bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.
Authors: Ratliff A F , Wilson J , Hum M , Marling-Cason M , Rose K , Winick N , Kamen B A
Published: February 2017

PURPOSE

Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT.

PATIENTS AND METHODS

Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration.

RESULTS

Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months.

CONCLUSION

We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.
Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.
Authors: Gamelin E , Boisdron-Celle M , Delva R , Regimbeau C , Cailleux P E , Alleaume C , Maillet M L , Goudier M J , Sire M , Person-Joly M C , Maigre M , Maillart P , Fety R , Burtin P , Lortholary A , Dumesnil Y , Picon L , Geslin J , Gesta P , Danquechin-Dorval E , Larra F , Robert J
Published: February 2017

PURPOSE

A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial.

PATIENTS AND METHODS

Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined.

RESULTS

A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase.

CONCLUSION

Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.
Nucleolar organizer region counts predict complete remission, remission duration, and survival in adult acute myelogenous leukemia patients.
Authors: Pich A , Chiusa L , Audisio E , Marmont F
Published: February 2017

PURPOSE

The analysis of the nucleolar organizer regions (AgNORs) was performed in patients with acute myelogenous leukemia (AML) to verify the role of cell proliferation in predicting complete remission (CR) and survival.

MATERIALS AND METHODS

Bone marrow biopsies from 40 adult patients with AML were stained with the argyrophilic method. The mean AgNOR number (AgNOR count) was calculated for each case. After induction therapy, patients who achieved CR received intensive consolidation; two underwent autologous and four allogeneic bone marrow transplantations (BMT).

RESULTS

The mean AgNOR count for the whole series was 6.6 (SD = 1.35); it was higher in CR patients than in resistant ones (P = .02). The median duration of CR was 26 months for patients with an AgNOR count greater than 6.6, but only 6 months for those with lower counts (P = .01). Sixteen patients who achieved a CR relapsed and 14 reached a second CR; the median duration of second CR was 16 months for patients with AgNOR count greater than 6.6, but only 5 months for those with lower counts (P = .01). The median survival time for the whole series was 14 months, with 30% of patients alive and in continuous CR at 103 months. Survival was longer for patients with an AgNOR count greater than 6.6 (33 months) than for those with lower counts (6 months; P = .0009). In multivariate analysis, when CR was excluded from the model, AgNOR count appeared as an independent prognostic variable (P = .005).

CONCLUSION

AgNOR analysis is a suitable method to assess cell proliferation in bone marrow biopsies and can predict CR, remission duration, and survival in AML patients.
Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients.
Authors: Zinzani P L , Pileri S , Bendandi M , Buzzi M , Sabattini E , Ascani S , Gherlinzoni F , Magagnoli M , Albertini P , Tura S
Published: February 2017

PURPOSE

In the last few years, the search for new biologic markers in high-grade non-Hodgkin's lymphomas has provided important results. In particular, soluble CD30 (sCD30) levels were elevated in most patients with Hodgkin's disease (HD) and anaplastic large-cell lymphoma (ALCL).

PATIENTS AND METHODS

From September 1988 to October 1993, treatment was completed in 70 previously untreated patients with ALCL, of whom 38 had the common type (ALCL-CT) and 32 had the Hodgkin's-like subtype (ALCL-HL). Serum sCD30 levels were measured at the time of diagnosis and after induction polychemotherapy in all patients; in addition, the initial sCD30 levels were compared with those obtained from 50 stage-matched patients with HD.

RESULTS

Pretreatment levels of sCD30 were highly elevated in the stage-matched group of HD patients compared with healthy controls; median sCD30 levels in patients with ALCL-CT and ALCL-HL were 18 and seven times higher, respectively, than in patients with HD. The sCD30 level normalized on achievement of complete response (CR). The risk of lower relapse-free survival was associated with bulky disease, advanced stage, and high pretreatment sCD30 levels; the risk of lower overall survival was associated with advanced stage and pretreatment levels of sCD30 in both univariate and multivariate analysis.

