bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of Attitudes Regarding Physician-Assisted Suicide and Euthanasia Among Oncology Patients, Physicians, and the General Public
Authors: Wolfe Joanne , Fairclough Diane L. , Clarridge Brian R. , Daniels Elisabeth R. , Emanuel Ezekiel J.
Published: February 2017

PURPOSE: Attitudes regarding the ethics of physician-assisted suicide (PAS) and euthanasia have been examined in many cross-sectional studies. Stability of these attitudes has not been studied, and this is important in informing the dialog on PAS in this country. We evaluated the stability of attitudes regarding euthanasia and PAS among three cohorts.

METHODS: Subjects included 593 respondents: 111 oncology patients, 324 oncologists, and 158 members of the general public. We conducted initial and follow-up interviews separated by 6 to 12 months by telephone, regarding acceptance of PAS and euthanasia in four different clinical vignettes.

RESULTS: The proportion of respondents with stable responses to vignettes ranged from 69.2% to 94.8%. In comparison to patients and the general public, physicians had less stable responses concerning the PAS pain vignette (69.1% v 80.8%; P = .001) and more stable responses for all euthanasia vignettes (P < .001) except for pain. Over time, physicians were significantly more likely to change toward opposing PAS and euthanasia in all vignettes (P < .05). Characteristics previously associated with attitudes regarding PAS and euthanasia, such as Roman Catholic religion, were not predictive of stability.

CONCLUSION: Up to one third of participants changed their attitudes regarding the ethical acceptability of PAS and euthanasia in their follow-up interview. This lack of consistency mandates careful interpretation of referendums and requests for physician-assisted suicide. Furthermore, in this study, we found that physicians are becoming increasingly opposed to PAS and euthanasia. The growing disparity between physicians and patients regarding the role of these practices is large enough to suggest possible conflicts in the delivery of end-of-life care.
Comparative Efficacy of Adjuvant Chemotherapy in Patients With Dukes' B Versus Dukes' C Colon Cancer: Results From Four National Surgical Adjuvant Breast and Bowel Project Adjuvant Studies (C-01, C-02, C-03, and C-04)
Authors: Mamounas Eleftherios , Wieand Samuel , Wolmark Norman , Bear Harry D. , Atkins James N. , Song Kyunghee , Jones Judy , Rockette Howard
Published: February 2017

PURPOSE: Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment.

PATIENTS AND METHODS: The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV.

RESULTS: Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors.

CONCLUSION: Patients with Dukes' B colon cancer benefit from adjuvant chemotherapy and should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.
Phase II Trial of Liposome-Encapsulated Doxorubicin, Cyclophosphamide, and Fluorouracil as First-Line Therapy in Patients With Metastatic Breast Cancer
Authors: Valero Vicente , Buzdar Aman U. , Theriault Richard L. , Azarnia Nozar , Fonseca Gustavo A. , Willey Jie , Ewer Michael , Walters Ronald S. , Mackay Bruce , Podoloff Donald , Booser Daniel , Lee Lily W. , Hortobagyi Gabriel N.
Published: February 2017

PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed.

RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to ≤ 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related.

CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.
Phase II Trial of High-Dose Liposome-Encapsulated Doxorubicin With Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer
Authors: Shapiro C. L. , Ervin T. , Welles L. , Azarnia N. , Keating J. , Hayes Daniel F.
Published: February 2017

PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer.

PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (IV) bolus of TLC D-99 with 5 μg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days.

RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value ≥ 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months).

CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by IV bolus infusion does not warrant further investigation.
Tumor Characteristics and Clinical Outcome of Tubular and Mucinous Breast Carcinomas
Authors: Diab Sami G. , Clark Gary M. , Osborne C. Kent , Libby Arlene , Allred D. Craig , Elledge Richard M.
Published: February 2017

PURPOSE: To comprehensively characterize the clinical and biologic features of tubular and mucinous carcinomas in a large cohort of patients and to relate this to clinical outcome and management.

