NSABP FC-6: Surgical conversion rate in colorectal cancer patients with unresectable, KRAS wild-type liver metastases receiving mFOLFOX7 plus cetuximab.

PURPOSE: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment. METHODS: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m2 every 14 days with dose reductions to 400 and 300 mg/m2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m2 were allowed. The mean dose of cetuximab (mg/m2 /week) throughout the study was 289 mg/m2 . Paired samples were collected for correlative studies, where feasible. RESULTS: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels. CONCLUSIONS: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy.

Recurrence rates for patients with early-stage breast cancer treated with IOERT at a community hospital per the ASTRO consensus statement for APBI.

PURPOSE: To report the recurrence rates after single-fraction intraoperative electron radiotherapy (IOERT) in patients with early-stage breast cancer treated on a single institution prospective Phase I/II protocol at a community hospital. Results were retrospectively analyzed according to suitability criteria from the updated American Society for Radiation Oncology (ASTRO) consensus statement for accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Patients over 40 years with early-stage invasive or in situ breast cancer (<2.5 cm and node negative) were enrolled. IOERT 2100 cGy was delivered during breast conservation surgery, and patients were followed up for a median of 3 years (0.8-6.5 years) to determine toxicity and recurrence rates. RESULTS: Single-fraction IOERT was performed in 215 cases (6 bilateral treatments, 196 patients) with 13 patients receiving whole-breast radiation (WBR) after IOERT for adverse pathologic features. Of 202 cases of IOERT without WBR, 89 patients experienced an ipsilateral breast tumor recurrence (IBTR) giving a cumulative incidence of 3.96%. When the ASTRO APBI suitability criteria were applied, the IBTR rate was significantly lower for suitable patients vs. cautionary or unsuitable patients (1.6% vs. 3.4% vs. 21.0%, p = 0.0002). 3-year progression-free survival after IOERT alone was 93.4%. For patients who received standard WBR (4500-5040 cGy) after IOERT, no Grade 3 or 4 toxicities (acute or late) occurred and all patients are disease-free. CONCLUSIONS: Single-fraction IOERT results in a low rate of IBTR when strictly adhering to ASTRO criteria for APBI suitability. Standard dose WBR for unfavorable pathologic results after 2100 cGy IOERT is well tolerated.

TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2, MSH6, MLH1, PMS2 and EPCAM. Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.

A prospective phase I comparison of toxicity and cosmesis outcomes of single-fraction IORT and hypofractionated radiotherapy with IORT boost in early-stage breast cancer.

PURPOSE: Radiation therapy is proven to reduce local recurrence in patients with early-stage breast cancer. To reduce toxicity, treatment time, and improve accuracy, intraoperative radiation therapy was used as definitive treatment or as a boost. The study's objective was to compare the short-term toxicity and cosmesis of single-fraction (SF) IORT and hypofractionated radiotherapy with IORT boost (HfB) given as definitive treatment. METHODS AND MATERIALS: Between March 2011 and December 2013, 57 patients aged 45-91 years and 24 patients aged 43-83 years (total n = 81) with Stage 0-II were treated with SF or HfB (Mobetron, IntraOp Medical, Sunnyvale, CA). For SF treatment, 21 Gy was delivered using 4.5-6 cm applicators with electron energies from 6 to 12 MeV. For HfB, an intraoperative boost of 10 Gy was delivered using 4-7 cm applicators with energies from 4 to 12 MeV followed by whole-breast radiation with 40.5 Gy over 15 fractions. Toxicity was assessed at 2 weeks, 6 months, and 12 months per Radiation Therapy Oncology Group acute skin toxicity criteria and cosmesis. RESULTS: At 12 months, SF and HfB were well tolerated by all patients with no Grade 3+ toxicity. At 1 year, Grade-2 toxicity was resolved. Ninety-eight percent of SF patients and ninety percent of HfB patients had 0-1 grade toxicity. In the SF and HfB groups, 100% of patients had excellent or good cosmesis at 12-month followup interval. The SF exhibited a more favorable cosmesis with a higher percentage of excellent scores compared with HfB (80.4% vs. 45%; p = 0.0033). CONCLUSIONS: After breast conservation surgery, SF or HfB may be an option for patients with early-stage breast cancer compared to conventional external beam radiotherapy.

Phase I/II Trial of Anticarcinoembryonic Antigen Radioimmunotherapy, Gemcitabine, and Hepatic Arterial Infusion of Fluorodeoxyuridine Postresection of Liver Metastasis for Colorectal Carcinoma.

