bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between polysialic-neural cell adhesion molecule levels in CSF and medulloblastoma outcomes.
Authors: Figarella-Branger D , Dubois C , Chauvin P , De Victor B , Gentet J C , Rougon G
Published: February 2017

PURPOSE

To quantify CSF levels of polysialic-neural cell adhesion molecule (PSA-NCAM) in patients with medulloblastoma (MB) metastasis, to assess the correlation with other diagnostic techniques (imaging and cytology) and clinical features, and to determine whether it is a suitable marker to monitor response to treatment and subsequent follow-up data.

PATIENTS AND METHODS

PSA-NCAM levels were measured using a double-site enzyme-linked immunoadsorbant assay (ELISA) in 145 samples from 14 controls and 29 patients with MB. Clinical status of patients, imaging, and cytologic data were available at the time of each lumbar puncture. Medians and ranges for the 131 pooled PSA-NCAM concentrations were calculated for the MB versus the control groups, and for MB patients for normal versus abnormal groups at cytology or imaging, and for four clinical subgroups, respectively. For patients with MB, three PSA-NCAM measurements that corresponded to punctures performed during three time periods following surgery were selected. The kappa measure of agreement was calculated between normal and abnormal groups at cytology or imaging, and between groups of patients in remission and refractory, respectively. For the same phases, sensitivity and specificity of PSA-NCAM and cytology tests and their 95% confidence intervals (95% CIs) were computed.

RESULTS

PSA-NCAM was never detected in control CSF. PSA-NCAM concentration medians were higher in CSF with metastatic cells or that corresponded to abnormal imaging than in the corresponding normal groups (P < .05). The PSA-NCAM concentration median was significantly higher (P < .05) in CSF from patients refractory to treatment or who relapsed than from patients in remission. Agreements between PSA-NCAM and clinical status and between PSA-NCAM and cytology were excellent during and after treatment. The sensitivity of PSA-NCAM test was always better than that of cytology, whereas its specificity was lower for phases that corresponded to more than 1 month following surgery. However, specificity was 100% for patients refractory to treatment or with relapse.

CONCLUSION

PSA-NCAM measurement appears to be a new biologic marker of possible use in the management of patients with MB.
Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco.
Authors: Willis B , Ablin A , Weinberg V , Zoger S , Wara W M , Matthay K K
Published: February 2017

PURPOSE

The purpose of our investigation was to correlate the extent and degree of organ involvement at presentation of Langerhans' cell histiocytosis (LCH) with subsequent disease course, survival, and late sequelae.

MATERIALS AND METHODS

The medical records of 71 patients with a pathologic diagnosis of LCH, age 0 to 21 years, who presented between January 1, 1969 and June 30, 1994, were reviewed for organ involvement at diagnosis, treatment, disease course, and late sequelae. Supplementary data were obtained by mailed questionnaire.

RESULTS

The median follow-up time from diagnosis for all patients was 8.1 years. Involvement at diagnosis included nine patients with skin-only disease, 22 with monostotic disease, 12 with polyostotic disease, and 28 with multisystem presentation. Treatment was surgery only in 17 and chemotherapy and/or radiotherapy in 54 patients. Recurrences were seen in 35 patients, with the highest rate in the polyostotic group. Ten patients died: seven with the multisystem presentation, two with monostotic disease, and one with skin-only disease. Causes included progressive LCH (n = 6) and late sequelae of either treatment (n = 3) or disease (n = 1). Late sequelae were seen in 64% of 51 patients with more than 3 years of follow-up data. The most common were skeletal defects in 42%, dental problems in 30%, diabetes insipidus in 25%, growth failure in 20%, sex hormone deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and other CNS dysfunction in 14%. The overall estimated survival rates at 5, 15, and 20 years are 88%, 88%, and 77%, with an estimated event-free survival rate of only 30% at 15 years.

CONCLUSION

Despite the favorable survival, more than half of LCH patients will have further dissemination of disease or late sequelae, including even some patients with single-system disease at diagnosis. Future treatment needs to be designed to prevent disease progression and late sequelae.
p53 and bcl-2 proteins as prognostic markers in human papillomavirus-associated cervical lesions.
Authors: Kurvinen K , Syrjänen K , Syrjänen S
Published: February 2017

PURPOSE

The present study was designed to analyze the expression of p53, mdm2, and bcl-2 proteins, with special emphasis on their association with the grade of squamous intraepithelial lesion (SIL), human papillomavirus (HPV) type, and clinical course of the disease. Special attention was focused on the value of individual protein expressions, as well as combined p53/mdm2 and p53/bcl-2 phenotypes, in predicting the clinical course of cervical lesions.

