bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study.
Authors: Taylor C W , Green S , Dalton W S , Martino S , Rector D , Ingle J N , Robert N J , Budd G T , Paradelo J C , Natale R B , Bearden J D , Mailliard J A , Osborne C K
Published: February 2017

PURPOSE

To compare failure-free survival (FFS) and overall survival (OS) for patients with metastatic breast cancer treated with the gonadotropin-releasing hormone (GN-RH) agonist, goserelin versus surgical ovariectomy.

PATIENTS AND METHODS

Between August 1, 1987 and July 15, 1995 138 (136 eligible) premenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive metastatic breast cancer were entered by the Southwest Oncology Group (SWOG), North Central Cancer Treatment Group (NCCTG), and Eastern Cooperative Oncology Group (ECOG). Prior chemotherapy or hormone therapy for metastatic disease was not allowed. Patients were randomly assigned to goserelin (3.6 mg subcutaneously every 4 weeks; (n = 69) versus surgical ovariectomy (n = 67). The study was initially designed as an equivalence trial with 80% power to rule out a 50% improvement in survival due to ovariectomy. However, accrual was slow and the study was terminated early, which resulted in a final power of 60% for the alternative hypothesis of equal survival distributions.

RESULTS

FFS and OS were similar for goserelin and ovariectomy. The goserelin/ovariectomy death hazards ratio was .80 and the associated 95% confidence interval (CI) was .53 to 1.20. The test of 50% improvement in survival due to ovariectomy was rejected at P = .006. Goserelin lowered serum estradiol to postmenopausal levels. Hot flashes (75% v 46%) and tumor flare (16% v 3%) were more common with goserelin.

CONCLUSION

Goserelin and ovariectomy resulted in similar FFS and OS. We can rule out a moderate advantage for ovariectomy. Goserelin was safe and well tolerated.
Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study.
Authors: Matthay K K , Perez C , Seeger R C , Brodeur G M , Shimada H , Atkinson J B , Black C T , Gerbing R , Haase G M , Stram D O , Swift P , Lukens J N
Published: February 2017

PURPOSE

To identify a biologically favorable and unfavorable subset of patients with Evans stage III neuroblastoma and to determine whether treatment stratification would improve the event-free survival (EFS) for high-risk patients and maintain excellent EFS for the lower-risk patients.

PATIENTS AND METHODS

Risk stratification was performed by age, MYCN gene copy number, Shimada histopathologic classification, and serum ferritin level. Lower-risk patients were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas high-risk patients were treated on CCG-3891, which included more intensive multimodality therapy and, in some cases, autologous bone marrow transplantation (ABMT).

RESULTS

Of 228 Evans stage III patients entered onto the study, 92% also met the definition of International Neuroblastoma Staging System (INSS) stage 3. One hundred forty-three patients met the lower-risk criteria, which included 89 patients less than 1 year of age and 54 patients 1 year of age or greater, and favorable biology, whereas 85 patients were 1 year of age or greater and biologically unfavorable. Biologically unfavorable patients 1 year of age or greater who underwent gross surgical resection had improved survival, whereas the outcome of infants or biologically favorable older patients did not change according to resection. The EFS rate at 4 years was 100% for the patients with favorable biology of any age, 90% for those less than 1 year of age but with at least one unfavorable characteristic, and 54% for Evans stage III patients 1 year of age or greater with unfavorable biology. Age, ferritin level, MYCN copy number, Shimada histopathology, primary site, and intraspinal extension were significant univariate prognostic factors for all patients, but only MYCN copy number and age were independent factors in multivariate analyses.

CONCLUSION

The excellent survival of the biologically favorable group and the historically improved EFS of the biologically unfavorable group suggest that biologic staging should be used to define the prognosis and treatment of stage III neuroblastoma.
Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels.
Authors: Zon R T , Nichols C , Einhorn L H
Published: February 2017

PURPOSE

To determine the therapeutic results in advanced germ cell tumor (GCT) patients with initial human chorionic gonadotropin (hCG) elevation greater than 50,000 mIU/mL and to document the levels of hCG decline and subsequent plateau and outcome of this patient population.

PATIENTS AND METHODS

We conducted a retrospective review of 41 patients who presented to Indiana University (IU) with hCG levels greater than 50,000 mIU/mL between December 1976 and August 1996. All patients had received cisplatin-containing regimens and were monitored with serial hCG levels.

