bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Trial of Intravenous Thymidine and Carboplatin in Patients With Advanced Cancer
Authors: Robins H. Ian , Tutsch Kendra , Katschinski Doerthe M. , Jacobson Elaine , Mehta Minesh , Olsen Mark , Cohen Justin D. , Tiggelaar Cynthia L. , Arzoomanian Rhoda Z. , Alberti Dona , Feierabend Chris , Wilding George
Published: February 2017

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m2 in a phase I trial.

PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m2 (n = 3); 300 mg/m2 (n = 7); 350 mg/m2 (n = 4); 400 mg/m2 (n = 3); 480 mg/m2 (n = 10); and 576 mg/m2 (n = 5). At the maximum-tolerated dose (480 mg/m2), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy.

RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m2-dose level, and disease stabilization (7 months) at the 400-mg/m2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m2-dose level.

CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.
Phase III Randomized Study of Cisplatin Versus Paclitaxel Versus Cisplatin and Paclitaxel in Patients With Suboptimal Stage III or IV Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Muggia Franco M. , Braly Patricia S. , Brady Mark F. , Sutton Gregory , Niemann Theodore H. , Lentz Samuel L. , Alvarez Ronald D. , Kucera Paul R. , Small James M.
Published: February 2017

PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m2) or 24-hour infusion paclitaxel (200 mg/m2) or the combination of paclitaxel (135 mg/m2) followed by cisplatin (75 mg/m2).

PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined.

RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P < .001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P < .001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0.929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P = .31).

CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.
Angiogenesis in Neuroblastoma: Relationship to Survival and Other Prognostic Factors in a Cohort of Neuroblastoma Patients
Authors: Cañete A. , Navarro S. , Bermúdez J. , Pellín A. , Castel V. , Llombart-Bosch A.
Published: February 2017

PURPOSE: To study angiogenesis in neuroblastoma, using morphometric and computerized image analysis, and correlate the results with survival and other prognostic factors.

PATIENTS AND METHODS: Sixty-nine patients from the Spanish Cooperative Study for Neuroblastoma were studied. Tumoral angiogenesis was studied using an avidin-biotin immunoperoxidase technique with an anti-CD34 antibody. Vascular parameters (VPs) were analyzed by a computerized system. Statistical analysis was also performed.

RESULTS: Sixty-six samples had adequate tumoral tissue, and their tumoral vessels were counted. Endothelial cells were more prominent in pure neuroblastomas than in maturing and more mature tumors. VPs showed no statistical difference between the groups of patients as defined by the levels of the other prognostic factors in neuroblastoma: age, stage, histopathology, TRK-A, P-glycoprotein expression, or MYCN copy number. In patients who relapsed, tumors did not show statistically significant difference in VPs when compared with tumors from patients who did not relapse. There was also no difference in VPs in tumors from living patients when compared with tumors from deceased patients. Overall survival was 75%, and event-free survival was 55% at 50 months.

CONCLUSION: VPs could be adequately determined by a computerized system in neuroblastoma; however, VPs were not predictive of survival for our patients. In our patients, neither disseminated nor local relapses were influenced by the angiogenic characteristics of the tumors.
Prognostic Factors in Nonmetastatic Ewing’s Sarcoma of Bone Treated With Adjuvant Chemotherapy: Analysis of 359 Patients at the Istituto Ortopedico Rizzoli
Authors: Bacci Gaetano , Ferrari Stefano , Bertoni Franco , Rimondini Simonetta , Longhi Alessandra , Bacchini Patrizia , Forni Cristiana , Manfrini Marco , Donati Davide , Picci Piero
Published: February 2017

PURPOSE: The identification of prognostic factors in patients with nonmetastatic Ewing’s sarcoma could allow the use of risk-adapted therapeutic strategies of treatment.

PATIENTS AND METHODS: Data on 359 patients with nonmetastatic Ewing’s sarcoma of bone treated at a single institution between January 1979 and April 1995 were retrospectively considered. The influence of clinical, hematologic, therapeutic, and histologic parameters on event-free survival was assessed.

