bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Biology of Neuroblastoma
Authors: Maris John M. , Matthay Katherine K.
Published: February 2017

PURPOSE AND RESULTS: Neuroblastoma, the most common solid extracranial neoplasm in children, is remarkable for its clinical heterogeneity. Complex patterns of genetic abnormalities interact to determine the clinical phenotype. The molecular biology of neuroblastoma is characterized by somatically acquired genetic events that lead to gene overexpression (oncogenes), gene inactivation (tumor suppressor genes), or alterations in gene expression. Amplification of the MYCN proto-oncogene occurs in 20% to 25% of neuroblastomas and is a reliable marker of aggressive clinical behavior. No other oncogene has been shown to be consistently mutated or overexpressed in neuroblastoma, although unbalanced translocations resulting in gain of genetic material from chromosome bands 17q23-qter have been identified in more than 50% of primary tumors. Some children have an inherited predisposition to develop neuroblastoma, but a familial neuroblastoma susceptibility gene has not yet been localized. Consistent areas of chromosomal loss, including chromosome band 1p36 in 30% to 35% of primary tumors, 11q23 in 44%, and 14q23-qter in 22%, may identify the location of neuroblastoma suppressor genes. Alterations in the expression of the neurotrophins and their receptors correlate with clinical behavior and may reflect the degree of neuroblastic differentiation before malignant transformation. Alterations in the expression of genes that regulate apoptosis also correlate with neuroblastoma behavior and may help to explain the phenomenon of spontaneous regression observed in a well-defined subset of patients.

CONCLUSION: The molecular biology of neuroblastoma has led to a combined clinical and biologic risk stratification. Future advances may lead to more specific treatment strategies for children with neuroblastoma.
Significance of Axillary Lymph Node Metastasis in Primary Breast Cancer
Authors: Jatoi Ismail , Hilsenbeck Susan G. , Clark Gary M. , Osborne C. Kent
Published: February 2017

PURPOSE: Axillary lymph node status is the single most important prognostic variable in the management of patients with primary breast cancer. Yet, it is not known whether metastasis to the axillary nodes is simply a time-dependent variable or also a marker for a more aggressive tumor phenotype. The purpose of this study was to determine whether nodal status at initial diagnosis predicts outcome after relapse and therefore also serves as a marker of breast cancer phenotype.

PATIENTS AND METHODS: Survival experience after first relapse in 1,696 primary breast cancer cases was analyzed using Cox proportional hazards regression. The following explanatory variables and their first-order interactions were considered: number of axillary lymph nodes involved (zero v one to three v four or more), hormone receptor status (any estrogen receptor [ER] negativity v ER negativity/progesterone receptor positivity v other ER positivity), primary tumor size (< 2 cm v 2 to 5 cm v > 5 cm), site of relapse (locoregional v distant), disease-free interval (< 1.5 years v 1.5 to 3 years v > 3 years), adjuvant endocrine therapy (none v any), adjuvant chemotherapy (none v any), and menopausal status (pre-, peri-, or postmenopausal).

RESULTS: Axillary lymph node status, site of relapse, and hormone receptor status were all highly significant as main effects in the model. After adjustment for other variables, disease-free interval alone was only modestly significant but interacted with nodal status. After disease-free interval, hormone receptor status, and site of relapse were accounted for, survival after relapse was poorer in node-positive cases, when compared with node-negative cases. The hazard ratios for patients with one to three and four or more involved nodes were 1.2 (95% confidence interval [CI], 0.8 to 1.9) and 2.5 (95% CI, 1.8 to 3.4), respectively.

CONCLUSION: Patients with four or more involved nodes at initial diagnosis have a significantly worse outcome after relapse than node-negative cases, regardless of the duration of the disease-free interval. We conclude that nodal metastasis is not only a marker of diagnosis at a later point in the natural history of breast cancer but also a marker of an aggressive phenotype.
Initial Paclitaxel Improves Outcome Compared With CMFP Combination Chemotherapy as Front-Line Therapy in Untreated Metastatic Breast Cancer
Authors: Bishop James F. , Dewar Joanna , Toner Guy C. , Smith Jennifer , Tattersall Martin H.N. , Olver Ian N. , Ackland Stephen , Kennedy Ian , Goldstein David , Gurney Howard , Walpole Euan , Levi John , Stephenson Jennifer , Canetta Renzo
Published: February 2017

PURPOSE: To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer.