OBJECTIVES: Report the feasibility, toxicities, and long-term results of a Phase I/II trial of 90Y-labeled anticarcinoembryonic antigen (anti-CEA) (cT84.66) radioimmunotherapy (RIT), gemcitabine, and hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUdR) after maximal hepatic resection of metastatic colorectal cancer to the liver. METHODS: Patients with metastatic colorectal cancer to the liver postresection or ablation to minimum disease were eligible. Each cohort received HAI of FUdR for 14 days on a dose escalation schedule. The maximum HAI FUdR dose level planned was 0.2 mg/kg/day, which is the standard dose for HAI FUdR alone. On day 9, 90Y-cT84.66 anti-CEA at 16.6 mCi/m2 as an i.v. bolus infusion and on days 9-11 i.v. gemcitabine at 105 mg/m2 were given. Patients could receive up to three cycles every 6 weeks of protocol therapy. Four additional cycles of HAI FUdR were allowed after RIT. RESULTS: Sixteen patients were treated on this study. A maximum tolerated dose of 0.20 mg/kg/day of HAI FUdR combined with RIT at 16.6 mCi/m2 and gemcitabine at 105 mg/m2 was achieved with only 1 patient experiencing grade 3 reversible toxicity (mucositis). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. With a median follow-up of 41.8 months (18.7-114.6), median progression free survival was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months. CONCLUSION: This study demonstrates the safety, feasibility, and potential utility of HAI FUdR, RIT, and systemic gemcitabine. The trimodality approach does not have higher hematologic toxicities than seen in prior RIT-alone studies. Future efforts evaluating RIT in colorectal cancer should integrate RIT with systemic and regional therapies in the minimal tumor burden setting.

TumorNext: A comprehensive tumor profiling assay that incorporates high resolution copy number analysis and germline status to improve testing accuracy.

The development of targeted therapies for both germline and somatic DNA mutations has increased the need for molecular profiling assays to determine the mutational status of specific genes. Moreover, the potential of off-label prescription of targeted therapies favors classifying tumors based on DNA alterations rather than traditional tissue pathology. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext, which can detect single nucleotide variants, small insertions and deletions in 142 genes that are frequently mutated in somatic and/or germline cancers. TumorNext also detects gene fusions and structural variants, such as tandem duplications and inversions, in 15 frequently disrupted oncogenes and tumor suppressors. The assay uses a matched control and custom bioinformatics pipeline to differentiate between somatic and germline mutations, allowing precise variant classification. We tested 170 previously characterized samples, of which > 95% were formalin-fixed paraffin embedded tissue from 8 different cancer types, and highlight examples where lack of germline status may have led to the inappropriate prescription of therapy. We also describe the validation of the Affymetrix OncoScan platform, an array technology for high resolution copy number variant detection for use in parallel with the NGS panel that can detect single copy amplifications and hemizygous deletions. We analyzed 80 previously characterized formalin-fixed paraffin-embedded specimens and provide examples of hemizygous deletion detection in samples with known pathogenic germline mutations. Thus, the TumorNext combined approach of NGS and OncoScan potentially allows for the identification of the "second hit" in hereditary cancer patients.

Novel MSH2 Mutation in the First Report of a Vietnamese-American Kindred with Lynch Syndrome.

•First report of Lynch syndrome in a Vietnamese kindred•A novel MSH2 mutation has been identified.•Culturally sensitive screening programs need to be developed in this growing population.

Importance of response to neoadjuvant therapy in patients with liver-limited mCRC when the intent is resection and/or ablation.

This review article provides an overview of treatment options for patients with liver metastases, with a focus on the importance of response rates on resectability. The inclusion of surgery provides the only potential for cure in this setting. There are several important surgical considerations for performing resections, and close communication between oncologists and surgeons is important for achieving the intended outcome. In patients with initially unresectable colorectal liver metastases, an association between tumor response rate and resection rates has been demonstrated, implying that greater response rates could increase resection rates. Neoadjuvant chemotherapy establishes expected response rates with the use of biologic agents, such as cetuximab or bevacizumab, further improving the response rate and potentially increasing the rate of resection and potential to cure the disease.

Intraoperative radiotherapy for breast cancer: its perceived simplicity.

Over one-quarter of a million cases of breast cancer are diagnosed in the United States each year, many of which are early stage.The radiotherapeutic options after breast-conserving surgery in early-stage breast cancer are evolving quickly, with a focus on minimizing treatment volume, toxicity, and treatment duration. One such emerging option is intraoperative radiotherapy (IORT), administered either as a single fraction or as a boost.With many centers seeking to adopt such technology, there are licensing, proctoring, staffing, technical support, and reimbursement issues that need to be considered. We have reviewed the current international experience and describe one community cancer center's experience with initiating an IORT breast cancer program.