RESULTS: By univariate analysis, the following features were found to be associated with a poor prognosis: male sex (P < .02), age older than 12 years (P < .006), fever (P < .0001), anemia (P < .0025), high serum lactate dehydrogenase (LDH) level (P < .0001), axial location (P < .04), radiation therapy only for local control (P < .009), type of chemotherapy regimen (P < .0001), and poor chemotherapy-induced necrosis (P < .001). After multivariate analysis, the adverse independent prognostic factors were male sex (P < .04), age older than 12 years (P < .001), fever (P < .0002), anemia (P < .02), high serum LDH level (P < .0003), axial location (P < .02), and type of chemotherapy regimen (P < .0003). When the multivariate analysis was restricted to surgically treated patients, the adverse independent prognostic factors were poor chemotherapy-induced necrosis (P < .0001), fever (P < .015), anemia (P < .02), and high serum LDH level (P < .025).

CONCLUSION: The prognosis in cases of nonmetastatic Ewing’s sarcoma is influenced by many different clinical and hematologic variables, all of which are to be considered when patients are being stratified according to the risk of relapse. In surgically treated patients, the most important prognostic factor is chemotherapy-induced necrosis.
Does Paclitaxel Improve the Chemoradiotherapy of Locoregionally Advanced Esophageal Cancer? A Nonrandomized Comparison With Fluorouracil-Based Therapy
Authors: Adelstein David J. , Rice Thomas W. , Rybicki Lisa A. , Larto Marjorie A. , Ciezki Jay , Saxton Jerrold , DeCamp Malcolm , Vargo John J. , Dumot John A. , Zuccaro Gregory
Published: February 2017

PURPOSE: A phase II trial of accelerated fractionation radiation with concurrent cisplatin and paclitaxel chemotherapy was performed to investigate the role of the paclitaxel, when substituted for fluorouracil (5-FU), in the chemoradiotherapy of esophageal cancer.

PATIENTS AND METHODS: Patients with an esophageal ultrasound stage of T3 or N1 or M1 (nodal) esophageal cancer were treated with two courses of a cisplatin infusion (20 mg/m2/d for 4 days) and paclitaxel (175 mg/m2 over 24 hours) concurrent with a split course of accelerated fractionation radiation (1.5 Gy bid to a total dose of 45 Gy). Surgical resection was performed 4 to 6 weeks later followed by a single identical postoperative course of chemoradiotherapy (24 Gy) in patients with significant residual tumor at surgery. Toxicity and results of this treatment were retrospectively compared with our previous 5-FU and cisplatin chemoradiotherapy experience.

RESULTS: Between September 1995 and July 1997, 40 patients were entered onto this study. Although dysphagia proved worse in our 5-FU–treated patients, profound leukopenia and a need for unplanned hospitalization were significantly more common in the paclitaxel group. Thirty-seven patients (93%) proved resectable for cure. The 3-year projected overall survival is 30%, locoregional control is 81%, and distant metastatic disease control is 44%. When compared with a similarly staged cohort of 5-FU–treated patients, there was no advantage for any survival function studied.

CONCLUSION: This paclitaxel-based treatment regimen for locoregionally advanced esophageal cancer produced increased toxicity with no improvement in results when compared with our previous 5-FU experience. Paclitaxel-based treatments must be carefully and prospectively studied before their incorporation into the standard management of esophageal cancer.
Concomitant Radiotherapy and Chemotherapy for Early-Stage Nasopharyngeal Carcinoma
Authors: Cheng Skye Hongiun , Tsai Stella Y. C. , Yen K. Lawrence , Jian James Jer-Min , Chu Nei-Min , Chan Kwan-Yee , Tan Tran-Der , Cheng Jason C. , Hsieh Cheng-Yee , Huang Andrew T.
Published: February 2017

PURPOSE: Early-stage nasopharyngeal carcinoma (NPC) continues to carry a failure rate of 15% to 30% when treated with radiotherapy alone; the benefit of concomitant radiotherapy and chemotherapy (CCRT) in early-stage NPC is unclear. The purpose of this report is to describe our efforts to improve treatment outcome in early-stage NPC after CCRT.

