Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials

PURPOSE: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine (131I) metuximab injection (Licartin), a novel 131I-labeled HAb18G/CD147-specific monoclonal antibody Fab'2 fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. METHODS AND MATERIALS: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. RESULTS: No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p = 0.0019). CONCLUSION: Iodine (131I) metuximab injection is safe and active for HCC patients.     

Phase I/II trial of hyperfractionated accelerated chemoradiotherapy for unresectable advanced pancreatic cancer

BACKGROUND: We conducted a Phase I/II study to evaluate the local efficacy and toxicity of hyperfractionated accelerated radiotherapy (HART) combined with 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with unresectable advanced pancreatic cancer. METHODS: Thirty-five patients (15 with Stage 4A and 20 with Stage 4B disease according to TNM classification) were enrolled between August 1997 and August 2001 into this Phase I/II trial. All patients received concurrent HART (1.5 Gy twice daily separated by 6 h for 5 days per week), 5-FU (375 mg/m(2) given as continuous intravenous infusion), and CDDP (2 mg/m(2) given as 30-min infusion just before each fraction of irradiation). In the Phase I trial, the total dose of radiation was escalated from 27 to 45 Gy. RESULTS: Twenty-one patients were enrolled in the Phase I study and six patients were given the final planned dose (45 Gy) which did not exceed the maximum tolerated dose. Eleven patients (52.4%) suffered from Grade 3 or worse neutropenia. Vomiting and mucositis were observed in 21 (100%) and 12 (57.1%) patients, respectively. An additional 14 patients were entered in the Phase II trial and received a total dose of 45 Gy, which is recommended in Phase I trial. Concerning the local tumor control of 20 patients with the recommended regimen, 7 patients (35%) achieved partial response, 10 (50%) remained stable and local progressive disease occurred in 3 (15%). The median survival time and the overall 1-year survival rate were 11.2 months and 40.0%, respectively, in 20 patients who received the recommended regimen. In Stage 4A patients, they were 13.0 months and 70.0%, respectively. The trend of toxicities in patients with the recommended regimen was almost the same as that observed in the Phase I study. CONCLUSION: The chosen combined modality treatment was well tolerated, and showed an expected local efficacy for the treatment of unresectable advanced pancreatic cancer.     

A Phase I/II trial of chemoradiotherapy concurrent with S-1 plus mitomycin C in patients with clinical Stage II/III squamous cell carcinoma of anal canal (JCOG0903: SMART-AC)

A Phase I/II trial of chemoradiotherapy concurrent with S-1 plus mitomycin C in patients with clinical Stage II/III squamous cell carcinoma of the anal canal was started in Japan. The aim of this trial is to determine the recommended dose of S-1 combined with a fixed dose of mitomycin C plus radiotherapy in Phase I and to evaluate the efficacy and safety in Phase II. The primary endpoint for the Phase II part of this study is the proportion of 3-year event-free survival, in which the following are defined as events: disease progression, residual tumor at the end of chemoradiotherapy, colostomy or death, whichever comes first. Secondary endpoints are progression-free survival, proportion of complete response and adverse events. In the Phase II part of this study, a total of 65 patients will be enrolled from 42 institutions over 6 years.     

How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system

BACKGROUND: The life expectancy of a patient with hepatocellular carcinoma (HCC) in cirrhosis is hard to predict, making it difficult to decide whether a certain treatment is indicated and what to say to the patient regarding prognosis. A new score recently has been proposed, which includes the parameters involved in the Child-Pugh stage, plus macroscopic tumor morphology, alpha-fetoprotein levels, and the presence or absence of portal thrombosis. The score has been validated in internal control series, but its general applicability has yet to be confirmed. The authors compared the discriminatory ability of the Cancer of the Liver Italian Program (CLIP) score with those of the Okuda and TNM staging systems and the Child-Pugh classification in a group of cirrhotic patients with HCC, diagnosed and followed up by their unit. METHODS: One hundred fifty-four patients with histologically ascertained HCC in cirrhosis were recruited (median age, 62.5 years; male/female ratio, 122/32) and prospectively followed up. Staging was performed at the baseline using the Child-Pugh, Okuda, TNM, and CLIP systems. RESULTS: The CLIP score was able to predict survival better than the Okuda or TNM staging system, as confirmed by the Kaplan-Meier comparison of survival curves and by the Cox regression analysis, with a median survival rate of 31, 27, 13, 8, 2, and 2 months in patients with CLIP Stages 0, I, II, III, IV, and V-VI, respectively. The Child-Pugh classification performed as well as the Okuda. The predictive capacity of CLIP score was confirmed in the subgroup of patients undergoing chemoembolization. Overall, the survival rate in the authors' series was higher than predicted on the basis of previous reports. CONCLUSIONS: The CLIP score, which is based on simple features of the patient and of the tumor, can accurately identify patients with different prognoses, particularly in the early phases of HCC, thus representing a useful tool in the management of the disease and of the affected patient.     