Intraoperative electron radiotherapy boost as a component of adjuvant radiation for breast cancer in the community setting.

To reduce toxicity/treatment time and improve accuracy, intraoperative electron radiotherapy (IOERT) was used as an alternative to electron beam radiation therapy boost. Primary objective was to determine feasibility and acute toxicity. From August 2009 to June 2011, 50 patients (age 32 to 76 years) with in situ or invasive breast cancer (Stage 0 to IIIA) were treated. Toxicity assessed according to standard National Cancer Institute scales. Median tumor size was 20 mm (range, 6 to 80 mm) with 43 infiltrating ductal, two infiltrating lobular, and five ductal in situ carcinoma. A single 10-Gy fraction boost was given to the tumor bed after resection followed by whole-breast radiotherapy. After IOERT, three patients required completion axillary lymph node dissection, eight had reexcision resulting from positive margins, and four opted for completion mastectomy. The median follow-up was 10 months (range, 2 to 24 months). Ten patients had Grade 1 and one reported Grade 2 breast pain 2 weeks after IOERT; all resolved at 6 weeks. Two patients had delay in wound healing, but none developed a wound infection. Three patients reported symptomatic fat necrosis. No other toxicities were reported. IOERT resulted in a reduction in treatment time, was not associated with additional toxicity or change in the acute toxicity profile, and is a feasible treatment option in a community hospital setting.

Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10.

PURPOSE: Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. PATIENTS AND METHODS: Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. RESULTS: Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). CONCLUSION: This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.

Oxaliplatin but not irinotecan impairs posthepatectomy liver regeneration in a murine model.

Introduction. We examined the murine hepatectomy model of liver regeneration (LR) in the setting of neoadjuvant chemotherapy. Methods. C57BL/6 mice were randomized to receive neoadjuvant intraperitoneal (IP) injections of a control, oxaliplatin (15 mg/kg), or irinotecan (100 mg/Kg or 250 mg/Kg) solution. Hepatectomy (70%) was performed 14 days after the final IP treatment. Animals were sacrificed at postoperative day (D) 0, 1, 2, 3, and 7. Liver remnants and serum were collected for analysis. T-tests for independent samples were used for statistical comparisons. Results. For oxaliplatin, percent LR did not differ at D1 or D2 but was significantly less at D3 (89.0% versus 70.0%, P = 0.048) with no difference on D7 (P = 0.21). Irinotecan-treated mice at both dose levels (100 mg/Kg and 250 mg/Kg) showed no significant differences in LR. BrdU incorporation was significantly decreased in oxaliplatin-treated animals (D1,2,3). Conclusions. Neoadjuvant oxaliplatin but not irinotecan impairs early LR in a posthepatectomy murine model which correlates with decreased DNA synthesis.

Transarterial radioembolization with Yttrium-90 for regional management of hepatocellular cancer: the early results of a nontransplant center.

Selective arterial radioembolization with Yttrium-90 (Y-90) microspheres has shown promise for regional management of hepatocellular cancer (HCC). Our objective was to report our early experience with this treatment modality from a nontransplant center. Treatment of patients with HCC was discussed in a multidisciplinary tumor board. Patients with unresectable disease resulting from high lesion number, ill location of the tumor, poor hepatic reserve, or medical comorbidities were offered Y-90 treatment. Liver treatment was either lobar or tumor-targeted. Response to therapy was assessed by CT scan obtained within 3 months using Response Evaluation Criteria in Solid Tumors criteria. During 2007 to 2009, 40 Y-90 radioembolizations were performed in 20 patients with age that ranged from 16 to 87 years; four patients were 80 years old or older. After the first therapy, CT assessment of the treated area showed stable disease (n=15), partial response (n=3), and progression (n=2). Of the two patients who progressed, one was retreated with a subsequent complete response. The other patient died of progressive disease. The most common side effects were mild fatigue, anorexia, and nausea. In summary, our nontransplant center experience shows that Y-90 radioembolization is a well-tolerated treatment in select patients with unresectable HCC with an associated high rate of local tumor control.

FXR regulates liver repair after CCl4-induced toxic injury.