RESULTS

Twenty-two of 41 (53.7%) patients continuously show no evidence of disease (NED) and eight additional patients (19.5%) are currently NED with salvage therapy. Only two of 41 patients had a normal hCG level at the start of the fourth and final course of cisplatin combination chemotherapy. Eight additional patients showed normalized hCG levels 1 month later. Seven of these 10 are continuously NED and three are currently NED with salvage therapy. Thirty-one patients had an abnormal hCG greater than 1 month after they completed primary chemotherapy; 15 of these patients (48%) are continuously NED despite no further therapy and five additional patients (16%) are currently NED with salvage therapy. Overall, there was an initial rapid decline in hCG followed by a plateau after the first two courses of therapy.

CONCLUSION

Less than 10% of patients who present with hCG levels greater than 50,000 mIU/mL will have a normal hCG at the institution of the fourth and final course of chemotherapy. However, 22 of 41 (53.7%) are continuously NED despite no further therapy. We feel that the optimal strategy for such patients is monthly observation with initiation of salvage therapy if and when there is serologic progression.
Costs of care associated with non-small-cell lung cancer in a commercially insured cohort.
Authors: Hillner B E , McDonald M K , Desch C E , Smith T J , Penberthy L T , Maddox P , Retchin S M
Published: February 2017

PURPOSE

To examine the cost of incident cases of non-small-cell lung cancer (NSCLC) in a commercially insured cohort.

METHODS

Claims from Virginia Blue Cross and Blue Shield (BCBS) beneficiaries with lung cancer from 1989 to 1991 were merged with records from the Virginia Cancer Registry (VCR). Data from the VCR identified incident cases, stage, and type of cancer at diagnosis. Costs for all medical care included insurance payment, copayments, and deductibles for 2 years after diagnosis or until death.

RESULTS

Three hundred forty-nine incident NSCLC patients were evaluated. The mean 2-year cost for each patient after diagnosis or until death was $47,941 (95% confidence interval, $43,758 to $52,124). Total average costs and hospital days were significantly lower for local disease ($37,514, 21.2 days), but were similar for regional ($52,797, 30.0 days) and distant ($49,382, 33.0 days) disease. Hospital days accounted for 48% and hospital-based claims for 70% of costs. Initial treatments, which included radiation, unadjusted for stage, had the lowest survival rates and the highest costs, and were associated with the most hospital days. Initial stage, race, gender, and age were not predictors of total 2-year costs. The independent predictors of total 2-year costs were type of treatment: any radiation therapy, any surgery, or any chemotherapy (all, P < .001). Inpatient hospital days was only a modest predictor of costs after adjusting for type of treatment. Patients who survived less than 1 year spent 30.5 days in hospital and had an average cost of $47,280.

CONCLUSION

The direct health care costs of younger NSCLC patients care are substantial. These results should serve as a benchmark for future comparisons as the United States market shifts to managed care.
Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.
Authors: Pehamberger H , Soyer H P , Steiner A , Kofler R , Binder M , Mischer P , Pachinger W , Auböck J , Fritsch P , Kerl H , Wolff K
Published: February 2017

PURPOSE

Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor.

PATIENTS AND METHODS

In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase).

RESULTS

Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated.

CONCLUSION

Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients.
Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine.
Authors: Payne R , Mathias S D , Pasta D J , Wanke L A , Williams R , Mahmoud R
Published: February 2017

PURPOSE

To compare pain-related treatment satisfaction, patient-perceived side effects, functioning, and well-being in patients with advanced cancer who were receiving either transdermal fentanyl (Duragesic, Janssen Pharmaceuticals, Titusville, NJ) or sustained-release oral forms of morphine (MS Contin, Perdue Frederick Co, Norwalk, CT, or Oramorph SR, Roxanne Laboratories, Columbus, OH).

PATIENTS AND METHODS

A total of 504 assessable cancer patients participated in this cross-sectional, quality-of-life study. Relevant elements of four validated scales were used--the Functional Assessment of Cancer Therapy-General (FACT-G) scale, the Brief Pain Inventory (BPI), the Medical Outcomes Study (MOS) questionnaire, and the Memorial Symptom Assessment Scale (MSAS)--as well as original scales that were developed and validated for this study.

