bluuebunny/crossref_metadata_2025 huggingface dataset:
Building Bridges Between Physicians and Patients: Results of a Pilot Study Examining New Tools for Collaborative Decision Making in Breast Cancer
Authors: Sepucha Karen R. , Belkora Jeffrey K. , Tripathy Debasish , Esserman Laura J.
Published: February 2017

PURPOSE: To present the results of a pilot study testing an intervention designed to improve the quality of medical consultations between breast cancer patients and physicians and, in particular, to report the effects of the intervention on the quality of treatment decisions, the quality of communication, and the satisfaction of patients and physicians.

PATIENTS AND METHODS: We enrolled 24 predominantly white, well-educated, early-stage breast cancer patients who were facing local or systemic treatment decisions in a sequential, controlled trial. All patients received a visit preparation session before the consultation in which a trained researcher helped patients organize their questions and concerns. In the control, a researcher observed the consultation. In the intervention, a researcher helped create an agenda, facilitated the discussion, and created a record of the consultation in real time. Valid and reliable surveys measured the quality of treatment decisions and satisfaction with the consultation.

RESULTS: Patients in the intervention achieved significantly higher final decision quality scores compared with control patients (median score, 14 v 10, respectively; P = .008) and a significantly higher level of intersubjective agreement with their physicians about decision quality (Cohen’s kappa, 0.49 v 0.285, respectively; P < .0001). Consultation recording methods did not affect the length of time required for the consultation.

CONCLUSION: Consultation recording methods provide a promising innovation for medical consultations. Further studies are warranted to broaden the findings, assess impacts on the quality of decisions, cost, and health, and develop practical ways to integrate consultation recording methods into clinics.
Radiation Therapy and High-Dose Tamoxifen in the Treatment of Patients With Diffuse Brainstem Gliomas: Results of a Brazilian Cooperative Study
Authors: Broniscer Alberto , Leite Cláudia da Costa , Lanchote Vera L. , Machado Telma M. S. , Cristófani Lilian M. ,   the Brainstem Glioma Cooperative Group
Published: February 2017

PURPOSE: The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial.

PATIENTS AND METHODS: TX was administered orally (maintenance dose: 200 mg/m2 per day) along with conventional local RT and then continued for 52 additional weeks. Survival, tumoral radiologic response, and toxicity were evaluated. Compliance was assessed using pharmacokinetic measurements.

RESULTS: Of 29 patients, 27 completed RT (median dose, 54 Gy). Of 22 assessable patients, 11 (50%) had an objective radiologic response. The mean TX steady-state serum level was 2.44 μmol/L ± 1.02 μmol/L. Only three patients completed the entire course of treatment without tumoral progression or significant toxicity. Common side effects included nausea and vomiting. Hepatotoxicity (five patients), neurotoxicity (two patients), venous thrombosis (one patient), bilateral ovarian cysts (two patients), and transient neutropenia (one patient) were also observed. Median survival was 10.3 months. Only four patients remain alive without tumoral progression. The 1-year survival rate (mean ± SD) was 37.0% ± 9.5%.

CONCLUSION: This treatment combination produced no significant change in the overall poor prognosis of these patients. Most tumors responded initially to treatment but recurred as the study progressed. A minority of patients seemed to benefit from the extended use of TX. Generally, treatment was well tolerated, with good patient compliance, but we recommend continuous close monitoring for side effects. Based on our poor results, we recommend that alternative treatments be tested in patients with this type of tumor.
Biologic Factors Determine Prognosis in Infants With Stage IV Neuroblastoma: A Prospective Children’s Cancer Group Study
Authors: Schmidt Mary Lou , Lukens John N. , Seeger Robert C. , Brodeur Garrett M. , Shimada Hiroyuki , Gerbing Robert B. , Stram Daniel O. , Perez Carlos , Haase Gerald M. , Matthay Katherine K.
Published: February 2017

PURPOSE: A prospective Children’s Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment.

PATIENTS AND METHODS: One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 105 bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment.