PATIENTS AND METHODS: Of 189 newly diagnosed NPC patients without evidence of distant metastases who were treated in our institution between 1990 and 1997, 44 presented with early-stage (stage I and II) disease according to the American Joint Committee on Cancer (AJCC) 1997 NPC staging system. Twelve of these patients were treated with radiotherapy alone and 32 with CCRT. Each patient’s head and neck area was evaluated by magnetic resonance imaging or computed tomography. Radiotherapy was administered at 2 Gy per fraction per day, Monday through Friday, for 35 fractions for a total dose of 70 Gy. Chemotherapy consisting of cis-diamine-dichloroplatinum and fluorouracil was delivered simultaneously with radiotherapy in weeks 1 and 6 and sequentially for two monthly cycles after radiotherapy.

RESULTS: Patients who were treated with radiotherapy alone primarily had stage I disease, whereas none of those who were treated with CCRT had stage I disease (11 of 12 patients v none of 32 patients; P = .001). The locoregional control rate at 3 years for the radiotherapy group was 91.7% (median follow-up period, 34 months) and was 100% for the CCRT group (median follow-up period, 44 months) (P = .10). The 3-year disease-free survival rate in the radiotherapy group was 91.7% and was 96.9% in the CCRT group (P = .66).

CONCLUSION: Our results reveal excellent prognosis of AJCC 1997 stage II NPC treated with CCRT. Stage II patients with a greater tumor burden treated with CCRT showed an equal disease-free survival, compared with stage I patients treated with radiotherapy alone. A prospective randomized trial is underway to confirm the role of CCRT in stage II NPC.
Early Depressive Symptoms in Cancer Patients Receiving Interleukin 2 and/or Interferon Alfa-2b Therapy
Authors: Capuron Lucile , Ravaud Alain , Dantzer Robert
Published: February 2017

PURPOSE: Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INFα-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INFα-2b in cancer patients during the first days of cytokine immunotherapy.

PATIENTS AND METHODS: The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INFα-2b (n = 6); or with INFα-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment.

RESULTS: Patients treated with IL-2 alone or in association with INFα-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INFα-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INFα-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints.

CONCLUSION: IL-2 and INFα-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.
Primary Cutaneous B-Cell Lymphoma: Review and Current Concepts
Authors: Pandolfino Tomi L. , Siegel Richard S. , Kuzel Timothy M. , Rosen Steven T. , Guitart Joan
Published: February 2017

PURPOSE: Primary cutaneous B-cell lymphoma (PCBCL) has only recently been recognized as a distinct clinical entity. With the advent of improved immunophenotyping and immunogenotyping, increasing numbers of PCBCL cases are being diagnosed. However, there is much confusion regarding the classification, treatment, and prognosis of these patients. The purpose of this article is to review and analyze the available data to provide the clinician with a concise summary of the diagnosis, prognosis, and treatment of PCBCL.

DESIGN: We conducted a thorough review of the medical literature on PCBCL, with a focus on classification, prognosis, and treatment trials.

RESULTS AND CONCLUSION: PCBCL is defined as a B-cell lymphoma originating in the skin. There is no evidence of extracutaneous disease at presentation and for 6 months after diagnosis, as assessed by adequate staging procedures. Currently, the European Organization for Research and Treatment of Cancer classification is the most concise disease classification scheme, dividing the subtypes of PCBCL by clinical behavior and histopathologic findings. Based on this classification, the most common subtype of PCBCL is follicular center cell lymphoma. PCBCL is generally an indolent form of lymphoma with a good prognosis. Although local cutaneous recurrences are observed in 25% to 68% of patients, dissemination to internal organs is rare. Five-year survival rates typically range from 89% to 96%. A specific subtype, large B-cell lymphoma of the leg, is noted to have a poorer prognosis, with a 5-year survival rate of 58%. Overly aggressive treatment of PCBCL has not been shown to improve survival or prevent relapse. The treatment of choice usually varies depending on the type of PCBCL, the body surface area, and the location of the involvement, as well as the age and general health condition of the patient. The majority of studies indicate that PCBCL is highly responsive to radiation therapy. Polychemotherapy should be reserved for involvement of noncontiguous anatomic sites or those with extracutaneous spread.
Radiation Therapy for Squamous Cell Carcinoma of the Tonsillar Region: A Preferred Alternative to Surgery?
Authors: Mendenhall William M. , Amdur Robert J. , Stringer Scott P. , Villaret Douglas B. , Cassisi Nicholas J.
Published: February 2017

PURPOSE: There are no definitive randomized studies that compare radiotherapy (RT) with surgery for tonsillar cancer. The purpose of this study was to evaluate the results of RT alone and RT combined with a planned neck dissection for carcinoma of the tonsillar area and to compare these data with the results of treatment with primary surgery.