RESULTS

The majority of patients in both treatment groups had late-stage (IV/D) cancer. Patients who received transdermal fentanyl were more satisfied overall with their pain medication than those who received sustained-release oral forms of morphine (P = .035). Fentanyl patients also experienced a significantly lower frequency (P < .002) and impact (P < .001) of pain medication side effects. These results occurred despite the fact that cancer patients who received fentanyl were significantly older (P < .001) and had significantly lower functioning and well-being scores (P = .001). Measures of pain intensity, sleep adequacy, and symptoms demonstrated no significant differences between treatment groups.

CONCLUSION

These data suggest that patients are more satisfied with transdermal fentanyl compared with sustained-release oral forms of morphine. A lower frequency and reduced impact of side effects with transdermal fentanyl may be one reason cancer patients who receive fentanyl are more satisfied with their pain management.
Vascular enumeration as a significant prognosticator for invasive breast carcinoma.
Authors: Aceñero M J , González J F , Gallego M G , Ballesteros P A
Published: February 2017

PURPOSE

Vascular enumeration has been claimed to be an independent prognosticator for invasive breast cancer. Most of the studies have performed a manual count of the vessels. Few investigators have used image analyzers to reduce subjectivity in the measures. The aim of this retrospective study was to compare the manual vessel count to the counts obtained with an image analyzer and to estimate their possible prognostic influence.

MATERIALS AND METHODS

We selected 112 patients with invasive ductal carcinoma, treated with radical mastectomy followed by chemotherapy and with a minimal follow-up time of 60 months (5 years). After immunostaining with factor VIII, we performed a double count of the vessels. First, we performed a manual count following Gasparini's criteria, and second, we used an image analyzer (Microm, Barcelona, Spain) to count the vessels in eight adjacent microscopic fields with a 20x objective, to reach a total area of 0.98 mm2. The image analyzer calculated the total number of vessels, their size and also the percentage of the field occupied by the vessels.

RESULTS

In our series, vascular enumeration showed no significant association with histologic grade (Bloom-Scarff-Richardson grading), tumor size, or staging.

CONCLUSION

Vascular enumeration with both methods was an independent prognosticator for relapse-free-survival (RFS) in both node-negative and -positive patients in the univariate analysis, but only vascular enumeration with the image analyzer was an independent prognostic factor in the multivariate analysis, together with lymph node metastases.
Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer.
Authors: Broeckel J A , Jacobsen P B , Horton J , Balducci L , Lyman G H
Published: February 2017

PURPOSE

Clinical reports suggest that many breast cancer patients experience persistent fatigue as a long-term side effect of adjuvant chemotherapy treatment. To investigate this issue further, we examined the characteristics and correlates of fatigue in women who had completed adjuvant chemotherapy for breast cancer and in a comparison group of women with no history of cancer.

PATIENTS AND METHODS

Participants were 61 women with breast cancer who had completed chemotherapy an average of 471 days previously and 59 women with no history of cancer. All participants completed standardized self-report measures of fatigue, sleep quality, menopausal symptoms, and coping and were administered a structured clinical interview to identify current and past psychiatric disorder.

RESULTS

Compared with women with no history of cancer, former adjuvant chemotherapy patients reported more severe fatigue (P < .01) and worse quality of life because of fatigue (P < .05). More severe fatigue among patients was significantly (P < .05) related to poorer sleep quality, more menopausal symptoms, greater use of catastrophizing as a coping strategy, and current presence of a psychiatric disorder.

CONCLUSION

These findings support the view that many breast cancer patients experienced heightened fatigue after completion of adjuvant chemotherapy treatment. Results yield a profile of women who are at increased risk for heightened fatigue after chemotherapy and suggest ways to intervene clinically to prevent or reduce fatigue in this patient population.
BRCA1 and BRCA2: from molecular genetics to clinical medicine.
Authors: Blackwood M A , Weber B L
Published: February 2017

Inherited susceptibility to breast cancer has been an area of intense investigation for the past 10 years. Early work focused on identifying modes of transmission, which culminated in the identification of chromosome 17q12-21 as the first human genomic region that harbored an autosomal dominant susceptibility gene for breast cancer (BRCA1) in 1990. BRCA1 was subsequently identified and was followed shortly by the identification of BRCA2. Research in the past 3 years has elucidated much about the mutation spectrum and mutation frequency of these genes in specific populations and is beginning to identify potential functions. Whereas progress in this area has been rapid and much is now known about inherited susceptibility to breast cancer, much more needs to be done to make these discoveries useful in the diagnosis, treatment, and ultimately, the prevention of breast cancer.
Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study.
Authors: Katzenstein H M , Bowman L C , Brodeur G M , Thorner P S , Joshi V V , Smith E I , Look A T , Rowe S T , Nash M B , Holbrook T , Alvarado C , Rao P V , Castleberry R P , Cohn S L
Published: February 2017

PURPOSE

Although a high rate of spontaneous regression is observed in infants with stage D(S) neuroblastoma (NB), survival is not uniform. To determine the prognostic relevance of age at diagnosis, therapy, and tumor biology in infants with stage D(S) NB, we reviewed the Pediatric Oncology Group (POG) experience.