RESULTS: The 3-year event-free survival (EFS) and overall survival (mean ± SD) for the 134 infants were 63% ± 5% and 71% ± 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% ± 4% 3-year EFS, whereas those with amplified MYCN had a 10% ± 7% 3-year EFS (P < .0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number.

CONCLUSION: Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children ≥ 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% ± 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.
Randomized Comparison of ACVBP and m-BACOD in the Treatment of Patients With Low-Risk Aggressive Lymphoma: The LNH87-1 Study
Authors: Tilly Hervé , Mounier Nicolas , Lederlin Pierre , Brière Josette , Dupriez Brigitte , Sebban Catherine , Bosly André , Biron Pierre , Nouvel Catherine , Herbrecht Raoul , Bordessoule Dominique , Coiffier Bertrand ,   for the Groupe d’Etudes des Lymphomes de l’Adulte
Published: February 2017

PURPOSE: To compare a short intensified regimen followed by sequential consolidation therapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone [ACVBP]) to the standard regimen of methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD) in patients with low-risk aggressive lymphoma.

PATIENTS AND METHODS: A total of 752 patients with intermediate- or high-grade lymphoma and no adverse prognostic factors (Eastern Cooperative Oncology Group performance status of 2 to 4, ≥ two extranodal sites of disease, tumor burden ≥ 10 cm in largest dimension, bone marrow or CNS involvement, Burkitt’s or lymphoblastic subtypes) were registered. Of 673 eligible patients, 332 received ACVBP and 341 received m-BACOD.

RESULTS: The complete remission rate was identical (86%) in the two groups. With a median follow-up duration of 7 years, the 5-year failure-free survival (FFS) rate was 65% in the ACVBP group and 61% in the m-BACOD group (P = .16). The 5-year overall survival rate was 75% in the ACVBP group and 73% in the m-BACOD group (P = .47). ACVBP was responsible for more severe and life-threatening infections (P < .01), but m-BACOD caused more pulmonary toxicity (P < .001). The number of treatment-related deaths did not differ between the two regimens. A multivariate analysis indicated that ACVBP was associated with a longer FFS in patients with two or three risk factors of the International Prognostic Index.

CONCLUSION: In this population of patients with low-risk aggressive lymphoma, toxicities of the regimens are different, but the rates of response and survival are identical. The survival advantage of ACVBP over standard regimen in patients with advanced disease is suggested by this analysis but remains to be assessed in prospective studies specifically designed for this purpose.
Value of Peptide Receptor Scintigraphy Using 123I-Vasoactive Intestinal Peptide and 111In-DTPA-D-Phe1-Octreotide in 194 Carcinoid Patients: Vienna University Experience, 1993 to 1998
Authors: Raderer Markus , Kurtaran Amir , Leimer Maria , Angelberger Peter , Niederle Bruno , Vierhapper Heinrich , Vorbeck Friedrich , Hejna Michael H. L. , Scheithauer Werner , Pidlich Johann , Virgolini Irene
Published: February 2017

PURPOSE: To report our experience with both 123I-vasoactive intestinal peptide (VIP) and 111In-DTPA-D-Phe1-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients.

PATIENTS AND METHODS: One hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with 111In-DTPA-D-Phe1-OCT for imaging purposes, while 133 patients underwent scanning with both 123I-VIP and 111In-DTPA-D-Phe1-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging.

RESULTS: Primary or recurrent carcinoid tumors could be visualized with 111In-DTPA-D-Phe1-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, 111In-DTPA-D-Phe1-OCT was found to be superior to 123I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with 111In-DTPA-D-Phe1-OCT and 123I-VIP, respectively.

CONCLUSION: Both peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with 111In-DTPA-D-Phe1-OCT scintigraphy being more sensitive than 123I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.
Capecitabine, an Oral Fluoropyrimidine Carbamate With Substantial Activity in Advanced Colorectal Cancer: Results of a Randomized Phase II Study
Authors: Van Cutsem Eric , Findlay Michael , Osterwalder Bruno , Kocha Walter , Dalley David , Pazdur Richard , Cassidy Jim , Dirix Luc , Twelves Chris , Allman David , Seitz Jean-Francois , Schölmerich Jürgen , Burger Hans Ulrich , Verweij Jaap
Published: February 2017

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III.

PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m2/d bid continuously; arm B, 2,510 mg/m2/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m2/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off).

RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity.

CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.
Phase II Trial of Docetaxel and Vinorelbine in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Miller Vincent A. , Krug Lee M. , Ng Kenneth K. , Pizzo Barbara , Perez Wendy , Heelan Robert T. , Kris Mark G.
Published: February 2017

PURPOSE: Docetaxel and vinorelbine are active agents in advanced non–small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m2) and vinorelbine (45 mg/m2) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed.

PATIENTS AND METHODS: Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used.

RESULTS: We delivered median doses of 450 mg/m2 of vinorelbine and 600 mg/m2 of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy.

CONCLUSION: Docetaxel 60 mg/m2 and vinorelbine 45 mg/m2, both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.
Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study Group
Authors: von Pawel Joachim , von Roemeling Reinhard , Gatzemeier Ulrich , Boyer Michael , Elisson Lars Ove , Clark Peter , Talbot Denis , Rey Augustin , Butler Thomas W. , Hirsh Vera , Olver Ian , Bergman Bengt , Ayoub Joseph , Richardson Gary , Dunlop David , Arcenas Anthony , Vescio Robert , Viallet Jean , Treat Joseph
Published: February 2017

PURPOSE: A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non–Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m2 infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m2 over 1 hour) or 75 mg/m2 of cisplatin alone, every 3 weeks for a maximum of eight cycles.

RESULTS: A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was ≥ 60 for all patients (for 10%, KPS = 60; for 90%, KPS = 70 to 100). Sixty patients (14%) had clinically stable brain metastases. The median survival was significantly longer (34.6 v 27.7 weeks; P = .0078) and the response rate was significantly greater (27.5% v 13.7%; P < .001) for patients who received tirapazamine plus cisplatin (n = 218) than for those who received cisplatin alone (n = 219). The tirapazamine-plus-cisplatin regimen was associated with mild to moderate adverse events, including acute, reversible hearing loss, reversible, intermittent muscle cramping, diarrhea, skin rash, nausea, and vomiting. There were no incremental increases in myelosuppression, peripheral neuropathy, or renal, hepatic, or cardiac toxicity and no deaths related to tirapazamine.

CONCLUSION: The CATAPULT I study shows that tirapazamine enhances the activity of cisplatin in patients with advanced NSCLC and confirms that hypoxia is an exploitable therapeutic target in human malignancies.
Suramin Therapy for Patients With Symptomatic Hormone-Refractory Prostate Cancer: Results of a Randomized Phase III Trial Comparing Suramin Plus Hydrocortisone to Placebo Plus Hydrocortisone
Authors: Small Eric J. , Meyer Mark , Marshall M. Ernest , Reyno Leonard M. , Meyers Frederick J. , Natale Ronald B. , Lenehan Peter F. , Chen Liang , Slichenmyer William J. , Eisenberger Mario
Published: February 2017

PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic–dependent pain.

PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared.

RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P = .0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P = .001), and duration of response was longer for suramin responders (median, 240 v 69 days; P = .0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P = .01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically.

CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.
Hyperfractionated Radiation Therapy With or Without Concurrent Low-Dose Daily Cisplatin in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Prospective Randomized Trial
Authors: Jeremic Branislav , Shibamoto Yuta , Milicic Biljana , Nikolic Nebojsa , Dagovic Aleksandar , Aleksandrovic Jasna , Vaskovic Zeljko , Tadic Ljiljana
Published: February 2017

PURPOSE: To investigate whether the addition of cisplatin (CDDP) to hyperfractionation (Hfx) radiation therapy (RT) offers an advantage over the same Hfx RT given alone in locally advanced (stages III and IV) squamous cell carcinoma of the head and neck.