Liver repair is key to resuming homeostasis and preventing fibrogenesis as well as other liver diseases. Farnesoid X receptor (FXR, NR1H4) is an emerging liver metabolic regulator and cell protector. Here we show that FXR is essential to promote liver repair after carbon tetrachloride (CCl(4))-induced injury. Expression of hepatic FXR in wild-type mice was strongly suppressed by CCl(4) treatment, and bile acid homeostasis was disrupted. Liver injury was induced in both wild-type and FXR(-/-) mice by CCl(4), but FXR(-/-) mice had more severe defects in liver repair than wild-type mice. FXR(-/-) livers had a decreased peak of regenerative DNA synthesis and reduced induction of genes involved in liver regeneration. Moreover, FXR(-/-) mice displayed increased mortality and enhanced hepatocyte deaths. During the early stages of liver repair after CCl(4) treatment, we observed overproduction of TNFalpha and a strong decrease of phosphorylation and DNA-binding activity of signal transducer and activator of transcription 3 in livers from FXR(-/-) mice. Exogenous expression of a constitutively active signal transducer and activator of transcription 3 protein in FXR(-/-) liver effectively reduced hepatocyte death and liver injury after CCl(4) treatment. These results suggest that FXR is required to regulate normal liver repair by promoting regeneration and preventing cell death.

Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States.

BACKGROUND: Racial, ethnic, and socioeconomic disparities in the survival of patients with hepatocellular carcinoma (HCC) continue to exist. The authors of this report hypothesized that these differences result from inequities in access to care and in response to therapy. METHODS: Patients with HCC (n = 20,920) were identified from the Surveillance, Epidemiology, and End Results (SEER) database, and patients who underwent liver transplantation for HCC (n = 4735) were identified from the United Network for Organ Sharing (UNOS) database. Clinical and pathologic factors were compared after patients were stratified by race and ethnicity. RESULTS: The survival of patients with HCC improved over time for all racial, ethnic, and income groups (P < .001). Black and low income individuals had the poorest long-term survival (P < .001). On multivariate analysis, black race was predictive of the poorest survival (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.09-1.22; P < .001), whereas Asian race was associated with the best survival (HR, 0.87; 95% CI, 0.83-0.91; P < .001). After liver transplantation, black patients had the worst graft survival and overall survival (median survival [MS], 30.5 months and 39.7 months, respectively; P < .001), whereas Hispanics had the best survival (MS, 83.4 months and 86.6 months, respectively; P < .001). In a multivariate analysis of transplantation patients, race and ethnicity were associated significantly with outcome. CONCLUSIONS: Significant racial and ethnic disparities in the outcome of patients with HCC persist despite the receipt of comparable treatment. The authors concluded that further investigations are warranted to identify the reasons for the stark disparity in outcomes between black patients and Hispanic patients after liver transplantation for HCC.

Alternating systemic and hepatic artery infusion therapy for resected liver metastases from colorectal cancer: a North Central Cancer Treatment Group (NCCTG)/ National Surgical Adjuvant Breast and Bowel Project (NSABP) phase II intergroup trial, N9945/CI-66.

PURPOSE Prior trials have shown that surgery followed by hepatic artery infusion (HAI) of floxuridine (FUDR) alternating with systemic fluorouracil improves survival rates. Oxaliplatin combined with capecitabine has demonstrated activity in advanced colorectal cancer. Based on this observation a trial was conducted to assess the potential benefit of systemic oxaliplatin and capecitabine alternating with HAI of FUDR. The primary end point was 2-year survival. PATIENTS AND METHODS Patients with liver-only metastases from colorectal cancer amenable to resection or cryoablation were eligible. HAI and systemic therapy was initiated after metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m(2)/d FUDR and dexamethasone, day 1 through 14 weeks 1 and 2. Systemic therapy included oxaliplatin 130 mg/m(2) day 1 with capecitabine at 1,000 mg/m(2) twice daily, days 1 through 14, weeks 4 and 5. Two additional 3-week courses of systemic therapy were given. Capecitabine was reduced to 850 mg/m(2) twice daily after interim review of toxicity. Results Fifty-five of 76 eligible patients were able to initiate protocol-directed therapy and completed median of six cycles (range, one to six). Three postoperative or treatment-related deaths were reported. Overall, 88% of evaluable patients were alive at 2 years. With a median follow-up of 4.8 years, a total of 30 patients have had disease recurrence, 11 involving the liver. Median disease-free survival was 32.7 months. CONCLUSION Alternating HAI of FUDR and systemic capecitabine and oxaliplatin met the prespecified end point of higher than 85% survival at 2 years and was clinically tolerable. However, the merits of this approach need to be established with a phase III trial.