MATERIALS AND METHODS

The expression of p53, mdm2, and bcl-2 was studied immunohistochemically in a series of 98 HPV lesions of the uterine cervix.

RESULTS

Frequent expression of p53, mdm2, and bcl-2 proteins was found in the cervical lesions. However, only p53 expression independently provided information for prediction of the clinical course of HPV lesions. High levels of p53 expression were detected in most low-grade SILs (LSILs) (83%) and HPV 6/11/42-associated lesions (86%). In high-grade SILs (HSILs) positive for high-risk HPV types, p53 expression was frequently either totally absent or it only occurred in a few scattered cells. These lesions were closely associated with disease progression. The evaluation of bcl-2 expression alone was not useful for predicting clinical outcome, although abnormal bcl-2 expression in suprabasal layers was more common in HSILs. By contrast, the combined p53/bcl-2 phenotype, which showed a low percentage of p53-positive cells with bcl-2 overexpression in upper epithelial layers, was found to be involved in the progression of HPV lesions.

CONCLUSION

The present study showed that HPV lesions with a high percentage of cells that express p53 are more likely to regress than those with low or absent p53. p53 thus seems to hold promise as a molecular marker for the risk of the progression of HPV-associated SILs. In addition, the assessment of p53 and bcl-2 expression patterns may be useful to predict the clinical course of cervical HPV lesions.
Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas.
Authors: Fowler F J , Barry M J , Lu-Yao G , Wasson J H , Bin L
Published: February 2017

PURPOSE

This study was designed to obtain representative estimates of the quality of life and probabilities of possible adverse effects among Medicare-age patients treated with external-beam radiation therapy for prostate cancer.

METHODS

Patients treated for local or regional prostate cancer with high-energy external-beam radiation between 1989 and 1991 were sampled from a claims data base of the Surveillance, Epidemiology, and End Results (SEER) program from three regions. Patients were surveyed primarily by mail, with telephone follow-up evaluation of non-respondents. There were 621 respondents (83% response rate). The results were compared with data from a previously published national survey of Medicare-age men who had undergone radical prostatectomy.

RESULTS

Although they were older at the time of treatment, radiation patients were less likely than surgical patients to wear pads for wetness (7% v 32%) and had a lower rate of impotence (23% v 56% for men < 70 years), while they were more likely to report problems with bowel dysfunction (10% v 4%). Both groups reported generally positive feelings about their treatments. Radiation and surgical patients reported similar rates of additional subsequent treatment (24% v 26% at 3 years after primary treatment). However, radiation patients were less likely to say they were cancer-free, and they reported more worry about cancer than did surgical patients.

CONCLUSION

The health-related quality of life of radiation and surgical patients, on average, is similar, but the pattern of experience with adverse consequences of treatment differs by treatment.
Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study.
Authors: Blijham G , Wagener T , Wils J , de Greve J , Buset M , Bleiberg H , Lacave A , Dalmark M , Selleslag J , Collette L , Sahmoud T
Published: February 2017

PURPOSE

Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks.

PATIENTS AND METHODS

Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria.

RESULTS

The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis.

CONCLUSION

Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.
Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.
Authors: Patt Y Z , Jones D V , Hoque A , Lozano R , Markowitz A , Raijman I , Lynch P , Charnsangavej C
Published: February 2017

PURPOSE

To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree.

PATIENTS AND METHODS

Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree.

RESULTS

Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients.

CONCLUSION

Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.
Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma.
Authors: Gill P S , Wernz J , Scadden D T , Cohen P , Mukwaya G M , von Roenn J H , Jacobs M , Kempin S , Silverberg I , Gonzales G , Rarick M U , Myers A M , Shepherd F , Sawka C , Pike M C , Ross M E
Published: February 2017

PURPOSE

To compare the safety and efficacy of liposomal daunorubicin (DaunoXome; NeXstar Pharmaceuticals, Inc, Boulder, CO) with a reference regimen of doxorubicin, bleomycin, and vincristine (ABV) in advanced AIDS-related Kaposi's sarcoma (KS).

