Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.

PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico.

Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.

Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer.

LESSONS LEARNED: Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer.There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. BACKGROUND: Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. METHODS: Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. RESULTS: Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%-50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%-89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%-74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%-93%) and 94% (95% CI: 77%-98%), respectively. CONCLUSION: Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%-78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

N08C9 (Alliance): A Phase 3 Randomized Study of Sulfasalazine Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy.

PURPOSE: To provide confirmatory evidence on the use of sulfasalazine to reduce enteritis during pelvic radiation therapy (RT), following 2 prior single-institution trials suggestive that benefit existed. METHODS AND MATERIALS: A multi-institution, randomized, double-blind, placebo-controlled phase 3 trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during RT including the posterior pelvis (45.0-53.5 Gy) and conducted through a multicenter national cooperative research alliance. Patients received 1000 mg of sulfasalazine or placebo orally twice daily during and for 4 weeks after RT. The primary endpoint was maximum severity of diarrhea (Common Terminology Criteria for Adverse Events version 4.0). Toxicity and bowel function were assessed by providers through a self-administered bowel function questionnaire taken weekly during RT and for 6 weeks afterward. RESULTS: Eighty-seven patients were enrolled in the trial between April 29, 2011, and May 13, 2013, with evenly distributed baseline factors. At the time of a planned interim toxicity analysis, more patients with grade ≥3 diarrhea received sulfasalazine than received placebo (29% vs 11%, P=.04). A futility analysis showed that trial continuation would be unlikely to yield a positive result, and a research board recommended halting study treatment. Final analysis of the primary endpoint showed no significant difference in maximum diarrhea severity between the sulfasalazine and placebo arms (P=.41). CONCLUSIONS: Sulfasalazine does not reduce enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. This trial illustrates the importance of confirmatory phase 3 trials in the evaluation of symptom-control agents.

A phase I study of the combination of temsirolimus with irinotecan for metastatic sarcoma.

mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.

Early breast cancer with positive margins: excellent local control with an upfront brachytherapy boost.

Standard breast conservation therapy consists of lumpectomy and whole breast radiation with boost. The effectiveness of radiation in cases of positive margins is controversial. Two potential treatment-related factors are time to initiation of radiation and localization of the boost. Here, we examine long-term outcomes of positive margin cases treated with an upfront interstitial brachytherapy boost. This particular treatment arrangement may reduce those treatment-related effects on local control. Historically, a low dose interstitial implant was a common boost technique. One approach administered the boost before external beam. A review of 521 cases treated at our institution was conducted. Patients were selected for this study if they received an upfront brachytherapy boost and had close or positive margins. Forty-four breast cancers were identified. Median follow-up of survivors was 11.3 years (8.1-21.7). Implant was performed at lumpectomy (12) or axillary dissection (32). Margin statuses were: focal carcinoma at ink (37), multifocal carcinoma at ink (1), carcinoma <1 mm from ink (2), and DCIS at ink (4). Median tumor size was 1.2 cm (0.5-3.5 cm). Ten patients had nodal involvement. Total median dose was 60 Gy (58.6-65.3 Gy). Median boost dose was 15 Gy (12-20.3 Gy). Lumpectomy to boost interval was median of 3 weeks (0-10.8). No ipsilateral breast recurrences or second primaries were identified. Four developed contralateral breast cancer. Eleven are deceased, four from breast cancer-all from metastasis. 12-year Kaplan-Meier estimates were: overall survival 78 ± 7 %, cause specific survival 93 ± 4 %, and recurrence-free survival 82 ± 6 %. Univariate analysis identified nodal disease as significant for cause specific survival (log rank p = 0.005). No ipsilateral breast recurrences were found. Early administered radiation and accurate boost localization were identified as suspected treatment-related factors for local recurrence. When these two treatment-related factors are minimized, long-term local control rates do not suffer.