PATIENTS AND METHODS

A review of patients diagnosed with stage D(S) NB registered on POG protocols was performed. Survival according to age at diagnosis, treatment, and tumor biology was determined.

RESULTS

Between 1987 and 1996, 110 infants with stage D(S) NB had an estimated 3-year survival rate of 85% +/- 4%; survival rate was 71% +/- 8% for infants 2 months of age or younger, and 68% +/- 12%, 44% +/- 33%, and 33% +/- 19% for patients with diploid, MYCN-amplified, and unfavorable histology tumors, respectively. Survival rates were similar for patients who received adjuvant chemotherapy versus those who did not (82% +/- 5% v 93% +/- 6%, respectively; P = .187). Furthermore, there was no statistical difference in survival rate for patients who underwent complete resection of their primary tumor compared with those who underwent partial resection or biopsy only (90% +/- 5% v 78% +/- 7%, respectively; P = .083).

CONCLUSION

Our review confirmed that the survival of infants with stage D(S) NB is excellent. However, subsets of patients with poor prognosis can be identified by young age and unfavorable biologic factors. More effective therapy is needed for the group of stage D(S) infants who show unfavorable clinical and biologic features.
Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study.
Authors: Hoskins P , Eisenhauer E , Beare S , Roy M , Drouin P , Stuart G , Bryson P , Grimshaw R , Capstick V , Zee B
Published: February 2017

PURPOSE

As topotecan is S-phase-specific, its efficacy is likely schedule-dependent. Therefore, a randomized study using a "pick the winner" design was undertaken to compare two schedules in patients with recurrent ovarian cancer.

PATIENTS AND METHODS

Patients with recurrent epithelial ovarian cancer previously treated with no more than two separate regimens of chemotherapy, one of which had to be platinum-containing, were randomized to either topotecan 1.5 mg/m2 intravenously (i.v.) over 30 minutes daily for 5 days repeated every 21 days (arm A, the standard arm), or topotecan 1.75 mg/m2 as a 24-hour infusion once a week for 4 weeks repeated every 6 weeks (arm B, the experimental arm).

RESULTS

Sixty-six patients were eligible and 63 were assessable for response. The response rate in arm A was 22.6% (95% confidence interval [CI], 9.6% to 41.2%), which was significantly superior to that in arm B, 3.1% (95% CI, 0.1% to 16%) (P = .026). The regimens were not equitoxic, with 94% of patients on arm A experiencing grade 3 or 4 granulocytopenia as opposed to 52% on arm B.

CONCLUSION

The weekly 24 hour infusion of topotecan at 1.75 mg/m2 was ineffective in relapsed ovarian cancer. The daily-times-five schedule remains the schedule of choice. As the regimens were not equitoxic, one cannot differentiate between an ineffective schedule and an ineffective dose as the reason for the differing response rates. However, the degree of myelotoxicity that already occurs will preclude any substantially higher dosing with the weekly regimen.
Telomerase activity as a biomarker for (pre)neoplastic cervical disease in scrapings and frozen sections from patients with abnormal cervical smear.
Authors: Wisman G B , Hollema H , de Jong S , ter Schegget J , Tjong-A-Hung S P , Ruiters M H , Krans M , de Vries E G , van der Zee A G
Published: February 2017

PURPOSE

To evaluate the diagnostic value of semi-quantitative telomerase activity assessment in cervical scrapings together with human papillomavirus (HPV) typing for detection of (pre)neoplastic cervical lesions and to compare telomerase activity in cervical scrapings and frozen specimens from the same patients.

PATIENTS AND METHODS

A cross-sectional study was performed in 161 patients referred for an abnormal cervical cytology report. In cervical scrapings, telomerase activity was determined by modified telomere repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with general and type-specific primers. Final diagnosis was made by pathologic examination of biopsy and/or loop excision specimens.