PATIENTS AND METHODS: Four hundred patients were treated between October 1964 and December 1997 and observed for at least 2 years. One hundred forty-one patients underwent planned neck dissection, and 18 patients received induction (17 patients) or concomitant (one patient) chemotherapy.

RESULTS: Five-year local control rates, by tumor stage, were as follows: T1, 83%; T2, 81%; T3, 74%; and T4, 60%. Multivariate analysis revealed that local control was significantly influenced by tumor stage (P = .0001), fractionation schedule (P = .0038), and external beam dose (P = .0227). Local control after RT for early-stage cancers was higher for tonsillar fossa/posterior pillar cancers than for those arising from the anterior tonsillar pillar. Five-year cause-specific survival rates, by disease stage, were as follows: I, 100%; II, 86%; III, 82%; IVa, 63%; and IVb, 22%. Multivariate analysis revealed that cause-specific survival was significantly influenced by overall stage (P = .0001), planned neck dissection (P = .0074), and histologic differentiation (P = .0307). The incidence of severe late complications after treatment was 5%.

CONCLUSION: RT alone or combined with a planned neck dissection provides cure rates that are as good as those after surgery and is associated with a lower rate of severe complications.
Subcutaneous Administration of Amifostine During Fractionated Radiotherapy: A Randomized Phase II Study
Authors: Koukourakis Michael I. , Kyrias George , Kakolyris Stelios , Kouroussis Charalambos , Frangiadaki Chryssi , Giatromanolaki Alexandra , Retalis George , Georgoulias Vassilios
Published: February 2017

PURPOSE: Amifostine (WR-2721) is an impotant cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy.

PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction.

RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P < .04). The delays in radiotherapy because of grade 3 mucositis were significanly longer in the group of patients treated with radiotherapy alone (P < .04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P < .0006).

CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy’s early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.
Gemcitabine Plus Cisplatin Repeating Doublet Therapy in Previously Treated, Relapsed Breast Cancer Patients
Authors: Nagourney Robert A. , Link John S. , Blitzer Jonathan B. , Forsthoff Cynthia , Evans Steven S.
Published: February 2017

PURPOSE: To determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed adenocarcinoma of the breast.

PATIENTS AND METHODS: Previously treated patients with adenocarcinoma of the breast received cisplatin (30 mg/m2) plus gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of each 28-day cycle, which was changed after patient no. 12 to cisplatin (30 mg/m2) plus gemcitabine (750 mg/m2) days 1 and 8 of each 21-day cycle.

RESULTS: Of 30 patients, three (10%) had complete and 12 (40%) had partial responses, for an overall response rate of 50%. Two objective responses were observed among the four patients accrued after relapse that followed high-dose/stem-cell therapies. The median time to progression was 14 weeks. The median time to progression for objective responders was 23.5 weeks, with a range of 8 to 68 weeks. Toxicities included grades III and IV neutropenia in 13%, anemia in 6%, thrombocytopenia in 31%, grade III nausea in 4%, and grade II peripheral neuropathy in 2% of 151 treatment cycles. Moderate alopecia occurred in four patients. There were no treatment-related deaths.

CONCLUSION: Cisplatin plus gemcitabine is active and tolerable for patients with relapsed breast cancer. Responses observed in previously treated patients, including high-dose/stem-cell failures, indicate activity in otherwise drug-refractory patients.
Intention to Undergo Prophylactic Bilateral Mastectomy in Women at Increased Risk of Developing Hereditary Breast Cancer
Authors: Meiser Bettina , Butow Phyllis , Friedlander Michael , Schnieden Vivienne , Gattas Michael , Kirk Judy , Suthers Graeme , Haan Eric , Tucker Katherine
Published: February 2017

PURPOSE: To assess intention to undergo prophylactic bilateral mastectomy and psychologic determinants in unaffected women at increased risk of developing hereditary breast cancer.