PATIENTS AND METHODS: Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m2 intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m2/d orally on days 1 to 14, methotrexate 40 mg/m2 IV on days 1 and 8, fluorouracil 600 mg/m2 IV on days 1 and 8, and prednisone 40 mg/m2/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy.

RESULTS: A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P = .025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P < .001), nausea or vomiting (P = .003), and fever without documented infection (P = .007), and less hospitalization for febrile neutropenia than did CMFP (P = .001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P < .0001). Overall, quality of life was similar for both treatments (P ≥ .07).

CONCLUSION: Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.
Risk of Menopause During the First Year After Breast Cancer Diagnosis
Authors: Goodwin Pamela J. , Ennis Marguerite , Pritchard Kathleen I. , Trudeau Maureen , Hood Nicky
Published: February 2017

PURPOSE: Premenopausal women with breast cancer often enter a premature menopause during initial treatment of their malignancy, with resulting loss of childbearing capacity, onset of menopausal symptoms, and subsequent prolonged exposure to long-term risks of menopause. Adjuvant therapy is believed to contribute to this early menopause.

PATIENTS AND METHODS: One hundred eighty-three premenopausal women with locoregional breast cancer (tumor-node-metastasis staging system classification, T1-3 N0-1 M0) who had undergone surgical treatment and provided information on menopausal status at diagnosis and 1 year later were enrolled. Systemic adjuvant therapy was recorded. Univariate and multivariate predictors of menopause were examined.

RESULTS: Age, weight gain, tumor stage, nodal stage, and systemic adjuvant therapy (chemotherapy, tamoxifen) were all significant univariate correlates of menopause. In multivariate analysis, age, chemotherapy, and hormone therapy (tamoxifen) made significant independent contributions to the onset of menopause.

CONCLUSION: Age and systemic chemotherapy are the strongest predictors of menopause in women with locoregional breast cancer. They independently contribute to menopause. A graphic representation of our multivariate model allows an estimation of risk of menopause according to patient age and planned adjuvant treatment, and it may facilitate clinical decision-making.
Nerve Growth Factor Expression Correlates With Perineural Invasion and Pain in Human Pancreatic Cancer
Authors: Zhu Zhaowen , Friess Helmut , diMola Fabio F. , Zimmermann Arthur , Graber Hans U. , Korc Murray , Büchler Markus W.
Published: February 2017

PURPOSE: The reasons for the high frequency of perineural invasion and the presence of pain in pancreatic cancer are still not clear. Nerve growth factor (NGF) and its high-affinity receptor TrkA are involved in stimulating epithelial cancer cell growth and perineural invasion, as well as in pain generation in chronic benign disorders.

PATIENTS AND METHODS: NGF and TrkA were examined by Northern blot analysis, in situ hybridization, and immunohistochemistry in 27 normal and 37 pancreatic cancer tissue samples. The molecular findings were correlated with the degree of perineural invasion, pain, and histopathologic tumor characteristics.

RESULTS: Northern blot analysis indicated that NGF and TrkA mRNA levels were increased 2.7-fold and 5.6-fold, respectively (P < .05 and P < .05), in pancreatic cancer tissues compared with the normal pancreas tissue. As shown by in situ hybridization and immunohistochemistry, NGF was strongly present in the cytoplasm of pancreatic cancer cells. TrkA was intensely present in the perineurium of pancreatic nerves but not in the cancer cells. There was no difference in NGF and TrkA expression between early (stages I and II) and advanced (stage III) tumor stages and between well-/moderately differentiated (grades 1 and 2) and poorly differentiated (grade 3) tumors. However, tumors with high NGF/TrkA expression levels exhibited more frequent perineural invasion (P < .01). Furthermore, increased NGF/TrkA expression levels were associated with a higher degree of pain (P < .01).

CONCLUSION: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.
Second Malignancies as a Consequence of Nucleoside Analog Therapy for Chronic Lymphoid Leukemias
Authors: Cheson Bruce D. , Vena Donald A. , Barrett Jane , Freidlin Boris
Published: February 2017

PURPOSE: The nucleoside analogs fludarabine, 2′-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA.

PATIENTS AND METHODS: We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared.

RESULTS: Median follow-up periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P = .05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases.