PATIENTS AND METHODS: One hundred thirty patients were randomized to receive either Hfx RT alone to a tumor dose of 77 Gy in 70 fractions in 35 treatment days over 7 weeks (group I, n = 65) or the same Hfx RT and concurrent low-dose (6 mg/m2) daily CDDP (group II, n = 65).

RESULTS: Hfx RT/chemotherapy offered significantly higher survival rates than Hfx RT alone (68% v 49% at 2 years and 46% v 25% at 5 years; P = .0075). It also offered higher progression-free survival (46% v 25% at 5 years; P = .0068), higher locoregional progression-free survival (LRPFS) (50% v 36% at 5 years; P = .041), and higher distant metastasis-free survival (DMFS) (86% v 57% at 5 years; P = .0013). However, there was no difference between the two treatment groups in the incidence of either acute or late high-grade RT-induced toxicity. Hematologic high-grade toxicity was more frequent in group II patients.

CONCLUSION: As compared with Hfx RT alone, Hfx RT and concurrent low-dose daily CDDP offered a survival advantage, as well as improved LRPFS and DMFS.
Health-Related Quality of Life in Patients Treated With Temozolomide Versus Procarbazine for Recurrent Glioblastoma Multiforme
Authors: Osoba D. , Brada M. , Yung W.K. A. , Prados M.
Published: February 2017

PURPOSE: To determine whether chemotherapy with temozolomide (TMZ) versus procarbazine (PCB) for recurrent glioblastoma multiforme (GBM) was associated with improvement in health-related quality of life (HRQOL).

PATIENTS AND METHODS: HRQOL was assessed at baseline and during treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a Brain Cancer Module (BCM20) in two clinical trials that enrolled a total of 366 patients. Two hundred eighty-eight patients provided HRQOL data that could be used for analysis; 109 patients received TMZ in a phase II study, whereas 89 patients received TMZ and 90 received PCB in a randomized phase III study. Changes from baseline in the scores of seven preselected HRQOL domains (role and social functioning, global quality of life [QOL], visual disorders, motor dysfunction, communication deficit, and drowsiness) were calculated for all groups. Statistical significance, effect sizes, and proportions of patients with improved HRQOL scores (changes of ≥ 10 points) were calculated.

RESULTS: Before disease progression, patients treated with TMZ were found to have an improvement in most of the preselected HRQOL domain scores compared with their baseline (pretreatment) scores. Those who were progression-free on TMZ at 6 months had improvement in all the preselected HRQOL domains. Conversely, patients treated with PCB reported deterioration in HRQOL that was independent of whether or not the disease had progressed by 6 months. Patients with disease progression, regardless of treatment, experienced a sharp decline in all domains at the time of progression.

CONCLUSION: Treatment with TMZ was associated with improvement in HRQOL scores compared with treatment with PCB. The deterioration reported by PCB-treated patients was likely because of toxicity. Delaying disease progression by treatment with TMZ is beneficial to the HRQOL status of patients with recurrent GBM.
Localized Childhood Hodgkin’s Disease: Response-Adapted Chemotherapy With Etoposide, Bleomycin, Vinblastine, and Prednisone Before Low-Dose Radiation Therapy—Results of the French Society of Pediatric Oncology Study MDH90
Authors: Landman-Parker J. , Pacquement H. , Leblanc T. , Habrand J.L. , Terrier-Lacombe M.J. , Bertrand Y. , Perel Y. , Robert A. , Coze C. , Thuret I. , Donadieu J. , Schaison G. , Leverger G. , Lemerle J. , Oberlin O.
Published: February 2017

PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin’s disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders.

PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT.

RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean ± SD) is 97.5% ± 2.1%, and the event-free survival rate (mean ± SD) is 91.1% ± 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, “b” biologic class, and nodular sclerosis.

CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.
Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of Childhood
Authors: Toyoda Yasunori , Manabe Atsushi , Tsuchida Masahiro , Hanada Ryohji , Ikuta Koichiro , Okimoto Yuri , Ohara Akira , Ohkawa Yohji , Mori Taijiroh , Ishimoto Kohichi , Sato Takeyuki , Kaneko Takashi , Maeda Miho , Koike Ken-ichi , Shitara Toshiji , Hoshi Yasutaka , Hosoya Ryohta , Tsunematsu Yukiko , Bessho Fumio , Nakazawa Shinpei , Saito Tomohiro ,   for the Acute Lymphoblastic Leukemia Committee of the Tokyo Children’s Cancer Study Group
Published: February 2017

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy.

PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92–13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis.

RESULTS: The mean (± SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% ± 3.4% and 81.5% ± 2.2%, respectively, at 5.5 years after diagnosis. EFS rates by risk category were similar (60.2% ± 6.0% for standard risk, 57.7% ± 5.6% for high risk, and 62.5% ± 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% ± 2.7%, 80.0% ± 4.1%, and 72.1% ± 4.5%, respectively, P < .0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% ± 7.9% (standard risk), 42.6% ± 8.1% (high risk), and 9.6% ± 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important.

CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.
Use of Recombinant Human Granulocyte Colony-Stimulating Factor to Increase Chemotherapy Dose-Intensity: A Randomized Trial in Very High-Risk Childhood Acute Lymphoblastic Leukemia
Authors: Michel G. , Landman-Parker J. , Auclerc M.F. , Mathey C. , Leblanc T. , Legall E. , Bordigoni P. , Lamagnere J.P. , Demeocq F. , Perel Y. , Auvrignon A. , Berthou C. , Bauduer F. , Pautard B. , Schneider P. , Schaison G. , Leverger G. , Baruchel A.
Published: February 2017

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 × 109/L and platelet count was > 100 × 109/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval).

RESULTS: CDI was significantly increased in the G-CSF group compared with the non–G-CSF group (mean ± 95% confidence interval, 105 ± 5% v 91 ± 4%; P < .001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups.

CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.
Adjuvant Therapy of Stage III and IV Malignant Melanoma Using Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Spitler Lynn E. , Grossbard Michael L. , Ernstoff Marc S. , Silver Gary , Jacobs Mark , Hayes F. Ann , Soong Seng Jaw
Published: February 2017

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence.

PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 μg/m2was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival.

RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P < .001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction).

CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.
Phase I Trial of Recombinant Immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in Patients With Hematologic Malignancies
Authors: Kreitman Robert J. , Wilson Wyndham H. , White Jeffrey D. , Stetler-Stevenson Maryalice , Jaffe Elaine S. , Giardina Steven , Waldmann Thomas A. , Pastan Ira
Published: February 2017

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin.

PATIENTS AND METHODS: Patients with CD25+hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 μg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD × 3).

RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 μg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 μg/kg QOD × 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin’s disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment.

CONCLUSION: LMB-2 has clinical activity in CD25+hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.
Phase I and Pharmacologic Study of Sequences of Gemcitabine and the Multitargeted Antifolate Agent in Patients With Advanced Solid Tumors
Authors: Adjei Alex A. , Erlichman Charles , Sloan Jeff A. , Reid Joel M. , Pitot Henry C. , Goldberg Richard M. , Peethambaram Prema , Atherton Pamela , Hanson Lorelei J. , Alberts Steven R. , Jett James
Published: February 2017

PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy.

PATIENTS AND METHODS: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m2 on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m2, given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses).

RESULTS: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m2 for group I and 1,250/500 mg/m2 for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non–small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA.

CONCLUSION: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m2.
Growth Factor Usage Patterns and Outcomes in the Community Setting: Collection Through a Practice-Based Computerized Clinical Information System
Authors: Swanson Grant , Bergstrom Kim , Stump Eva , Miyahara Tammi , Herfindal E.T.
Published: February 2017

PURPOSE: Although use of colony-stimulating factor (CSF) is widespread and guidelines for use have been disseminated, actual practice patterns of medical oncologists are unknown. The purpose of this study was to collect these data using an office-based computerized clinical information system.