PATIENTS AND METHODS: Three hundred thirty-three women who were awaiting their initial appointments for risk assessment, advice about surveillance, and prophylactic options at one of 14 familial cancer clinics participated in a cross-sectional, questionnaire-based survey.

RESULTS: Nineteen percent of women would consider and 47% would not consider a prophylactic mastectomy, should genetic testing identify a mutation in a breast cancer–predisposing gene, whereas 34% were unsure and 1% had already undergone a prophylactic mastectomy. In a bivariate analysis, women at a moderately increased risk of developing breast cancer had the highest proportion of subjects reporting that they would consider a prophylactic mastectomy (25%), compared with women at high risk (16%) (χ2 = 7.79; P = .051). In multivariate analyses, consideration of prophylactic mastectomy strongly correlated with high levels of breast cancer anxiety (odds ratio [OR] = 17.4; 95% confidence interval [CI], 4.35 to 69.71; P = .0001) and overestimation of one’s breast cancer risk (OR = 3.01; 95% CI, 1.43 to 6.32; P = .0036), whereas there was no association with objective breast cancer risk (P = .60).

CONCLUSION: A significant proportion of women at increased risk of developing hereditary breast cancer would consider prophylactic mastectomy. Although prophylactic mastectomy may be appropriate in women at high risk of developing breast cancer, it is perhaps less so in those who have a moderately increased risk. Such moderate-risk women are likely to benefit from interventions aimed at reducing breast cancer anxiety and correcting exaggerated breast cancer risk perceptions.
Declining Cancer Rates in the 1990s
Authors: McKean-Cowdin Roberta , Feigelson Heather Spencer , Ross Ronald K. , Pike Malcolm C. , Henderson Brian E.
Published: February 2017

PURPOSE: To provide evidence of a substantial decline in cancer rates for the period 1991 through 1995 and characterize major risk factors that seem to be driving secular trends in cancer mortality and incidence.

DESIGN: Incidence and mortality rates were calculated using national surveillance data collected through the Surveillance, Epidemiology, and End Results (SEER) program and the National Center for Health Statistics.

RESULTS: All-sites cancer incidence and mortality fell in the period 1991 through 1995; this decline is largely attributable to decreases in the smoking-related cancers, especially lung cancer. Of the 20 leading incident cancers today, both incidence and mortality are decreasing among 11 sites for men and 12 for women. In men, the decline in mortality has been notable and is especially apparent for the smoking-related cancers, including those of the lung, oral cavity and pharynx, larynx, and, to a lesser extent, bladder. In women, all-sites mortality decreased only approximately 0.4% from 1991 through 1995. Three cancers continued to show substantial increases in mortality through 1995 for both men and women (liver, multiple myeloma, and non-Hodgkin’s lymphoma), while incidence rates continued to climb for liver cancer, non-Hodgkin’s lymphoma, and melanoma.

CONCLUSION: Data from the SEER program on recent trends in cancer incidence and mortality show that cancer rates are generally on the decline, largely because of reductions in smoking-related cancers. A consistent increase in mortality rates due to liver cancer poses a new health care challenge, one that will require the development of an effective treatment for individuals currently infected with hepatitis C or B to prevent mortality rates from continuing to increase.
Phase I, Dose-Finding, and Pharmacokinetic Study of Raltitrexed Combined With Oxaliplatin in Patients With Advanced Cancer
Authors: Fizazi Karim , Ducreux Michel , Ruffié Pierre , Bonnay Marc , Daniel Catherine , Soria Jean-Charles , Hill Catherine , Fandi Abderrahim , Poterre Marc , Smith Mark , Armand Jean-Pierre
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors.

PATIENTS AND METHODS: Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m2 and from 85 to 130 mg/m2 for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels.