PATIENTS AND METHODS: The clinical and biologic features of 444 patients with tubular and 1,221 patients with mucinous carcinomas were compared with those of 43,587 patients with infiltrating ductal carcinoma, not otherwise specified (NOS). Disease-free survival (DFS) and overall survival (OS) for patients with tubular and mucinous carcinomas were compared with those of patients with NOS carcinomas and with age-matched sets from the general population.

RESULTS: Tubular and mucinous carcinomas were more likely to occur in older patients, be smaller in size (tubular only), have substantially less nodal involvement, be estrogen receptor– and progesterone receptor–positive, have a lower S-phase fraction, be diploid, and be c-erbB-2– and epidermal growth factor receptor–negative compared with NOS carcinomas. Axillary node involvement was a poor prognostic feature in mucinous but not tubular carcinomas. Mucinous carcinomas ≤ 1 cm had a ≤ 5% incidence of node involvement. The 5-year DFS and OS were 94% and 88% for tubular, 90% and 80% for mucinous, and 80% and 77% for NOS carcinoma, respectively (P < .001 for differences among all three types for both DFS and OS). The 5-year OS of females from the general population age-matched to the patients with tubular and mucinous carcinomas was 89% and 82%, respectively, which is not different from the OS of patients with tubular or mucinous carcinomas.

CONCLUSION: The biologic phenotype of tubular and mucinous carcinomas is quite favorable. Consistent with this observation, the survival of patients with tubular and mucinous carcinomas is similar to that of the general population. Systemic adjuvant therapy and node dissection may be avoided in many patients with these special types of carcinoma.
Prospective Study of Fluorodeoxyglucose–Positron Emission Tomography Imaging of Lymph Node Basins in Melanoma Patients Undergoing Sentinel Node Biopsy
Authors: Wagner Jeffrey D. , Schauwecker Donald , Davidson Darrell , Coleman III John J. , Saxman Scott , Hutchins Gary , Love Charlene , Hayes John T.
Published: February 2017

PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin.

METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated.

RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB.

CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma.
Cisplatin, Gemcitabine, and Vinorelbine Combination Therapy in Advanced Non–Small-Cell Lung Cancer: A Phase II Randomized Study of the Southern Italy Cooperative Oncology Group
Authors: Comella Pasquale , Frasci Giuseppe , Panza Nicola , Manzione Luigi , Lorusso Vito , Di Rienzo Gaetano , Cioffi Riccardo , De Cataldis Giuseppe , Maiorino Luigi , Bilancia Domenico , Nicolella Gianpaolo , Natale Michele , Carpagnano Franco , Pacilio Carmen , De Lena Mario , Bianco Andrea , Comella Giuseppe
Published: February 2017

PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non–small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen.

PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients, age ≤ 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate.

RESULTS: Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms.

CONCLUSION: The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.
Moral Concerns of Different Types of Patients in Clinical BRCA1/2 Gene Mutation Testing
Authors: Goelen Guido , Rigo Adelheid , Bonduelle Maryse , De Grève Jacques
Published: February 2017

PURPOSE: Implementing predictive genetic testing for a severe and common chronic disease such as breast cancer may raise unique ethical problems. Here we report on moral concerns experienced by patients in the setting of genetic counseling based on BRCA1/2 gene testing.

PATIENTS AND METHODS: Patients were members of breast or breast/ovarian cancer families in a consecutive series of 100 families who received counseling at a familial cancer clinic. The patients' moral concerns were identified using the grounded theory approach in the qualitative analysis of verbal transcripts of 45 counseling sessions. Included were sessions with patients who had breast and ovarian cancer, as well as their male and female relatives, before and after the specific BRCA1/2 gene mutation was identified in the family, and before and after those who opted for mutation analysis were informed of their carrier status.

RESULTS: There is an association of BRCA1/2 gene mutation carrier status and specific topics of moral concern. The moral preoccupations of patients with breast and ovarian cancer (probable carriers) related to their being instrumental in the detection of the specific mutation segregating in the family. The preoccupations of possible carriers concerned their own offspring. Individuals who tested positive (proven carriers) were concerned with issues of confidentiality. Patients who tested negative (proven noncarriers) were concerned with helping siblings and other relatives.

