Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors.

We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.

Peripheral monocytes and neutrophils predict response to immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer.

We carried out a retrospective cohort study on patients with metastatic non-small cell lung cancer (mNSCLC) to identify the peripheral blood count parameters associated with response to immune checkpoint inhibitors (ICIs). There were 17 males and 15 females. Their median age was 64.5 years (range 20-84). History of smoking was present in 25/32 (78%) patients. Twelve patients received pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial responses. There was no difference in the distribution of sex, age, and smoking status between responders and non-responders. The median time to response (TTR) was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs ≤ 700/mm3 (8 weeks vs 12 weeks; p = 0.048). Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs ≤ 4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.

PURPOSE: Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. PATIENTS AND METHODS: In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). RESULTS: One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. CONCLUSION: Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Hepatocellular Carcinoma with Cervical Spine and Pelvic Bone Metastases Presenting as Unknown Primary Neoplasm.

The occurrence of hepatocellular carcinoma (HCC) is closely associated with viral hepatitis or alcoholic hepatitis. Although active surveillance is ongoing in Korea, advanced or metastatic HCC is found at initial presentation in many patients. Metastatic HCC presents with a hypervascular intrahepatic tumor and extrahepatic lesions such as lung or lymph node metastases. Cases of HCC presenting as carcinoma of unknown primary have been rarely reported. The authors experienced a case of metastatic HCC in a patient who presented with a metastatic bone lesion but no primary intrahepatic tumor. This case suggests that HCC should be considered as a differential diagnosis when evaluating the primary origin of metastatic carcinoma.

A case-control study to identify risk factors for totally implantable central venous port-related bloodstream infection.

PURPOSE: To date, the risk factors for central venous port-related bloodstream infection (CVPBSI) in solid cancer patients have not been fully elucidated. We conducted this study in order to determine the risk factors for CVP-BSI in patients with solid cancer. MATERIALS AND METHODS: A total of 1,642 patients with solid cancer received an implantable central venous port for delivery of chemotherapy between October 2008 and December 2011 in a single center. CVP-BSI was diagnosed in 66 patients (4%). We selected a control group of 130 patients, who were individually matched with respect to age, sex, and catheter insertion time. RESULTS: CVP-BSI occurred most frequently between September and November (37.9%). The most common pathogen was gram-positive cocci (n=35, 53.0%), followed by fungus (n=14, 21.2%). Multivariate analysis identified monthly catheter-stay as a risk factor for CVP-BSI (p=0.000), however, its risk was lower in primary gastrointestinal cancer than in other cancer (p=0.002). Initial metastatic disease and long catheter-stay were statistically significant factors affecting catheter life span (p=0.005 and p=0.000). Results of multivariate analysis showed that recent transfusion was a risk factor for mortality in patients with CVP-BSI (p=0.047). CONCLUSION: In analysis of the results with respect to risk factors, prolonged catheter-stay should be avoided as much as possible. It is necessary to be cautious of CVP-BSI in metastatic solid cancer, especially non-gastrointestinal cancer. In addition, avoidance of unnecessary transfusion is essential in order to reduce the mortality of CVP-BSI. Finally, considering the fact that confounding factors may have affected the results, conduct of a well-designed prospective controlled study is warranted.

Definitive concurrent chemoradiotherapy in locally advanced pancreatic cancer.

PURPOSE: Survival outcome of locally advanced pancreatic cancer has been poor and little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiation. This study was to analyze overall survival and prognostic factors of patients treated with concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic cancer. MATERIALS AND METHODS: Medical records of 34 patients diagnosed with unresectable pancreatic cancer and treated with definitive CCRT, from December 2003 to December 2012, were reviewed. Median prescribed radiation dose was 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, five times per week, 1.8 to 3 Gy per fraction. RESULTS: With a mean follow-up of 10 months (range, 0 to 49 months), median overall survival was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Prognostic parameters related to overall survival were post-CCRT CA19-9 (p = 0.02), the Eastern Cooperative Oncology Group (ECOG) status (p < 0.01), and radiation dose (p = 0.04) according to univariate analysis. In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved overall survival (p < 0.01 and p = 0.02, respectively). CONCLUSION: Overall treatment results in locally advanced pancreatic cancer are relatively poor and few improvements have been accomplished in the past decades. Post-treatment CA19-9 below 180 U/mL and ECOG performance status 0 and 1 were significantly associated with an improved overall survival.

