bluuebunny/crossref_metadata_2025 huggingface dataset:
Recommended Colorectal Cancer Surveillance Guidelines by the American Society of Clinical Oncology
Authors: Desch Christopher E. , Benson Al B. , Smith Thomas J. , Flynn Patrick J. , Krause Carol , Loprinzi Charles L. , Minsky Bruce D. , Petrelli Nicholas J. , Pfister David G. , Somerfield Mark R.
Published: February 2017

OBJECTIVE: To determine the most effective, evidence-based, postoperative surveillance strategy for the detection of recurrent colon and rectal cancer. Tests are to be recommended only if they have an impact on the outcomes listed below.

POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring.

OUTCOMES: Outcomes of interest included overall and disease-free survival, quality of life, toxicity reduction, and cost-effectiveness. The American Society of Clinical Oncology (ASCO) Colorectal Cancer Surveillance Expert Panel was guided by the principle of cost minimization, ie, when two strategies were believed to be equally effective, the least expensive test was recommended.

EVIDENCE: A complete MEDLINE search was performed of the past 20 years of the medical literature. Keywords included colorectal cancer, follow-up, and carcinoembryonic antigen, as well as the names of the specific tests. The search was broadened by articlesfrom the tumor marker ASCO panel literature search, as well as from bibliographies of selected articles.

VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design.

BENEFITS/HARMS/COSTS: The possible consequences of false-positive and false-negative tests were considered in evaluating a preference for one of two tests that provide similar information. Cost alone was not a determining factor.

RECOMMENDATIONS: The expert panel's recommended postoperative monitoring schema is discussed in this article.

VALIDATION: Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board of Directors examined this document.

SPONSOR: American Society of Clinical Oncology.
Prognostic Significance of Angiogenesis and Ki-67, p53, and p21 Expression: A Population-Based Endometrial Carcinoma Study
Authors: Salvesen Helga B. , Iversen Ole Erik , Akslen Lars A.
Published: February 2017

PURPOSE: For endometrial carcinoma patients, there is a need for improved identification of high-risk groups that may benefit from postoperative adjuvant therapy. We therefore studied the prognostic impact of markers for cell proliferation, cell-cycle regulation, and angiogenesis among endometrial carcinoma patients in a population-based setting.

PATIENTS AND METHODS: All patients diagnosed with endometrial carcinoma between 1981 and 1985 in Hordaland County, Norway, were studied. The median follow-up for the survivors was 11.5 years (range, 8 to 15 years), with no patient lost because of insufficient follow-up information. Paraffin-embedded tumor tissue, available in 96% of the cases (n = 142), was studied immunohistochemically for microvessel density (MVD) and expression of Ki-67, p53, and p21 proteins. We used the hot spot method for calculation of MVD, and expression of Ki-67 and p21 protein, because this approach may increase the probability of detecting small aggressive clones of possible prognostic relevance. The importance of these tumor markers was investigated in univariate survival analyses and Cox regression analysis.

RESULTS: The majority of traditional clinicopathologic variables was significantly associated with the tumor biomarkers. Age, International Federation of Gynecology and Obstetrics (FIGO) stage, histologic type, histologic grade, MVD, as well as Ki-67, p53, and p21 protein expression, all significantly influenced survival in univariate analyses (P ≤ .05). In the Cox regression analysis, age, FIGO stage, MVD, Ki-67 expression, and p53 expression were the only variables with independent prognostic impact (P ≤ .05), whereas histologic type, histologic grade, and p21 expression had no independent influence. A group of high-risk patients with more than one unfavorable marker was identified.

CONCLUSION: In addition to age and FIGO stage, MVD, Ki-67, and p53 protein expression showed an independent prognostic impact. Thus, information derived from routine histologic specimens identified a subgroup of high-risk endometrial carcinoma patients in this population-based study.
Small Noncleaved, Non-Burkitt's (Burkitt-Like) Lymphoma: Cytogenetics Predict Outcome and Reflect Clinical Presentation
Authors: Macpherson Nicol , Lesack David , Klasa Richard , Horsman Doug , Connors Joseph M. , Barnett Michael , Gascoyne Randy D.
Published: February 2017

PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB).

PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype were evaluated between January 1989 and January 1996. All were from British Columbia, Canada, underwent uniform clinical staging, and were treated on investigational protocols by a small group of clinicians.

RESULTS: Three groups of patients were identified by clonal karyotype on cytogenetic analysis: (1) those with a c-myc translocation (n = 11); (2) those with dual translocation of c-myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n = 15). The c-myc group was younger, presented with earlier stage de novo disease, and had a better clinical prognostic factor profile. The dual-translocation and other groups were older and presented in advanced stage with poorer prognostic features, and a larger proportion of the dual-translocation group patients had transformed from previously diagnosed follicular lymphoma. The median overall survival (OS) time for all patients was 5 months. The median OS time for the dual-translocation group was only 2.5 months, as compared with 7 months and 8 months for the c-myc and other group, respectively (P < .001). There were no survivors beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2-year OS rates in the c-myc and other group.

CONCLUSION: SNC-NB lymphoma is a clinically and cytogenetically heterogenous disease. Dual translocation of c-myc and bcl-2 is characterized by a rapid clinical course and extremely poor outcome. This latter entity may represent the most clinically aggressive lymphoma thus far characterized and warrants intensive investigational treatment where feasible.
Tumor, Normal Tissue, and Plasma Pharmacokinetic Studies of Fluorouracil Biomodulation With N-Phosphonacetyl-l-aspartate, Folinic Acid, and Interferon Alfa
Authors: Harte Robert J.A. , Matthews Julian C. , O'Reilly Susan M. , Tilsley D.W. Owen , Osman Safiye , Brown Gavin , Luthra Sajinder J. , Brady Frank , Jones Terry , Price Patricia M.
Published: February 2017

PURPOSE: To evaluate the effect of N-phosphonacetyl-l-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-α) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration.

PATIENTS AND METHODS: Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-α in recognized schedules.

RESULTS: TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-α had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow.

CONCLUSION: The administration of PALA and IFN-α produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.
High-Dose Leucovorin as Sole Therapy for Methotrexate Toxicity
Authors: Flombaum Carlos D. , Meyers Paul A.
Published: February 2017

PURPOSE: Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been recommended together with high-dose (HD) leucovorin (LV) to treat patients at risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue as the sole salvage modality for severe MTX intoxication, we studied 13 patients who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New York, NY).

PATIENTS AND METHODS: To identify patients at high risk for severe MTX toxicity, we performed a retrospective review of all patients with MTX levels greater than 100 μmol/L at 24 hours and greater than 10 μmol/L at 48 hours after HD MTX.

RESULTS: A total of 13 patients were identified. The median MTX concentration was 164 μmol/L at 24 hours (range, 102 to 940 μmol/L), 16.3 μmol/L at 48 hours (range, 10.5 to 190 μmol/L), and 6.2 μmol/L at 72 hours (range, 1.35 to 39 μmol/L). MTX levels remained greater than 0.1 μmol/L for an average of 11 ± 3 days (mean ± SD) (range, 7 to 17 days). In addition to supportive treatment with hydration and sodium bicarbonate administration, all patients were treated solely with HD LV, which was started within the first 24 hours in nine patients, 48 hours in three patients, and 72 hours in one patient in doses that varied from 0.24 to 8 g/d. Significant neutropenia (neutrophil count < 1,000/μL) occurred in eight patients and lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/μL) occurred in seven patients and lasted for 5 to 10 days. Other toxic manifestations included mucositis of varying degrees, diarrhea, and neutropenic fever, but all patients recovered.

CONCLUSION: In the range of MTX levels observed, HD LV can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity.
Treatment of Pancreatic Cancer With Docetaxel and Granulocyte Colony-Stimulating Factor: A Multicenter Phase II Study
Authors: Androulakis Nikos , Kourousis Charalambos , Dimopoulos Meletios A. , Samelis George , Kakolyris Stelios , Tsavaris Nikos , Genatas Kostas , Aravantinos Gerasimos , Papadimitriou Christos , Karabekios Spyros , Stathopoulos George P. , Georgoulias Vassilis
Published: February 2017

PURPOSE: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer.

PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m2) and granulocyte colony-stimulating factor (150 μg/m2/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease.

RESULTS: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients.

CONCLUSION: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.
Total Body Irradiation, Thiotepa, and Cyclophosphamide as a Conditioning Regimen for Children With Acute Lymphoblastic Leukemia in First or Second Remission Undergoing Bone Marrow Transplantation With HLA-Identical Siblings
Authors: Zecca Marco , Pession Andrea , Messina Chiara , Bonetti Federico , Favre Claudio , Prete Arcangelo , Cesaro Simone , Porta Fulvio , Mazzarino Ida , Giorgiani Giovanna , Rondelli Roberto , Locatelli Franco
Published: February 2017

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR.

PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d.

RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%.

CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle–independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.
Expression of Beta-Integrin Adhesion Molecules in Non-Hodgkin's Lymphoma: Correlation With Clinical and Evolutive Features
Authors: Terol María-José , López-Guillermo Armando , Bosch Francesc , Villamor Neus , Cid María-Cinta , Campo Elías , Montserrat Emilio
Published: February 2017

PURPOSE: To analyze beta-integrin expression in non-Hodgkin's lymphomas (NHLs) in order to assess its distribution among histologic subtypes and correlate with clinical features and outcome.

PATIENTS AND METHODS: The expression of α2 through α6 and β1 common chains of very late activation antigen (VLA ) molecules and αL (CD11a) and β2 common (CD18) chains of leukocyte function-associated antigen 1 molecule were studied in 137 patients with NHL. Immunostaining was performed by a streptavidin-biotin alkaline phosphatase method, and integrin expression was semiquantitatively assessed. Correlation with clinical features was analyzed in 80 patients consecutively diagnosed as having immunocytoma (five cases), follicular lymphoma (19 cases), mantle-cell lymphoma (MCL; four cases), diffuse large-cell lymphoma (DLCL; 40 cases), lymphoblastic lymphoma (LL; six cases), anaplastic Ki-1–positive lymphoma (one case), and other peripheral T-cell lymphoma (five cases).

RESULTS: MCL cells did not show α2 and α6 expression, whereas most expressed weak to moderate levels of α3, α4, and α5. LL mostly showed α2 to α5 expression, whereas α6 was observed in seven of 11 cases (higher proportion than that shown in other subgroups). Alpha chains of VLA molecules were present more frequently in T-cell than in B-cell lymphomas. Patients with moderate/strong α4, CD11a, and β2 common chain expression presented more frequently with advanced stage and bone marrow infiltration. Moderate/strong α4, α5, and β1 common chain expression correlated with extranodal involvement. In the subset of B-cell DLCL patients, negative/weak expression of α3 and α4 chains was related to a higher complete response rate. Moreover, negative or weak expression of α2, α3, α4, and β1 common chain had favorable significance for overall and failure-free survivals.

CONCLUSION: In NHL, beta-integrin expression is related to histologic subtype. The expression pattern of these molecules probably influences disease dissemination and patients' prognoses.
Epirubicin Plus Tamoxifen Versus Tamoxifen Alone in Node-Positive Postmenopausal Patients With Breast Cancer: A Randomized Trial of the International Collaborative Cancer Group
Authors: Wils J.A. , Bliss J.M. , Marty M. , Coombes G. , Fontaine C. , Morvan F. , Olmos T. , Pérez-López F.R. , Vassilopoulos P. , Woods E. , Coombes R.C.
Published: February 2017

PURPOSE: To assess whether the addition of epirubicin (EPI) therapy to prolonged treatment with tamoxifen (TAM) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer.

PATIENTS AND METHODS: Six hundred four patients entered onto a randomized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m2 intravenously on days 1 and 8 every 4 weeks for six cycles. Analysis was performed according to allocated treatment, with all randomized patients included (intention to treat), irrespective of eligibility status.

