to examine the utility of second-line GEMNAB versus gemcitabine (GEM) alone. Methods: We identified patients treated with first-line FOLFIRINOX between 2013 and 2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier method and compared with log-rank test. Results: A total of 368 patients were treated with first-line FOLFIRINOX (143 AB/MB, 225 BC): median age 61 (interquartile range: 55 to 68) years, 42% comprising female individuals, and 67% with metastatic disease. Receipt of second-line therapy was 48% in AB/MB versus 44% in BC (P=0.35), and time from diagnosis to second-line therapy was 7.7 (AB/MB) versus 9.4 months (BC; P=0.1). Distribution of second-line GEM use: 73% GEMNAB, 23% GEM (AB/MB) versus 27% GEMNAB, 66% GEM (BC; P<0.001). Median overall survival (OS) from diagnosis was similar: 12.4 (AB/MB) versus 11.5 months (BC; P=0.91). On Cox regression analysis, region was not significant. Secondary survival analysis by second-line regimen demonstrated a median OS of 18.0 months with GEMNAB versus 14.3 months with GEM (P<0.01). Conclusions: In this population-based comparison of APC patients treated with first-line FOLFIRINOX, survival outcomes were comparable regardless of funded access to second-line GEMNAB. OS by regimen favored second-line GEMNAB, but patient selection may be largely responsible for this difference.

The Effect of Metformin on Prognosis in Patients With Locally Advanced Gastric Cancer Associated With Type 2 Diabetes Mellitus Objectives: This study examined the effect of metformin use on the prognosis of gastric cancer patients. Materials and Methods: The study population comprised 2187 patients who underwent curative gastrectomy for the treatment of gastric cancer. They were divided into 3 groups: metformin (n=103), non-metformin (n=139), and non-diabetes mellitus (DM) (n=1945) according to their history of type 2 DM and metformin use. Survival, disease recurrence, and the pathologic stage were analyzed. Results: Overall survival was better in the metformin group than in the non-DM group (P=0.005). Metformin use was an independent prognostic factor of overall survival, cancer recurrence, and peritoneal recurrence. An effect of metformin use was especially notable in patients with T4 or N0 disease. Conclusions: Metformin improves the survival of patients with gastric cancer and type 2 DM.

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study Objective: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. Materials and Methods: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. Results: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) μg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. Conclusions: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

Role of Perioperative Chemotherapy in Lymph Node-negative Esophageal Cancer After Resection: A Population-based Study With Propensity Score-matched Analysis Background: Multimodality treatment is increasingly accepted and becoming the standard care for local advanced esophageal cancer (EC) patients. However, for early stage lymph node-negative EC patients, surgery alone is still the primary treatment approach, and the role of perioperative chemotherapy remains unclear. Methods: Patients with lymph node-negative EC were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Survival was compared by the log-rank test. Cox proportional hazards analysis was used to identify covariates associated with overall survival (OS). Propensity score-matched analysis was also performed to control for confounding. Results: A total of 3071 patients (T1-4N0M0) were identified, 1363 (44.4%) of which received perioperative chemotherapy. The effect of chemotherapy on OS was remarkably dependent on the T stage. For stage T1 patients, chemotherapy was inversely associated with OS (hazard ratio [HR]=1.54; 95% confidence interval [CI], 1.27-1.86), and no impact of chemotherapy on OS was found for T2 patients (HR=0.92; 95% CI, 0.712-1.18), whereas a significant improvement in OS was observed with the addition of chemotherapy for patients with stages T3 (HR=0.52; 95% CI, 0.43-0.62) and T4 (HR=0.60; 95% CI, 0.36-0.98) disease. Multivariable analysis with demonstrated that chemotherapy usage, age, sex, tumor grade, and T stage (P<0.05) were significantly associated with OS in T3-T4 patients. The results were similar in subgroup analyses stratified by confounding covariates, and the propensity score-matched analysis. Conclusions: This population-based study indicates perioperative chemotherapy is associated with improved survival in stage T3-4N0M0 patients with EC, which needs to be further validated by randomized trials.

The Role of Partial Breast Radiation in the Previously Radiated Breast Objectives: The aim of this study was to analyze breast cancer patients who previously had mantle-field or breast radiation (RT) followed by retreatment with external beam partial breast irradiation (EB PBI). Materials and Methods: We retrospectively reviewed all women with newly diagnosed early-stage breast cancer treated with lumpectomy and partial breast irradiation between 2007 and 2017 who had undergone prior chest or breast RT. Results: Of 11 patients recorded, 8 (73%) had Hodgkin lymphoma, and 3 (27%) had ipsilateral breast cancer diagnosis. Median age at initial and second diagnosis was 28 and 48 years, respectively. The lymphoma patients received a dose of 35 Gy in 16 to 20 fractions to a classic mantle-upper abdomen field. Patients with an initial diagnosis of breast cancer received whole-breast RT (2 with 50 Gy/25 fractions, 1 with 40 Gy in 16 fractions). Median time from initial to second diagnosis was 22.6 years (range, 13.5 to 32.6 y). All had early-stage (I to II) invasive ductal carcinoma and were treated with lumpectomy or repeat lumpectomy and EB PBI. Four received a dose of 45 Gy/25 fractions, 4 to 50 Gy/25 fractions, and 3 to 42.4 Gy/16 fractions. All patients received adjuvant systemic treatment. Two patients had toxicity, 1 had grade 1 induration, and the other had grade 2 fat atrophy and grade 1 fibrosis. One patient developed a contralateral breast cancer. No locoregional recurrences were reported at the median follow-up of 4.6 years (range, 0.6 to 10.5 y). Conclusion: EB PBI after lumpectomy seems to be a safe and effective RT treatment option for selected patients with prior RT and localized early-stage breast cancer.