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX. METHODS: This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 (p = 0.012). CONCLUSION: TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.

Two-week course of preoperative chemoradiotherapy followed by delayed surgery for rectal cancer: a phase II multi-institutional clinical trial (KROG 11-02).

PURPOSE: The aim of this study was to evaluate the efficacy and safety of a two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer. METHODS AND MATERIALS: Eighty patients with rectal cancer located in the mid to low rectum, staged cT3-4N0-2M0, were prospectively enrolled. They underwent preoperative chemoradiotherapy and delayed surgery 6-8 weeks after the completion of radiation therapy. A radiation dose of 33 Gy in 10 fractions was delivered to the pelvis for 2 weeks. One cycle of oral capecitabine was administered at a dose of 1650 mg/m(2)/day during radiotherapy. Tumor response and toxicity were the study endpoints. This study was registered at ClinicalTrials.gov (number, NCT01431599). RESULTS: All included patients underwent total mesorectal excisions including 12 cases of robot assisted surgery and 50 cases of laparoscopic surgery. Of the 80 patients, 27 (33.8%) achieved downstaging (ypT0-2N0) of a rectal tumor and 11 (13.8%) had a pathologically complete response (ypCR). Downstaging rates were 45% for T classification and 65% for N classification. Sphincter saving was achieved in 73 (91.3%) of the 80 patients. Of the 80 patients, 3 (3.8%) experienced grade 3 hematologic toxicity, and 2 (2.5%) had grade 3 postoperative complications such as ileus and wound dehiscence. There was no grade 4 toxicity. CONCLUSION: A two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer patients showed low toxicity profiles and promising results in terms of tumor response.

Effects and safety of gyejibongnyeong-hwan on dysmenorrhea caused by blood stagnation: a randomized controlled trial.

Objective. This study was a multicenter, randomized, double-blind, and controlled trial with two parallel arms: the GJBNH group and the placebo group. This trial recruited 100 women aging 18 to 35 years with primary dysmenorrhea caused by blood stagnation. The investigational drugs, GJBNH or placebo, were administered for two menstrual periods (8 weeks) to the participants three times per day. The participants were followed up for two menstrual cycles after the administration. Results. The results were analyzed by the intention-to-treat (ITT) dataset and the per-protocol (PP) dataset. In the ITT dataset, the change of the average menstrual pain VAS score in the GJBNH group was statistically significantly lower than that in the control group. Significant difference was not observed in the SF-MPQ score change between the GJBNH group and the placebo group. No significant difference was observed in the PP analyses. In the follow-up phase, the VAS scores of the average menstrual pain and the maximum menstrual pain continually decreased in the placebo group, but they increased in the GJBNH group. Conclusion. GJBNH treatment for eight weeks improved the pain of the dysmenorrhea caused by blood stagnation, but it should be successively administered for more than two menstrual cycles. Trial Registration. This trial is registered with Current Controlled Trials no. ISRCTN30426947.

Comparison between preoperative and postoperative concurrent chemoradiotherapy for rectal cancer: an institutional analysis.

