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.

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.

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.

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.

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.

Managing colorectal cancer liver metastases.

The treatment of resectable colorectal cancer metastases to the liver has undergone changes with the addition of active chemotherapeutic agents, innovations and definition in the surgical procedures, understanding of the benefits and toxicities of the surgical and chemotherapeutic (cytotoxic and biologic) interventions, and use of the team approach. Patients are initially evaluated for the overall risk of their disease, which includes the standard parameters for disease recurrence and blends in disease and patient comorbidities and likelihood of surgical success. Advanced imaging techniques are mandatory in the initial evaluation. Rather than approaching the patient with sequential, independent therapies and handoff from specialist to specialist, a continuous interaction is required. This article outlines the initial consultation, required team components, surgical decision-making, and use of cytotoxic and biologic agents. The implication is that the best outcomes can only be achieved with the use of all modalities.

Liver resection using a four-prong radiofrequency transection device.

Multiple techniques are available for division of hepatic parenchyma. This is the largest United States report examining the use of the Habib 4X tissue coagulator (AngioDynamics, Queensbury, NY). The objective was to collect standard parameters associated with successful, benchmarked liver surgery outcomes using this new device, and in particular, examine the risk of margin failure. Ninety-four consecutive operations using the Habib 4X were analyzed with special attention to local failure at resection margin, blood loss/transfusion, and operative times. An institutional review board approved protocol allowed collection and analysis of demographic information and outcomes for intraoperative, perioperative, and long-term follow-up. Eighteen patients had biopsy only. Thirty-one had lobar resections and 46 had wedge or segmental resections. There were 30 primary hepatic and 46 metastatic tumor diagnoses. There were a total of 33 (43%) recurrences with a mean time to recurrence of 212 days (range 15-974). Of the 27 intrahepatic recurrences, four (15%) were at the margin. The OR time ranged from 115 to 642 minutes (average 283 min). The average recorded blood loss was 427 mL; 11 patients were transfused (average 0.43 units). The Habib 4X is a safe tool to use when evaluating the parameters of blood loss, transfusion, and margin recurrence.

Surgical resection of primary and metastatic hepatic malignancies following portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) has been used to induce hypertrophy in future liver remnants (FLRs) in preparation for major hepatic resection. We report our initial experience with PVE and identify potential predictors of unresectability following PVE. METHODS: Patients with primary and metastatic hepatic malignancies (n = 20) who underwent PVE between 2004 and 2008 were categorized by surgical resection status and clinicopathologic factors were compared. RESULTS: The cohort had the following histologies: colorectal adenocarcinoma (45%, n = 9), hepatocellular carcinoma (20%), cholangiocarcinoma (20%), and other (15%). Seven patients (35%) had previous liver-directed or regional therapy; 55% subsequently underwent successful liver resection, whereas 45% were deemed unresectable. Patients who underwent successful resection had tumor shrinkage after PVE compared to unresectable patients (% change in maximal tumor diameter, -6% vs. +45%, respectively; P = 0.027) and had a lower rate of baseline liver function test abnormality (0% vs. 56%, respectively; P = 0.004). Resected patients had an 83% 5-year overall survival. CONCLUSIONS: Baseline liver dysfunction may predict subsequent unresectable hepatic disease following PVE and tumor progression after PVE appears to increase the likelihood for finding unresectable hepatic disease. Select patients should be considered for PVE with careful surveillance during the period of FLR hypertrophy.

Phase II study of oxaliplatin in patients with unresectable, metastatic, or recurrent hepatocellular cancer: a California Cancer Consortium Trial.

PURPOSE: Prolonged survival for patients with unresectable hepatocellular carcinoma (HCC) is consistently reported at lower than 6 months. Oxaliplatin has recently demonstrated activity in HCC. The objective of this study was to determine the response rate, survival, time to progression, and toxicity in patients with poor prognosis HCC when treated with oxaliplatin. EXPERIMENTAL DESIGN: Patients were required to have measurable recurrent, metastatic or unresectable HCC, and to have previously been exposed to no more than 2 prior chemotherapy regimens. Karnofsky performance of 70% or above and adequate organ and hematologic function were required. All patients received treatment with oxaliplatin 100 mg/m on day 1 and 15 as a 2-hour intravenous infusion and were pretreated with antiemetics. Treatment was repeated every 28 days. RESULTS: Thirty-six patients were enrolled and evaluated, although 6 expired before the first planned evaluation. Karnofsky performance status was 70/80/90/100% in 5/9/9/13 patients, respectively. The median time to progression was 2 months; median survival was 6 months. The 6-month overall survival was 55% (95% confidence interval 41%-74%), and the 6 month event-free survival was 11% (95% confidence interval 4%-28%). CONCLUSION: Single agent, oxaliplatin, has produced one partial response of good duration in 36 patients, but failed to meet the a priori criterion for promise in this trial. Sixteen patients were observed to have stable disease with a well tolerated toxicity profile. The combination of oxaliplatin and other agents should be considered to treat HCC in those patients with good functional status.

Chemotherapy for colorectal cancer liver metastases.

Colorectal cancer (CRC) is a highly prevalent malignant disease in industrialized nations. The annual incidence of invasive CRC in the U.S. is among the highest in the world, and the liver is the only metastatic site in approximately one third of patients. Without treatment, patients with metastatic disease have a poor prognosis; however, long-term survival benefits and even cure have been reported in patients undergoing surgical resection of metastases. In addition, advances in chemotherapy, imaging, and surgical techniques have increased the proportion of patients who are eligible for resection. Combination therapy with fluorouracil and leucovorin has been the mainstay of treatment for metastatic CRC; however, the introduction of newer agents, such as oxaliplatin and irinotecan, and targeted agents, such as cetuximab and bevacizumab, has yielded improvements in response rates (RRs) and survival. Maximizing the exposure of hepatic metastases to high target concentrations of cytotoxic drugs using hepatic arterial infusion (HAI) increases RRs further than with systemic chemotherapy; however, the impact of HAI on survival is unclear. As the goals of chemotherapeutic treatment for metastatic CRC increasingly shift from palliation to prolongation of survival, improvement in RRs, and downsizing of tumors in order to enable or optimize resection, treatment in a multidisciplinary environment involving a medical oncologist, radiologist, and surgical oncologist with hepatobiliary expertise will become central to deciding the best course of therapy and timing of surgery.