CONCLUSION

The results of this study suggest that sCD30 is a specific prognostic indicator of the risk for lower complete response rate and relapse-free expectancy for patients with ALCL.
High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?
Authors: Glantz M J , Cole B F , Recht L , Akerley W , Mills P , Saris S , Hochberg F , Calabresi P , Egorin M J
Published: February 2017

PURPOSE

Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis.

PATIENTS AND METHODS

Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval.

RESULTS

Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003).

CONCLUSION

HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.
Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy.
Authors: Gralla R J , Navari R M , Hesketh P J , Popovic W , Strupp J , Noy J , Einhorn L , Ettinger D , Bushnell W , Friedman C
Published: February 2017

PURPOSE

To compare the antiemetic efficacy of a single dose of an oral antiemetic (granisetron 2 mg) with a single dose of an intravenous (i.v.) antiemetic (ondansetron 32 mg) given before cisplatin-based chemotherapy.

PATIENTS AND METHODS

This was a multicenter, randomized, double-blind, parallel-group study. Patients (N = 1,054) scheduled to receive cisplatin (> or = 60 mg/m2)-based chemotherapy were randomized to receive either 2 mg of oral granisetron tablets 1 hour before chemotherapy (n = 534) or i.v. ondansetron (32 mg) 30 minutes before chemotherapy (n = 520). The primary efficacy end point was total control (no emesis, no nausea, and no use of antiemetic rescue medication) over the initial 24 hours after the start of chemotherapy. Dexamethasone or methylprednisolone were permitted, but not required, as concomitant prophylactic antiemetics.

RESULTS

Total control was equivalent 24 hours after cisplatin chemotherapy for single-dose oral granisetron (54.7%) and i.v. ondansetron (58.3%) (95% confidence interval [CI], -9.6 to 2.4). Similar proportions of patients remained nausea-free in the granisetron group (55.4%) and the ondansetron group (59%) (95% CI, -9.6 to 2.4). The rate of complete control of emesis was 61.2% in the granisetron group and 67.1% in the ondansetron group (95% CI, -11.7 to -0.1). Both treatment regimens were well tolerated, with similar patterns of adverse reactions, generally of a mild degree. The most common side effects included constipation (14%), headache (15%), and diarrhea (10%).

CONCLUSION

Oral granisetron, administered as a single 2-mg dose, provided equivalent total antiemetic control when compared with i.v. ondansetron (32 mg) in patients who received highly emetogenic, cisplatin-based chemotherapy.
Comorbidity and functional status are independent in older cancer patients.
Authors: Extermann M , Overcash J , Lyman G H , Parr J , Balducci L
Published: February 2017

PURPOSE

Comorbidity is a frequent and often therapeutically limiting problem in older cancer patients. However, to date, there is no standard measure of the comorbidity burden available for these patients. We tested the performance of two comorbidity scales and their relationship with functional status.

PATIENTS AND METHODS

The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was compared with the Charlson scale in 203 patients who received a comprehensive geriatric assessment (CGA) in our Senior Adult Oncology Program (SAOP). Study end points were variability, reliability, correlation with Eastern Cooperative Oncology Group (ECOG) performance status (PS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). The relative weight of comorbidity versus tumor stage in the correlations with functional status was assessed.

RESULTS

Median age was 75 years (range, 63 to 91). Sixty-four percent of patients scored 0 on the Charlson scale versus 6% on the CIRS-G. The correlation between the Charlson and CIRS-G was fair (p = 0.25 to 0.39). CIRS-G grade 3/4 had a fair correlation with ADL (p = 0.27). Otherwise, there was low or no correlation between comorbidity and functional status across the measures. Tumor stage was not correlated with functional status either. Correlation of ECOG PS with ADL (p = 0.51)c and IADL (p = 0.61) was moderate. Interrater and test-retest correlations were good or very good for both the Charlson and CIRS-G.