RESULTS

Telomerase activity was detectable in assessable scrapings from one of nine (11%) patients without cervical intraepitheleal neoplasia (CIN), in three of 26 (12%) with CIN I, eight of 35 (22%) with CIN II, 18 of 62 (29%) with CIN III, and four of 13 (31%) with cancer. Sensitivity and negative predictive value of the TRAP assay for CIN II/III and cancer lesions were 25% and 28%, respectively, while specificity for no CIN or CIN I was 89%. In representative frozen sections, frequency of detectable telomerase activity was related to grade of CIN/cancer; none of 21 normal cervices, none of two CIN I, two of 12 (17%) CIN II, 10 of 31 (32%) CIN III, and 18 of 21 (86%) cervical cancer lesions were telomerase-positive (P < .0005). Telomerase activity levels in paired scrapings and frozen sections appeared to be only weakly related; telomerase-positive sections with negative scrapings and vice versa (only in CIN III) were observed. In oncogenic HPV-negative scrapings (n = 14), no telomerase activity was detected, but in frozen sections, telomerase activity levels appeared to be unrelated to presence of specific HPV types.

CONCLUSION

Telomerase activity is more frequent in higher grade CIN/cervical cancer lesions. Telomerase activity assessment in cervical scrapings has a low sensitivity for CIN II/III and/or cervical cancer and does not appear to be useful in primary screening for cervical cancer. However, increased telomerase activity in frozen CIN sections may be a possible marker of progressive disease.
Plasma c-erbB-2 levels in breast cancer patients: prognostic significance in predicting response to chemotherapy.
Authors: Mehta R R , McDermott J H , Hieken T J , Marler K C , Patel M K , Wild L D , Das Gupta T K
Published: February 2017

PURPOSE

To determine the significance of plasma c-erbB-2 levels to assess the extent of disease spread and to predict the response to chemotherapy in node-positive breast cancer patients.

METHODS

We determined plasma levels of c-erbB-2 in 79 stages II and III breast cancer patients who received cyclophosphamide, methotrexate, and flourouracil (CMF)/cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) chemotherapy. All patients had a minimum follow-up of greater than 60 months or until disease recurrence. Plasma samples were obtained before and after chemotherapy. Plasma c-erbB-2 levels were quantified by enzyme-linked immunoassay. c-erbB-2 levels were analyzed in relation to the patients' axillary lymph node status, menopausal status, disease status, disease-free survival (DFS), and steroid receptor status of tumor.

RESULTS

Plasma c-erbB-2 levels varied widely in breast cancer patients. In general, when all patients were included in the analyses, plasma c-erbB-2 levels before chemotherapy correlated significantly with the number of positive axillary lymph nodes and with postchemotherapy c-erbB-2 levels. No association was observed between pre- or postchemotherapy c-erbB-2 levels and other variables (patients' age at diagnosis, receptor status of the tumor, or disease status). The prognostic significance of different factors (ie, nodal status [one to three v > three positive nodes], menopausal status [pre- v postmenopausal women], estrogen receptor [ER] status [ER+ v ER-], and pre- and postchemotherapy c-erbB-2 levels) in predicting DFS was determined in all study patients. Among the variables examined, nodal status was the strongest predictor of DFS in these patients. The second most significant prognostic marker was postchemotherapy c-erbB-2 level. Prechemotherapy c-erbB-2 levels showed prognostic significance for DFS in a subset of breast cancer patients (ie, patients with > three positive nodes). Patients with greater than three positive lymph nodes and those with greater than 100 fmol/mL of plasma c-erbB-2 levels before therapy had significantly shorter DFS than did those patients with 100 fmol/mL or less c-erbB-2 levels.

CONCLUSION

In breast cancer patients, determination of c-erbB-2 levels before therapy is an important biomarker to assess the extent of disease spread in the lymph nodes. Postchemotherapy c-erbB-2 levels are also a prognostic indicator for DFS in patients who receive chemotherapy. Finally, in a subgroup of patients with greater than three positive nodes, prechemotherapy c-erbB-2 levels are a prognostic marker for response of patients to standard chemotherapy.
Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.
Authors: Meyers C A , Weitzner M A , Valentine A D , Levin V A
Published: February 2017

PURPOSE

Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration.