PURPOSE: To evaluate the treatment outcomes of preoperative versus postoperative concurrent chemoradiotherapy (CRT) on locally advanced rectal cancer. MATERIALS AND METHODS: Medical data of 114 patients with locally advanced rectal cancer treated with CRT preoperatively (54 patients) or postoperatively (60 patients) from June 2003 to April 2011 was analyzed retrospectively. 5-Fluorouracil (5-FU) or a precursor of 5-FU-based concurrent CRT (median, 50.4 Gy) and total mesorectal excision were conducted for all patients. The median follow-up duration was 43 months (range, 16 to 118 months). The primary end point was disease-free survival (DFS). The secondary end points were overall survival (OS), locoregional control, toxicity, and sphincter preservation rate. RESULTS: The 5-year DFS rate was 72.1% and 48.6% for the preoperative and postoperative CRT group, respectively (p = 0.05, the univariate analysis; p = 0.10, the multivariate analysis). The 5-year OS rate was not significantly different between the groups (76.2% vs. 69.0%, p = 0.23). The 5-year locoregional control rate was 85.2% and 84.7% for the preoperative and postoperative CRT groups (p = 0.98). The sphincter preservation rate of low-lying tumor showed significant difference between both groups (58.1% vs. 25.0%, p = 0.02). Pathologic tumor and nodal down-classification occurred after the preoperative CRT (53.7% and 77.8%, both p < 0.001). Acute and chronic toxicities were not significantly different between both groups (p = 0.10 and p = 0.62, respectively). CONCLUSION: The results confirm that preoperative CRT can be advantageous for improving down-classification rate and the sphincter preservation rate of low-lying tumor in rectal cancer.

Status of hepatocellular carcinoma in South Korea.

In South Korea, liver cancer is the 4th most common cancer in men and 6th most common cancer in women. However, the incidences of liver cancer among Korean men and women have been declining from 1999 to 2010. The reason for the declining incidence appears secondary to decreased hepatitis B virus (HBV) infection, which is the leading risk factor for hepatocellular carcinoma (HCC), with successful implementation of HBV vaccination since 1983. Despite recent advances in the treatment of HCC, including liver transplantation (LT), radiofrequency ablation (RFA), transarterial embolization, and the use of molecularly targeted agents, many patients cannot be cured due to the advanced stage of HCC at the time of diagnosis in South Korea. While the 5-year survival rate of HCC patients in Korea is relatively lower than other cancers, it has been gradually increased from the early 1990s to the late 2000s. The reason for the improvement in 5-year survival rates is attributed that early detection of HCC becomes possible by well-established surveillance program in high-risk populations for HCC in Korea. In Korea, national surveillance program for HCC was established in 2003, in which repeated applications of screening tests [serum α-fetoprotein (AFP) and liver ultrasound] at 6-month intervals have been recommended in patients at high risk for developing HCC, such as men and women older than 40 years of age with positive hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) or underlying liver cirrhosis. It is essential that the nationwide surveillance program for HCC should be effectively executed in high-risk patients for developing HCC. Optimal application of multidisciplinary team approach and active involvement in clinical studies with new agents in HCC patients are critically important not only for the management of advanced HCC patients but also for the improvement in natural history and therapeutic outcomes of HCC patients in the future.

Effect of oriental medicine music therapy on patients with Hwa-byung: a study protocol for a randomized controlled trial.

BACKGROUND: Hwa-byung, a Korean culture-bound syndrome with both psychological and somatic symptoms, is also known as 'anger syndrome'. It includes various physical symptoms including anxiety, a feeling of overheating, a sensation of pressure on the chest, heart palpitations, respiratory stuffiness, insomnia, and anxiety. METHODS/DESIGN: The proposed study is a single-center, double-blind, randomized, controlled trial with two parallel arms: an oriental medicine music therapy (OMMT) group and a control music therapy (CMT) group. In total, 48 patients will be enrolled into the trial. The first visit will be the screening visit. At baseline (visit 2), all participants fulfilling both the inclusion and the exclusion criteria will be split and randomly divided into two equal groups: the OMMT and the CMT (n = 24 each). Each group will receive treatment sessions over the course of 4 weeks, twice per week, for eight sessions in total. The primary outcome is the State-Trait Anxiety Inventory (STAI), and the secondary outcomes are the Hwa-byung scale (H-scale), the Center for Epidemiologic Studies Depression Scale (CES-D), the Hwa-byung visual analogue scale (H-VAS) for primary symptoms, the World Health Organization Quality of Life scale, brief version (WHOQOL-BREF), and levels of salivary cortisol. Patients will be asked to complete questionnaires at the baseline visit (visit 2), after the last treatment session (visit 9), and at 4 weeks after the end of all trial sessions (visit 10). From the baseline (visit 2) through the follow-up (visit 10), the entire process will take a total of 53 days. DISCUSSION: This proposed study targets patients with Hwa-byung, especially those who have exhibited symptoms of anxiety. Therefore, the primary outcome is set to measure the level of anxiety. OMMT is music therapy combined with traditional Korean medicinal theories. Unlike previously reported music therapies, for which patients simply listen to music passively, in OMMT, patients actively move their bodies and play the music. Because Hwa-byung is caused by an accumulation of blocked emotions and anger inside the body, OMMT, because of its active component, is expected to be more efficacious than pre-existing music therapies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11939282.