Ovarian cancer BRCA1 gene therapy: Phase I and II trial differences in immune response and vector stability.

Gene therapy with viral vectors has shown some promise in nude mice models and in initial Phase I trials of patients with extensive metastatic cancer. A Phase I clinical trial (D. L. Tait et al., Clin. Cancer Res., 3: 1959-1968, 1997) of ovarian cancer patients treated with i.p. retroviral LXSN-BRCA1sv gene therapy reported stable vector, minimal antibody response, and tumor reduction. We initiated a Phase II trial on patients with less extensive disease to evaluate vector pharmacokinetics, immune response, toxicity, and efficacy. Patients received a surgically implanted peritoneal catheter to administer infusions of vector, as well as to retrieve daily samples of peritoneal fluid for analysis. Ovarian cancer patients received four daily i.p. injections of LXSN-BRCA1sv vector therapy for three cycles, 4 weeks apart. Patient peritoneal fluid and plasma were analyzed extensively by PCR, Western blot, complement level (CH50), and chemical and hematological tests. Phase II patients showed no response, no disease stabilization, and little or no vector stability. Because of vector instability and rapid antibody development, which differed dramatically from the Phase I trial data, the trial was terminated after treatment of six patients. Immune system status appears to have played a major role in whether gene therapy was effective. Comparison of Phase I and II patients showed significant differences in tumor burden, immune system status, and response to BRCA1 gene therapy.     

Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization

BACKGROUND: The purpose of our study was to evaluate the outcome of unresectable hepatocellular carcinoma (HCC) patients, who had either failed with or were unsuited for transcatheter arterial chemoembolization (TACE), treated with three-dimensional conformal radiation therapy (3DCRT) and to determine the prognostic outcome factors. METHODS: From September 1999 to March 2003, 44 patients with unresectable HCC underwent 3DCRT. Thirty-seven patients were male and seven female. Mean age was 62 years, ranging from 34 to 88. Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 10 patients, 1 in 19 patients, and 2 in 15 patients. According to Child-Pugh classification for cirrhosis of the liver, 32 patients were in class A and 12 patients in class B. There were 14 patients with main portal vein thrombosis. Twenty patients had alpha-fetoprotein (AFP) level >400 ng/ml. Tumor size was <5 cm in 16 patients, 5-10 cm in 16 patients, and >10 cm in 12 patients. Thirty-two patients had tumors of confluent type, the remaining patients presented a single hepatic tumor. Serum hepatitis antigen markers were positive for type B in 35 patients and type C in nine patients. Twenty-one patients had Okuda Stage I, 22 patients Stage II, and one patient Stage III. According to the AJCC staging system (5th edition), eight patients were in Stage II (T2N0M0), 19 in Stage IIIA (T3N0M0) and 17 in Stage IVA (T4N0M0). RESULTS: An objective response was observed in 27 of 44 patients, giving a response rate of 61.4%.The survival rates at 1, 2 and 3 years were 60.5%, 40.3% and 32.0%, respectively. In the analysis of prognostic factors, Okuda stage, AJCC stage, portal vein thrombosis, pretreatment AFP level, and total dose of radiotherapy all had significant impact on survival. CONCLUSIONS: 3DCRT induced a substantial tumor response rate of 61.4% with survival rates at 1, 2 and 3 years of 60.5%, 40.3% and 32.0%, respectively, and a median survival time of 15.2 months in patients with unresectable HCC who had either failed with or were unsuited for TACE. The complications are acceptable and can be managed with conservative treatment. Although we do not know whether there is a survival benefit through the use of this treatment, 3DCRT seems to be a practical method of salvage for this subset of patients. Further study is warranted to evaluate the survival of such patients with and without this treatment.     

Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma.

PURPOSE: We conducted a Phase II clinical trial with randomized patients to determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against postsurgical recurrence of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Forty-one patients with HCC who had undergone curative resection were randomly allocated to the vaccine treatment (n = 19) or no adjuvant control group (n = 22). Three intradermal vaccinations were administered at 2-week intervals beginning 4-6 weeks after hepatic resection. A delayed-type hypersensitivity test was performed before and after vaccination. Primary and secondary end points are recurrence-free survival and overall survival, respectively. Observation continued until the majority of surviving patients had lived >12 months after the curative resection. RESULTS: In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33-95%; P = 0.003). Vaccination significantly prolonged the time to first recurrence (P = 0.003) and improved recurrence-free survival (P = 0.003) and overall survival rates (P = 0.01). AFTV played a significant role in preventing recurrence in patients with small tumors. Adverse effects were limited to grade 1 or 2 skin toxicities such as erythema, dry desquamation, and pruritus. CONCLUSIONS: AFTV therapy is a safe, feasible, and effective treatment for preventing postoperational recurrence of HCC. Patients with low tumor burdens benefit from the treatment. This treatment should be advanced to a large-scale randomized trial.     

Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients

A total of 850 patients with hepatocellular carcinoma seen during the last 8 years were analyzed retrospectively for survival in relation to treatment and disease stage. A new staging scheme based on tumor size, ascites, jaundice and serum albumin was used. Clearly, the prognosis depended on disease stage. The median survival of 229 patients who received no specific treatment was 1.6 months, 0.7 month for Stage III patients, 2.0 months for Stage II, and 8.3 months for Stage I. The median survival of Stage I patients who had hepatic resection (n = 115) was 25.6 months and Stage II patients with resection (n = 42) was 12.2 months. In patients who had a small cancer (less than or equal to 25% of liver area in size) the median survival was 29.0 months. Survival of the surgically treated patients, which represented a highly selected group, was better than that of medically treated patients of a comparable stage. Median survival of Stage I medically treated patients (n = 124) was 9.4 months, for Stage II (n = 290) 3.5 months, and for Stage III (n = 50) 1.6 months. Medical treatment prolonged survival in Stage II and III patients, but not in Stage I. Transcatheter arterial embolization gave a better survival compared with chemotherapy, whether intra-arterial bolus administration of mitomycin C, systemic mitomycin C, or oral/rectal tegafur, in Stage II. Among various chemotherapeutic modalities, intra-arterial bolus injection was superior to systemic chemotherapy in survival in Stage II. In Stage III, chemotherapy improved survival as compared with no specific treatment. The major causes of death were hepatic failure and gastrointestinal bleeding, probably due to the coexistent advanced cirrhosis. These results in survival are much improved over the past reports, and the differences are probably a result of earlier diagnosis and frequent hepatic resections.     

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PURPOSE: Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. EXPERIMENTAL DESIGN: Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. RESULTS: The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. CONCLUSIONS: PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.     

Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma.

