bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Morbidity in Long-Term Survivors of Metastatic Testicular Cancer
Authors: Meinardi M.T. , Gietema J.A. , van der Graaf W.T. A. , van Veldhuisen D.J. , Runne M.A. , Sluiter W.J. , de Vries E.G. E. , Willemse P.B. H. , Mulder N.H. , van den Berg M.P. , Koops H. Schraffordt , Sleijfer D. Th.
Published: February 2017

PURPOSE: To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy.

PATIENTS AND METHODS: Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were ≤ 50 years at the time of analysis were evaluated for the occurrence of cardiovascular events. Sixty-two of 87 patients were additionally evaluated for cardiac damage and cardiovascular risk factors. Their cardiovascular risk profile was compared with that of 40 patients with comparable age and follow-up duration treated with orchidectomy only for stage I disease.

RESULTS: Major cardiac events were found in five (6%) of the 87 patients (age at time of event, 30 to 42 years; time after chemotherapy, 9 to 16 years): two with myocardial infarction and three with angina pectoris with proven myocardial ischemia. An increased observed-to-expected ratio of 7.1 (95% confidence interval, 1.9 to 18.3) for coronary artery disease, as compared with the general male Dutch population, was found. In addition, one patient experienced a cerebrovascular accident. Exercise ECG did not reveal cases of subclinical coronary artery disease. Echocardiography showed normal systolic left ventricular function in most patients, but diastolic left ventricular function was disturbed in 33% of the patients. Of 62 chemotherapy patients, 79% had hypercholesterolemia, 39% had hypertension, 25% still experienced Raynaud’s phenomenon, and 22% had microalbuminuria. Compared with patients with stage I disease, the chemotherapy patients had higher blood pressure and higher total cholesterol and triglyceride levels and were more insulin-resistant.

CONCLUSION: In long-term survivors of metastatic testicular cancer, we observed a significantly increased risk for occurrence of cardiac events accompanied by a persisting unfavorable cardiovascular risk profile. Accurate follow-up, focused on cardiovascular complications and aimed at intervention in these young cancer survivors, seems to be important.
Pathology Data in the Central Databases of Multicenter Randomized Trials Need to Be Based on Pathology Reports and Controlled by Trained Quality Managers
Authors: Nagtegaal I.D. , Kranenbarg E. Klein , Hermans J. , van de Velde C.J. H. , van Krieken J.H. J. M. ,   the Pathology Review Committee
Published: February 2017

PURPOSE: Randomized multicenter trials form the basis of health care development. Regarding cancer research, pathology data are crucial. To maintain the quality of these trials, the auditing of subsequent processes is necessary. The aim of the present study was to examine the completeness and accuracy of data obtained from a special-purpose standardized pathology form compared with the data available through traditional hospital pathology reports.

PATIENTS AND METHODS: A retrospective comparison of pathology data case record forms with hospital pathology reports was performed using the data from 300 patients with primary rectal cancer. All of these patients had been included in a large multicenter trial in the Netherlands. Three independent audits were carried out. Special attention was given to the accuracy of parameters, which are important for prognosis and treatment decisions. Furthermore, various factors that possibly influence the occurrence of errors were investigated.

RESULTS: Quality control of the pathology data revealed a high accuracy of 86.5% of all data items. However, only one third of the forms were complete and correct. Missing values were most prominent in the number of lymph nodes examined, whereas most errors were made in relation to the circumferential margin. Trained review pathologists made fewer major errors. Discrepancies were detected in all control rounds.

CONCLUSION: Successive rounds of quality control are required for accuracy and completeness of pathology data in multicenter trials. In addition to the special-purpose pathology forms, original pathology reports have to be collected, and the data should also be controlled by a trained pathology quality manager.
Prognostic Impact of Trisomies of Chromosomes 10, 17, and 5 Among Children With Acute Lymphoblastic Leukemia and High Hyperdiploidy (> 50 Chromosomes)
Authors: Heerema Nyla A. , Sather Harland N. , Sensel Martha G. , Zhang Tracy , Hutchinson Raymond J. , Nachman James B. , Lange Beverly J. , Steinherz Peter G. , Bostrom Bruce C. , Reaman Gregory H. , Gaynon Paul S. , Uckun Fatih M.
Published: February 2017

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients.

MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children’s Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods.

RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P < .0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P = .01), or neither trisomy (P < .0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P = .02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects.

CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.
Effect of Cytokine Therapy on Survival for Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Mazumdar Madhu , Bacik Jennifer , Russo Paul , Berg William J. , Metz Erica M.
Published: February 2017

PURPOSE: To evaluate the relationship between treatment with cytokine therapy and survival, investigate the effect of nephrectomy on survival, and identify long-term survivors among a cohort of 670 patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: A total of 670 patients with advanced RCC treated on 24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects of this retrospective analysis. Treatment was categorized as cytokine (containing interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy (cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with survival times of greater than 5 years were identified as long-term survivors.

RESULTS: Patients treated with cytokine therapy had a longer survival time than did those treated with chemotherapy, regardless of the year of treatment or risk category based on pretreatment features. The median survival times for favorable-, intermediate-, and poor-risk patients were 27, 12, and 6 months for those treated with cytokines and 15, 7, and 3 months for those treated with chemotherapy, respectively. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group for both treatment programs. Median survival time was 14 months among patients with prior nephrectomy plus time from diagnosis to treatment greater than 1 year versus 8 months among those with time from diagnosis to treatment less than 1 year, regardless of pretreatment nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified as long-term survivors; 12 were free of disease after nephrectomy and treatment with interferon alfa, interleukin-2, or surgical resection of metastasis.

CONCLUSION: The low proportion of patients with advanced RCC who achieve long-term survival emphasizes the need for clinical investigation to identify more effective therapy.
Results of a Phase II Study Using Estramustine Phosphate and Vinblastine in Combination With High-Dose Three-Dimensional Conformal Radiotherapy for Patients With Locally Advanced Prostate Cancer
Authors: Zelefsky Michael J. , Kelly William K. , Scher Howard I. , Lee Henry , Smart Tracy , Metz Erica , Schwartz Lawrence , Fuks Zvi , Leibel Steven A.
Published: February 2017

PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer.

PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score ≥ 8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months).

RESULTS: Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed.

CONCLUSION: Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.
Thymidine Kinase as a Proliferative Marker: Clinical Relevance in 1,692 Primary Breast Cancer Patients
Authors: Broët P. , Romain S. , Daver A. , Ricolleau G. , Quillien V. , Rallet A. , Asselain B. , Martin P.M. , Spyratos F. ,   for the Groupe d’Oncobiologie of the Fédération Nationale des Centres de Lutte Contre le Cancer
Published: February 2017

PURPOSE: To assess the prognostic value of thymidine kinase (TK), an enzyme involved in the DNA synthesis salvage pathway, relative to other prognostic factors in primary breast cancer.

PATIENTS AND METHODS: This retrospective study involved 1,692 patients with operable breast cancer treated in six institutions (median follow-up, 82 months). Among the 857 node-negative patients, 135 received adjuvant chemotherapy (fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, etoposide, and cisplatin [FEC]). TK was assayed in cytosol with a quantitative radioenzymatic technique. Disease-specific survival (DSS), local recurrence-free interval (LRI), and distant-relapse-free interval (DRI) were investigated.

RESULTS: High TK levels were associated with large tumor size, high histologic grade, and steroid hormone receptor negativity. Univariate analysis of the entire data set showed that high TK levels were related to shorter DSS (P < 10-5), LRI (P < 10-3), and DRI (P < 10-5). In time-dependent Cox models, high TK levels remained an independent predictor of the three outcomes, both in the overall population and in node-negative patients, although its prognostic value decreased over time. In node-negative patients, the introduction of an interaction term in multivariate analysis suggested that chemotherapy was more efficacious for patients who had tumors with high TK contents. In node-positive patients, high TK levels were related only to an increased risk of LRI.

CONCLUSION: High TK values are an important risk factor in node-negative patients and seem to be associated with a beneficial effect of adjuvant FAC or FEC in patients who received adjuvant chemotherapy. The rationale of chemotherapy for patients with slowly proliferating tumors has to be discussed from a risk-benefit point of view.
Switching From Morphine to Methadone to Improve Analgesia and Tolerability in Cancer Patients: A Prospective Study
Authors: Mercadante Sebastiano , Casuccio Alessandra , Fulfaro Fabio , Groff Liliana , Boffi Roberto , Villari Patrizia , Gebbia Vittorio , Ripamonti Carla
Published: February 2017

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine.

PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching.

RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P < .005) and an average of a 33% increase in methadone doses necessary (P < .01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P < .0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P < .0005), nausea and vomiting (P < .03), constipation (P < .001), and drowsiness (P < .01), but a significant increase in the methadone dose of an average of 20% (P < .004) was required.

CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.
Improved Outcome for Patients With Middle Ear Rhabdomyosarcoma: A Children’s Oncology Group Study
Authors: Hawkins Douglas S. , Anderson James R. , Paidas Charles N. , Wharam Moody D. , Qualman Stephen J. , Pappo Alberto S. , Scott Baker K. , Crist William M. ,   for the Intergroup Rhabdomyosarcoma Study Group of the Children’s Oncology Group
Published: February 2017

PURPOSE: The goal of this study was to define the clinical features and optimal therapy for children and adolescents with middle ear (ME) rhabdomyosarcoma (RMS).

PATIENTS AND METHODS: We reviewed demographic data, clinical features, therapy (including chemotherapy, surgery, and radiation), and outcome for the 179 eligible patients with ME RMS who were enrolled onto Intergroup Rhabdomyosarcoma Studies (IRS) I through IV or pilot studies between November 1972 and December 1997.

RESULTS: Most patients were younger than 10 years old (90%), and 63% were male. Because of the parameningeal location, most tumors were not resected before chemotherapy (group I, < 1%; group II, 4%; group III, 84%; group IV, 12%). Although most tumors were locally invasive (T2, 89%), the majority were small (≤ 5 cm, 66%), lacked nodal metastases (N0, 86%), and had embryonal histology (85%). The 5-year failure-free survival (FFS) and overall survival (OS) estimates were 67% and 72%, respectively. Both FFS and OS improved significantly over the course of IRS I through IV (3-year FFS and OS: IRS-I, 42% and 42%; IRS-II, 70% and 74%; IRS-III, 65% and 72%; IRS-IV pilot, 81% and 96%; IRS-IV, 88% and 88%, P < .001). Lower clinical group or stage and smaller tumor size were associated with better outcome. Age, sex, tumor invasiveness, and nodal metastases were not predictive of outcome.

CONCLUSION: Patients with ME RMS generally present with small, unresectable, invasive tumors at a site traditionally considered prognostically unfavorable. Nevertheless, such patients have benefited markedly from improvements in multimodal, risk-based therapy during the course of IRS I through IV, and with contemporary therapy, most are cured.
Outpatient Biochemotherapy With Interleukin-2 and Interferon Alfa-2b in Patients With Metastatic Malignant Melanoma: Results of Two Phase II Cytokine Working Group Trials
Authors: Flaherty L. E. , Atkins M. , Sosman J. , Weiss G. , Clark J. I. , Margolin K. , Dutcher J. , Gordon M. S. , Lotze M. , Mier J. , Sorokin P. , Fisher R. I. , Appel C. , Du W.
Published: February 2017

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials.

PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m2/d intravenously (IV) and cisplatin 25 mg/m2/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m2 subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m2, and in group 2, SC IL-2 was given at 5.0 mU/m2.

RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever.

CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.
High-Dose Intra-Arterial Cisplatin Boost With Hyperfractionated Radiation Therapy for Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Regine William F. , Valentino Joseph , Arnold Susanne M. , Haydon Richard C. , Sloan David , Kenady Daniel , Strottmann James , Pulmano Calixto , Mohiuddin Mohammed
Published: February 2017

PURPOSE: To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN).

PATIENTS AND METHODS: Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m2 received at the start of and during RT boost treatment).

RESULTS: Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months.

CONCLUSION: In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.
Marimastat as First-Line Therapy for Patients With Unresectable Pancreatic Cancer: A Randomized Trial
Authors: Bramhall S. R. , Rosemurgy A. , Brown P. D. , Bowry C. , Buckels J. A.C. ,   for the Marimastat Pancreatic Cancer Study Group
Published: February 2017

PURPOSE: The prognosis for unresectable pancreatic cancer remains dismal (1-year survival rate, < 10%; 5-year survival rate, < 5%). Recent advances in conventional chemotherapy and novel molecular treatment strategies warrant investigation. This, the largest randomized study in pancreatic cancer performed to date, compares marimastat, the first of a new class of agents, with gemcitabine.

PATIENTS AND METHODS: Four hundred fourteen patients with unresectable pancreatic cancer were randomized to receive marimastat 5, 10, or 25 mg bid or gemcitabine 1,000 mg/m2. The primary end point was survival. Progression-free survival, patient benefit, and safety were also assessed.

RESULTS: There was no significant difference in survival between 5, 10, or 25 mg of marimastat and gemcitabine (P = .19). Median survival times were 111, 105, 125, and 167 days, respectively, and 1-year survival rates were 14%, 14%, 20%, and 19%, respectively. There was a significant difference in survival rates between patients treated with gemcitabine and marimastat 5 and 10 mg (P < .003). Both agents were well tolerated, although grade 3 or 4 toxicities were reported in 22% and 12% of the gemcitabine- and marimastat-treated patients, respectively. The major toxicity of marimastat was musculoskeletal (44% of marimastat patients, compared with 12% of gemcitabine patients; musculoskeletal toxicity was severe in only 8% of marimastat patients).