PATIENTS AND METHODS

In a prospective randomized phase III trial, 232 patients were randomized to receive DaunoXome 40 mg/m2 or a combination regimen of doxorubicin 10 mg/m2, bleomycin 15 U, and vincristine 1 mg, administered intravenously every 2 weeks. Treatment was continued until complete response (CR), disease progression, or unacceptable toxicity.

RESULTS

Of 232 patients randomized, 227 were treated: 116 with DaunoXome and 111 with ABV. The overall response rate (CR or partial response [PR]) was 25% (three CRs and 26 PRs) for DaunoXome and 28% (one CR and 30 PRs) for ABV. The difference in response rates was not statistically significant. The median survival time was 369 days for DaunoXome patients and 342 days for ABV patients (P = .19). The median time to treatment failure was 115 days for DaunoXome and 99 days for ABV (P = .13). ABV patients experienced significantly more alopecia and neuropathy (P < .0001). DaunoXome patients experienced more grade 4 neutropenia (P = .021). Cardiac function remained stable, with no instances of congestive heart failure on either treatment arm.

CONCLUSION

In this large phase III trial, the efficacy of DaunoXome was comparable to that of ABV. Response rates, time to treatment failure, and overall survival were similar on both treatment arms. DaunoXome is a safe and effective primary therapy for advanced AIDS-related KS.
Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer.
Authors: Murren J R , Anderson S , Fedele J , Pizzorno G , Belliveau D , Zelterman D , Burtness B A , Tocino I , Flynn S D , Beidler D , Cheng Y C
Published: February 2017

PURPOSE

Based on preclinical data that demonstrated synergy between alkylating agents and topoisomerase (topo) I poisons, we determined the maximum-tolerated dose (MTD) of topotecan, using a 5 day bolus schedule, that could be given in combination with a single, fixed dose of cyclophosphamide. Pharmacodynamics of this combination were explored by analyzing biochemical effects of treatment in peripheral-blood mononuclear cells (PBMCs).

PATIENTS AND METHODS

Patients with refractory cancer were treated with cyclophosphamide 600 mg/m2 on day 1, followed by topotecan given as a 30-minute infusion for 5 consecutive days. Cycles were repeated every 3 weeks. Once the MTD was defined, granulocyte colony-stimulating factor (G-CSF) was added to the regimen in an attempt to escalate further the dose of topotecan. Plasma concentrations of topotecan were determined during the first treatment cycle by high-performance liquid chromatography. PBMCs were sampled at baseline and throughout the 5-day treatment period for analysis of topo I protein concentrations and to determine drug-induced DNA fragmentation.

RESULTS

Twenty-six patients were treated with topotecan at doses that ranged from 0.5 mg/m2/d to 1.2 mg/ m2/d for a total of 74 cycles. Reversible neutropenia was dose-limiting, with mild to moderate suppression of the other blood-cell elements commonly occurring. Transfusions of RBCs and platelets were required in 24% and 7% of treatment cycles, respectively. The most prominent nonhematologic toxicities were fatigue and weight loss. Compared with previously published data in which topotecan was administered alone, cyclophosphamide did not appear to alter the pharmacokinetics of topotecan. Significant increases in topo I concentration were identified in PBMCs following the administration of cyclophosphamide on day 1 and there was a significant decrease in topo 1 during the 5-day course of treatment (P < .01, sign test). DNA fragmentation as a result of drug treatment was identified in 11 of 15 (73%) cycles analyzed.

CONCLUSION

For previously treated patients, the recommended dose of topotecan in this schedule is 0.75 mg/m2/d without growth factor support and 1.0 mg/ m2/d if it is administered with G-CSF. Biochemical changes in cells induced by exposure to camptothecins can be measured in vivo and these effects may have important implication in the design of combination therapies and the optimal scheduling of this class of agents.
Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125.
Authors: Rustin G J , Nelstrop A E , Crawford M , Ledermann J , Lambert H E , Coleman R , Johnson J , Evans H , Brown S , Oster W
Published: February 2017

PURPOSE

A phase II study was performed of oral altretamine in 71 patients with ovarian carcinoma who entered clinical complete remission with CA125 levels less than 35 U/mL after initial or second-line chemotherapy, and relapsed more than 6 months later. Response was compared between standard and CA125-based criteria.

