Definitive chemoradiation in patients with inoperable oesophageal carcinoma.
ABSTRACT: We performed a retrospective study of 90 consecutive cases with inoperable carcinoma of the oesophagus treated with definitive chemoradiation at a single cancer centre between 1995 and 2002. For the last 4 years, 73 patients have received therapy according to an agreed protocol. This outpatient-based regimen involves four cycles of chemotherapy, cycles 3 and 4 given concurrently with 50 Gy external beam radiotherapy (XRT) delivered in 25 fractions over 5 weeks. Cisplatin 60 mg m(-2) day(-1) is given every 3 weeks together with continuous infusional 5-fluorouracil 300 mg m(-2) day(-1), reduced to 225 mg m(-2) day(-1) during the XRT. In all, 45 (50%) patients suffered one or more WHO grade 3/4 toxicity, grade 3 in 93% cases. Patients received more than 90% of the planned chemoradiation schedule. The median overall survival was 26 (15, >96) months, 51% (41, 64) and 26% (13, 52) surviving 2 and 5 years, respectively. Advanced stage, particularly T4 disease, was associated with a worse prognosis. Patients considered not suitable for surgery for reasons other than their disease, mainly co-morbidity, had a significantly better outcome, median survival 40 (26, >96) months, 2- and 5-year survivals 67% (54, 84) and 32% (13, 79), respectively (P<0.001). This schedule is a feasible, tolerable and effective treatment for patients with oesophageal cancer considered unsuitable for surgery.
Project description:Phase II studies have suggested that weekly paclitaxel has a higher response rate and better toxicity profile than the conventional schedule of once every 3 or 4 weeks. Our aim was to evaluate the efficacy of weekly paclitaxel plus cisplatin (PC) vs vinorelbine plus cisplatin (VC) in chemonaïve non-small-cell lung cancer (NSCLC) patients. From October 2000 to May 2002, 140 patients were enrolled. The treatment dose was P 66 mg m(-2) intravenous infusion (i.v.) on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, or V 23 mg m(-2) i.v. on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, every 4 weeks. In all, 281 cycles of PC and 307 cycles of VC were given to the patients in the PC and VC arms, respectively. There were 26 partial responses and one complete response (overall 38.6%) in the PC arm, and no complete responses, but 27 partial responses (overall 38.6%) in the VC arm. Myelosuppression was more common in the VC arm (P<0.001). Peripheral neuropathy and myalgia were significantly more common in the PC arm (P<0.001). The median time to disease progression was 6 months in the PC arm and 8.4 months in the VC arm (P=0.0344). The median survival time was 11.7 months in the PC arm and 15.4 months in the VC arm (P=0.297). We concluded that weekly PC is not suggested for NSCLC patients due to the relatively shorter progression-free survival and more common nonhaematological toxicities. British Journal of Cancer (2004) 90, 359-365. doi:10.1038/sj.bjc.6601526 www.bjcancer.com
Project description:BACKGROUND:No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS:We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS:A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ?1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS:In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).
Project description:BACKGROUND:Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5-fluorouracil [5-FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction nab-paclitaxel and cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial. METHODS:Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab-paclitaxel 100 mg/m(2) /week; cetuximab 250 mg/m(2) /week; cisplatin 75 mg/m(2) on day 1; 5-FU 750 mg/m(2) /day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m(2) on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint. RESULTS:Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survival rates were 84% and 65%, respectively. CONCLUSIONS:Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted.
Project description:This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6).Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD.Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [n = 1]; grades 3 and 4 thrombocytopenia [n = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug-drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6.Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.
Project description:We performed a phase 1/2 trial to investigate the safety and activity of the second-generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200?mg/m2 (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36?mg/m2 days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). The patients had received a median of 3 previous lines of therapy, 56% had undergone previous AHCT, and 51% had received previous K therapy. During phase 1 (n?=?15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27?mg/m2 (on day -3) and 56 mg/m2 (on day -2) was used in phase 2. The rate of?very good partial response after K-MEL therapy (n?=?44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n?=?27), 12-month progression-free survival was 66.7% and 12-month overall survival was 88.1%. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in patients with MM.
Project description:BACKGROUND:Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. METHODS:Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The first 40 patients were allocated equally to the two treatment groups by computer-generated block randomisation (block size 40), after which a response-adaptive randomisation algorithm used all previous patients' treatment and response data to decide the allocation of each following patient favouring the group with superior response. Patients were assigned to receive 20 mg/m2 decitabine intravenously for 5 or 10 consecutive days as induction therapy, every 4-8 weeks for up to three cycles. Responding patients received decitabine as consolidation therapy on a 5-day schedule for up to 24 cycles. We assessed a composite primary endpoint of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete haematological recovery (CRi) achieved at any time and assessed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01786343. FINDINGS:Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26-60, and 17 [40%] of 43 in the 10-day schedule group, 26-54, p=0·78; difference 3%, -21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1-11·7) in the 5-day group and 6·0 months (1·9-11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3-4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. INTERPRETATION:In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. FUNDING:University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.
Project description:Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ?6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.
Project description:BACKGROUND:Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS:In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000?mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ?3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS:DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6?mg/m2 day 1 for schedule 1 and 1.4?mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4?mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS:The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.
Project description:PURPOSE:This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799. EXPERIMENTAL DESIGN:Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles. RESULTS:Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles. CONCLUSION:CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity.
Project description:Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated.After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS).Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively.This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.