CONCLUSION: The results of this study provide evidence of a dose response for marimastat in patients with advanced pancreatic cancer. The 1-year survival rate for patients receiving marimastat 25 mg was similar to that of patients receiving gemcitabine. In view of the manageable tolerability of marimastat and its ease of administration, further studies are warranted.
Dose-Dense Doxorubicin, Docetaxel, and Granulocyte Colony-Stimulating Factor Support With or Without Tamoxifen as Preoperative Therapy in Patients With Operable Carcinoma of the Breast: A Randomized, Controlled, Open Phase IIb Study
Authors: von Minckwitz Gunter , Costa Serban D. , Raab Günter , Blohmer Jens-Uwe , Eidtmann Holger , Hilfrich Jörn , Merkle Elisabeth , Jackisch Christian , Gademann Günther , Tulusan Augustinos H. , Eiermann Wolfgang , Graf Erika , Kaufmann Manfred ,   for the German Preoperative Adriamycin-Docetaxel and German Adjuvant Breast Cancer Study Groups
Published: February 2017

PURPOSE: To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer.

PATIENTS AND METHODS: Patients (tumor size ≥ 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2, either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment.

RESULTS: Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of −1.2% in favor of ADoc, with a 95% confidence interval of −8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status.

CONCLUSION: A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.
Biology of Osteoclast Activation in Cancer
Authors: Roodman G. David
Published: February 2017

ABSTRACT: Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells. Local bone destruction also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, including interleukin (IL)-1, IL-6, receptor activator of NF-kappaB (RANK) ligand, parathyroid hormone-related protein (PTHrP), and macrophage inflammatory protein-1-alpha (MIP-1α), have been implicated as factors that enhance osteoclast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteoclast formation through upregulation of RANK ligand. Enhanced RANK ligand expression also plays an important role in bone destruction in patients with myeloma. RANK ligand can act to enhance the effects of other factors produced by myeloma cells or in response to myeloma cells, such as MIP-1α and/or IL-6, to induce osteoclast formation. Understanding of the molecular mechanisms responsible for osteoclast activation in osteolytic metastases should lead to development of novel therapeutic approaches for this highly morbid and potentially fatal complication of cancer.
Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation
Authors: Bosi Alberto , Laszlo Daniele , Labopin Myriam , Reffeirs Josy , Michallet Mauricette , Gluckman Eliane , Alessandrino Paolo Emilio , Locatelli Franco , Vernant Jean Paul , Sierra Jorge , Jouet Jean Pierre , Frassoni Francesco ,   for the Acute Leukemia Working Party of the European Blood and Marrow Transplant Group
Published: February 2017

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry.

PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered.

RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade ≥ 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome.

CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.
Impact of Surgical and Pathologic Variables in Rectal Cancer: A United States Community and Cooperative Group Report
Authors: Stocchi Luca , Nelson Heidi , Sargent Daniel J. , O’Connell Michael J. , Tepper Joel E. , Krook James E. , Beart Robert ,   the North Central Cancer Treatment Group
Published: February 2017

PURPOSE: Substantial and successful effort has been focused on decreasing the risk of local failure after rectal cancer surgery through the use of adjuvant therapies. Our study examined data from studies conducted by United States cooperative groups to investigate the impact of surgical and pathologic variables in rectal cancer outcomes.

PATIENTS AND METHODS: Surgical and pathologic reports from 673 patients with stage II/III rectal cancer enrolled onto three adjuvant clinical trials were reviewed for tumor and surgical variables. Additional information on individual institutions and operating surgeon was collected. Variables were tested for association with 5-year local recurrence and survival after adjustment for adjuvant treatments and other important prognostic factors.

RESULTS: Five-year local recurrence and survival rates were 16% and 59%, respectively. Surgeons treating more than 10 study cases had lower local recurrence rates than those treating ≤ 10 (11% v 17%, P = .02). Free radial margins also correlated with local recurrence (P = .01). Type of surgery, distal margins, and tumor radial spread were not significant. Tumor adherence to adjacent structures predicted local recurrence (35% v 14%, P < .001) and survival (30% v 63%, P < .001), regardless of en bloc resection. Although T and N classification predicted survival (P < .001), only N classification correlated with local recurrence. The number and percentage of positive nodes correlated with survival, but only the percentage independently predicted local recurrence. Several pathologic and surgical variables were reported suboptimally.