CONCLUSION: Knowledge of the moral concerns of subjects in the study sample may help health care providers be aware of the moral concerns of their own patients. This report may also contribute to the debate on predictive testing for familial adult-onset diseases from the patient's perspective.
Defining Clinical Benefit in Postmenopausal Patients With Breast Cancer Under Second-Line Endocrine Treatment: Does Quality of Life Matter?
Authors: Bernhard J. , Thürlimann B. , Schmitz S.-F. Hsu , Castiglione-Gertsch M. , Cavalli F. , Morant R. , Fey M.F. , Bonnefoi H. , Goldhirsch A. , Hürny C.
Published: February 2017

PURPOSE: In endocrine therapy trials in advanced breast cancer, patients with response (complete response/partial response [CR/PR]) and patients with stable disease for at least 6 months (SD6m) have shown similar survival and therefore are often defined as a population with clinical benefit (patients with CR/PR or SD6m). We evaluated the impact of response and/or clinical benefit on quality of life (QL) in postmenopausal patients under second-line endocrine treatment after failure of tamoxifen.

PATIENTS AND METHODS: One hundred twenty-eight of 177 eligible patients of a randomized trial (Swiss Group for Clinical Cancer Research 20/90) receiving either formestane (250 mg intramuscularly biweekly) or megestrol acetate (160 mg orally daily) were analyzed. The baseline characteristics (with the exception of site of metastases) were balanced among patients with CR/PR, SD6m, and progressive disease (PD). Patients completed QL indicators at baseline and at 1, 3, 5, 7, 9, and 11 months. Responders were separately compared with nonresponders (patients with SD6m or PD) and with patients with SD6m, and patients with clinical benefit were compared with patients with PD by analysis of covariance with adjustment for baseline scores.

RESULTS: Overall, 88% (557 of 634) of expected QL forms were received. In the comparison of responders versus patients with both SD6m and PD, responders indicated better physical well-being (P = .004) and mood (P = .02) at month 3. Compared only with patients with SD6m, responders showed no significant difference in baseline QL and time to treatment failure (328.5 v 340 days). While under treatment, responders reported significantly better physical well-being (months 3 to 11), mood (months 5 to 11), coping (months 5 to 9), and appetite (months 7 to 11) and less dizziness (month 9) than patients with SD6m. The changes between baseline and months 5 and 7, respectively, indicated improvement in responders but heterogeneous patterns in patients with SD6m.

CONCLUSION: Although the CR/PR and SD6m groups had similar times to treatment failure, patients with CR/PR reported better QL, suggesting more beneficial response to second-line endocrine treatment. Patients' subjective perspective should be taken into account in this mainly palliative setting. Future trials should be designed so that the CR/PR and SD6m groups are investigated separately.
Expression of BAG-1 in Invasive Breast Carcinomas
Authors: Tang Shou-Ching , Shaheta Nadine , Chernenko Garry , Khalifa Mohmoud , Wang Xikui
Published: February 2017

PURPOSE: The purpose of this study was to retrospectively evaluate the expression of BAG-1 in invasive breast carcinomas. The intensity and subcellular distribution of BAG-1 expression was correlated with conventional prognostic factors and with disease-free and overall survival.

PATIENTS AND METHODS: One hundred forty patients diagnosed with invasive breast cancer in St. John's, Newfoundland, between 1986 and 1996 were included in the study. The median follow-up of the study was 8 years. Expression of BAG-1 was determined by immunohistochemical staining of paraffin-embedded breast tumor tissues.

RESULTS: Of the 140 breast carcinomas examined, 77.1% were positive for BAG-1 expression. Except for differentiation, no correlation was observed between BAG-1 expression and conventional prognostic factors such as age, histology, stage, and estrogen and progesterone receptor status. In multivariate analysis, BAG-1 expression was significantly associated with shorter disease-free (P = .0052) and overall survival (P = .0033). Patients whose tumors expressed nuclear BAG-1 tended to have a shorter disease-free (63 v 84 months; P = 0.4493) and overall (69 v 99 months, P = .1009) survival.