CONCLUSION: Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies.
CNS Involvement in Primary Mediastinal Large B-Cell Lymphoma
Authors: Bishop Philippe C. , Wilson Wyndham H. , Pearson Debra , Janik John , Jaffe Elaine S. , Elwood Patrick C.
Published: February 2017

PURPOSE: The risk of CNS involvement by non-Hodgkin's Lymphoma (NHL) has been associated with bone marrow and/or testicular involvement; however, it was recently reported that the number of extranodal sites is a more reliable predictor of CNS disease. Because primary mediastinal thymic large B-cell lymphoma (PMLCL) has a high propensity for involving extranodal sites, we investigated the frequency and pattern of CNS involvement in PMLCL.

PATIENTS AND METHODS: The medical records of 219 patients with aggressive NHL, consecutively entered onto protocols at the National Cancer Institute between 1987 and 1998, were retrospectively reviewed.

RESULTS: Twenty-three patients (11%) had clinical and pathologic features of PMLCL. These patients were young (median age, 29 years), female (61%), and presented with massive mediastinal adenopathy (70%). Extranodal disease occurred at presentation in 70% and at relapse in 93% of patients and involved contiguous intrathoracic structures and/or distant sites, including the lungs, kidneys, liver, adrenals, ovaries, pancreas, and bone. Six patients (26%) developed CNS involvement, two (9%) at presentation and four (27%) at relapse. All had extranodal disease, but only one had bone marrow involvement. Parenchymal and leptomeningeal CNS disease occurred in four and three patients, respectively.

CONCLUSION: CNS involvement in PMLCL is associated with extranodal involvement other than bone marrow and may reflect the unique biology of this disease. The propensity to involve the CNS parenchyma raises the concern that intrathecal prophylaxis may not be effective and suggests that CNS imaging should be considered in patients with extranodal disease.
Paclitaxel and Cisplatin as First-Line Therapy in Recurrent or Advanced Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study
Authors: Rose Peter G. , Blessing John A. , Gershenson David M. , McGehee Ramon
Published: February 2017

PURPOSE: On the basis of the activity of paclitaxel as a single agent in chemotherapy-naive squamous cell carcinoma of the cervix in a prior Gynecologic Oncology Group (GOG) trial, a phase II study of paclitaxel and cisplatin as first-line therapy was conducted by the GOG.

PATIENTS AND METHODS: Eligibility included squamous cell cancer of the cervix not curable by surgery or radiation, measurable disease, WBC count ≥ 3,000/μL, platelet count ≥ 100,000/μL, serum creatinine ≥ 2 mg/100 mL, and adequate hepatic function. The starting dose was paclitaxel 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 every 21 days. On the basis of toxicity, a dose escalation of paclitaxel to a maximum dose of 170 mg/m2/d was prescribed.

RESULTS: Forty-seven patients were enrolled onto this study; 44 patients were assessable for toxicity and 41 for response. Forty (90.9%) had received prior radiation therapy. A median of six courses of chemotherapy was given (range, one to 10 courses). Neutropenia grade 3 (15.9%) and 4 (61.4%) was the most frequent severe adverse effect and was associated with fever in 13 patients (27.7%). Two patients (4.5%) died from neutropenic sepsis. Grade 4 thrombocytopenia occurred in 6.8% of patients. Of 41 assessable patients, five (12.2%) had complete responses and 14 (34.1%) had partial responses for an overall response rate of 46.3% (95% confidence interval, 30.7% to 62.6%). The median progression-free interval, was 5.4+ months (range, 0.3 to 22+ months) with a median survival of 10.0+ months (range, 0.9 to 22.2 months). Response was more frequent in patients with disease in nonirradiated sites (70% v 23%, P = .008).

CONCLUSION: This regimen seems highly active in advanced and recurrent squamous cell carcinoma of the cervix and is currently being evaluated by the GOG in a phase III randomized study comparing the combination of paclitaxel and cisplatin with cisplatin alone.
Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Mitomycin, Vindesine, and Cisplatin in Unresectable Stage III Non–Small-Cell Lung Cancer
Authors: Furuse Kiyoyuki , Fukuoka Masahiro , Kawahara Masaaki , Nishikawa Hideki , Takada Yoshiki , Kudoh Shinzoh , Katagami Nobuyuki , Ariyoshi Yutaka
Published: February 2017

PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m2 on days 1 and 29), vindesine (3 mg/m2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m2 on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions).

RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84.0%) than that of the sequential arm (66%) (P = .0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P = .03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P = .0001).

CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.
Prophylactic Cranial Irradiation in Locally Advanced Non–Small-Cell Lung Cancer After Multimodality Treatment: Long-Term Follow-Up and Investigations of Late Neuropsychologic Effects
Authors: Stuschke M. , Eberhardt W. , Pöttgen C. , Stamatis G. , Wilke H. , Stüben G. , Stöblen F. , Wilhelm H. H. , Menker H. , Teschler H. , Müller R.-D. , Budach V. , Seeber S. , Sack H.
Published: February 2017

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle.

RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P = .005) and that of overall brain relapse from 54% to 13% (P < .0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P = .01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not.

CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.
Advantages of Concurrent Biochemotherapy Modified by Decrescendo Interleukin-2, Granulocyte Colony-Stimulating Factor, and Tamoxifen for Patients With Metastatic Melanoma
Authors: O'Day Steven J. , Gammon Guy , Boasberg Peter D. , Martin Maureen A. , Kristedja Tim S. , Guo Matthew , Stern Stacey , Edwards Shirley , Fournier Patricia , Weisberg Monica , Cannon Maureen , Fawzy Nancy W. , Johnson Timothy D. , Essner Richard , Foshag Leland J. , Morton Donald L.
Published: February 2017

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen.

PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days.

RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths.

CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.
Expression of HER2/erbB-2 Correlates With Survival in Osteosarcoma
Authors: Gorlick Richard , Huvos Andrew G. , Heller Glenn , Aledo Alex , Beardsley G. Peter , Healey John H. , Meyers Paul A.
Published: February 2017

PURPOSE: In osteosarcoma, prognostic factors at diagnosis other than clinical stage have not been clearly identified. The aim of this study was to determine whether human epidermal growth factor receptor 2 (HER2)/erbB-2, p-glycoprotein, or p53 expression correlated with histologic response to preoperative chemotherapy or event-free survival.

PATIENTS AND METHODS: We performed a retrospective immunohistochemical study on material obtained from patients treated on the Memorial Sloan-Kettering Cancer Center T12 protocol between 1986 and 1993. Paraffin-embedded tissue was identified from 53 patients (73% of patients enrolled onto protocol) and stained for HER2/erbB-2, p53, and p-glycoprotein expression using standard monoclonal antibodies and methods.

RESULTS: At the time of initial biopsy, 20 (42.6%) of 47 samples demonstrated high levels of HER2/erbB-2 expression. Higher frequencies of expression were observed in samples from patients with metastatic disease at presentation and at the time of relapse. Expression of HER2/erbB-2 correlated with a significantly worse histologic response (P = .03). In patients presenting with nonmetastatic disease, expression of HER2/erbB-2 at the time of initial biopsy was associated with a significantly decreased event-free survival (47% v 79% at 5 years, P = .05). p53 and p-glycoprotein expression did not correlate with histologic response or patient event-free survival.

CONCLUSION: The correlation of HER2/erbB-2 expression with histologic response to preoperative chemotherapy and event-free survival in this study suggests that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator. The correlation also suggests that clinical trials of antibodies that target this receptor, such as recombinant humanized anti-HER2 monoclonal antibody (Herceptin; Genentech, San Francisco, CA), should be considered for the treatment of osteosarcoma.
High-Dose Melphalan With Autologous Stem-Cell Rescue in Metastatic Rhabdomyosarcoma
Authors: Carli M. , Colombatti R. , Oberlin O. , Stevens M. , Masiero L. , Frascella E. , Koscielniak E. , Treuner J. , Pinkerton C. R.
Published: February 2017

PURPOSE: The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma.

PATIENTS AND METHODS: Fifty-two patients in complete remission after six courses of chemotherapy received “megatherapy”: 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases.

RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P = .3 and P = .2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P = .05).

CONCLUSION: The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.
Risk Model for Severe Anemia Requiring Red Blood Cell Transfusion After Cytotoxic Conventional Chemotherapy Regimens
Authors: Ray-Coquard I. , Le Cesne A. , Rubio M. T. , Mermet J. , Maugard C. , Ravaud A. , Chevreau C. , Sebban C. , Bachelot T. , Biron P. , Blay J. Y.
Published: February 2017

PURPOSE: Cancer patients frequently experience anemia as a consequence of myelosuppressive therapy or bone marrow invasion.