PURPOSE: Randomized studies on tamoxifen treatment of hepatocellular carcinoma (HCC) produced conflicting results. The aim of this study was to assess the efficacy of tamoxifen administration in improving overall survival of patients with advanced HCC. PATIENTS AND METHODS: A total of 420 patients with HCC who were not suitable for surgery or local treatment were randomly assigned between April 1995 and May 2000: 210 in the control group and 210 in the tamoxifen group (20 mg/d orally). Patients with WHO performance status greater than 2, belonging to Child-Pugh class C, or with serum creatinine greater than 130 mumol/L were not eligible. RESULTS: Tolerance was good and the main reported adverse effects were thrombophlebitis (three patients), nausea (two patients), and hot flushes (three patients). Outcome did not differ between the two treatment arms: estimated median survival was 4.8 and 4.0 months in the tamoxifen and in the control groups, respectively (P = .25). Univariate analysis showed significant association of survival with age, Okuda stage, WHO performance status, Child-Pugh class, intrahepatic tumor stage, alpha-fetoprotein serum concentration, and presence of extrahepatic spread, portal vein thrombosis, hepatomegaly, or hepatalgia. In a Cox proportional hazards model we found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda I or II stages. CONCLUSION: In this large study, tamoxifen did not improve the survival of patients with advanced HCC, but there is a suggestion that patients without major hepatic insufficiency seem to have some survival benefit. New trials involving this specific population are warranted.     

Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988.

BACKGROUND. The outlook for patients with germ cell tumors was poor before the advent of effective chemotherapy. The authors assessed the outcome of treatment with multiagent chemotherapy (with or without radiation therapy) in children treated for germ cell tumors at St. Jude Children's Research Hospital (SJCRH). METHODS. Sixty children with germ cell tumors were treated between January 1979 and June 1988. Postsurgical treatment was based on tumor site, stage, and histology. Most patients received chemotherapy with vincristine, actinomycin-D, and cyclophosphamide (VAC), or a modified Einhorn regimen (cisplatin, bleomycin, and vinblastine [PVB]); in the absence of response to initial therapy, patients received alternating courses of VAC and PVB (VAC/PVB regimen). Exceptions were patients with Stage I testicular tumors (observation only) and ovarian germinomas (Stage I tumors measuring less than 10 cm, observation only; tumors larger than 10 cm or Stage II-III disease, radiation only; and Stage IV disease, VAC plus radiation). RESULTS. The estimated 5-year survival is 100% for patients with Stage I disease (n = 18), 87% for patients with Stage II (n = 8), 72% for Stage III (n = 25), and 56% for Stage IV (n = 9). Patients with testicular tumors of any stage or with Stage I-II ovarian tumors had 100% 5-year survival. Extragonadal tumors responded poorly to VAC alone with recurrent or progressive disease in eight of nine patients. Treatment for those tumors was changed to alternating courses of VAC and PVB, which failed in only one of seven patients. Nine of 19 patients with advanced ovarian tumors had disease recurrence with VAC; these patients then received PVB, which was effective in four cases. CONCLUSIONS. For patients with advanced germ cell cancers, intensification of therapy or the development of new approaches is necessary. In contrast, future trials in children with limited stage should focus on reducing acute and long-term toxicities.     

Specific active lung cancer immunotherapy. Immune correlates of clinical responses and an update of immunotherapy trials evaluations

The mechanisms of action of the specific active immunotherapy of solid tumors have not been defined. In an attempt to characterize some of these mechanisms, we report controlled studies of humoral immune responses and cell-mediated immune (CMI) responses in lung cancer patients with Stage I and Stage II adenocarcinoma and squamous cell cancer receiving pure tumor-associated antigen (TAA) specific active immunotherapy or combination immunochemotherapy. At 5 to 6 months postimmunotherapy, the humoral immune response measurements are predictive of response to therapy/survival in early lung cancer patients, permitting decisions as to whether to continue therapy. Patients with adenocarcinoma respond to combination chemoimmunotherapy by showing stronger or earlier responses to tests of immunity. Cell-mediated immunity to TAA at 17 to 24 months was far greater in patients receiving immunotherapy or immunochemotherapy compared with control patients, and also correlated with early humoral immune response and with 5-year survival. Here we report a further subset analysis of Stage I and Stage II lung cancer patients in a successful Phase III US specific active immunotherapy trial as substantiating the experience with Stage I patients in a successful Phase II Canadian trial. We analyze failures and suggest additional therapies, especially a chemoimmunotherapy trial indicated by our analyses of humorocellular immune variables reported here.     