CONCLUSION: BAG-1 is overexpressed in the majority of invasive breast carcinomas. Although BAG-1 did not correlate with conventional prognostic factors, its overexpression, especially the nuclear expression, may be associated with a shorter disease-free and overall survival. Our preliminary data strongly indicate that further investigation is warranted to define the role of BAG-1 as an independent prognostic factor in patients with newly diagnosed breast cancer.
Expression of the Deleted in Colorectal Cancer Gene Is Related to Prognosis in DNA Diploid and Low Proliferative Colorectal Adenocarcinoma
Authors: Sun Xiao-Feng , Rütten Sabine , Zhang Hong , Nordenskjöld Bo
Published: February 2017

PURPOSE: Whether or not the deleted in colorectal cancer (DCC) gene is implicated in metastases or in predicting prognosis in patients with colorectal cancer has not previously been substantiated. Our aims were to investigate DCC expression in primary colorectal cancers and in metastases to identify any prognostic significance.

PATIENTS AND METHODS: DCC expression was examined immunohistochemically in 195 primary colorectal adenocarcinomas and in 23 paired primary tumors and lymph node metastases. DNA content and S-phase fraction were measured by flow cytometry.

RESULTS: The absence of DCC expression was observed in 55 primary tumors (28%). DCC negativity was significantly related to poor prognosis in patients with DNA diploid tumors (P = .03) and those with a low S-phase fraction (< 5%, P = .02) but not in patients with nondiploid tumors or those with a higher S-phase fraction. Furthermore, DCC expression retained its prognostic significance in the diploid subgroup after adjusting for sex, age, site, stage, growth pattern, and differentiation (P = .01). DCC expression was similar in primary tumors and their metastases.

CONCLUSION: The absence of DCC predicted a poor outcome in the patients with diploid tumors and those tumors with a low S-phase fraction. Immunohistochemistry may be considered as a practical test to assess prognosis in this subgroup of patients.
Trilateral Retinoblastoma: A Meta-Analysis of Hereditary Retinoblastoma Associated With Primary Ectopic Intracranial Retinoblastoma
Authors: Kivelä Tero
Published: February 2017

PURPOSE: To obtain refined knowledge regarding trilateral retinoblastoma (TRb), which is a syndrome that consists of hereditary retinoblastoma associated with an intracranial neuroblastic tumor.

MATERIALS AND METHODS: Using a systematic literature review, we contacted authors to obtain missing information. Data from 106 children were used in a meta-analysis including frequency distributions and Kaplan-Meier survival curves.

RESULTS: TRb showed no sex predilection. Median age at diagnosis of retinoblastoma was 5 months (range, 0 to 29 months); age at diagnosis was younger among 47 children (47%) with familial retinoblastoma compared with age at diagnosis among 52 children (53%) with sporadic retinoblastoma (2 v 6.5 months, P < .0001). TRb usually affected the second or third generation with retinoblastoma. Median time from retinoblastoma to TRb was 21 months (range, 6 months before to 141 months after); time to TRb was longer for 78 (77%) pineal tumors compared with 23 (23%) suprasellar tumors (32 v 6.5 months, P < .0001). The size (27 v 32 mm, P = .57) and prognosis (survival of 9 v 8 months, P = .91) of pineal and suprasellar tumors were similar. TRb was detected earlier (1 v 22 months, P = .0007) and the child survived longer if neuroimaging was routinely performed (16 v 8 months, P = .001), but age at death was similar (36 v 37 months, P = .98). Cumulative 5-year survival (which was likely to indicate cure) was 27% (v 0%) if screening was undertaken. All children whose TRb exceeded 15 mm in size died.

CONCLUSION: The family history, age at diagnosis, and laterality of retinoblastoma in children with TRb resembled that of ordinary hereditary retinoblastoma. Suprasellar TRb were diagnosed earlier, and may arise earlier, than pineal TRb. Screening by neuroimaging could improve the cure rate if cases of TRb were detected when tumors were 15 mm or smaller in size.
Phase III Clinical Trial of the Combination of Cisplatin, Dacarbazine, and Carmustine With or Without Tamoxifen in Patients With Advanced Malignant Melanoma
Authors: Creagan Edward T. , Suman Vera J. , Dalton Robert J. , Pitot Henry C. , Long Harry J. , Veeder Michael H. , Vukov Allen M. , Rowland Kendrith M. , Krook James E. , Michalak John C.
Published: February 2017

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma.

PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m2 given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and ½ normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m2 IV for 1 hour in 500 mL of dextrose and ½ NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m2 IV for 2 to 3 hours in 750 to1,000 mL of dextrose and 5% water onday 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning.

RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P = .429) and overall survival (P = .545) were not found to differ by treatment.

CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.
Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine Capecitabine in Combination With Paclitaxel in Patients With Advanced Solid Malignancies
Authors: Villalona-Calero Miguel A. , Weiss Geoffrey R. , Burris Howard A. , Kraynak Maura , Rodrigues Gladys , Drengler Ronald L. , Eckhardt S. Gail , Reigner Bruno , Moczygemba Judy , Burger Hans Ulrich , Griffin Tom , Von Hoff Daniel D. , Rowinsky Eric K.
Published: February 2017

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined.

PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m2/d, whereas the paclitaxel dose was fixed at 135 mg/m2. In stage II, paclitaxel was increased to a target dose of 175 mg/m2, and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently.

RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Othertoxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m2/d and paclitaxel 175 mg/m2 developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m2/d and paclitaxel 175 mg/m2 developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted.

CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m2/d and paclitaxel 175 mg/m2/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.
Essence of Evidence-Based Medicine: A Case Report
Authors: Browman George P.
Published: February 2017

PURPOSE: To illustrate the complexities of the evidence-based approach in clinical oncology practice and the implications for guidelines and evaluation of processes of care.

PATIENT AND METHODS: A case report is presented in which a limited systematic review of the literature was used to address a specific clinical problem in an individual patient. Experts' opinions were also sought.

RESULTS: A reasonable clinical decision was made by a participating patient based on indirect evidence of benefit that would be insufficient to support the same decision as a health policy in some jurisdictions.

CONCLUSION: The practice of evidence-based oncology requires clinical judgment about the validity and applicability of research evidence. The factors that influence an evidence-based decision in the clinical context differ from those in the broader policy context, which could lead to legitimate differences in recommendations based on the same information. Used properly, the individual case report can be a powerful tool to illustrate complex clinical decision phenomena.
Successful Treatment of Metastatic Renal Cell Carcinoma With a Nonmyeloablative Allogeneic Peripheral-Blood Progenitor-Cell Transplant: Evidence for a Graft-Versus-Tumor Effect
Authors: Childs Richard W. , Clave Emmanuel , Tisdale John , Plante Michelle , Hensel Nancy , Barrett John
Published: February 2017

PURPOSE: A 50-year-old man developed progressive pulmonary metastasis resistant to interferon alfa-2b treatment 7 months after he underwent left nephrectomy for stage III renal cell carcinoma. We performed a nonmyeloablative allogeneic peripheral-blood stem-cell transplant in this patient to exploit a possible graft-versus-tumor effect from allogeneic lymphocytes.

MATERIALS AND METHODS: The conditioning regimen consisted of fludarabine and cyclophosphamide followed by a T-cell replete, granulocyte-colony stimulating-factor–mobilized peripheral-blood stem-cell transplant from his HLA-identical brother. Cyclosporine was administered from days –4 to +45 to prevent graft rejection and acute graft-versus-host disease (GVHD).

RESULTS: Serial polymerase chain reaction analysis of hematopoietic lineage-specific minisatellites initiallyshowed mixed chimerism in CD14+ and CD15+ myeloid cells, CD3+ T cells, and CD34+ progenitor cells, with rapid conversion to 100% donor T-cell chimerism by day +60 and 100% donor myeloid cells by day +100. Serial computed tomography scans of the chest showed stable disease at day +30, slight regression of pulmonary lesions at day +63, and complete disappearance of all pulmonary metastatic disease by day +110. Mild transient acute GVHD disease of the skin occurred on day +60 and limited chronic GVHD of the skin occurred by day +200.