PATIENTS AND METHODS: A risk model for chemotherapy-induced severe anemia requiring RBC transfusions (SARRT) within 31 days after the administration of chemotherapy was delineated in the cohort of cancer patients treated with chemotherapy in the Department of Medicine of Centre Léon Bérard in 1996 (CLB-1996). The risk model was tested on a series of 797 patients treated in 1997 (CLB-1997) and on 295 patients included in a multicenter prospective series (ELYPSE 1).

RESULTS: One hundred seven of the 1,051 patients of the CLB-1996 cohort (10%) experienced SARRT. In univariate analysis, only female sex, performance status greater than 1, hemoglobin level less than 12 g/dL before chemotherapy on day 1 (d1), and d1 lymphocyte count ≤ 700/μL significantly correlated with the risk of SARRT. Using logistic regression, d1 hemoglobin level less than 12 g/dL (odds ratio [OR] = 14.0; 95% confidence interval [CI], 7 to 30), performance status greater than 1 (OR = 2.2; 95% CI, 1.4 to 3.5), and d1 lymphocyte count ≤ 700/μL (OR = 1.7; 95% CI, 1.1 to 2.6) were identified as independent risk factors for SARRT. These three factors were given arbitrary risk coefficients of 3, 1, and 1 respectively, and a risk score for each individual patient was obtained by adding the coefficients. The calculated probability of RBC transfusions was 30% for patients with a score ≥ 4, and 11%, 4%, and 1% in patients with a score of 2 or 3, 1, and 0 respectively. This model was then tested and validated in the CLB-1997 and ELYPSE 1 series.

CONCLUSION: This risk index could be useful to identify patients at high risk for chemotherapy-induced SARRT who might be appropriate candidates for prophylactic erythropoietin treatment.
Gemcitabine Plus Cisplatin, an Active Regimen in Advanced Urothelial Cancer: A Phase II Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Moore Malcolm J. , Winquist Eric W. , Murray Nevin , Tannock Ian F. , Huan Susan , Bennett Katherine , Walsh Wendy , Seymour Lesley
Published: February 2017

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2′,2′-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma.

PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m2 over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry.

RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for anoverall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having ≥ grade 3 granulocytopenia and 17 of 31 (55%) having ≥ grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia.

CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.
Clinical and Immune Responses in Resected Colon Cancer Patients Treated With Anti-Idiotype Monoclonal Antibody Vaccine That Mimics the Carcinoembryonic Antigen
Authors: Foon Kenneth A. , John William J. , Chakraborty Mala , Das Ruma , Teitelbaum April , Garrison Juanita , Kashala Oscar , Chatterjee Sunil K. , Bhattacharya-Chatterjee Malaya
Published: February 2017

PURPOSE: We generated an anti-idiotype antibody, designated CeaVac, that is an internal image of the carcinoembryonic antigen (CEA). We previously demonstrated that the majority of patients with advanced colorectal cancer generate specific anti-CEA responses. The purpose of the current study was to treat patients with surgically resected colon cancer with CeaVac to determine the immune response and clinical outcome to treatment with vaccine. We also compared the immune responses between patients treated with fluorouracil (5-FU) chemotherapy regimens plus vaccine versus vaccine alone.

PATIENTS AND METHODS: Thirty-two patients with resected Dukes' B, C, and D, and incompletely resected Dukes' D disease were treated with 2 mg of CeaVac every other week for four injections and then monthly until tumor recurrence or progression. Fourteen patients were treated concurrently with 5-FU chemotherapy regimens.

RESULTS: All 32 patients entered onto this trial generated high-titer immunoglobulin G and T-cell proliferative immune responses against CEA. The 5-FU regimens did not have a qualitative or quantitative effect on the immune response. Three of 15 patients with Dukes' B and C disease progressed at 19, 24, and 35 months. Seven of eight patients with completely resected Dukes' D disease remained on study from 12 to 33 months; one patient with resected Dukes' D disease relapsed at 9 months. One patient with incompletely resected Dukes' D disease remained on study at 14 months without evidence of progression; eight experienced disease progression at 6 to 31 months.