CONCLUSION

Comorbidity needs to be assessed independently from functional status. Both the Charlson and CIRS-G scales are reliable tools for use in trials of older cancer patients. Both can be tested in further studies as predictors of outcomes such as toxicity of treatment, changes in functional status, or survival.
Radiation therapy and survival in breast cancer patients with 10 or more positive axillary lymph nodes treated with mastectomy.
Authors: Diab S G , Hilsenbeck S G , de Moor C , Clark G M , Osborne C K , Ravdin P M , Elledge R M
Published: February 2017

PURPOSE

Adjuvant loco-regional radiation (XRT) frequently is recommended after mastectomy and adjuvant systemic therapy in patients with 10 or more positive axillary lymph nodes (ALN) to reduce the high loco-regional failure rate observed in this subset. In this study, we explored the possibility that adjuvant loco-regional radiation therapy (LR-XRT) also could decrease distant failure and improve overall survival (OS) in this subset of poor-prognosis patients.

PATIENTS AND METHODS

Retrospectively, 618 breast patients with 10 or more positive ALN were studied. The median follow-up time was 7.5 years. All patients received systemic adjuvant therapy and 35% also received adjuvant radiation therapy. Loco-regional failure, distant failure, and OS analyses were adjusted for age, tumor size, number of positive ALN, and estrogen receptor (ER) status using Cox regression model.

RESULTS

As expected, patients had a very high risk of loco-regional and distant failure. At 5 years, 30% of patients had loco-regional failure as a first event and 54% had distant failure. Radiation dramatically reduced loco-regional failure (hazards rate ratios [RR]=0.29; 95% confidence interval [CI], 0.19 to 0.45). The adjusted 5-year loco-regional failure rate was 13% with radiation and 38% without radiation (P=.0001). Radiation also was associated with improved distant control (RR=0.75; 95% CI, 0.58 to 0.96). The adjusted 5-year distant failure rate was 48% with radiation and 58% without radiation (P=.02). OS also improved with radiation (RR=0.68; 95% CI, 0.53 to 0.85). The adjusted 5-year OS was 56% with radiation and 42% without radiation (P=.001).

CONCLUSION

In this cohort of high-risk breast cancer patients, XRT was associated with less loco-regional and distant failure and improved OS. This suggests that improved loco-regional control might decrease secondary systemic spread and improve survival.
Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. Société Française d'Oncologie Pédiatrique.
Authors: Fagnou C , Michon J , Peter M , Bernoux A , Oberlin O , Zucker J M , Magdelenat H , Delattre O
Published: February 2017

PURPOSE

Gene fusions that result from the chromosome translocations observed in Ewing's tumor (ET) provide tumor-specific markers that can be used to detect the presence of tumor cells in peripheral blood (PB), bone marrow (BM), and stem cell collection (SCC). These markers were used to evaluate, at diagnosis, a series of 67 ET patients.

PATIENTS AND METHODS

RNA was extracted from nucleated cells from PB and BM and a nested reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to search for EWS-FLI-1 or EWS-ERG fusion transcripts that resulted from the t(11;22) or t(21;22) translocations, respectively.

RESULTS

At diagnosis, 16 of 62 (26%) patients had circulating tumor cells. This was not correlated with any clinical parameter. In contrast, Ewing's cells were detected by RT-PCR in BM in 14 of 43 (33%) patients and were associated with the presence of clinically detectable metastases and a statistically significant unfavorable outcome in univariate analysis. There was no correlation between the RT-PCR results in PB and in BM.

CONCLUSION

These results suggested that the monitoring of BM but not of PB by RT-PCR might constitute an important criterion for the staging, at diagnosis, of patients with ET. Further studies should appreciate the relationship or independence of this marker toward other classical prognostic factors in ET, particularly to the presence of clinically detectable metastases.
Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study.
Authors: Mulhern R K , Kepner J L , Thomas P R , Armstrong F D , Friedman H S , Kun L E
Published: February 2017

PURPOSE

The purpose of this study was to test the hypothesis that survivors of medulloblastoma who were younger at diagnosis and those who received standard-dose cranial irradiation (SRT) of 36 Gy would have a lower performance on standardized tests of cognitive function and achievement than children who were older and those treated with reduced-dose cranial irradiation (RRT) of 23.4 Gy.