A phase I/II study of carboplatin and paclitaxel in patients with epithelial ovarian cancer

BACKGROUND: This study was conducted to investigate the recommended dose of paclitaxel for use in combination with a fixed dose of carboplatin and to evaluate the toxicity and efficacy of carboplatin-paclitaxel combination chemotherapy in patients with epithelial ovarian cancer. METHODS: One hundred and ten patients were enrolled in the Phase I/II study and 97 patients were evaluated for further analysis, excluding 13 ineligible patients or patients with infringement of protocol: 15 patients for the Phase I and 82 for the Phase II study. In the Phase I trial, we studied dose escalation using a carboplatin dose of AUC 5 and paclitaxel levels of 150, 175 and 200 mg/m(2). The grades of toxicity of the regimen of all patients enrolled in the Phase II study (n = 82), the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62) and the response rate of suboptimal-debulked patients (n = 39) were investigated. RESULTS: After observing grade 4 neutropenia in four of six patients in the paclitaxel 200 mg/m(2) administration group, we chose 175 mg/m(2) as the recommended dose of paclitaxel in this regimen. At this dose, the median of PFS and response rate were 432 days (range, 19-907 days) and 66.7%, respectively. CONCLUSION: Combination chemotherapy using paclitaxel 175 mg/m(2) and carboplatin AUC 5 is very well tolerated and highly effective for the treatment of ovarian cancer.     

Lessons learned from independent central review

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin^® trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210–7]. In addition, clinical trial sponsors have used ICR in Phase I–II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180–6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407–14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171–7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293–300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin’s lymphoma. JCO 2006(September):4123–8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354–60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502–12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663–7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803. JCO 2004(November):4319–28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.     

A study of oral etoposide, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small-cell lung cancer. A Mid-Atlantic Oncology Program study.

A combination of oral etoposide, infusional cisplatin (24-hr) and infusional 5-fluorouracil (5-day) was used to treat 87 patients with non-small-cell lung cancer in a Phase II trial. Twenty-six patients were Stage IIIB, and 61 patients were Stage IV (new international classification). The regimen was well tolerated, with 49% grade 3 or 4 toxicities of all types. Response rates, partial and complete, were 40%, (95% confidence interval: 30%, 51%) for Stage IV patients and 20% (95% confidence interval: 10%, 32%), in Stage IIIB. An additional 68% of patients in Stage IIIB and 45% of patients in Stage IV achieved stable disease and had a median survival of 8.8 months, similar to that of patients in partial remission. Median survival was 5.6 months (95% confidence interval: 4.4 months, 10.8 months) for Stage IV patients and 11.0 months (95% confidence interval: 8.8 months, 12.4 months), for Stage IIIB. Of interest was the finding of a higher response rate in patients with a shorter duration of symptoms (less than 6 months versus greater than 6 months).     

Particle embolization of recurrent hepatocellular carcinoma after hepatectomy

BACKGROUND: Complete surgical resection is the mainstay of treatment for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients ultimately develop disease recurrence and the median survival from the time of recurrence is <1 year. The purpose of the current study was to review the authors' experience using bland hepatic arterial embolization to treat recurrent HCC after definitive surgical resection. METHODS: The authors reviewed their single-center hepatic embolization database from 1995 through 2004 to identify patients who underwent bland hepatic arterial embolization for disease recurrence. Data analyzed included patient demographics, Okuda stage and Child score, imaging findings, and embolization variables. Recurrence-free survival (from surgery to disease recurrence) and survival time (from recurrence to last follow-up) were calculated using the Kaplan-Meier method. RESULTS: The authors identified 45 patients treated with bland embolization for recurrent HCC after resection. Six patients also underwent ablative therapy after embolization. Of the 45 patients, 42 (93.3%) patients had Okuda Stage 1 disease. The median time to recurrence was 13 months. The median survival after embolization was 46 months, and actuarial survival rates at 1 year, 2 years, and 5 years after recurrence were 86%, 74%, and 47%, respectively, with a median follow-up of 31 months. Patients who developed disease recurrence with a solitary lesion had a significantly improved survival (P = .03) At the time of last follow-up, 3 patients (6.6%) were alive with no evidence of viable disease. CONCLUSIONS: Bland arterial embolization was found to be an effective method of salvage therapy for patients with good liver function with recurrent HCC after prior surgical resection. Patients whose disease recurred with a solitary lesion appear to have a significantly increased survival compared with patients who develop disease recurrence with multiple tumors. A small proportion of patients can be rendered without evidence of viable disease.     

Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I-II trial.

BACKGROUND: We determined the maximum tolerated dose (MTD) and then further evaluated the response rate and safety profile of gemcitabine (Gem) plus doxorubicin (Dox) in chemona?ve patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Dose escalation was tested over four dose levels in each 21-day cycle: level 1 (Gem 1000 mg/m(2) on days 1 and 8, Dox 30 mg/m(2) on day 1), level 2 (Gem/Dox 1250/30), level 3 (Gem/Dox 1250/45) and level 4 (Gem/Dox 1250/60). The MTD was further evaluated in phase II. RESULTS: Patients' characteristics were: 47 men, three women; median age 53 years (range 28-70); Zubrod performance status (PS) scores 0-1 (74%), PS 2 (26%); Okuda stage I (24%) and stage II (76%). Fifteen patients were enrolled in phase I: level 1 (n = 3), level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Level 2 was identified as the MTD. Dose-limiting toxicities included esophageal bleeding, grade 4 neutropenia and neutropenic fever. Of the 34 patients evaluable for response in phase II (of 35 total), there were four (11.8%) partial responses (95% CI, 0.8% to 22.8%) and six (17.6%) minor responses; nine (26.5%) had stable disease and 15 (44.1%) progressed. Sixteen per cent of patients had a decline of >or=50% in alpha-fetoprotein levels after treatment. Median survival and progression-free survival were 4.6 months (range 0.3-19.2) and 2.5 months (range 0.2-7.8), respectively, for 35 patients. Grade 3/4 hematological toxicities included anemia (45.7%), neutropenia (51.4%), thrombocytopenia (25.7%); febrile neutropenia (11.8%) and non-hematological toxicities were mild to moderate. CONCLUSIONS: Gemcitabine plus doxorubicin produces modest activity and moderate toxicity in this cohort of Chinese patients with advanced HCC.     

Nodular hepatocellular carcinoma. Treatment with subsegmental intraarterial injection of iodine 131-labeled iodized oil.

Internal radiation therapy with subsegmental arterial injection of iodine 131(131I)-labeled iodized oil (Lipiodol; Laboratorie, Guerbet, France) was evaluated in 24 patients with nodular hepatocellular carcinoma (HCC) ranging from 2.5 to 8.0 cm in size. 131I Lipiodol (555 to 2220 MBq in 3 to 8 ml) was injected depending on the tumor size. Tumor reduction was seen in 88.9% of tumors smaller than 4.0 cm in diameter, 65.5% of tumors between 4.1 to 6.0 cm, and 25.0% of tumors larger than 5.1 cm. The tumor size reduction corresponded to the gradual drop of serum alpha-fetoprotein (AFP) levels and devascularization on follow-up angiography. Adverse reactions from treatment included fever, mild abdominal pain, nausea, and elevation of transaminases. These were mild and well tolerated by patients. This method provided long-term local control without complications related to the thyroid, lung, gastrointestinal tract, and bone marrow.     

Intratumoral and parametrial infusion of a 3-nitrotriazole (AK-2123) in the radiotherapy of the uterine cervix cancer: stage II-III--preliminary positive results.

Based on a clinical differential effect of the action of a new hypoxic cell radiosensitizer, AK-2123 (a 3-nitro-1,2,4-triazole), on locally advanced cervix cancer (Stage II-B and III-B), a Phase I/II clinical trial has been carried out on 80 consecutive patients. They were intratumorally injected with AK-2123, wt 1% and 2%, 30 min before the delivery of external radiation therapy. The short-term effects show that exophytic types of lesions respond far better than endophytic types and AK-2123 may be replacing intracavitary radium for exophytic Stage II-B cervix cancer as the standard therapy for this neoplasm in our patients. Treatment is well tolerated and no neurological toxicity has been noted.