RESULTS: Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m2 and oxaliplatin 130 mg/m2). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m2 and oxaliplatin 130 mg/m2) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction.

CONCLUSION: The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m2 and oxaliplatin 130 mg/m2 every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.
Cancer Risk and Low-Penetrance Susceptibility Genes in Gene-Environment Interactions
Authors: Shields Peter G. , Harris Curtis C.
Published: February 2017

PURPOSE: To provide a concise review for human cancer risk related to low-penetrance genes and their effects on environmental carcinogen exposure.

METHODS: Citation of relevant and recent references for molecular epidemiology, focusing on lung cancer, ethical issues, and some clinical implications of recent molecular epidemiology studies.

RESULTS: Low-penetrance genes contribute to cancer risk by augmenting the effects of carcinogen exposures. These exposures can be measured in the body through molecular dosimetry (ie, the amount of DNA damage), which reflects a biologically effective dose. The examination of tumors and the mutations within tumor suppressor genes, such as p53, can provide etiologic clues for both exposure and susceptibility. Although many studies have focused on carcinogen metabolism and cancer risk, more recent studies are considering DNA repair. Also, we are learning that behavior, such as tobacco addiction, also may be genetically controlled.

CONCLUSION: Sporadic cancers are caused by genen-environmentn interactions rather than a dominant effect by a specific gene, environmental exposure, or gene-environment interaction. New paradigms, where we categorize genes as caretaker or gatekeeper genes, will allow for new hypotheses to be tested and will require advanced methods of analysis. The goal of molecular epidemiology is to develop risk assessment models for individuals, but currently the most achievable goal will be population risk assessment and a better understanding of carcinogenesis.
Hospital and Physician Volume or Specialization and Outcomes in Cancer Treatment: Importance in Quality of Cancer Care
Authors: Hillner Bruce E. , Smith Thomas J. , Desch Christopher E.
Published: February 2017

PURPOSE: To conduct a comprehensive review of the health services literature to search for evidence that hospital or physician volume or specialty affects the outcome of cancer care.

METHODS: We reviewed the 1988 to 1999 MEDLINE literature that considered the hypothesis that higher volume or specialization equals better outcome in processes or outcomes of cancer treatments.

RESULTS: An extensive, consistent literature that supported a volume-outcome relationship was found for cancers treated with technologically complex surgical procedures, eg, most intra-abdominal and lung cancers. These studies predominantly measured in-hospital or 30-day mortality and used the hospital as the unit of analysis. For cancer primarily treated with low-risk surgery, there were fewer studies. An association with hospital and surgeon volume in colon cancer varied with the volume threshold. For breast cancer, British studies found that physician specialty and volume were associated with improved long-term outcomes, and the single American report showed an association between hospital volume of initial surgery and better 5-year survival. Studies of nonsurgical cancers, principally lymphomas and testicular cancer, were few but consistently showed better long-term outcomes associated with larger hospital volume or specialty focus. Studies in recurrent or metastatic cancer were absent. Across studies, the absolute benefit from care at high-volume centers exceeds the benefit from break-through treatments.

CONCLUSION: Although these reports are all retrospective, rely on registries with dated data, rarely have predefined hypotheses, and may have publication and self-interest biases, most support a positive volume-outcome relationship in initial cancer treatment. Given the public fear of cancer, its well-defined first identification, and the tumor-node-metastasis taxonomy, actual cancer care should and can be prospectively measured, assessed, and benchmarked. The literature suggests that, for all forms of cancer, efforts to concentrate its initial care would be appropriate.
Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients With Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy Regimens
Authors: Fossella Frank V. , DeVore Russell , Kerr Ronald N. , Crawford Jeffrey , Natale Ronald R. , Dunphy Frank , Kalman Leonard , Miller Vincent , Lee Jin Soo , Moore Melvin , Gandara David , Karp Daniel , Vokes Everett , Kris Mark , Kim Yong , Gamza Francis , Hammershaimb Luz ,   the TAX Non–Small-Cell Lung Cancer Study Group
Published: February 2017

PURPOSE: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy.

PATIENTS AND METHODS: A total of 373 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics.