PATIENTS AND METHODS

Eligible patients had been treated on Pediatric Oncology Group (POG) study 8631 for low-risk medulloblastoma that randomized patients to receive RRT or SRT after surgical resection. Those who were alive and free of progressive disease 6.1 to 9.9 years from completion of treatment were eligible for this study. Of the 35 eligible patients, 22 patients (13 SRT, nine RRT) participated in a battery of tests that included intellectual and academic development as well as ratings of health-related quality of life.

RESULTS

Patients were stratified by treatment group (SRT v RRT) and into younger (Y) and older (O) groups by the median age at diagnosis (8.85 years), which resulted in four groups that we hypothesized would show neuropsychologic test scores in the following order: Y/SRT less than Y/RRT less than O/SRT less than O/RRT. Evidence to support the hypothesized ordering of groups in terms of neuropsychologic toxicity was obtained with regard to Performance Intelligence Quotient (IQ), Full Scale IQ, Attention, Reading, and Arithmetic.

CONCLUSION

Children treated for medulloblastoma experienced less severe neuropsychologic toxicity when treated with 23.4 Gy instead of 36 Gy cranial irradiation. Older children experienced less toxicity than children who were younger at the time of irradiation.
Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design.
Authors: Brader K R , Morris M , Levenback C , Levy L , Lucas K R , Gershenson D M
Published: February 2017

PURPOSE

To identify characteristics that predict response to chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix.

PATIENTS AND METHODS

Between January 1986 and May 1996, 190 chemotherapy-naive patients with advanced or recurrent squamous cell carcinoma of the cervix not amenable to curative radiation therapy or surgery were treated on 14 different chemotherapy protocols at M.D. Anderson Cancer Center. Patient's charts were retrospectively reviewed for patient demographics, tumor and treatment characteristics, and patterns of response and survival.

RESULTS

Of 190 patients, 22 had advanced or persistent disease and 168 had recurrent disease. Patients were treated with platinum-based (n=95) and non-platinum-based (n=95) regimens. The overall response rate was 20.0% (4.2% complete response; 15.8% partial response), with a median response duration of 4.8 months. Race, socioeconomic class, tumor stage and grade, mode of primary treatment, time from primary diagnosis to disease recurrence, initial performance status, and use of platinum-based therapy were not significant predictors of response. Age at time of chemotherapy (P=.001) and site of recurrence (P=.044) were significant determinants by multivariate analysis. Patients who were older were more likely to respond to therapy, and the response rate for patients in whom disease recurred outside the irradiated field was 25.2%, compared with a 5.3% response rate for patients with recurrent disease limited to a previously irradiated field.

CONCLUSION

The site of disease recurrence and patient age should be taken into account when designing chemotherapy trials and also when considering chemotherapy in the patient with recurrent cervix cancer.
Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia.
Authors: Weiss R B , Freiman J , Kweder S L , Diehl L F , Byrd J C
Published: February 2017

PURPOSE

A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL).

PATIENTS AND METHODS

Data on 24 patients who developed HA related to fludarabine therapy were collected from the Spontaneous Reporting System of the Food and Drug Administration (FDA) and the Walter Reed Army Medical Center (Washington, DC).

RESULTS

Seventeen (71%) patients developed HA after either the first, second, or third cycle of this drug. The longest duration of fludarabine therapy before HA occurred was six cycles. The median decline in hematocrit from baseline during the hemolytic episode was 14.1 (range, 8.0 to 28.9) for the 18 patients for whom this information was available. For the 11 patients for whom transfusion requirements were known, the number of transfusions administered ranged between three and 36. Seven (29%) patients died of medical complications associated with the HA. Seven of eight patients who were re-challenged with fludarabine after an episode of HA developed recurrent HA, and three of these patients died.

CONCLUSION

HA associated with fludarabine therapy appears to be uncommon, but it can be severe and fatal, especially if a patient is re-treated with this drug after a previous episode of HA. The mechanism of this toxicity is unknown, but it may be caused by the release of a suppressed auto-antibody to a native red cell antigen.
Inversion of chromosome 16 and uncommon rearrangements of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia: rare events related to DNA-topoisomerase II inhibitors?
Authors: Dissing M , Le Beau M M , Pedersen-Bjergaard J
Published: February 2017

PURPOSE

To evaluate the frequency of inversion of chromosome 16 (inv[16]) and the type of rearrangement of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia (t-AML) and to evaluate a possible relationship to specific types of previous chemotherapy.

