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.

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.

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.

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.

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.

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.

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.

Surgical palliation of advanced gastrointestinal tumors.

Patients with advanced gastrointestinal tumors suffer a spectrum of progressive symptoms that reduce their quality of life (QOL). Operative palliative strategies seeking to improve QOL and decrease symptom burden are poorly studied. This study seeks to measure the effect of operations on symptoms and QOL in patients with advanced gastrointestinal malignancies. Patients undergoing World Health Organization (WHO)-defined palliative operations for gastrointestinal cancers were prospectively followed with monthly QOL and Distress Thermometer surveys until 6 months post-operatively. Comparisons were made between preoperative and 3-month postoperative data. Parameters of physical, psychological, social, and spiritual QOL were measured on a scale of 0 (worst) to 5 (best). Frequency of occurrence and degree of distress caused by that specific symptom were scored from 0 (rarely/not at all) to 5 (most of the time/severely). Thirty-five patients had gastrointestinal cancer. The median age was 55.3 years. The most common symptoms were pain and obstruction. Thirty-three operations were abdominal. Ultimately, 34 patients (97%) were discharged home. When preoperative data were compared to 3 months postoperative, the frequency of the primary symptom improved by 2.22 (p = 0.001) and the distress it caused decreased by 1.82 (p = 0.004). Physical QOL decreased by 0.61 (p = 0.009), psychological QOL decreased by 0.50 (p = 0.015), social QOL decreased by 0.48 (p = 0.017), spiritual QOL decreased by 0.42 (p = 0.008), and overall QOL decreased by 0.50 (p = 0.012). Because of the unrelenting nature of gastrointestinal tumors, QOL over time will inevitably decrease. Palliative operations effectively improve symptom frequency and distress without greatly affecting the expected decline in QOL and its parameters.

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.

Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.

PURPOSE: To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases. PATIENTS AND METHODS: Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute-designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy. RESULTS: Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity. CONCLUSION: The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.

Pump removal in infected patients with hepatic chemotherapy pumps: when is it necessary?

Hepatic chemotherapy pumps have been shown to be an effective and well-tolerated treatment for metastatic colorectal cancer confined to the liver. The importance of completing chemotherapy in long-term outcome makes it desirable to salvage hepatic pumps where possible. Concerns of persistent and systemic infection have resulted in premature removal of pumps in patients with infection. We report our experience in this clinical scenario. We placed 75 hepatic chemotherapy pumps from January 1998 to August 2005 for treatment of colorectal liver metastases. Information was collected on the patients' courses of treatment, complications, and demographics via chart review. The rate of infection was 22.7% (n = 17), including eight infections localized to the abdomen (entailing five wound infections, three hepatic abscesses, and two pump pocket infections). Of these, two pumps had to be removed because of pump pocket infection, and these patients received more cycles of chemotherapy compared with the four removed for noninfectious complications (12.3 vs 3.2, P = 0.0349). Time to infection was found to be significantly higher in these patients (12.5 months) than in the patients with infections overall (4.87 months, P = 0.029), and age was found to be lower (42.5 vs 57.6 years, P = 0.0068).

Radioactive iodine offers survival improvement in patients with follicular carcinoma of the thyroid.

BACKGROUND: The use of radioactive iodine (RAI) in patients with follicular thyroid carcinoma is well established. How its use affects patient outcome and which patients benefit is understood poorly. This study seeks to determine how RAI influences survival and to delineate the populations that are impacted most. METHODS: The Surveillance, Epidemiology, and End Results database is a sample of approximately 14% of the US population. It was used to identify patients with follicular thyroid carcinomas and the treatment that they received. Factors such as the presence of lymph node and distant metastases, age, and tumor size were included for analysis. RESULTS: A total of 4317 patients were identified with follicular thyroid carcinoma. Of these, the records of 2112 patients who were entered in the study after 1988 contained the required data and were included for analysis. Median follow-up time was 95 months. Factors that were associated with increased risk of death included distant metastatic disease, cervical lymph node disease, and the lack of RAI use. Protective factors were tumor size of <2 cm and age of <45 years. Some patients with a greater number of risk factors benefited from RAI. CONCLUSION: RAI provides survival benefit to some patients with follicular carcinoma of the thyroid. The greatest improvements were seen in those patients with locoregional or distant disease spread.

Paint-only is equivalent to scrub-and-paint in preoperative preparation of abdominal surgery sites.