CONCLUSION: CeaVac consistently generated a potent anti-CEA humoral and cellular immune response in all 32 patients entered onto this trial. A number of very high-risk patients continue on study. 5-FU regimens, which are the standard of care for patients with Dukes' C disease, did not affect the immune response. These data warrant a phase III trial for patients with resected colon cancer.
Paclitaxel-Associated Hypersensitivity Reactions: Experience of the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center
Authors: Markman Maurie , Kennedy Alexander , Webster Kenneth , Kulp Barbara , Peterson Gertrude , Belinson Jerome
Published: February 2017

PURPOSE: : This study expands the existing limited data as to whether patients developing clinically significant paclitaxel-induced hypersensitivity reactions can continue to be treated with this important antineoplastic agent and how such retreatment might be undertaken.

PATIENTS AND METHODS: More than 450 patients received paclitaxel, either as a single agent or in a combination regimen, for a female pelvic malignancy in the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center from January 1995 through December 1998.

RESULTS: Of the more than 450 patients, 44 (approximately 9%) developed at least one episode of a clinically relevant hypersensitivity reaction to the cytotoxic drug. All 43 individuals (plus an additional four patients referred to our center after having previously experienced a severe paclitaxel-associated hypersensitivity reaction at another institution) who were retreated with paclitaxel were ultimately able to receive the agent. Five patients required treatment with a standardized desensitization regimen, developed by our group, to successfully receive paclitaxel.

DISCUSSION: On the basis of this large single-institution study of paclitaxel-associated hypersensitivity reactions, we conclude that with appropriate precautions essentially all individuals experiencing these reactions can be safely treated with this agent.
Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer
Authors: Giacchetti S. , Perpoint B. , Zidani R. , Le Bail N. , Faggiuolo R. , Focan C. , Chollet P. , Llory J.F. , Letourneau Y. , Coudert B. , Bertheaut-Cvitkovic F. , Larregain-Fournier D. , Le Rol A. , Walter S. , Adam R. , Misset J.L. , Lévi F.
Published: February 2017

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer.

PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans.

RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively.

CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.
Adjuvant Active Specific Immunotherapy for Stage II and III Colon Cancer With an Autologous Tumor Cell Vaccine: Eastern Cooperative Oncology Group Study E5283
Authors: Harris Jules E. , Ryan Louise , Hoover Herbert C. , Stuart Robert K. , Oken Martin M. , Benson Al B. , Mansour Edward , Haller Daniel G. , Manola Judith , Hanna Michael G.
Published: February 2017

PURPOSE: A randomized phase III clinical trial of adjuvant active specific immunotherapy (ASI) with an autologous tumor cell–bacillus Calmette-Guérin (BCG) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients.

PATIENTS AND METHODS: Patients (n = 412) with colon cancer (297 with stage II disease, 115 with stage III disease) were randomly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 107 irradiated autologous tumor cells beginning approximately 4 weeks after surgery. The first two weekly injections also contained 107 BCG organisms. Patients were observed for determination of time to recurrence and disease-free and overall survival.

RESULTS: This was a negative study in that after a 7.6-year median follow-up period, there were no statistically significant differences in clinical outcomes between the treatment arms. However, there were disease-free survival (P = .078) and overall survival (P = .12) trends in favor of ASI when treatment compliance was evaluated, ie, patients who received the intended treatment had a delayed cutaneous hypersensitivity (DCH) response to the third vaccination (induration ≥5 mm). Also, the magnitude of the DCH response correlated with improved prognosis. The 5-year survival proportion was 84.6% for those with indurations greater than 10 mm, compared with 45.0% for those with indurations less than 5 mm.

CONCLUSIONS: When all randomized patients were evaluated, no significant clinical benefit was seen with ASI in surgically resected colon cancer patients with stage II or III colon cancer. However, there was an indication that treatment compliance with effective immunization results in disease-free and overall survival benefits.
Waldenström’s Macroglobulinemia: Clinical Features, Complications, and Management
Authors: Dimopoulos Meletios A. , Panayiotidis Panayiotis , Moulopoulos Lia A. , Sfikakis Petros , Dalakas Marinos
Published: February 2017

PURPOSE: To review the clinical features, complications, and treatment of Waldenström’s macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal immunoglobulin (Ig) M.

METHODS: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus.

RESULTS: The clinical manifestations associated with Waldenström’s macroglobulinemia can be classified according to those related to direct tumor infiltration, to the amount and specific properties of circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. For symptomatic patients, standard treatment consists primarily of oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one third of previously treated patients and in up to 80% of previously untreated patients. Preliminary evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of previously treated patients and that high-dose therapy with autologous stem-cell rescue is effective in most patients, including some with resistance to nucleoside analogs.