PATIENTS AND METHODS

Thirty patients with primary brain tumors underwent neuropsychologic assessment before and during treatment with methylphenidate. Ability to function in activities of daily living and magnetic resonance imaging (MRI) findings were also documented. Patients were assessed on 10, 20, and 30 mg of methylphenidate twice daily.

RESULTS

Significant improvements in cognitive function were observed on the 10-mg twice-daily dose. Functional improvements included improved gait, increased stamina and motivation to perform activities, and in one case, increased bladder control. Adverse effects were minimal and immediately resolved when treatment was discontinued. There was no increase in seizure frequency and the majority of patients on glucocorticoid therapy were able to decrease their dose. Gains in cognitive function and ability to perform activities were observed in the setting of progressive neurologic injury documented by MRI in half of the subjects.

CONCLUSION

This study demonstrated improved patient function in the setting of a progressive neurologic illness. Methylphenidate should be more widely considered as adjuvant brain tumor therapy.
Oral chemotherapy: rationale and future directions.
Authors: DeMario M D , Ratain M J
Published: February 2017

PURPOSE AND METHODS

The expanding role of oral chemotherapy in oncology is suggested by the abundance of orally formulated agents currently in development. The pharmacoeconomic principles that drive oral drug formulation are discussed. Patient preference for oral therapy is identified as a second major impetus for the design of oral cytotoxics. While the rationale for oral formulations is apparent, substantial patient compliance and pharmacokinetic limitations have been identified for this route of administration. Specific aspects of bioavailability limitations and patient compliance are discussed. Relevant pharmacokinetic data for each orally formulated chemotherapy agent are compared and selected novel oral cytotoxics and cytotoxic modulators are discussed.

RESULTS

A review of pharmacokinetic literature suggests substantial variability in bioavailability for many orally formulated cancer cytotoxics. While these findings are observed for all classes of oral drugs, the issue is especially critical for cancer chemotherapy, in which a narrow therapeutic index is frequently observed. Improved bioavailability and reduced interpatient biovariability are therefore desirable for new cytotoxic formulations. Pharmacologic manipulations to improve bioavailability and reduce costs are examined.

CONCLUSION

Oral chemotherapy represents a fundamental change in contemporary oncology practice, driven by pharmacoeconomic issues, patient convenience, and the potential for improved patient quality of life. Novel cytostatic therapies that require protracted drug administration periods will also favor an oral formulation. While the use of oral chemotherapy may initially be limited to metastatic disease palliation, demonstration of equivalent efficacy would allow for its subsequent use in adjuvant settings. This efficacy is contingent on circumventing bioavailability limitations and patient noncompliance. The development of specific, low-toxicity inhibitors of CYP3A4, P-glycoprotein (P-gp), and other drug metabolizing enzymes such as dihydropyrimidine dehydrogenase represents a major innovative step in the successful formulation of oral chemotherapy.
Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.
Authors: Christodoulou C V , Ferry D R , Fyfe D W , Young A , Doran J , Sheehan T M , Eliopoulos A , Hale K , Baumgart J , Sass G , Kerr D J
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine.

PATIENTS AND METHODS

Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi).

RESULTS

At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi.

CONCLUSION

The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.
Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.
Authors: Shuster J J , Wacker P , Pullen J , Humbert J , Land V J , Mahoney D H , Lauer S , Look A T , Borowitz M J , Carroll A J , Camitta B
Published: February 2017

PURPOSE

In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis.

PATIENTS AND METHODS

All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996.

RESULTS

A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years.

CONCLUSION

This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.
Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children.
Authors: Skapek S X , Hawk B J , Hoffer F A , Dahl G V , Granowetter L , Gebhardt M C , Ferguson W S , Grier H E
Published: February 2017

PURPOSE

We report the treatment of 10 children for progressive desmoid tumor not amenable to standard surgical or radiation therapy with the use of vinblastine (VBL) and methotrexate (MTX).

PATIENTS AND METHODS

Ten patients aged 6.4 to 18 years with primary (two patients) or recurrent (eight patients) desmoid tumor were treated with VBL and MTX for 2 to 35 months. Patients with recurrent tumors had been previously treated with surgical resection with (two patients) or without (five patients) radiation therapy or with radiation therapy alone (one patient). No patient had previously received cytotoxic chemotherapy. The tumor response was assessed at routine intervals by physical examination and magnetic resonance imaging (MRI).