CONCLUSION: The complete regression of metastatic disease, which has now been maintained for more than 1 year, is compatible with a graft-versus-tumor effect.
A Novel Anti-Apoptosis Gene: Re-expression of Survivin Messenger RNA as a Prognosis Marker in Non–Small-Cell Lung Cancers
Authors: Monzó Mariano , Rosell Rafael , Felip Enriqueta , Astudillo Julio , Sánchez José Javier , Maestre José , Martín Cristina , Font Albert , Barnadas Agustí , Abad Albert
Published: February 2017

PURPOSE: The survivin gene is a novel apoptosis inhibitor, related to the baculovirus gene, which is believed to play a pivotal role in fetal development and in cancer. We hypothesised that survivin would be expressed in tumors of patients with non–small-cell lung cancer (NSCLC), and we attempted to determine the influence of survivin re-expression on clinical outcome in patients with up to stage IIIA NSCLC who had undergone radical surgery.

METHODS: We designed a reverse transcriptase polymerase chain reaction (RT-PCR) assay to study the expression of the survivin gene in 83 NSCLC tumor samples and compared the results with relevant clinical and pathologic data.

RESULTS: The RT-PCR identified survivin gene transcript in 71 (85.5%) of the tumor samples and in only 10 (12%) of the paired, histopathologically normal lung samples. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression. The 12 patients without survivin expression had significantly better overall survival than the 71 patients with survivin expression (P = .01 by univariate analysis; relative risk, 2.1). There was no significant correlation between survivin expression and age, sex, cigarette smoking, histologic subtype, tumor differentiation, tumor size, or the presence of mediastinal lymph node metastases in surgical specimens.

CONCLUSION: The survivin gene was expressed in a vast majority of NSCLC tumors. We conclude that survivin transcript is a defining diagnostic marker for NSCLC that may also yield prognostic information and, as an apoptosis inhibitor, be an important target in cancer therapy.
High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993
Authors: Atkins Michael B. , Lotze Michael T. , Dutcher Janice P. , Fisher Richard I. , Weiss Geoffrey , Margolin Kim , Abrams Jeff , Sznol Mario , Parkinson David , Hawkins Michael , Paradise Carolyn , Kunkel Lori , Rosenberg Steven A.
Published: February 2017

PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma.

PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996.

RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis.

CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.
Quality-Adjusted Survival After Treatment for Acute Myeloid Leukemia in Childhood: A Q-TWiST Analysis of the Pediatric Oncology Group Study 8821
Authors: Parsons S. K. , Gelber S. , Cole B. F. , Ravindranath Y. , Ogden A. , Yeager A. M. , Chang M. , Shuster J. , Weinstein H. J. , Gelber R. D.
Published: February 2017

PURPOSE: To describe quality-of-life considerations in postremission therapies for children with acute myelogenous leukemia.

PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle.

RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P < .001), more time in TWiST (P = .06), and had more relapse-free time (P = .03) and time alive (P = .07). Allo BMT was superior to ABMT with greater time in TWiST (P = .02), relapse-free time (P = .01), and time alive P = .002).

CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.
Thymoma: State of the Art
Authors: Thomas Charles R. , Wright Cameron D. , Loehrer Patrick J.
Published: February 2017

Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes, such as myasthenia gravis, hypogammaglobulinemia, and pure red cell aplasia. The rarity of this tumor, however, has somewhat obscured the optimal treatment for this disease. For the majority of patients who present with localized tumor, surgical extirpation remains the standard of choice. Adjuvant radiotherapy seems to improve local control and survival. In more advanced disease, systemic therapy has been demonstrated to produce a 50% to 80% objective response rate. These observations have led to the development of multimodality therapy for the treatment of patients with advanced thymoma. In this article, we will review the current perspectives on the management of early stage and advanced thymoma.
Cisplatin, Etoposide, and Paclitaxel in the Treatment of Patients With Extensive Small-Cell Lung Carcinoma
Authors: Glisson Bonnie S. , Kurie Jonathan M. , Perez-Soler Roman , Fox Nikolous J. , Murphy William K. , Fossella Frank V. , Lee Jin S. , Ross Michael B. , Nyberg David A. , Pisters Katherine M.W. , Shin Dong M. , Hong Waun Ki
Published: February 2017

PURPOSE: The combination of cisplatin, etoposide, and paclitaxel was studied in patients with extensive small-cell lung cancer in a phase I component followed by a phase II trial to determine the maximum-tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates.