BACKGROUND: Antiseptic preoperative skin site preparation is used to prepare the operative site before making a surgical incision. The goal of this preparation is a reduction in postoperative wound infection. The most straightforward technique necessary to achieve this goal remains controversial. STUDY DESIGN: A prospective randomized trial was designed to prove equivalency for two commonly used techniques of surgical skin site preparation. Two hundred thirty-four patients undergoing nonlaparoscopic abdominal operations were consented for the trial. Exclusion criteria included presence of active infection at the time of operation, neutropenia, history of skin reaction to iodine, or anticipated insertion of prosthetic material at the time of operation. Patients were randomized to receive either a vigorous 5-minute scrub with povidone-iodine soap, followed by absorption with a sterile towel, and a paint with aqueous povidone-iodine or surgical site preparation with a povidone-iodine paint only. The primary end point of the study was wound infection rate at 30 days, defined as presence of clinical signs of infection requiring therapeutic intervention. RESULTS: Patients randomized to the scrub-and-paint arm (n = 115) and the paint-only arm (n = 119) matched at baseline with respect to age, comorbidity, wound classification, mean operative time, placement of drains, prophylactic antibiotic use, and surgical procedure (all p > 0.09). Wound infection occurred in 12 (10%) scrub-and-paint patients, and 12 (10%) paint-only patients. Based on our predefined equivalency parameters, we conclude equivalence of infection rates between the two preparations. CONCLUSIONS: Preoperative preparation of the abdomen with a scrub with povidone-iodine soap followed by a paint with aqueous povidone-iodine can be abandoned in favor of a paint with aqueous povidone-iodine alone. This change will result in reductions in operative times and costs.

Surgical management of hepatic breast cancer metastases.

Tremendous gains have been made regarding the treatment of breast cancer. The combination of chemotherapy, radiation therapy, and surgery have vastly improved patient course. Hepatic manifestations of metastatic breast cancer are extremely difficult to treat. Traditionally, chemotherapy and hormonal treatment of hepatic metastases of breast carcinoma have not significantly improved survival. For patients with breast cancer metastases isolated to the liver, operative treatment is increasingly being used to prolong life and disease-free intervals. This article reviews the use of surgery for treatment of isolated breast cancer metastases to the liver.

The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer.

Though survival for well-differentiated thyroid cancer is very good, specific populations suffer greater recurrence and mortality. Defining these cohorts can significantly influence prognosis and extent of treatment. This study, using a large, multi-institutional database, seeks to determine how the presence of lymph node disease in patients with well-differentiated thyroid cancer affects outcome. The Surveillance, Epidemiology, and End Results (SEER) database is a large-scale sample of 14 per cent of the U.S. population. It was used to identify patients with papillary and follicular thyroid carcinomas and identify the prognostic implications of lymph node metastasis. Additional factors, including presence of metastasis, age, and tumor size, were compared using multivariate and chi2 analyses. Of 19,918 patients identified, lymph node status was known for 9,904 (49.7%). On multivariate analysis, age > 45 years, presence of distant metastasis, large tumor size, and lymph node involvement significantly predicted poor outcome. Overall survival at 14 years was 82 per cent for node negative and 79 per cent for node positive patients (P < 0.05). This study shows that the survival of patients with well-differentiated thyroid cancer is adversely affected by lymph node metastases. The optimum treatment for this cohort needs further delineation, as particular populations are at greater risk of recurrence and death.

Full-thickness chest wall resection for recurrent breast carcinoma: an institutional review and meta-analysis.

Locoregional recurrence of breast cancer can occur in up to 30 per cent of patients and has often been considered to indicate a poor prognosis. We reviewed our experience with full-thickness chest wall resection for recurrent breast cancer and conducted a meta-analysis of the English literature to determine patient characteristics and outcomes. Twenty-two women with isolated chest wall recurrence of breast cancer were treated between 1970 and 2000 at our institution. We reviewed their preoperative demographics, operative management and outcome, and combined our results with seven other English language studies. A majority of women (90%) underwent a mastectomy as initial management of their breast cancer. Only 18 per cent of patients had metastatic disease at the time of chest wall resection, and 71 per cent of patients had an R0 resection. The 5-year disease-free survival at City of Hope National Medical Center (COH) was 67 per cent and was 45 per cent for the entire group of 400 patients. The 5-year overall survival was 71 per cent for the COH group and 45 per cent for the entire group. Several studies reported prognostic factors, the most common being a better prognosis in patients with a disease-free interval greater than 24 months. Full-thickness chest wall resection for patients with isolated local recurrence of breast cancer can provide long-term palliation and even cure in some 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.