RESULTS: After a median follow-up period of 5.7 years, an improvement in relapse-free survival (RFS) was observed for the TAM and EPI–treated patients, compared with those who received TAM alone. The unadjusted hazard ratio was 0.72 (95% confidence interval, 0.54 to 0.96), with a corresponding reduction in the odds of recurrence of 27.9% (SD, 12.3), which was statistically significant (P = .023). Adjustment for prognostic and/or predictive factors did not materially affect the hazard ratio. No difference was observed in terms of overall survival (reduction in odds of death, 11.9% [SD, 16.3]; P = .46). Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity. Twelve nonbreast second malignancies, including five hematologic malignancies (two of which were cases of acute myelogenous leukemia), were observed.

CONCLUSION: The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer. No evidence was found, however, for an improvement in overall survival. The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists' Collaborative Group overview. The trial presented here, however, provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM.
Detection of Circulating Mammary Carcinoma Cells in the Peripheral Blood of Breast Cancer Patients Via a Nested Reverse Transcriptase Polymerase Chain Reaction Assay for Mammaglobin mRNA
Authors: Zach Otto , Kasparu Hedwig , Krieger Otto , Hehenwarter Wolfgang , Girschikofsky Michael , Lutz Dieter
Published: February 2017

PURPOSE: According to current medical research, mammaglobin (hMAM) is expressed exclusively in the mammary glands of adult women and in mammary tumor cell lines. Therefore, we examined hMAM expression as a marker for the detection of carcinoma cells in the peripheral blood of patients with breast cancer (BC).

PATIENTS AND METHODS: Blood samples obtained from 114 BC patients at the various stages of their disease and from 68 individuals without BC were screened for hMAM mRNA by a nested reverse transcriptase polymerase chain reaction (RT-PCR) assay.

RESULTS: The assay exhibited a calculated analytical limit of one tumor cell per 106 to 107 WBCs. None of the samples from peripheral blood of 27 healthy individuals were positive, whereas 29 (25%) of 114 samples from BC patients were positive for hMAM mRNA. hMAM mRNA expression was detected in five (28%) of 18 BC patients at diagnosis, in three (6%) of 53 with no evidence of disease, and in 21 (49%) of 43 with metastatic disease. These results correlate with patients' carcinoembryonic antigen (CEA) plasma level and, to some extent, with estrogen receptor status. Two of 41 samples from patients with malignancies other than BC were also positive.

CONCLUSION: In contrast to healthy volunteers, hMAM transcripts were detected in the peripheral blood of BC patients. The percentage of positivity relates to the clinical stages of disease, CEA plasma level, and estrogen receptor status. Aberrant hMAM expression might occur occasionally in malignancies other than BC. The clinical relevance of hMAM RT-PCR–based tumor cell detection in the peripheral blood of BC patients should be further evaluated in prospective studies.
Interobserver Variability in the Detection of Cervical-Thoracic Hodgkin's Disease by Computed Tomography
Authors: Fletcher Barry D. , Glicksman Arvin S. , Gieser Peter
Published: February 2017

PURPOSE: Computed tomography (CT) scans of the neck and chest are obtained at diagnosis of Hodgkin's disease to establish disease extent, plan radiotherapy, and serve as baseline studies for subsequent evaluation of response to therapy. However, differences in interpretation may occur even among experienced radiologists. This study was designed to test the extent of variation among expert radiologists' interpretations and to assess how their interpretations differed from that of the primary (institutional) radiologists.

MATERIALS AND METHODS: Five radiologists independently reviewed randomly selected CT scans of 59 patients enrolled onto two Pediatric Oncology Group Hodgkin's disease treatment protocols. For each patient, 31 potential disease sites were scored as positive, negative, uncertain, or unassessable. Agreement among the reviewers and between the reviewers and the primary readers was analyzed.

RESULTS: For 58% of the sites, at least four of the five reviewers agreed in ≥ 80% of the cases. Kappa analysis showed moderate agreement in approximately two thirds of the sites and poor agreement in the remainder. There was moderate agreement between a majority of the expert readers and the primary radiologist reports for approximately one third of the sites, and agreement was poor in two thirds.