PATIENTS AND METHODS

Cytogenetic studies were performed in 180 consecutive patients with therapy-related myelodysplasia (t-MDS) or t-AML in Copenhagen and in 270 consecutive patients in Chicago. Leukemic cells were available for studies of the molecular biology in 72 patients, including four with inv(16).

RESULTS

An inv(16)(p13q22) was observed in only two of 180 cases of t-MDS and t-AML in Copenhagen and in only four of 270 cases of t-MDS and t-AML in Chicago. Four patients with t-AML and inv(16) previously had received combination chemotherapy, which included an alkylating agent, and in two a DNA topoisomerase II inhibitor was included (mitoxantrone and etoposide). One patient had received paclitaxel followed by etoposide and one patient had received radiotherapy only. One patient, previously treated with mitoxantrone and cyclophosphamide for breast cancer, presented a new and, to our knowledge not previously reported, type of fusion transcript, with breakpoint at nt 399 of the CBFB gene and at nt 2134 of the MYH11 gene. Two patients previously treated with alkylating agents both presented the less common type D transcript, whereas the most common A transcript, observed in 80% of acute myeloid leukemia (AML) de novo with inv(16), only was observed in the patient treated with paclitaxel and etoposide for leiomyosarcoma. Bone marrow or blood cells from 68 patients with t-MDS and t-AML without an inv(16) all were found to be negative for chimeric rearrangement between the CBFB gene and the MYH11 gene.

CONCLUSION

The present study and a review of the literature shows that inv(16) is an uncommon aberration in t-AML and, like balanced translocations to chromosome bands 11q23 and 21q22 and the t(15;17), often is associated with prior chemotherapy with DNA topoisomerase II inhibitors. Breakpoints within the MYH11 gene may vary between t-AML and AML de novo.
Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.
Authors: Zalcberg J , Millward M , Bishop J , McKeage M , Zimet A , Toner G , Friedlander M , Barter C , Rischin D , Loret C , James R , Bougan N , Berille J
Published: February 2017

PURPOSE

Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study.

PATIENTS AND METHODS

Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation.

RESULTS

A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported.

CONCLUSION

Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.
Psychologic and neuropsychologic functioning of patients with limited small-cell lung cancer treated with chemotherapy and radiation therapy with or without warfarin: a study by the Cancer and Leukemia Group B.
Authors: Ahles T A , Silberfarb P M , Herndon J , Maurer L H , Kornblith A B , Aisner J , Perry M C , Eaton W L , Zacharski L L , Green M R , Holland J C
Published: February 2017

PURPOSE

The current study assessed the psychologic and neuropsychologic functioning of patients with small-cell lung cancer who were randomized in a large clinical trial to receive intensive doxorubicin, cyclophosphamide, etoposide (ACE)/cisplatin, cyclophosphamide, etoposide (PCE) chemotherapy and radiation therapy (RT) to the primary tumor and prophylactic whole-brain irradiation with (regimen I) or without (regimen II) warfarin.

PATIENTS AND METHODS

Patients' emotional states and cognitive functioning were assessed using the Profile of Mood States (POMS) and Trail Making B Test (Trails B), respectively. Two hundred ninety-five patients completed the POMS and Trails B at pretreatment, 224 patients after the completion of the ACE course of chemotherapy (week 9), and 177 patients after the completion of the PCE chemotherapy and RT (week 17).

RESULTS

No differences on the POMS or Trails B measures were found between the two treatment arms as predicted, given that the only difference between the two treatment arms was the presence or absence of warfarin. Analysis of the POMS revealed that, overall, mean scores remained stable over the course of treatment; however, women showed a trend toward higher mean scores, which indicated a higher level of distress, compared with men at the pretreatment assessment. Examination of cognitive functioning, measured by the Trails B, revealed improved performance from baseline to post-ACE chemotherapy, which is consistent with a practice effect, but a significant worsening of Trails B scores post-RT compared with the pre-RT assessments, which is consistent with impaired cognitive functioning because of treatment (P < .0001).