Definitive Radiation Treatment Patterns and Outcomes for Low and Intermediate Risk Prostate Cancer Patients: A Cross-Continental Comparative Study Purpose: To evaluate early-stage prostate cancer (PCa) radiotherapy treatment patterns and outcomes among Ghanaian men (GM) compared with US men (USM). Materials and Methods: This retrospective study consists of 987 National Comprehensive Cancer Network low risk, favorable intermediate risk, and unfavorable intermediate risk PCa patient subgroups; GM (173) and USM (814). Differences in baseline covariates and clinical characteristics between GM and USM were analyzed using χ2 and Mann-Whitney test while Cox Proportional Hazards model was used to assess freedom from biochemical failure differences between the study groups. Results: Median follow-up for this study was 40 months. GM were diagnosed at a younger median age (64 vs. 68 y, P<0.001) with heavier unfavorable intermediate risk disease burden (32.4% vs. 19.2%) compared with USM. Significant differences were identified in median external beam radiotherapy dose (72.4 vs. 78 Gy, P<0.001); brachytherapy utilization (49.7% vs. 80.6%, P<0.001) and androgen deprivation therapy for intermediate risk disease (48.4% vs. 21.0%, P<0.001) between GM and USM, respectively. GM with low risk and favorable intermediate risk PCa were at increased risk of biochemical recurrence compared with USM with adjusted hazard ratio: 5.15 (1.27 to 20.7), P=0.02 and 4.64 (1.20 to 17.92), P=0.02, respectively. Conclusions: Compared with USM, GM with low and favorable intermediate risk PCa may experience less durable disease control following standard treatment recommendations. Results suggest differences in radiation treatment and possible inherent differences between the 2 populations. This data will aid in developing research strategies to improve treatment outcomes in GM.

The Prognostic Role of Pretreatment Neutrophil to Lymphocyte Ratio (NLR) in Malignant Adrenal Lesions Treated With Stereotactic Body Radiation Therapy (SBRT) Objective: The objective of this study was to evaluate a single institution’s experience with stereotactic body radiotherapy (SBRT) in treating malignant adrenal lesions, as well as the prognostic value of systemic inflammation biomarkers. Materials and Methods: From November 2007 to February 2018, 27 patients with malignant adrenal lesions received 31 SBRT treatments. Outcomes, measured from the date of SBRT, included overall survival (OS), local control (LC), and freedom from progression. Cox proportional hazard model was utilized to identify potential prognostic factors. Tumor response was assessed with PET Response Evaluation Criteria In Solid Tumors (PERCIST)/Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Acute toxicity was evaluated with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 criteria. Results: Median follow-up for all patients was 8 months. The complete response, partial response, stable disease, and progressive disease rates were 59%, 9%, 32%, and 0%, respectively. One-year LC, OS, and freedom from progression were 77.7%, 38.0%, and 10.0%, respectively. There was a trend toward significance upon multivariate analysis for pretreatment neutrophil to lymphocyte ratio >4.1 to predict inferior OS (adjusted hazard ratio=3.29, P=0.09, 1-year OS: 11% vs. 80%). There were 3 cases (10%) complicated by grade 2 acute toxicity, including nausea and fatigue. There was 1 grade 5 toxicity, as 1 case was complicated by a fatal gastric ulcer occurring 3 months after SBRT to the left adrenal gland (112.5 BED10). Conclusions: These results support the limited existing literature, demonstrating that SBRT provides adequate LC for adrenal lesions with minimal toxicity. Pretreatment neutrophil to lymphocyte ratio may serve as a prognostic factor in these patients.

Extracranial Abscopal Effects Induced by Brain Radiation in Advanced Lung Cancer An extracranial abscopal effect induced by central nervous system (CNS)-radiation therapy is considered an unusual event because of the belief that brain has a distinctive immune microenvironment. Regular immune responses from radiation therapy or other interventions were thought to be very limited in the CNS. In addition, CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounters with CNS antigens. Moreover, the traditional assumption is that nascent tumor-associated antigens produced by radiation therapy could not pass through the blood-brain barrier back into the rest of the body to modulate the immune system and induce extracranial abscopal responses. Emerging data from a small number of case series and individual case reports of various malignancies have radically altered our earlier understanding by revealing that the CNS is neither isolated nor passive in its interactions with the body’s immune system. Furthermore, current data indicate that the CNS is both immune-competent and interacts actively with the peripheral immune system. Therefore, radiation treatment to ≥1 location of CNS metastases can induce abscopal responses in tumors away from the treated CNS metastatic sites. These observations suggest the abscopal effect traverses the blood-brain barrier. In this article, we reviewed and assessed the clinical evidence of extracranial abscopal responses of CNS-radiation therapy in patients with advanced lung cancer.