CONCLUSION: Waldenström’s macroglobulinemia has a wide clinical spectrum that practicing physicians need to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is the standard primary treatment, but cladribine or fludarabine can be used when a rapid cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of nucleoside analogs on patients’ survival. A nucleoside analog is the treatment of choice for patients who have been previously treated with an alkylating agent.
Predicting Costs of Stem-Cell Transplantation
Authors: Lee Stephanie J. , Klar Neil , Weeks Jane C. , Antin Joseph H.
Published: February 2017

PURPOSE: Few studies have formally evaluated the relationship between costs, baseline patient characteristics, and major complications of stem-cell transplantation. We sought (1) to determine whether obtaining baseline information enabled identification of patients whose treatments would be the most costly and (2) to estimate inpatient costs for managing specific transplantation complications.

PATIENTS AND METHODS: We collected inpatient costs and clinical information for 236 consecutive patients undergoing transplantation at a single institution between July 1, 1994, and February 20, 1997. Multivariable linear regression was used to evaluate the associations between baseline patient characteristics and costs of hospitalization for initial transplantation and between clinical events and such costs.

RESULTS: The median initial inpatient cost in 1997 dollars was $55,500 for autologous transplantation (range, $28,200 to $148,200) and $105,300 for allogeneic transplantation (range, $32,500 to $338,000). When only baseline variables were considered, use of a mismatched allogeneic donor and year of transplantation were significant predictors of costs. No characteristics predicted which patients would incur the highest 10% of costs. When clinical events were considered, infection and in-hospital death were associated with higher costs in autologous transplant recipients ($18,400 and $20,500, respectively), whereas infection, veno-occlusive disease, acute graft-versus-host disease, and death were predicted to add between $15,300 and $28,100 each to allogeneic transplantation costs.

CONCLUSION: We were not able to identify before transplantation the patients whose treatments would be the most costly. However, the association between clinical complications and higher costs suggests that prevention may have significant economic benefits. Interventions that decrease these complications may have favorable cost-benefit ratios even if they do not affect overall survival.
Pamidronate in Prevention of Bone Complications in Metastatic Breast Cancer: A Cost-Effectiveness Analysis
Authors: Hillner Bruce E. , Weeks Jane C. , Desch Christopher E. , Smith Thomas J.
Published: February 2017

PURPOSE: Pamidronate is effective in reducing bony complications in patients with metastatic breast cancer who have known osteolytic lesions. However, pamidronate does not increase survival and is associated with additional financial costs and inconvenience. We conducted a post-hoc evaluation of the cost-effectiveness of pamidronate using the results of two randomized trials that evaluated pamidronate 90 mg administered intravenously every month versus placebo.

PATIENTS AND METHODS: The trials differed only in the initial systemic therapy administered (hormonal or chemotherapy). Total skeletal related events (SREs), including surgery for pathologic fracture, radiation for fracture or pain control, conservatively treated pathologic fracture, spinal cord compression, or hypercalcemia, were taken directly from the trials. Using a societal perspective, direct health care costs were assigned to each SRE. Each group’s monthly survival was equal and was projected to decline using observed median survivals. The cost of pamidronate reflected the average wholesale price of the drug plus infusion. The value or disutility of an adverse event per month was evaluated using a zero value (events avoided) or an assigned one (range, 0.2 to 0.8).

RESULTS: The cost of pamidronate therapy exceeded the cost savings from prevented adverse events. The difference between the treated and placebo groups was larger with hormonal systemic therapy than with chemotherapy (additional $7,685 compared with $3,968 per woman). The projected net cost per SRE avoided was $3,940 with chemotherapy and $9,390 with hormonal therapy. The cost-effectiveness ratios were $108,200 with chemotherapy and $305,300 with hormonal therapy per quality-adjusted year.

CONCLUSION: Although pamidronate is effective in preventing a feared, common adverse outcome in metastatic breast cancer, its use is associated with high incremental costs per adverse event avoided. The analysis is most sensitive to the costs of pamidronate and pathologic fractures that were asymptomatic or treated conservatively.
Reduced MLH1 Expression in Breast Tumors After Primary Chemotherapy Predicts Disease-Free Survival
Authors: Mackay H.J. , Cameron D. , Rahilly M. , Mackean M.J. , Paul J. , Kaye S.B. , Brown R.
Published: February 2017

PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival.

PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively.

RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P = .010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P = .0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors.

CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.