CONCLUSION

Emotional state, measured by the POMS, did not differ between the groups or change significantly over time in this study of small-cell lung cancer patients treated with a combination of chemotherapy and RT plus or minus warfarin. However, the pattern of relatively stable POMS scores and poorer Trails B performance post-RT suggested that this combination of chemotherapy and RT had a negative impact on cognitive functioning.
Teaching senior oncologists communication skills: results from phase I of a comprehensive longitudinal program in the United Kingdom.
Authors: Fallowfield L , Lipkin M , Hall A
Published: February 2017

PURPOSE

To determine the communication difficulties experienced by clinicians in cancer medicine and to develop, implement, and evaluate communication skills training courses.

METHODS

One hundred seventy-eight senior clinicians attended 1 1/2- or 3-day residential courses designed to enhance skills development, knowledge acquisition, and personal awareness. Course content included structured feedback, video review of interviews, interactive group demonstrations, and discussion in groups of four led by trained facilitators. The main outcomes were self-rated confidence in key aspects of communication, attitudinal shift toward more patient-centered interviewing, perceived changes in personal practice, and initiation of teaching programs for junior staff.

RESULTS

Less than 35% of the participants had received any previous communications training. Time, experience, and seniority had not improved skills; before the course, oncologists expressed difficulty with 998 different communication issues. Primary problems concerned giving complex information, obtaining informed consent, and handling ethnic and cultural differences. Confidence ratings for key communication areas were significantly improved postcourse (P < .01). Three months postcourse, 95% of the physicians reported significant changes in their practice of medicine. Seventy-five percent had started new teaching initiatives in communication for junior clinicians. Clinicians showed positive shifts in attitude toward patients' psychosocial needs (P=.0002) and were more patient centered (P=.03). The courses were highly rated and 97% would "definitely" recommend them to colleagues.

CONCLUSION

Oncologists are hampered by inadequate communication skills training and will give up time to correct this. Subjective improvements reported immediately postcourse were maintained at 3 months. Resources for educational initiatives are needed to help both patients and their physicians.
Survival impact of adjuvant tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes.
Authors: Ragaz J , Coldman A
Published: February 2017

PURPOSE

This study provides estimates of the effect of tamoxifen treatment on mortality from four conditions known to be affected by tamoxifen in women who survive their breast cancer: contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic events. These estimates are in addition to tamoxifen's impact on primary breast cancer mortality.

METHODS

The effects of tamoxifen were calculated by the use of the published relative risk (RR) rates of the four conditions as affected by adjuvant tamoxifen and their application to the respective Canadian age-specific mortality rates for the same conditions. The final mortality impact of tamoxifen was expressed as net mortality difference between users and nonusers of tamoxifen.

RESULTS

At 10 years of follow-up, the sum of avoided deaths (contralateral breast cancer, cardiovascular events) and excess deaths (uterine cancer, thromboembolic episodes) resulted in an overall (net) mortality reduction because of tamoxifen use, with 3 to 41 avoided deaths per 1,000 tamoxifen-treated patients who were 50 to 80 years of age. With the follow-up projected until the age of 90 years, the numbers of avoided late deaths attributed to tamoxifen ranged from 38 to 56 per 1,000 patients.

CONCLUSION

Our calculations that pertain to late breast cancer survivors indicate that there is a more substantial mortality reduction as a result of deaths avoided from contralateral breast cancer and cardiovascular events, despite the moderately increased mortality from endometrial cancer and thromboembolic episodes. The overall tamoxifen-associated mortality reduction occurs, in different magnitudes, in patients of all ages from 50 to 80 years at diagnosis of the primary breast cancer.
bcl-2 automated and quantitative immunocytochemical assays in breast carcinomas: correlation with 10-year follow-up.
Authors: Charpin C , Garcia S , Bonnier P , Martini F , Andrac L , Horschowski N , Lavaut M N , Allasia C
Published: February 2017

PURPOSE

bcl-2 protein is detectable in human cancers and may be involved in the response to antineoplastic drugs or endocrine therapy in breast carcinomas. In a previous study, we had developed optimal technical conditions for bcl-2 immunodetection. The aim of the present report was to determine the prognostic significance of bcl-2 expression in breast carinomas by the use of a similar immunocytochemical procedure.