RESULTS: Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P = .001 and P = .036, respectively). Patients who received docetaxel had a longer time to progression (P = .046, by log-rank test) and a greater progression-free survival at 26 weeks (P = .005, by χ2 test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treatment (32% v 19%; P = .025, by χ2 test). Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it impact survival. There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2. Toxicity was greatest with D100, but the D75 arm was well-tolerated.

CONCLUSION: This first randomized trial in this setting demonstrates that D75 every 3 weeks can offer clinically meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy.
Phase II Trial of Doxorubicin and Docetaxel Plus Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer: Eastern Cooperative Oncology Group Study E1196
Authors: Sparano Joseph A. , O’Neill Anne , Schaefer Paul L. , Falkson Carla I. , Wood William C.
Published: February 2017

PURPOSE: The purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%.

PATIENTS AND METHODS: Fifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m2 by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m2 by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF.

RESULTS: Objective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7.6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27.5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m2 (range, 60 to 480 mg/m2). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure.

CONCLUSION: Using criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.
Low-Dose Oral Fluorouracil With Eniluracil as First-Line Chemotherapy Against Advanced Breast Cancer: A Phase II Study
Authors: Smith Ian E. , Johnston Stephen R. D. , O’Brien Mary E. R. , Hickish Tamas F. , de Boer Richard H. , Norton Alison , Cirkel Deborah T. , Barton Claire M.
Published: February 2017

PURPOSE: Eniluracil (776C85) is an effective inactivator of dihydropyrimidine dehydrogenase that allows continuous low-dose oral fluorouracil (5-FU) to be given with predicable oral bioavailability. We have assessed this as first-line oral chemotherapy for patients with advanced/metastatic breast cancer.

PATIENTS AND METHODS: Patients with histologically proven, locally advanced or metastatic breast cancer without previous chemotherapy for advanced disease were entered onto this open-label phase II study. Patients received oral 5-FU 1.0 mg/m2 with eniluracil 10 mg/m2, both given twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity.

RESULTS: Thirty-three patients were entered, with a median age of 53 years. Sixteen partial responses were seen in twenty-nine assessable patients (55%; 95% confidence interval, 37% to 73%), including responses in four (40%) out of 10 patients who had received prior adjuvant 5-FU. Seven patients had stable disease for at least 3 months with symptom improvement. Median response duration was 14 months (range, 10 to 18+ months). Toxicity was low. There were only two episodes of drug-related grade 3 nonhematologic toxicity (diarrhea and infection), and only 6%, 3%, and 3% of patients developed granulocytopenia, thrombocytopenia, and neutropenic sepsis, respectively. Mild (grade 1/2) diarrhea occurred in 39% of patients, hand-foot syndrome in 15%, nausea in 27%, and mucositis in 18%. Toxicity-associated delay and dose reduction occurred in only 2% and 5% of courses, respectively.

CONCLUSION: First-line treatment with the combination of oral 5-FU and eniluracil has high activity in patients with advanced breast cancer comparable with the most active conventional cytotoxic agents but with strikingly less toxicity.
Phase III Comparative Study of Vinorelbine Combined With Doxorubicin Versus Doxorubicin Alone in Disseminated Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8
Authors: Norris B. , Pritchard K.I. , James K. , Myles J. , Bennett K. , Marlin S. , Skillings J. , Findlay B. , Vandenberg T. , Goss P. , Latreille J. , Rudinskas L. , Lofters W. , Trudeau M. , Osoba D. , Rodgers A.
Published: February 2017

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL).

PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m2 intravenously (IV) on day 1 and VNB 25 mg/m2 IV on days 1 and 8 (arm 1) or DOX 70 mg/m2 IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m2. After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m2 on day 1 and VNB 20 mg/m2 on days 1 and 8 versus DOX 60 mg/m2 on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC.

RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P = .4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1.

CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.
Second Malignancies After Treatment of Early-Stage Breast Cancer: Lumpectomy and Radiation Therapy Versus Mastectomy
Authors: Obedian Edward , Fischer Diana B. , Haffty Bruce G.
Published: February 2017

PURPOSE: To determine the risk of second malignancies after lumpectomy and radiation therapy (LRT), and to compare it with that in a similar cohort of early-stage breast cancer patients undergoing mastectomy without radiation (MAST).