Effects of Gyejibongnyeong-hwan on dysmenorrhea caused by blood stagnation: study protocol for a randomized controlled trial.

BACKGROUND: Gyejibongnyeong-hwan (GJBNH) is one of the most popular Korean medicine formulas for menstrual pain of dysmenorrhea. The concept of blood stagnation in Korean medicine is considered the main factor of causing abdominal pain, or cramps, during menstrual periods. To treat the symptoms, GJBNH is used to fluidify the stagnated blood and induce the blood flow to be smooth, reducing pain as the result. The purpose of this trial is to identify the efficacy of GJBNH in dysmenorrhea caused by blood stagnation. METHODS: This study is a multi-centre, randomised, double-blind, controlled trial with two parallel arms: the group taking GJBNH and the group taking placebo. 100 patients (women from age 18 to 35) will be enrolled to the trial. Through randomization 50 patients will be in experiment arm, and the other 50 patients will be in control arm. At the second visit (baseline), all participants who were already screened that they fulfil both the inclusion and the exclusion criteria will be randomised into two groups. Each group will take the intervention three times per day during two menstrual cycles. After the treatment for two cycles, each patient will be followed up during their 3rd, 4th and 5th menstrual cycles. From the screening (Visit 1) through the second follow-up (Visit 6) the entire process will take 25 weeks. DISCUSSION: This trial will provide evidence for the effectiveness of GJBNH in treating periodical pain due to dysmenorrhea that is caused by blood stagnation. The primary outcome between the two groups will be measured by changes in the Visual Analogue Score (VAS) of pain. The secondary outcome will be measured by the Blood Stagnation Scale, the Short-form McGill questionnaire and the COX menstrual symptom scale. Analysis of covariance (ANCOVA) and repeated measured ANOVA will be used to analyze the data analysis. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN30426947.

Retroperitoneal smooth muscle tumor of uncertain malignant potential after hysterectomy: a case report.

INTRODUCTION: Smooth muscle tumors of uncertain malignant potential represent a histologically heterogeneous group of uterine smooth muscle tumors that cannot be diagnosed as either benign or malignant. Smooth muscle tumors of uncertain malignant potential are usually clinically benign, but should be considered tumors of low malignant potential because they can occasionally recur or metastasize to distant sites. CASE PRESENTATION: We report the case of a 62-year-old Mongol woman diagnosed with a retroperitoneal smooth muscle tumor of uncertain malignant potential and lung metastasis, with a history of prior hysterectomy. The case was initially misdiagnosed as retroperitoneal sarcoma, and our patient received chemotherapy. However, no interval change in the size of the retroperitoneal mass and metastatic lung nodules was seen over a period of at least five years. She underwent partial resection of the retroperitoneal mass for the purposes of debulking and establishing a histopathological diagnosis. The diagnosis of the retroperitoneal mass was then confirmed as a smooth muscle tumor of uncertain malignant potential. CONCLUSION: Smooth muscle tumors of uncertain malignant potential have an unpredictable clinical course, and relapses generally appear to occur after a long disease-free interval of up to several years. Therefore, patients diagnosed with smooth muscle tumors of uncertain malignant potential should receive long-term follow-up.

High-dose chemotherapy with autologous stem cell rescue in stage IIIB inflammatory breast cancer.