RESULTS

Five patients had clinical evidence of response to therapy with complete resolution (three patients) or partial resolution (two patients) of physical examination and radiographic abnormalities. Three patients had stable disease during 10 to 35 months of treatment. Two of these patients had progressive disease 9 and 37 months after treatment stopped; one patient had no progression 16 months after therapy. Two additional patients with stable disease had chemotherapy discontinued after 2 and 3 months. Common side effects included mild alopecia and myelosuppression and moderate nausea and vomiting. In patients with responding tumors, MRI showed decreased tumor size and, in two patients, changes consistent with fibrosis and decreased cellularity of the tumor.

CONCLUSION

Combination chemotherapy with VBL and MTX appears to control desmoid tumor without significant acute or long-term morbidity in most children. This may allow for further growth and development in these patients, which may decrease the morbidity of subsequent definitive therapy.
Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients.
Authors: Paulussen M , Ahrens S , Craft A W , Dunst J , Fröhlich B , Jabar S , Rübe C , Winkelmann W , Wissing S , Zoubek A , Jürgens H
Published: February 2017

PURPOSE

To analyze event-free survival (EFS) and prognostic factors in patients who present with Ewing's tumors (ET) of bone and synchronous pulmonary and/or pleural metastases (ppm).

PATIENTS AND METHODS

Of 1,270 patients (pts) registered at the continental office of the German/European Intergroup Cooperative Ewing's Sarcoma Studies (CESS81, CESS86, EICESS92), 114 were diagnosed ET with ppm. Patients underwent neoadjuvant therapy and local treatment of the primary tumor. Whole-lung irradiation 15 to 18 Gy was applied to 75 ppm-pts. EFS and 95% confidence intervals (CIs) were estimated according to the Kaplan-Meier method, and prognostic factors were analyzed by log-rank tests and Cox and logistic regression procedures.

RESULTS

On November 1, 1997, at a median time under study of 5.9 years, the 5-year EFS was 0.36 (95% CI, 0.26 to 0.46) and the 10-year EFS was 0.30 (95% CI, 0.19 to 0.41). Thirty-seven of 59 (63%) first relapses involved lung and/or pleura, and the lungs were the only site of relapse in 26 of 59 (44%) ppm-pts. Risk factors identified in univariate and multivariate tests were poor response of the primary tumor toward chemotherapy, metastatic lesions in both lungs, and treatment without additional lung irradiation.

CONCLUSION

Chemotherapy response of the primary tumor is a prognostic factor in patients with ET with ppm. Strategies of treatment intensification warrant further evaluation.
Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma.
Authors: Pignataro L , Pruneri G , Carboni N , Capaccio P , Cesana B M , Neri A , Buffa R
Published: February 2017

PURPOSE

To investigate the prognostic relevance of cyclin D1 gene overexpression in laryngeal squamous cell carcinomas (LSCCs).

PATIENTS AND METHODS

The overexpression of cyclin D1 was analyzed in 149 LSCC patients with a median follow-up duration of 60 months using the DCS6 monoclonal antibody; only cases that overexpressed cyclin D1 in more than 5% of neoplastic cells were considered positive.

RESULTS

Forty-eight cases (32.2%) were immunoreactive to the DCS6 antibody. Cyclin D1 overexpression was significantly associated with tobacco smoking and alcohol consumption, tumor extension, advanced clinical stage, and the presence of lymph node metastases. Univariate analysis showed that a shorter disease-free and overall survival were significantly associated with supraglottic site, tumor extension, advanced clinical stage, and cyclin D1 overexpression. At multivariate analysis, tumor extension and cyclin D1 overexpression were significantly associated with tumor recurrence, whereas tumor extension, supraglottic site and, at a borderline level of statistical significance, cyclin D1 overexpression, were associated with reduced overall survival.

CONCLUSION

The overexpression of cyclin D1 in LSCC is associated with unfavorable clinicopathologic features and represents an independent significant predictor of laryngeal carcinoma prognosis, particularly for disease-free survival. This indicates that cyclin D1 evaluation may be a further useful element for selecting subgroups of patients who should be treated with more aggressive therapies.
Phase II Study of a Combination of Irinotecan and Cisplatin Against Metastatic Gastric Cancer
Authors: Boku Narikazu , Ohtsu Atsushi , Shimada Yasuhiro , Shirao Kuniaki , Seki Shigeki , Saito Hiroshi , Sakata Yuh , Hyodo Ichinosuke
Published: February 2017

PURPOSE: A phase II study of a combination chemotherapy regimen of cisplatin (CDDP) and irinotecan (CPT-11) was conducted to assess its efficacy and feasibility in patients with metastatic gastric cancer.