PATIENTS AND METHODS

Altretamine 260 mg/m2 was given in divided doses daily for 14 days per month. Response was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 45 of 66 eligible patients. Response was assessed according to precise CA125 criteria in 51 patients based on either a confirmed > or = 50% or > or = 75% decrease in CA125 levels.

RESULTS

A combination of domperidone, dexamethasona, and chlorpromazine at night controlled toxicity in most patients, which was mainly nausea (National Cancer Institute criteria grade 2 or 3 in 27), vomiting (grade 2 or 3 in 19, grade 4 in one), and tiredness (grade 2 or 3 in 15). Responses (complete plus partial) were seen in 18 (40%; 95% confidence interval [CI], 25.4% to 54.6%) of those evaluated according to EORTC criteria and in 20 (39%; 95% CI, 25.5% to 52.9%) of those evaluated according to CA125 level. The overall response rate was 26 of 57 (45.6%) and was related to treatment-free interval: 6 to 12 months, 35%; 12 to 24 months, 52%; and greater than 24 months, 67%. The medium duration of response was 8 months.

CONCLUSION

Oral altretamine is a useful agent in patients-who relapse after previously responsive ovarian cancer. Response evaluation by a strict CA125 definition gave a similar estimate of the efficacy of altretamine as EORTC criteria.
Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial.
Authors: Bartelink H , Rubens R D , van der Schueren E , Sylvester R
Published: February 2017

PURPOSE

To assess the long-term contribution of adjuvant chemotherapy (CT) and hormonal therapy (HT) in patients with locally advanced breast cancer, and to evaluate the impact of time of analysis on the results during accrual and up to 8 years after closure of a randomized phase III trial.

MATERIALS AND METHODS

In a trial using a factorial design, 410 patients were randomized between radiotherapy (RT) alone, RT plus CT, RT plus HT, and RT plus HT plus CT.

RESULTS

CT and HT each produced a significant prolongation of the time to locoregional tumor recurrence and to distant progression of disease, with the combined treatments providing the greatest therapeutic effect. At the time of trial closure, a significant improvement of survival was observed in patients who received CT (P = .004); however, with a longer follow-up duration, this effect disappeared (P > .05). HT did not initially appear to improve survival (P = .16); however, in the latest analysis with a long-term follow-up duration, a significant improvement of survival was seen (P = .02). A consistent 25% reduction in the death hazards ratio has been seen at all evaluations since trial closure in patients who received HT. The best survival results were observed in patients who received RT, HT, and CT (P = .02), with a reduction of 35% in the death hazards ratio.

CONCLUSION

An improvement in survival attributable to HT has been shown in patients with locally advanced breast cancer. The greatest therapeutic effect was seen in the treatment group that received both CT and HT. The improvement obtained with HT became apparent only after long-term follow-up evaluation.
Compliance with practice guidelines for node-negative breast cancer.
Authors: Olivotto A , Coldman A J , Hislop T G , Trevisan C H , Kula J , Goel V , Sawka C
Published: February 2017

PURPOSE

Practice guidelines for cancer management have been in use in the province of British Columbia (BC), Canada, since the mid 1970s. To evaluate practice guideline compliance, treatment received was compared with treatment recommended in a population-based cohort of women with breast cancer.

METHODS

All incident cases (n = 939) of invasive, pathologically node-negative breast cancer diagnosed in 1991 were identified from the BC Cancer Registry. Treatment details were abstracted from cancer clinic records for cases referred to the BC Cancer Agency (BCCA) (n = 661) and original source documents for nonreferred cases. Management decisions were considered compliant if the patient received the recommended treatment or was entered onto a randomized trial of the modality being assessed.

RESULTS

Overall compliance with adjuvant therapy guidelines was 97% for radiotherapy, 96% for chemotherapy, and 89% for tamoxifen. An oncology specialist was consulted by 94% of patients with an indication for adjuvant treatment and by 58% of those without an indication (odds ratio [OR] = 10.7; 95% confidence interval, 7.0 to 16.4). Compliance with a guideline to deliver radiotherapy was 95%; with chemotherapy, 77%; and with tamoxifen, 68%. Compliance with a guideline that stated no adjuvant treatment was indicated was 99% for radiotherapy, 98% for chemotherapy, and 92% for tamoxifen. Noncompliance among patients with an indication for treatment was related to nonreferral to an oncology specialist and less complete implementation of guideline changes in the community as compared with cancer center practices.