PATIENTS AND METHODS: Data were collected on patients at 10 community-based oncology practices. Information regarding CSF use was captured at the time of prescribing through a computerized clinical support tool and stored in a data warehouse, and an analysis was carried out retrospectively.

RESULTS: A total of 6,813 cancer regimens administered to 5,034 patients were evaluated for growth factor use. Overall, CSFs were used in 14% of regimens, with breast, lymphoma, lung, and ovarian being the most common cancers for which CSFs were used. In 49.4% of regimens, CSF was initiated during cycle 1, with an average duration of 1 week, and was used in two or three cycles per regimen. Afebrile neutropenia is rarely followed by CSF initiation. Granulocyte colony-stimulating factor (G-CSF) is associated with fewer dose adjustments, delays, and hospitalizations when compared with granulocyte-macrophage colony stimulating factor (GM-CSF). There is wide variation among oncologists in CSF use, and several substantial differences were noted between the prescribing behavior of American Society of Clinical Oncology (ASCO) survey–reported oncologists and actual clinical practice, as captured by the computerized clinical information system.

CONCLUSION: Computerized clinical information systems can collect detailed information regarding practice patterns of medical oncologists. ASCO physician practice survey data do not accurately reflect actual practice patterns and must be interpreted with caution. Substantial deviations from ASCO growth factor guidelines remain, and oncologists’ use of CSFs demonstrates wide variation. There may be important clinical differences between G-CSF and GM-CSF, but definitive phase III trials are needed for confirmation.
Mitoxantrone, Etoposide, and Cyclosporine Therapy in Pediatric Patients With Recurrent or Refractory Acute Myeloid Leukemia
Authors: Dahl Gary V. , Lacayo Norman J. , Brophy Nathalie , Dunussi-Joannopoulos Kyriaki , Weinstein Howard J. , Chang Myron , Sikic Branimir I. , Arceci Robert J.
Published: February 2017

PURPOSE: To determine the remission rate and toxicity of mitoxantrone, etoposide, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/or refractory acute myeloid leukemia.

PATIENTS AND METHODS: MEC therapy consisted of mitoxantrone 6 mg/m2/d for 5 days, etoposide 60 mg/m2/d for 5 days, and CSA 10 mg/kg for 2 hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of pharmacokinetic interactions, drug doses were decreased to 60% of those found to be effective without coadministration of CSA. MDR1 expression was evaluated by reverse transcriptase polymerase chain reaction, flow cytometry, and the ability of CSA at 2.5 μmol/L to increase intracellular accumulation of 3H-daunomycin in blasts from bone marrow specimens.

RESULTS: The remission rate was 35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n = 6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59). Toxicities included infection, cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum creatinine and bilirubin. In most who had relapsed while receiving therapy or whose induction therapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients.

CONCLUSION: Serum levels of CSA capable of reversing multidrug resistance are achievable in children with acceptable toxicity. The CR rate of 35% achieved in this study is comparable to previously reported results using standard doses of mitoxantrone and etoposide. The use of CSA may have improved the response rate for the MDR1-positive patients so that it was not different from that for the MDR1-negative patients.
Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group
Authors: Estlin E.J. , Cotterill S. , Pratt C.B. , Pearson A.D. J. , Bernstein M.
Published: February 2017

PURPOSE: To identify areas of concern regarding the conduct of phase I trials, the perceived expectations and motivations of the parents of children entered, the expectations of toxicity and benefit, and the ethical concerns of pediatric hematologists and oncologists in the United Kingdom and North America.

METHODS: A survey instrument consisting of 19 open- and closed-ended questions was sent to United Kingdom Children’s Cancer Study Group (UKCCSG)– and Pediatric Oncology Group (POG)–affiliated pediatricians.