BACKGROUND: Despite the advances in breast cancer care, inflammatory breast cancer (IBC) has a poor prognosis. The purpose of this study was to determine the efficacy of high-dose chemotherapy (HDCT) with thiotepa, mitoxantrone and carboplatin (TMJ regimen) in women with TNM stage IIIB IBC. PATIENTS AND METHODS: Between 1991 and 1998, twenty-eight patients with stage IIIB IBC underwent an autologous stem cell transplant after undergoing chemotherapy, surgery and/or radiation. Stem cells were collected from the bone marrow and periphery after mobilization with growth factors. Patients received thiotepa 250 mg/m2 once daily i.v. for 3 days, mitoxantrone 40 mg/m2 for 1 day and carboplatin 333 mg/m2 once daily i.v. for 3 days as the conditioning regimen for the HDCT. Radiation therapy and tamoxifen was offered to patients post HDCT if appropriate. Progression-free survival and overall survival was assessed over a 15-year period. RESULTS: At the time of last follow-up in May, 2007, sixteen patients had relapsed. The median overall survival was 49.5 months. The median progression free survival was 40 months. There were no transplant-related deaths. Mucositis and infections were the major side-effects. These results show that HDCT with the TMJ regimen is safe and effective in patients with stage IIIB IBC.

Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation.

BACKGROUND: There is no clear consensus regarding the best treatment strategy for patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with cirrhosis and HCC beyond Milan who had undergone liver resection (LR) or primary orthotopic liver transplantation (OLT) between November 1995 and December 2005 were included in this study. Pathological tumor staging was based on the American Liver Tumor Study Group modified Tumor-Node-Metastasis classification. RESULTS: A total of 23 HCC patients were primarily treated by means of LR, 5 of whom eventually underwent salvage OLT. An additional 32 patients underwent primary OLT. The overall actuarial survival rates at 3 and 5 years were 35% after LR, and 69% and 60%, respectively, after primary OLT. Recurrence-free survival at 5 years was significantly higher after OLT (65%) than after LR (26%). Of the patients who underwent LR, 11 (48%) experienced HCC recurrence only in the liver; 6 of these 11 presented with advanced HCC recurrence, poor medical status, or short disease-free intervals and were not considered for transplantation. Salvage OLT was performed in 5 patients with early stage recurrence (45% of patients with hepatic recurrence after LR and 22% of all patients who underwent LR). At a median of 18 months after salvage OLT, all 5 patients are alive, 4 are free of disease, and 1 developed HCC recurrence 16 months after salvage OLT. CONCLUSION: For patients with HCC beyond Milan criteria, multimodality treatment-including LR, salvage OLT, and primary OLT-results in long-term survival in half of the patients. When indicated, LR can optimize the use of scarce donor organs by leaving OLT as a reserve option for early stage HCC recurrence.

Phase I clinical trial of irinotecan with oral capecitabine in patients with gastrointestinal and other solid malignancies.

The purpose of this study was to determine the safety of irinotecan and capecitabine in patients with advanced solid tumors. Thirty-four patients received 122 courses of irinotecan 200 to 300 mg/m(2) as an intravenous infusion during 30 minutes on day 1 and capecitabine 1,500 to 3,000 mg/d orally 12 hours apart starting on day 2 for 14 days, repeated every 21 days (one course). Three to seven patients were treated in six dose-escalation cohorts. Three of 7 (43%) patients treated with irinotecan 300 mg/m(2) and capecitabine 2,300 mg/d had course 1 dose-limiting toxicity (DLT) defining maximum tolerated dosage (MTD). Fatigue and diarrhea were the major DLTs, and other events included neutropenia, anorexia, and hand-foot syndrome. At one dose level below the MTD, none of 7 patients treated with irinotecan 275 mg/m(2), and capecitabine 2,300 mg/d (36 courses) had course 1 DLT. Grade III to IV toxicities beyond course 1 included neutropenia (11% of all courses), fatigue (3.4%) and hand-foot syndrome (3.4%). There were only two episodes of febrile grade II neutropenia. There were no toxic deaths. Transient antitumor response was noted in one patient with irinotecan and 5-fluorouracil-refractory colon cancer. The combination of irinotecan 275 mg/m(2) and capecitabine 2,300 mg/d represents a safe, favorable, and convenient outpatient regimen warranting further phase II evaluation.

Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma.

PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.