CONCLUSION: There are disparities among radiologists' interpretations of cervical-thoracic CT imaging of patients with Hodgkin's disease. This variability may affect patient care and the performance and results of multi-institutional clinical trials. We propose that a standardized method of reporting might improve the consistency of interpretation of CT scans in these patients.
Phase I/II Trial of Radiation With Chemotherapy “Boost” for Advanced Squamous Cell Carcinomas of the Head and Neck: Toxicities and Responses
Authors: Garden Adam S. , Glisson Bonnie S. , Ang K. Kian , Morrison William H. , Lippman Scott M. , Byers Robert M. , Geara Fady , Clayman Gary L. , Shin Dong M. , Callender David L. , Khuri Fadlo R. , Goepfert Helmuth , Hong Waun K. , Peters Lester J.
Published: February 2017

PURPOSE: Extrapolating from our experience delivering a “boost” field of radiation concurrently with fields treating both gross and subclinical disease at the end of a course of radiation therapy, we developed a regimen to deliver concurrent chemotherapy during the last 2 weeks of a conventionally fractionated course of radiation.

PATIENTS AND METHODS: Patients had stage III or IV biopsy-proven squamous cell carcinoma originating from a head and neck mucosal site. The regimen was 70 Gy delivered over 7 weeks with concurrent fluorouracil (5-FU) and cisplatin given daily with each radiation dose during the last 2 weeks. A phase I study was performed to determine the maximum-tolerated dose (MTD) before a phase II study was conducted.

RESULTS: The MTD was 400 mg/m2 per day for 5-FU and 10 mg/m2 per day for cisplatin. Mucositis persisting more than 6 weeks after therapy was the dose-limiting toxicity. A total of 60 patients were treated on the two phases of the study. Eighteen patients (35%) treated at the MTD developed prolonged mucositis. There were two cases of neutropenic sepsis, including one fatality. The actuarial 2-year rates for overall survival, freedom from relapse, and local control were 62%, 59%, and 80%, respectively.

CONCLUSION: Preliminary locoregional control rates seem to be higher than those reported for treatment with radiation alone. Toxicity was also greater than that seen with radiation alone, but the regimen was designed to deliver an intense treatment schedule, which could be completed without significant interruptions, and to obtain high control rates above the clavicles. These end points were achieved.
Patient Selection for Salvage Cryotherapy for Locally Recurrent Prostate Cancer After Radiation Therapy
Authors: Pisters Louis L. , Perrotte Paul , Scott Shellie M. , Greene Graham F. , von Eschenbach Andrew C.
Published: February 2017

PURPOSE: Our objective was to identify clinical pretreatment factors associated with early treatment failure after salvage cryotherapy.

PATIENTS AND METHODS: Between 1992 and 1995, 145 patients underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Treatment failure was defined as an increasing postcryotherapy serial prostate-specific antigen (PSA) level of more than or equal to 2 ng/mL above the postcryotherapy nadir or as a positive posttreatment biopsy. We evaluated the following factors as predictors of treatment failure: tumor stage and grade at initial diagnosis, type of prior therapy, stage and grade of locally recurrent tumor, number of positive biopsy cores at recurrence, and precryotherapy PSA level.

RESULTS: Among patients with a prior history of radiation therapy only, the 2-year actuarial disease-free survival (DFS) rates were 74% for patients with a precryotherapy PSA less than 10 ng/mL and 28% for patients with a precryotherapy PSA more than 10 ng/mL, P < .00001. The DFS rates were 58% for patients with a Gleason score of less than or equal to 8 recurrence and 29% for patients with a Gleason score greater than or equal to 9 recurrence, P < .004. Among patients with a precryotherapy PSA less than 10 ng/mL, DFS rates were 74% for patients with a prior history of radiation therapy only and 19% for patients with a history of prior hormonal therapy plus radiation therapy, P < .002.

CONCLUSION: Patients failing initial radiation therapy with a PSA more than 10 ng/mL and Gleason score of the recurrent cancer more than or equal to 9 are unlikely to be successfully salvaged. Patients failing initial hormonal therapy and radiation therapy are less likely to be successfully salvaged than patients failing radiation therapy only.
Treatment of Invasive Thymoma With Single-Agent Ifosfamide
Authors: Highley M. S. , Underhill C. R. , Parnis F. X. , Karapetis C. , Rankin E. , Dussek J. , Bryant B. , Rowland C. , Hodson N. , Hughes J. , Harper P. G.
Published: February 2017

PURPOSE: To evaluate single-agent ifosfamide in the treatment of invasive thymoma.