PATIENTS AND METHODS: Between January 1970 and December 1990, 1,029 breast cancer patients at our institution underwent LRT. A cohort of 1,387 breast cancer patients who underwent surgical treatment by mastectomy (MAST), and who did not receive postoperative radiation during the same time period, served as a comparison group. Second malignancies were categorized as contralateral breast versus nonbreast. In the cohort of patients undergoing LRT, a detailed analysis was carried out with respect to age, disease stage, smoking history, radiation therapy technique, dose, the use of chemotherapy or hormone therapy, and other clinical and/or pathologic characteristics.

RESULTS: As of March 1999, the median follow-up was 14.6 years for the LRT group and 16 years for the MAST group. The 15-year risk of any second malignancy was nearly identical for both cohorts (17.5% v 19%, respectively). The second breast malignancy rate at 15 years was 10% for both the MAST and LRT groups. The 15-year risk of a second nonbreast malignancy was 11% for the LRT and 10% for the MAST group. In the subset of patients 45 years of age or younger at the time of treatment, the second breast and nonbreast malignancy rates at 15 years were 10% and 5% for patients undergoing LRT versus 7% and 4% for patients undergoing mastectomy (P, not statistically significant). In the detailed analysis of LRT patients, second lung malignancies were associated with a history of tobacco use. There were fewer contralateral breast tumors in patients undergoing adjuvant hormone therapy, although this did not reach statistical significance. The adjuvant use of chemotherapy did not significantly affect the risk of second malignancies.

CONCLUSION: There seems to be no increased risk of second malignancies in patients undergoing LRT using modern techniques, compared with MAST. Continued monitoring of these patient cohorts will be required in order to document that these findings are maintained with even longer follow-up periods. With nearly 15 years median follow-up periods, however, these data should be reassuring to women who are considering LRT as a treatment option.
Second Cancers Among Long-Term Survivors of Hodgkin’s Disease Diagnosed in Childhood and Adolescence
Authors: Metayer Catherine , Lynch Charles F. , Clarke E. Aileen , Glimelius Bengt , Storm Hans , Pukkala Eero , Joensuu Timo , van Leeuwen Flora E. , van’t Veer Mars B. , Curtis Rochelle E. , Holowaty Eric J. , Andersson Michael , Wiklund Tom , Gospodarowicz Mary , Travis Lois B.
Published: February 2017

PURPOSE: To quantify the risk of second cancers among long-term survivors of Hodgkin’s disease (HD) diagnosed before 21 years of age and to explore sex-, age-, and site-related differences.

PATIENTS AND METHODS: We analyzed data from 5,925 pediatric HD patients, including 2,646 10-year and 755 20-year survivors, who were reported to 16 population-based cancer registries in North America and Europe between 1935 and 1994.

RESULTS: A total of 157 solid tumors (observed/expected ratio [O/E] = 7.0; 95% confidence interval [CI], 5.9 to 8.2.) and 26 acute leukemias (O/E = 27.4; 95% CI, 17.9 to 40.2) were reported. Risk of solid tumors remained significantly increased among 20-year survivors (O/E = 6.6, observed [O] = 40, cumulative risk = 6.5%) and persisted for 25 years (O/E = 4.6, O = 15, cumulative risk = 11.7%). Temporal trends for cancers of thyroid, female breast, bone/connective tissue, stomach, and esophagus were consistent with the late effects of radiotherapy. Greater than 50-fold increased risks were observed for tumors of the thyroid and respiratory tract (one lung and one pleura) among children treated before age 10. At older ages (10 to 16 years), the largest number of second cancers occurred in the digestive tract (O/E = 19.3) and breast (O/E = 22.9). Risk of solid tumors increased with decreasing age at HD on a relative but not absolute scale.

CONCLUSION: Children and adolescents treated for HD experience significantly increased risks of second cancers at various sites for 2 to 3 decades. Although our results reflect the late effects of past therapeutic modalities, they underscore the importance of lifelong follow-up of pediatric HD patients given early, more aggressive treatments.