CONCLUSION

Compliance was high, but scheduled updating and more effective community implementation could further improve consistency of care.
Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer.
Authors: O'Connell M J , Mailliard J A , Kahn M J , Macdonald J S , Haller D G , Mayer R J , Wieand H S
Published: February 2017

PURPOSE

The goal of this study was to determine the efficacy of intensive-course fluorouracil (5FU) plus low-dose leucovorin given for 6 months following potentially curative resection of colon cancer.

PATIENTS AND METHODS

Three hundred seventeen patients with high-risk stage II or stage III colon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m2) plus leucovorin (20 mg/m2) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation.

RESULTS

The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant improvement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths.

CONCLUSION

These results indicate that intensive-course 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration.
Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study.
Authors: Crinò L , Scagliotti G , Marangolo M , Figoli F , Clerici M , De Marinis F , Salvati F , Cruciani G , Dogliotti L , Pucci F , Paccagnella A , Adamo V , Altavilla G , Incoronato P , Trippetti M , Mosconi A M , Santucci A , Sorbolini S , Oliva C , Tonato M
Published: February 2017

PURPOSE

The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC.

PATIENTS AND METHODS

Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients.

RESULTS

Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71).

CONCLUSION

The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.
Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.
Authors: Huizing M T , Giaccone G , van Warmerdam L J , Rosing H , Bakker P J , Vermorken J B , Postmus P E , van Zandwijk N , Koolen M G , ten Bokkel Huinink W W , van der Vijgh W J , Bierhorst F J , Lai A , Dalesio O , Pinedo H M , Veenhof C H , Beijnen J H
Published: February 2017

PURPOSE

To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS

Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses.

RESULTS

The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06).

CONCLUSION

There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.
Trading treatment toxicity for survival in locally advanced non-small cell lung cancer.
Authors: Brundage M D , Davidson J R , Mackillop W J
Published: February 2017

PURPOSE

To determine how patients weigh potential survival benefits against the potential toxicity of different treatment strategies for locally advanced non-small cell lung cancer (NSCLC). Specifically, we were interested in what improvement in survival probability patients would want to have before accepting more toxic therapy.

PATIENTS AND METHODS

Fifty-six outpatients who had experienced lung cancer (n = 22) or prostate cancer (n = 34), and 20 clinic nurses and radiation therapy technologists participated. A treatment trade-off interview was conducted with each participant that compared low-dose versus high-dose radiotherapy and high-dose radiotherapy versus combination chemo-radiotherapy. Preferences for treatments were assessed by systematically increasing the hypothetical survival advantage of the more toxic treatment until the person reached his or her threshold for choosing the more toxic treatment.

RESULTS

A wide range of thresholds was observed for both groups. The distributions of survival advantage thresholds for lung cancer and prostate cancer patients were not significantly different but were generally lower thresholds than those declared by staff. If the 3-year survival advantage was 10%, 60% of patients and 15% of staff would consider combination therapy over high-dose radiotherapy. Within patients, apparent willingness to consider more toxic treatments was not significantly related to age, sex, education, or preferred role in decision making. The treatment trade-off method had good test-retest reliability.

CONCLUSION

There is great interindividual variability in willingness to accept aggressive treatments for locally advanced NSCLC. When choosing NSCLC treatment, each patient should be provided with comprehensive information about the options so that he or she may express his or her preferences should he or she wish to participate in the decision.
Phase I study of direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7, in patients with metastatic melanoma.
Authors: Stopeck A T , Hersh E M , Akporiaye E T , Harris D T , Grogan T , Unger E , Warneke J , Schluter S F , Stahl S
Published: February 2017

PURPOSE

To determine the safety, toxicity, and efficacy of direct intratumoral injection of an allogeneic major histocompatibility complex (MHC) class I gene, HLA-B7, in a cationic lipid vector (Allovectin-7; Vical Inc, San Diego, CA) in patients with metastatic melanoma.

