Phase II Trial

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diag-nosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated b2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.

Jeffrey A. Coderre,1 Eric H. Elowitz,2 Manjeet Chadha,3 Richard Bergland,2 Jacek Capala,1 Darrel D. Joel,1 Hungyuan B. Liu,1 Daniel N. Slatkin1 and Arjun D. Chanana1 1Medical Department Brookhaven National Laboratory, Upton, NY, 11973, USA; Departments of 2 ...

Introduction Cancer cervix is the second most common cancer
among women worldwide and is the cause of largest number of
cancer-related deaths among women in the developing countries.
In India cervical cancer is the commonest cancer among women
(126 000 new cases, 71 000 deaths around the year 2000). Due to
the lack of any population based screening in India nearly 80% of
the patients are detected at stage III or higher. There are trials
that do not conclusively prove that currently recommended
chemo-radiation will be equally effective in treating these large
number of advanced cases. With the objectives to evaluate
response and survival rates in patients with stage-III cervical
cancer treated with immunotherapy concomitant with
radiotherapy and compare the same with concomitant
chemo-radiation and to evaluate the safety of concomitant
immunotherapy and radiation this phase II trial was conducted by
Chittaranjan National Cancer Institute from 2008 to 2010 and
patients were followed up at 3 monthly intervals for 3 years.
Methods Stage III cervical cancer patients were randomized to study
arm (N = 104) or control arm (N = 105). In both arms the patients
received standard external beam radiation followed by brachytherapy.
In the study arm the patients received interferon-alpha 2b (3 mIU
subcutaneously thrice a week for 4 weeks) and retinoic acid (40 mg/
day orally for 30 days) starting from first day of radiation. Patients in
the control arm received cisplatin (40 mg/m2 once a week for
5 weeks) starting from first day of radiation. Patients were evaluated
for response 1 month after completion of treatment. They were
followed up every 3 months for 3 years or till death.
Results The study arms were comparable for demographic and
disease variables. Complete response was seen in 84.6% in study
arm and 80.0% in control arm (P = 0.47). The 3 years overall
survival was superior in the control arm (Log Rank analysis:
X2 = 7.93; P = 0.005). The study and the control arms were
comparable for disease-free survival (Log Rank analysis:
X2 = 2.69; P = 0.10). The most frequently observed grade 3/4
toxicities were anemia, neutropenia and gastro-intestinal toxicities,
which were significantly more frequent in chemo-radiation arm
compared to immuno-radiation arm.
Conclusions Immuno-radiation therapy had the same response
rate and disease-free survival as chemo-radiation but better
toxicity profile. The overall survival was inferior.

Background and purposeWe aim to report on local control in a phase II trial on preoperative hyperfractionated and accelerated radiotherapy schedule (HART) in locally advanced resectable rectal cancer (LARC). This fractionation schedule was designed to keep the overall treatment time (OTT) as short as possible.

This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m 2 ) plus high-dose cyclophosphamide (3000-4000 mg/m 2 ). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 × 10 9 /l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Evaluation of this regimen is being done in a phase II trial. Bone Marrow Transplantation (2001) 27, 117-123.

Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration^approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients.We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-nB (NF-nB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-nB and cyclooxygenase-2 were monitored. Results:Twenty-five patients were enrolled, with 21evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4-to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-nB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900 mg BPA/kg body weight was shown to be safe and resulted in the average blood-boron concentration of 24 µg/g (range: 15-32 µg/g) at the time of irradiation (approximately 2-3 h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0-15.5 Gy(W) and 3.3-6.1 Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.

To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC). Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5-8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment. Patients with the T allele of ERCC1-118 showed significa...

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7...

Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferatoractivated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.

Our goal was to determine if a healing flare response seen on bone scintigraphy occurs following chemotherapy with Taxol (paclitaxel; Bristol-Myers Squibb Co., Princeton, NJ), a novel antimicrotubule agent for metastatic breast cancer. We performed 74 bone scans on 21 females with breast cancer and bone metastases entering a Phase II trial of Taxol chemotherapy with granulocyte colony stimulating factor (G-CSF). All patients had baseline scans within 6 wk prior to therapy, after the second cycle (4-6 wk) of Taxol, and then after 6-12 mo. All bone scans were reviewed by two nuclear medicine physicians, without knowledge of the patients&#39; clinical history. Skeletal radiographs, CT and MRI scans, as well as clinical history were compared with scan findings. Seven of the 21 patients showed improvement in bone scan findings. Of these seven, three had a flare response following two cycles (4-6 wk) of Taxol, characterized by increased activity in baseline lesions and the appearance of n...