PATIENTS AND METHODS: Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m2 was given on days 1 to 5, with mesna as a uroprotector.

RESULTS: Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated.

CONCLUSION: Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.
Irinotecan Combined With Bolus Fluorouracil, Continuous Infusion Fluorouracil, and High-Dose Leucovorin Every Two Weeks (LV5FU2 Regimen): A Clinical Dose-Finding and Pharmacokinetic Study in Patients With Pretreated Metastatic Colorectal Cancer
Authors: Ducreux Michel , Ychou Marc , Seitz Jean-François , Bonnay Marc , Bexon Alice , Armand Jean-Pierre , Mahjoubi Monder , Méry-Mignard Dominique , Rougier Philippe
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC).

PATIENTS AND METHODS: All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m2). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2.

RESULTS: Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m2, and a dose level of 300 mg/m2 was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m2. Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months.

CONCLUSION: The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m2 in combination with LV5FU2 has been selected as the recommended dose for further studies.
Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma
Authors: Middleton M.R. , Grob J.J. , Aaronson N. , Fierlbeck G. , Tilgen W. , Seiter S. , Gore M. , Aamdal S. , Cebon J. , Coates A. , Dreno B. , Henz M. , Schadendorf D. , Kapp A. , Weiss J. , Fraass U. , Statkevich P. , Muller M. , Thatcher N.
Published: February 2017

PURPOSE: : To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC).

PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m2/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m2/d for 5 days every 21 days.

RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P = .012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC.

CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.
Randomized Trial of Filgrastim, Sargramostim, or Sequential Sargramostim and Filgrastim After Myelosuppressive Chemotherapy for the Harvesting of Peripheral-Blood Stem Cells
Authors: Weaver Charles H. , Schulman Kevin A. , Wilson-Relyea Barbara , Birch Robert , West William , Buckner C. Dean
Published: February 2017

PURPOSE: The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34+ cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC).

PATIENTS AND METHODS: One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81).

RESULTS: Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 × 109/L or greater (a median of 11 v 14 days; P = .0001), with fewer patients requiring RBC transfusions (P = .008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P = .013), and less intravenous antibiotic therapy (24% v 69%; P = .001). Patients who received filgrastim yielded more CD34+ cells (median, 7.1 v 2.0 × 106/kg/apheresis; P = .0001), and a higher fraction achieved 2.5 × 106 (94% v 78%; P = .021) and 5 × 106 (88% v 53%; P = .001) or more CD34+ cells/kg with fewer aphereses (median, 2 v 3; P = .002) and fewer days of growth-factor treatment (median, 12 v 14; P = .0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34+ cells and had faster platelet recovery (P = .015), with fewer patients (P = .014) receiving fewer platelet transfusions (P = .001) than patients receiving sargramostim-mobilized PBSCs.

CONCLUSION: It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34+ cells and reduction of toxicities after MC.
Thromboembolic Events During Chemotherapy for Germ Cell Cancer: A Cohort Study and Review of the Literature
Authors: Weijl Nir I. , Rutten Marc F. J. , Zwinderman Aeilko H. , Keizer H. Jan , Nooy Marianne A. , Rosendaal Frits R. , Cleton Frans J. , Osanto Susanne
Published: February 2017

PURPOSE: To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject.

PATIENTS AND METHODS: One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens.

RESULTS: Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83.3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (≥ 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1.2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications.

CONCLUSION: Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.
Filgrastim as an Alternative to Donor Leukocyte Infusion for Relapse After Allogeneic Stem-Cell Transplantation
Authors: Bishop Michael R. , Tarantolo Stefano R. , Pavletic Z. Steven , Lynch James C. , Morris Mary E. , Zacharias Diane , Armitage James O. , Kessinger Anne
Published: February 2017

PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT.

PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse.

RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively.

CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.
Palliative Effect of Chemotherapy: Objective Tumor Response Is Associated With Symptom Improvement in Patients With Metastatic Breast Cancer
Authors: Geels Paul , Eisenhauer Elizabeth , Bezjak Andrea , Zee Benny , Day Andrew
Published: February 2017

PURPOSE: Because one of the goals of chemotherapy for metastatic breast cancer is to provide symptom palliation, we were interested in identifying the relationship between tumor shrinkage and improvement in disease-related symptoms.

PATIENTS AND METHODS: Three hundred patients enrolled onto a randomized trial of metastatic breast cancer formed the basis of our study. The nine most common baseline symptoms were identified and followed. Changes from baseline (improvement, stable, worsening) were defined using patient responses to a quality-of-life (QoL) questionnaire (the European Organization for Research and Treatment of Cancer EORTC QLQ-C30) as well as using graded toxicity data collected on case report forms (CRFs). The association between symptom improvement and tumor response was assessed using a linear trend test via a logistic regression model.

RESULTS: The most commonly reported baseline symptoms were cancer pain in 38% (CRF data) and 81% of patients (QoL data) and tiredness in 26% (CRF data) and 89% (QoL data) of patients. Three symptoms—cancer pain, shortness of breath, and abnormal mood—showed a significant relationship between improvement and objective response, using both CRF and QoL assessments. Constipation, anorexia, and nausea showed a similar trend when QoL data were used but not when CRF information was used. The converse was seen for lethargy. There was no correlation between symptom change and response for cough and insomnia.

CONCLUSION: For some symptoms, we found a significant association between symptom improvement and objective tumor regression. In these cases, symptom improvement was greatest in those patients who had complete or partial responses, followed by those with stable disease and then those with progressive disease. Further work in this area will be useful in determining the surrogate value of objective tumor response in identifying the efficacy of palliative chemotherapy.
Paclitaxel, Ifosfamide, and Cisplatin Second-Line Therapy for Patients With Relapsed Testicular Germ Cell Cancer
Authors: Motzer Robert J. , Sheinfeld Joel , Mazumdar Madhu , Bains Manjit , Mariani Tania , Bacik Jennifer , Bajorin Dean , Bosl George J.
Published: February 2017

PURPOSE: To evaluate the dose, toxicity, and efficacy of paclitaxel in combination with ifosfamide and cisplatin as salvage therapy for patients with relapsed testicular germ cell tumors (GCTs).

PATIENTS AND METHODS: Thirty patients with previously treated GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. All had favorable prognostic features for response (testis primary tumor site and prior complete response to first-line chemotherapy program). Four cycles of paclitaxel, ifosfamide 5 g/m2, and cisplatin 100 mg/m2 were given 21 days apart with granulocyte colony-stimulating factor support, followed by resection of radiographic residua. The dose of paclitaxel was increased among cohorts with dose levels of 175, 215, and 250 mg/m2; the largest dose was selected for the phase II part of the trial.

RESULTS: Twenty-three (77%) of 30 patients achieved a complete response to chemotherapy alone, and one patient achieved a durable partial response with normal tumor markers. Therefore, 24 (80%) achieved a favorable response. Eleven patients with normalized markers after chemotherapy underwent resection of residual tissue, with only necrosis found in 10 and mature teratoma in one. Two patients relapsed, and 22 (73%) of the favorable responses remain durable at a median follow-up duration of 33 months. Myelosuppression was the major toxicity, and two patients had grade 3 neurotoxicity.

CONCLUSION: Four cycles of TIP was associated with a high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing salvage regimen for testicular GCTs. The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors for a favorable outcome to conventional-dose salvage therapy.
Gemcitabine in the Treatment of Refractory Hodgkin’s Disease: Results of a Multicenter Phase II Study
Authors: Santoro A. , Bredenfeld H. , Devizzi L. , Tesch H. , Bonfante V. , Viviani S. , Fiedler F. , Parra H. Soto , Benoehr C. , Pacini M. , Bonadonna G. , Diehl V.
Published: February 2017

PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin’s disease.

PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m2, was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1,250 mg/m2 to 1,500 mg/m2.

RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients’ main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study.

CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin’s disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.