PATIENTS AND METHODS

Seventeen HLA-B7-negative patients were treated with intralesional injection of Allovectin-7. Twelve patients received a single intralesional injection containing 10 micrograms (four patients), 50 micrograms (five patients), or 250 micrograms (three patients) of plasmid DNA. Five patients received two or three injections of 10 micrograms DNA to a single tumor site at 2-week intervals. Tumor biopsies pretherapy and 2 and 4 weeks after gene injection were obtained to determine expression of the plasmid by polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, flow cytometry, and immunohistochemistry.

RESULTS

Toxicities were related to technical aspects of the injections or biopsies. These included pain, hemorrhage, pneumothorax, and hypotension. Two patients were hospitalized overnight for observation. Seven patients (50%) had tumor responses insofar as the injected nodule decreased > or = 25% by radiologic or physical examination. One patient with a single site of disease achieved a complete remission. Ninety-three percent of the patients' post-gene therapy biopsies contained HLA-B7 plasmid DNA, mRNA, or protein.

CONCLUSION

Intratumoral injection of the allogeneic histocompatibility gene, HLA-B7, in a lipid vector can be performed safely at plasmid DNA doses < or = 250 micrograms. The safety profile and biologic activity of this therapy warrants further studies to define the mechanism of action, predictors of response, and antitumor efficacy of this approach.
Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation.
Authors: Sobrero A F , Aschele C , Bertino J R
Published: February 2017

PURPOSE

To determine if fluorouracil (FUra) has different mechanisms of action as a function of the dose schedule used.

DESIGN

The preclinical and clinical literature relating toxicity and antitumor effects of FUra as a function of its dose schedule, with and without modulating agents, was reviewed.

RESULTS

The data support the hypothesis that FUra may be considered to be two different drugs, depending on its dose schedule (bolus v continuous infusion [CI]).

CONCLUSION

These results suggest that additional therapeutic benefit may be obtained from FUra regimens by (1) appropriate schedule-dependent modulation, (2) the sequential or alternating use of cycles of bolus followed by cycles of CI FUra appropriately modulated, or (3) hybrid regimens, ie, those that contain both pulse and CI schedules.
Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia.
Authors: Saven A , Lee T , Schlutz M , Jacobs A , Ellison D , Longmire R , Piro L
Published: February 2017

PURPOSE

De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan, NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders.

PATIENTS AND METHODS

We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14 mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two to five). There were five men and three women, with a median age of 62 years and a median pretreatment duration of 6 months; four patients were previously untreated.

RESULTS

All eight patients were assessable: five achieved a complete response with a median response duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating B-PLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four had bacterial infections, and two had herpes zoster infections.

CONCLUSION

In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a high overall and complete response rate. These results require confirmation in larger numbers of B-PLL patients.
Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm.
Authors: Small E J , Vogelzang N J
Published: February 2017

PURPOSE

To discuss the evolution of new concepts in the Use of second-line hormonal therapy for patients with progressive prostate cancer despite androgen deprivation.

DESIGN

Pertinent contemporary prostate-specific antigen (PSA)-based reports of the utility of secondary hormonal maneuvers after treatment with combined androgen blockade (CAB) were reviewed.

RESULTS

The use of PSA as an end point in hormonerefractory prostate cancer (HRPC) trials is more widely accepted, but still remains somewhat controversial. Using PSA as an end point, it is clear that a variety of secondary hormonal maneuvers can result in responses. Antiandrogen withdrawal is efficacious in approximately 20% of patients and can be observed with a variety of antiandrogens, including flutamide, bicalutamide, and megestrol acetate. A variety of regimens, including megestrol, bicalutamide, glucocorticoids, aminoglutethimide, and ketoconazole, retain activity (14% to 75% PSA response proportion) even in patients who have failed to respond to CAB and flutamide withdrawal.

CONCLUSION

Once CAB (suppression of gonadal and adrenal androgen) is undertaken, further hormonal maneuvers remain efficacious in some patients with progressive prostate cancer. Antiandrogen withdrawal is now a mandatory maneuver before proceeding to other regimens. It is clear that certain patients will continue to respond to hormonal maneuvers even after antiandrogen withdrawal. An understanding of the molecular basis of these responses may result in the development of a more targeted therapy in the future.
Case/control study of the role of splenectomy in chronic lymphocytic leukemia.
Authors: Seymour J F , Cusack J D , Lerner S A , Pollock R E , Keating M J
Published: February 2017

PURPOSE

This retrospective analysis was performed to evaluate critically the morbidity and mortality of splenectomy in patients with chronic lymphocytic leukemia and to determine the probability of hematologic response. Further, using a case/control format based on multivariate analysis-derived predictors of survival, we evaluated the influence of splenectomy on survival.