PATIENTS AND METHODS: Eligibility criteria included the following: (1) histologically proven gastric cancer with measurable metastatic lesions, (2) performance status of 2 or less, (3) age of 75 years or younger, (4) one or no prior chemotherapy regimens, (5) adequate bone marrow, liver, renal, and cardiac functions, and (6) written informed consent. The treatment consisted of CPT-11 (70 mg/m2) on day 1 and day 15 and CDDP (80 mg/m2) on day 1, repeated every 4 weeks.

RESULTS: Forty-four patients were entered onto the study. The overall response rate was 48% (21 of 44 patients, 95% confidence interval [CI], 33% to 63%) and included one complete remission (2%). The response rate of the patients who had not received prior chemotherapy was 59% (17 of 29 patients, 95% CI, 39% to 77%). The median survival time was 272 days for all patients and 322 days for the 29 patients who had not received prior chemotherapy. Grade 4 neutropenia was observed in 25 patients (57%), and grade 3 or 4 diarrhea was observed in nine patients (20%). Other adverse reactions were mild. No treatment-related deaths occurred.

CONCLUSION: This combination chemotherapy regimen is active and well tolerated. It may be an appropriate regimen for future phase III trials.
Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation
Authors: Schlitt Hans J. , Neipp Michael , Weimann Arved , Oldhafer Karl J. , Schmoll Ekkehard , Boeker Klaus , Nashan Björn , Kubicka Stefan , Maschek Hansjörg , Tusch Günter , Raab Rudolf , Ringe Burckhardt , Manns Michael P. , Pichlmayr Rudolf
Published: February 2017

PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies.

PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics.

RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (≤ 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence.

CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.
First Year After Head and Neck Cancer: Quality of Life
Authors: Gritz Ellen R. , Carmack Cindy L. , de Moor Carl , Coscarelli Anne , Schacherer Christopher W. , Meyers Eric G. , Abemayor Elliot
Published: February 2017

PURPOSE: Treatment regimens for head and neck cancer patients profoundly affect several quality-of-life domains. Rehabilitative needs have been identified through cross-sectional analyses; however, few studies have prospectively assessed quality of life, included assessment of psychosocial variables, and identified predictors of long-term follow-up.

PARTICIPANTS AND METHODS: The present study addresses these limitations through a prospective assessment of 105 patients with a newly diagnosed first primary squamous cell carcinoma of the oral cavity, pharynx, or larynx. Participants were enrolled onto a larger randomized controlled trial comparing a provider-delivered smoking cessation intervention with a usual-care-advice control condition. Participants completed a battery of self-report measures after diagnosis and before treatment and additional quality-of-life instruments at 1 and 12 months after initial smoking cessation advice.

RESULTS: Participants displayed improvements at 12 months in functional status (P = .006) and in the areas of eating, diet, and speech; however, the latter three represent areas of continued dysfunction, and the changes were not statistically significant. Despite these improvements, patients reported a decline in certain quality-of-life domains, including marital (P = .002) and sexual functioning (P = .017), as well as an increase in alcohol use (P < .001). Predictors of quality of life at 12 months included treatment type, the Vigor subscale of the Profile of Mood States instrument, and quality-of-life scores obtained 1 month after initial smoking cessation advice.

CONCLUSION: Results reinforce the need for rehabilitation management through the integration of psychologic and behavioral interventions in medical follow-up.
Sequential Dose-Dense Doxorubicin, Paclitaxel, and Cyclophosphamide for Resectable High-Risk Breast Cancer: Feasibility and Efficacy
Authors: Hudis C. , Seidman A. , Baselga J. , Raptis G. , Lebwohl D. , Gilewski T. , Moynahan M. , Sklarin N. , Fennelly D. , Crown J. P.A. , Surbone A. , Uhlenhopp M. , Riedel E. , Yao T. J. , Norton L.
Published: February 2017

PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A → T → C) as adjuvant therapy.

METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m2 × 3, then paclitaxel 250 mg/m2/24 hours × 3, and then cyclophosphamide 3.0 g/m2 × 3; all doses were given with subcutaneous injections of 5 μg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy.

RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease.

CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A → T → C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.