CONCLUSION: Moderate variability in outcomes among surgeons was detected in this high-risk population. Efforts to improve surgical results will require changes in reporting practices to allow for more accurate assessment of the quality of surgery.
Does Histologic Grade Have a Role in the Management of Head and Neck Cancers?
Authors: Fortin André , Couture Christian , Doucet René , Albert Michele , Allard Josée , Tetu Bernard
Published: February 2017

PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy.

PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis.

RESULTS: There is a strong correlation of grade with N stage (P < .000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P < .000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P = .001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P = .008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P = .000001) as well as T stage (P = .003), N stage (P = .000001), and neck failure (P = .0003). Higher grade was also an independent predictor of survival (P = .02).

CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.
MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer
Authors: Ramnath Nithya , Hernandez Francisco J. , Tan Dong-Feng , Huberman Joel A. , Natarajan Nachimuthu , Beck Amy F. , Hyland Andrew , Todorov Ivan T. , Brooks John S.J. , Bepler Gerold
Published: February 2017

PURPOSE: Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non–small-cell lung cancer (NSCLC) was studied.

PATIENTS AND METHODS: We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and ≥ 75%. MCM2 and Ki-67 immunoreactivities were compared with each other, and associations with pathologic and clinical parameters predictive of survival were analyzed with the χ2 test. Cox regression models were used to assess associations between MCM2 and Ki-67 and survival while controlling for confounders.

RESULTS: Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with ≥ 25% MCM2 immunoreactivity (46 v 31 months; P = .039) and a lower relative risk (RR) of death (RR, 0.55, 95% confidence interval, 0.34 to 0.88). There was no significant association between survival and Ki-67 expression.

CONCLUSION: Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.
Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has Activity in Patients With Advanced Leukemia
Authors: Giles Francis J. , Cortes Jorge E. , Baker Sharyn D. , Thomas Deborah A. , O’Brien Susan , Smith Terry L. , Beran Miloslav , Bivins Carol , Jolivet Jacques , Kantarjian Hagop M.
Published: February 2017

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel l-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia.

PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m2/d (3.6 mg/m2/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined.

RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m2/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m2. Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease.

CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.
Phase Ib Trial of Intravenous Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor in Combination With Chemotherapy in Patients With Advanced Cancer: Pharmacologic and Long-Term Safety Data
Authors: Margolin K. , Gordon M. S. , Holmgren E. , Gaudreault J. , Novotny W. , Fyfe G. , Adelman D. , Stalter S. , Breed J.
Published: February 2017

PURPOSE: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens.

PATIENTS AND METHODS: Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m2 every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m2 every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m2 with leucovorin 20 mg/m2 weekly, weeks 1 to 6 every 8 weeks.

RESULTS: The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (± SD) peak serum level of rhuMAbVEGF was 167 ± 46 μg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 ± 39 pg/mL (day 0) to 211 ± 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities.

CONCLUSION: rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.
Phase I and Pharmacokinetic Study of the Oral Farnesyl Transferase Inhibitor SCH 66336 Given Twice Daily to Patients With Advanced Solid Tumors
Authors: Eskens Ferry A.L.M. , Awada Ahmad , Cutler David L. , de Jonge Maja J.A. , Luyten Gré P.M. , Faber Marije N. , Statkevich Paul , Sparreboom Alex , Verweij Jaap , Hanauske Axel-R. , Piccart Martine
Published: February 2017

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined.

PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed.

RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment.

CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.
Effectiveness of Breast Cancer Surveillance in BRCA1/2 Gene Mutation Carriers and Women With High Familial Risk
Authors: Brekelmans C.T.M. , Seynaeve C. , Bartels C.C.M. , Tilanus-Linthorst M.M.A. , Meijers-Heijboer E.J. , Crepin C.M.G. , van Geel A.N. , Menke M. , Verhoog L.C. , van den Ouweland A. , Obdeijn I.M. , Klijn J.G.M.
Published: February 2017

PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic.

PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups.

RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40.

CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.
Phase I Study of Paclitaxel Given by Seven-Week Continuous Infusion Concurrent With Radiation Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Rosenthal David I. , Lee Jason H. , Sinard Robert , Yardley Denise A. , Machtay Mitchell , Rosen D. Marc , Egorin Merrill J. , Weber Randal S. , Weinstein Gregory S. , Chalian Ara A. , Miller Linda K. , Frenkel Eugene P. , Carbone David P.
Published: February 2017

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute–sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT).

PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks).

RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed ≥ 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m2/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m2/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels ≥ 6.5 mg/m2/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%).

CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m2/d with RT for SCCHN.