PATIENTS AND METHODS

Between 1971 and 1993, 55 patients with chronic lymphocytic leukemia underwent splenectomy. They were compared with 55 fludarabine-treated patients who had been matched for age, serum albumin level, sex, hemoglobin level, Rai stage, number of prior therapies, and time from diagnosis.

RESULTS

In the perioperative period, blood-product usage was modest, and common morbidities were limited to minor infections in 18% of the patients and pneumonia/atelectasis in 25%. Perioperative mortality was 9%. Deaths were related to septic complications in all cases and associated with a preoperative performance status > or = 2 (P = .05). The only predictor identified for hemoglobin and neutrophil increments was spleen weight (P < .05). No factors predictive of platelet increment were identified. The early death rate (within 30 days) and overall survival of splenectomy and control patients were not significantly different (P > .2). Among Rai stage IV patients, those who were splenectomized displayed a strong trend for improved overall survival (P = .15 by log-rank test). The 2-year actuarial survival rate of Rai stage IV patients was 51% +/- 9% in the splenectomy group and 28% +/- 9% in the control group.

CONCLUSION

Splenectomy can be performed with modest morbidity, mortality, and resource utilization in patients with advanced chronic lymphocytic leukemia and significant cytopenias. The procedure results in major hematologic benefits in most patients, with hemoglobin and neutrophil increments correlated with spleen weight. Overall, the survival of splenectomized patients is equivalent to control patients. Thrombocytopenic patients (< 100 x 10(9)/L) are most likely to obtain hematologic benefit, and potentially enjoy improved survival. These patients would be suitable for a randomized study to establish definitively the role of splenectomy in chronic lymphocytic leukemia.
Conservative treatment of rectal adenocarcinoma with endocavitary irradiation or wide local excision and postoperative irradiation.
Authors: Mendenhall W M , Rout W R , Vauthey J N , Haigh L S , Zlotecki R A , Copeland E M
Published: February 2017

PURPOSE

To evaluate the role of endocavitary irradiation and wide local excision followed by irradiation in the treatment of early-stage rectal adenocarcinoma.

MATERIALS AND METHODS

Sixty-five patients with early-stage adenocarcinoma of the rectum were treated with endocavitary irradiation (n = 20) or wide local excision followed by external-beam irradiation (n = 45) between 1974 and 1994 at the University of Florida. All patients were monitored for a minimum of 2 years or until death.

RESULTS

The rates of local-regional control at 5 years were 80% after endocavitary irradiation and 86% after wide local excision and radiotherapy. The ultimate 5-year local-regional control rates were 85% and 92%, respectively. Multivariate analysis of local-regional control with sphincter preservation showed that tumor configuration (exophytic v ulcerative) significantly influenced this end point; local-regional control was decreased in patients with ulcerated cancers. Five-year cause-specific survival rates were 84% after endocavitary irradiation and 88% after wide local excision and radiotherapy. Multivariate analysis revealed that tumor configuration significantly influenced cause-specific survival; patients with ulcerated tumors had a worse prognosis.

CONCLUSION

Endocavitary irradiation is a highly effective treatment for properly selected patients with early-stage rectal adenocarcinoma. Patients with less favorable lesions that appear to be limited to the muscularis propria have a high chance of cure with sphincter preservation after wide local excision and external-beam irradiation.
Evaluation of newer prognostic markers for adult soft tissue sarcomas.
Authors: Levine E A , Holzmayer T , Bacus S , Mechetner E , Mera R , Bolliger C , Roninson I B , Das Gupta T K
Published: February 2017

PURPOSE

In addition to tumor size, grade, location, and the presence of metastases, other factors may be useful in prognostication for adults with soft tissue sarcoma (STS). This study examines the relationship of MDR-1 mRNA, p-glycoprotein (P-gp), Ki-67 expression, and DNA content expression to clinical outcome in adults with STS.

PATIENTS AND METHODS

Snap-frozen STS specimens from 65 patients were analyzed and compared with clinical outcomes. Immunohistochemistry was performed for the Ki-67 antigen and P-gp. DNA content was determined using the Feulgen reaction and quantitated using image analysis. MDR-1 mRNA expression was determined using a reverse-transcriptase polymerase chain reaction (RT-PCR)-based assay.