RESULTS: Fifty-three UKCCSG- and 78 POG-affiliated pediatricians responded. Thirty-two UKCCSG and 51 POG respondents had previously entered at least one child into a phase I study. Overall, respondents believed that parents entered their children for medical benefit, altruism, and hope of cure. Although many respondents believed that children could benefit from medical improvement, feelings of altruism, and maintenance of hope, the chance of cure or complete remission was thought to be small. Similarly, parents were thought to potentially benefit through altruism and maintenance of hope. Whereas 83% of UKCCSG respondents indicated that phase I trials were associated with ethical difficulties, this was a concern for 48% of POG respondents. The main ethical concerns of respondents were risk of toxicity, consent of the child, unrealistic hope, and coercion.

CONCLUSION: The respondents in this survey expressed mainly ethical concerns regarding the conduct of phase I trials and had realistic expectations of the potential for toxicity and benefit for those children who participate in these studies.
Prognostic Value of p53 for Local Failure in Mastectomy-Treated Breast Cancer Patients
Authors: Zellars R.C. , Hilsenbeck S.G. , Clark G.M. , Allred D.C. , Herman T.S. , Chamness G.C. , Elledge R.M.
Published: February 2017

PURPOSE: The loss of p53 function is a recognized adverse prognostic factor in invasive breast cancer. Several studies have shown a relationship between the nuclear accumulation of p53 protein (a surrogate marker of p53 inactivation) and poor disease-free and overall survival. In general, however, these studies did not report the prognostic value of p53 for local failure, which we have therefore assessed retrospectively here.

MATERIALS AND METHODS: Accumulation of p53 protein was evaluated by immunohistochemistry in 1,530 mastectomy-treated breast cancer patients (259 radiation therapy [RT]– and 1,271 mastectomy only [No RT]–treated patients). Statistical comparisons were made between p53 protein accumulation, estrogen/progesterone receptors, nodal status, tumor size, and local failure rate (LFR). Local failure was defined as tumor recurrence involving the chest wall and/or the ipsilateral supraclavicular/axillary lymph nodes. The median follow-up period was 62 months.

RESULTS: In the No RT group, the LFR was 9.1% and 16.5% in p53-negative and p53-positive patients, respectively (P < .001). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2 to 2.4). Nodal status and tumor size were also significant factors. In the RT group, the LFR was 9.3% and 21.5% in p53-negative and p53-positive patients, respectively (P = .009). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (RR, 2.5; 95% CI, 1.1 to 5.7), as was nodal status.

CONCLUSION: Nuclear accumulation of p53 protein is independently associated with a significantly increased local failure rate in breast cancer patients treated with mastectomy, with or without radiation.
Profile of Men Randomized to the Prostate Cancer Prevention Trial: Baseline Health-Related Quality of Life, Urinary and Sexual Functioning, and Health Behaviors
Authors: Moinpour Carol M. , Lovato Laura C. , Thompson Ian M. , Ware John E. , Ganz Patricia A. , Patrick Donald L. , Shumaker Sally A. , Donaldson Gary W. , Ryan Anne , Coltman Charles A.
Published: February 2017

PURPOSE: To describe men who agreed to be randomized to the Prostate Cancer Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the efficacy of finasteride in preventing prostate cancer.

METHODS: Comprehensive health-related quality-of-life data are presented for 18,882 randomized PCPT participants.

RESULTS: PCPT participants are highly educated, middle to upper income, and primarily white (92%). Participants reported healthy lifestyles. The mean American Urological Association Symptom Index score was well below the maximum entry score of less than 19; existing urinary symptoms were generally not bothersome. The scores for two sexual functioning scales could range from 0 to 100, with higher scores reflecting worse sexual functioning. The mean score for the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study 36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20 points higher than those reported by a general population sample and differed minimally by race but not by age. Previously reported associations between sexual dysfunction and hypertension, diabetes, and depression were also observed. Men who never smoked reported less sexual dysfunction than did those who either had quit or still smoked.

CONCLUSION: Individuals who are likely to enroll in primary prevention trials have a high socioeconomic status, healthy lifestyle behaviors, and better health than the general population. These data help oncologists design chemoprevention trials with respect to the selection of health-related quality-of-life assessments and recruitment strategies.