METHODS

bcl-2 immunocytochemical assays were performed on frozen sections by automated immunoperoxidase technique (Ventana) and computer-assisted analysis of digitized colored microscopic images (SAMBA) in a series of 170 breast carcinomas. The results of automated quantitative immunocytochemical assays were correlated with patient follow-up (120 months).

RESULTS

Intense bcl-2 immunocytochemical expression in tumors (cutpoint, 15%) significantly correlated with longer disease-free survival and longer recurrence-free survival in the entire cohort of patients (P = .028 and P = .035, respectively) and also in node-negative subgroups of patients (P = .028 and P = .01; Kaplan-Meier long-rank test; NCSS 6.0.1 software). But bcl-2 immunostained surfaces (cutpoint, 15%) did not correlate with overall survival. In multivariate analysis (proportional hazards regression, Cox model), bcl-2 prognostic significance in terms of disease-free survival was only independent of the tumor size and grade and histoprognostic index (Nottingham prognostic index [NPI]).

CONCLUSION

bcl-2 immunohistochemical expression is a significant indicator of favorable outcome only in terms of disease-free and local recurrence-free survival. However, bcl-2 expression in tumors is an independent weakly prognostic indicator in breast carcinomas. bcl-2 immunodetection assessed in optimal technical conditions (frozen samples, automation, quantitative analysis, scatter diagram cutoffs) may have some limited practical clinical relevance for the management of patients with breast carcinomas.
Activity of fludarabine in previously treated Waldenström's macroglobulinemia: a report of 71 cases. Groupe Coopératif Macroglobulinémie.
Authors: Leblond V , Ben-Othman T , Deconinck E , Taksin A L , Harousseau J L , Delgado M A , Delmer A , Maloisel F , Mariette X , Morel P , Clauvel J P , Duboisset P , Entezam S , Hermine O , Merlet M , Yakoub-Agha I , Guibon O , Caspard H , Fort N
Published: February 2017

PURPOSE

There is no consensus on the treatment of patients with Waldenström's macroglobulinemia (WM) who develop primary or secondary resistance to frontline therapies. We report our experience on the activity and toxicity of fludarabine in 71 patients with WM resistant to prior chemotherapy regimens.

PATIENTS AND METHODS

From January 1991 to June 1995, 71 patients were included in this retrospective study. The median age, median time from diagnosis to treatment, median immunoglobulin M (IgM) level, and median number of previous treatments were 68 years (range, 42 to 81), 5.9 years (range, 0.6 to 20), 35 g/L (range, 5 to 126), and two (range, one to four), respectively.

RESULTS

Seventy-one patients received a median of six courses of fludarabine. Twenty-one (30%) responded with a partial response and 50 (70%) were considered as treatment failures. Forty-six patients died: 10 in the responder group and 36 in the failure group. Twenty-five patients were alive with a median follow-up time of 34 months. The overall median survival time of all treated patients was 23 months. The time to treatment failure was 32 months. The only factor that favorably influenced the response to fludarabine was a longer interval between the first treatment and the start of fludarabine. Pretreatment factors associated with shorter survival in the entire population were hemoglobin level less than 95 g/L (P = .02) and platelet count less than 75 x 10(9)/L (P = .02).

CONCLUSION

The responses rate in this population with a poor prognosis is close to that reported in shorter series. Patients with WM who are resistant to alkylating agents should be identified early, so that salvage therapy with nucleoside analogs can be started without delay.
Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients.
Authors: Vansteenkiste J F , Stroobants S G , De Leyn P R , Dupont P J , Bogaert J , Maes A , Deneffe G J , Nackaerts K L , Verschakelen J A , Lerut T E , Mortelmans L A , Demedts M G
Published: February 2017

PURPOSE

To compare the accuracy of computed tomography-(CT) scan and the radiolabeled glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) visually correlated with CT (PET + CT) in the locoregional lymph node (LN) staging of non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Sixty-eight patients with potentially operable NSCLC underwent thoracic CT, PET, and invasive surgical staging (ISS). Imaging studies were read prospectively and blinded to the surgical and pathologic data. A five-point visual scale was used for the interpretation of LNs on PET. Afterwards, with knowledge of the pathology, the relationship between standardized uptake values (SUVs) and the presence of metastasis in LNs was explored in a receiver operating characteristic (ROC) analysis, and the likelihood ratios (LRs) for SUVs of LNs were determined.