RESULTS

P-glycoprotein expression was found by immunohistochemistry in 48% of cases with 5-year overall (54% v 14%, P = .07) and disease-free survival rates (32% v 18%, P = .039) higher in high-grade tumors that did not express P-gp. MDR-1 mRNA was detected in 51% of cases and no patient with high levels of MDR-1 mRNA expression was a long-term survivor. Patients with diploid tumors had significantly better survival than those with nondiploid tumors (51% v 31%, P = .03). High levels of Ki-67 were associated with poorer overall survival (46% v 31%, P = .04). On multivariate analysis, American Joint Committee on Cancer (AJCC) staging, DNA content, Ki-67, and P-gp staining were significant prognostic factors for 5-year overall and disease-free survival.

CONCLUSION

P-gp expression, high-level Ki-67 expression, and nondiploid DNA content are independent prognostic indicators that correlate with poor outcomes in STS patients. However, MDR-1 mRNA was not found to be predictive of survival. These newer markers are useful additions to AJCC staging for prognostication for patients with STS. Such markers may be useful in selecting high-risk STS patients who could benefit from systemic adjuvant therapy.
Lung cancer metastatic cells detected in blood by reverse transcriptase-polymerase chain reaction and dot-blot analysis.
Authors: Castaldo G , Tomaiuolo R , Sanduzzi A , Bocchino M L , Ponticiello A , Barra E , Vitale D , Bariffi F , Sacchetti L , Salvatore F
Published: February 2017

PURPOSE

We analyzed the blood of patients with lung cancer at different stages of presentation for the presence of carcinoembryonic antigen (CEA) mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) combined with the dot-blot procedure as an indicator of micrometastatic malignant cells.

PATIENTS AND METHODS

We studied 24 lung cancer patients (10 with distant metastases and 14 with no evidence of distant metastases), eight age- and sex-matched patients affected by nonneoplastic respiratory diseases (four smokers), and eight healthy subjects. We used immunohistochemistry and RT-PCR dot-blot analysis to evaluate CEA expression in the neoplastic tissue, and the RT-PCR dot-blot procedure to analyze CEA mRNA in circulating cells.

RESULTS

The RT-PCR dot-blot procedure was highly sensitive aspecific: it detected CEA mRNA in samples of RNA from lung cancer diluted 10(6)-fold with RNA extracted from normal blood cells, and sequence analysis confirmed that the amplified product was CEA. CEA mRNA was found in circulating cells from eight of 10 lung cancer patients with distant metastases (diagnostic sensitivity, 80%) and in four of 14 patients with no evidence of distant metastases. Two of the latter had distant metastases within 6 months of analysis. Thus, the diagnostic specificity of the analysis toward lung cancer without distant metastases was 86%. The analysis was negative in the eight nonneoplastic patients and in the eight healthy controls.

CONCLUSION

The RT-PCR dot-blot analysis of CEA mRNA in blood cells seems to be a promising tool for the early detection of micrometastatic circulating cells in patients with lung cancer.
Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer.
Authors: Stadler W M , Kuzel T , Roth B , Raghavan D , Dorr F A
Published: February 2017

PURPOSE

To determine the activity of single-agent gemcitabine in previously untreated patients with metastatic transitional cell cancer.

METHODS

Forty patients with measurable disease and a Karnofsky performance status > or = 60% were enrolled at five institutions between March 1994 and October 1995. Treatment consisted of gemcitabine (1,200 mg/m2) administered weekly times three on a 4-week cycle. One patient was ineligible for response evaluation because pathology review showed a metastatic melanoma. Responses were confirmed by all investigators and an independent radiologist and were maintained for at least 4 weeks.

RESULTS

There were four complete and seven partial responses, for an overall response rate of 28%. Responses were seen at all sites, including liver. Median progression-free and overall survival times were 20 and 54 weeks, respectively. Toxicity was mild, with only two grade 4 toxicities. Twenty-five percent of patients experienced grade 3 neutropenia or thrombocytopenia that was rapidly reversible.

CONCLUSION

Gemcitabine exhibits significant activity in metastatic transitional cell cancer with minimal toxicity, but survival remains short. Trials of gemcitabine in combination with other active agents are thus suggested.