PATIENTS AND METHODS: Forty-one patients were treated between October 1993 and April 1997. Doses for the initial cohort were cisplatin 75 mg/m2 on day 1, etoposide 80 mg/m2/d on days 1 to 3, and paclitaxel 130 mg/m2 on day 1 over 3 hours. Cycles were repeated every 3 weeks for up to six cycles. The MTD was reached in the first six patients. In these six patients and in the next 35 patients, who were entered onto the phase II trial, response and survival were estimated.

RESULTS: At the initial dose level, one of six patients developed febrile neutropenia, and five of six achieved targeted neutropenia (nadir absolute granulocyte count, 100 to 1,000/μL) without any other dose-limiting toxicity, defining this level as the MTD. Grade 4 neutropenia was observed in 88 (47%) of 188 total courses administered at or less than the MTD. Neutropenia was associated with fever in only 17 (9%) of 188 courses, but two patients experienced neutropenic sepsis that was fatal. Nonhematologic toxicity greater than grade 2 was observed in 10 (5%) of 188 total courses, with fatigue, peripheral neuropathy, and nausea/vomiting most common. The overall objective response rate was 90% of 38 assessable patients: six complete responses (16%) and 28 partial responses(74%). Median progression-free and overall survival durations were 31 and 47 weeks, respectively.

CONCLUSION: The combination of cisplatin, etoposide, and paclitaxel produced response and survival rates similar to those of other combinations and was well tolerated.
10-Year Results After Sector Resection With or Without Postoperative Radiotherapy for Stage I Breast Cancer: A Randomized Trial
Authors: Liljegren G. , Holmberg L. , Bergh J. , Lindgren A. , Tabár L. , Nordgren H. , Adami H.O.
Published: February 2017

PURPOSE: To study the long-term effectiveness of postoperative radiotherapy after sector resection for breast cancer in a randomized trial in which mammography is a major pathway to diagnosis.

PATIENTS AND METHODS: Three hundred eighty-one women with a unifocal breast cancer ≤ 20 mm in diameter on the preoperative mammogram and without histopathologic signs of axillary metastases were treated by sector resection plus axillary dissection. Of these patients, 184 women were randomized to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group).

RESULTS: The local recurrence rate was 8.5% (95% confidence interval [CI], 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (P = .0001). Survival free from regional and distant recurrence was 83.3% in the XRT group (95% CI, 77.5% to 89.1%) and 80.0% in the non-XRT group (95% CI, 73.9% to 86.1%) (P = .23). Overall survival was 77.5% in the XRT group (95% CI, 70.9% to 84.1%) and 78% in the non-XRT group (95% CI, 71.7% to 84.3%) (P = .99). A subgroup analysis suggested that women older than 55 years of age without comedo or lobular carcinomas had a low risk of local recurrence of 6.1% (95% CI, 0.1% to 9.1%) in the XRT-group and 11.0% (4.0% to 18.0%) in the non-XRT group (P = .16).

CONCLUSION: Sector resection plus radiotherapy resulted in an absolute reduction in local recurrence of 16% at 10 years compared with surgery alone. Women older than 55 years of age without comedo or lobular carcinomas may have a low risk of local recurrence. Postoperative radiotherapy was not shown to reduce distant recurrences or improve overall survival.
Enhanced Staging and All Chemotherapy Preoperatively in Patients with Potentially Resectable Gastric Carcinoma
Authors: Ajani Jaffer A. , Mansfield Paul F. , Lynch Patrick M. , Pisters Peter W. , Feig Barry , Dumas Pamela , Evans Douglas B. , Raijman Issac , Hargraves Kristin , Curley Stephen , Ota David M.
Published: February 2017

PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma.

PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m2/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m2/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed.

RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (≥ 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity.

CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.