RESULTS

ISS was available for 690 LN stations. CT correctly identified the nodal stage in 40 of 68 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET + CT was accurate in 59 patients (87%), with understaging in five patients and overstaging in four patients. In the detection of locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy of CT were 75%, 63%, and 68%, respectively. For PET + CT, this was 93%, 95%, and 94% (P = .0004). In the ROC curve, the best SUV threshold to distinguish benign from malignant LNs was 4.40. The analysis with this SUV threshold was not superior to the use of a five-point visual scale. The LR of a SUV less than 3.5 in an LN was 0.152; for a SUV between 3.5 and 4.5, it was 3.157; and for a SUV greater than 4.5, it was 253.096.

CONCLUSION

PET + CT is significantly more accurate than CT alone in LN staging of NSCLC. A five-point visual scale is as accurate as the use of an SUV threshold for LNs in the distinction between benign and malignant nodes. The very high negative predictive value of mediastinal PET could reduce the need for mediastinal ISS in NSCLC substantially.
Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.
Authors: Wojtowicz-Praga S , Torri J , Johnson M , Steen V , Marshall J , Ness E , Dickson R , Sale M , Rasmussen H S , Chiodo T A , Hawkins M J
Published: February 2017

PURPOSE

This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies.

PATIENTS AND METHODS

A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied.

RESULTS

The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment.

CONCLUSION

Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.
Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer.
Authors: Hainsworth J D , Burris H A , Erland J B , Thomas M , Greco F A
Published: February 2017

PURPOSE

Docetaxel is a highly active antineoplastic agent; however, grade IV leukopenia occurs in the large majority of patients treated with a dose of 100 mg/m2 every 3 weeks. Recent experience with weekly paclitaxel has demonstrated a bone marrow-sparing effect when a weekly administration schedule is used. We investigated a weekly schedule of docetaxel in an attempt to alter the toxicity profile and improve the therapeutic index.

PATIENTS AND METHODS

Thirty-eight patients with advanced, refractory malignancy entered this phase I trial between October 1996 and June 1997. Docetaxel was administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Sequential cohorts of patients were treated at the following dose levels: 20, 25, 30, 36, 43, and 52 mg/m2. Patients were reevaluated after one course (8 weeks); patients with objective response or stable disease continued treatment for a maximum of four courses or until disease progression.

RESULTS

Thirty-five patients completed at least one course of therapy. Myelosuppression was not a dose-limiting toxicity (DLT) at any of the doses tested. Only five episodes of grade III leukopenia occurred (14% of patients, 2% of doses), and no grade IV leukopenia was produced. No grade III or IV thrombocytopenia or anemia was observed. Grade III fatigue and asthenia were observed in all three patients treated at 52 mg/m2/wk and in two of 10 at 43 mg/m2/wk. Other grade III toxicity included acral erythema (n = 1), neuropathy (n = 1), peripheral edema (n = 1), and diarrhea (n = 1). The DLTs of this docetaxel schedule are fatigue and asthenia. Although the maximum-tolerated dose by definition of this study was 43 mg/m2/wk, we selected 36 mg/m2/wk for ongoing phase II studies.

CONCLUSION

The toxicity profile of docetaxel is markedly altered when the drug is administered by a weekly schedule. Myelosuppression is mild and uncommon. Fatigue and asthenia are the DLTs; other nonhematologic toxicities, which included peripheral edema and neuropathy, are uncommon, and the arthralgia/myalgia syndrome was not observed. Weekly administration of docetaxel may provide a better tolerated, efficacious use of this drug; further investigation of weekly docetaxel as a single agent and in combination regimens is warranted.