bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer
Authors: Harvey Jennet M. , Clark Gary M. , Osborne C. Kent , Allred D. Craig
Published: February 2017

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up.

PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome.

RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively).

CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.
Testicular Function After Cytotoxic Chemotherapy: Evidence of Leydig Cell Insufficiency
Authors: Howell S. J. , Radford J. A. , Ryder W.D.J. , Shalet S. M.
Published: February 2017

PURPOSE: To evaluate testicular function in men after treatment with cytotoxic chemotherapy.

PATIENTS AND METHODS: We measured testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 209 men after treatment with mechlorethamine, vinblastine, procarbazine, and prednisone, hybrid chemotherapy, or high-dose chemotherapy and in 54 healthy age-matched controls.

RESULTS: The mean age of the patients was 38 years (range, 19 to 68 years), and all patients had received chemotherapy between 1 and 22 years previously. Patients had significantly higher mean LH (7.9 v 4.1 IU/L; P < .0001) and FSH levels (18.8 v 3.1 IU/L; P < .0001) than controls. There was no significant difference in mean total testosterone level between the patients and controls, but there was a trend toward a lower mean testosterone/SHBG ratio in the patients (0.63 v 0.7; P = .08). Analysis of the hormonal parameters using a model that allowed for the effects of increasing age on testicular function showed evidence of significant recovery of gonadal function in the first 10 years after treatment. Fifty-two percent of patients had LH levels at or above the upper limit of normal, and 32% of patients had increased LH with testosterone levels in the lower half of the normal range, suggesting a degree of Leydig cell impairment.

CONCLUSION: In a significant proportion of men, there is good evidence of Leydig cell dysfunction after cytotoxic chemotherapy. The clinical significance of this Leydig cell dysfunction is not clear, but some of these men may benefit from testosterone replacement. Further studies are warranted.
Locoregional Failure 10 Years After Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen Without Irradiation: Experience of the Eastern Cooperative Oncology Group
Authors: Recht Abram , Gray Robert , Davidson Nancy E. , Fowble Barbara L. , Solin Lawrence J. , Cummings Frank J. , Falkson Geoffrey , Falkson Hendrika C. , Taylor Samuel G. , Tormey Douglass C.
Published: February 2017

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation.

PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years).

RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF.

CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.
Sentinel Lymph Node Biopsy With Metastasis: Can Axillary Dissection Be Avoided in Some Patients With Breast Cancer?
Authors: Reynolds Carol , Mick Rosemarie , Donohue John H. , Grant Clive S. , Farley David R. , Callans Linda S. , Orel Susan G. , Keeney Gary L. , Lawton Thomas J. , Czerniecki Brian J.
Published: February 2017

PURPOSE: Recent studies have suggested that the sentinel lymph node (SLN) biopsy is an accurate alternative staging procedure for women with breast cancer. The goal of this study was to identify a subset of breast cancer patients in whom metastatic disease was confined only to the SLN.

MATERIALS AND METHODS: From two institutions, we recruited 222 women with breast cancer for SLN biopsy. A SLN biopsy was performed in each patient, followed by an axillary dissection in 182 patients. Histologic and immunohistochemical cytokeratin stains were used on all SLNs.

RESULTS: The SLN was identified in 220 (97.8%) of the 225 biopsies. Evidence of metastatic breast cancer in the SLN was found in 60 (27.0%) of the 222 patients. Of these patients, 32 (53.3%) had evidence of tumor in the SLN only. By multivariate analysis, two factors were found to be significantly associated with a higher likelihood of tumor involvement in the non-SLNs: primary tumor size larger than 2.0 cm (P = .0004) and macrometastasis (> 2.0 mm) in the SLN (P = .002). Additional analysis revealed that none (0%; 95% confidence interval, 0% to 18.5%) of the 18 patients with primary tumors ≤ 2.0 cm and micrometastasis to the SLN had remaining axillary lymph node involvement.

CONCLUSION: The primary tumor size and metastasis size in the SLN are independent factors in predicting the incidence of tumor in the non-SLNs. Therefore, the SLN biopsy alone may be adequate for staging and/or therapy decision making in patients with primary breast tumors ≤ 2.0 cm and micrometastasis in the SLN.
EWS-FLI1 and EWS-ERG Gene Fusions Are Associated With Similar Clinical Phenotypes in Ewing's Sarcoma
Authors: Ginsberg Jill P. , de Alava Enrique , Ladanyi Marc , Wexler Leonard H. , Kovar Heinrich , Paulussen Michael , Zoubek Andreas , Dockhorn-Dworniczak Barbara , Juergens Herbert , Wunder Jay S. , Andrulis Irene L. , Malik Rajesh , Sorensen Poul H.B. , Womer Richard B. , Barr Frederic G.
Published: February 2017

PURPOSE: There are a variety of solid tumors in which alternative chromosomal translocations generate related fusion products. In alveolar rhabdomyosarcoma and synovial sarcoma, these variant fusions have been found to have major clinical significance. We investigated whether the two alternative gene fusion products, EWS-FLI1 and EWS-ERG, define different clinical subsets within the Ewing's sarcoma family of tumors.

PATIENTS AND METHODS: We selected 30 cases of Ewing's sarcoma with the EWS-ERG gene fusion and 106 cases with the EWS-FLI1 fusion. Clinical data were obtained for each case and compared with the molecular diagnostic findings.

RESULTS: There were no significant clinical differences observed between the two groups in age of diagnosis, sex, metastasis at diagnosis, primary site, event-free survival, or overall survival.

CONCLUSION: Differences in the C-terminal partner in the Ewing's sarcoma family gene fusions are not associated with significant phenotypic differences.
American Society of Clinical Oncology Technology Assessment on Breast Cancer Risk Reduction Strategies: Tamoxifen and Raloxifene
Authors: Chlebowski Rowan T. , Collyar Deborah E. , Somerfield Mark R. , Pfister David G.
Published: February 2017

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether tamoxifen and raloxifene as breast cancer risk-reduction strategies are appropriate for broad-based conventional use in clinical practice.

POTENTIAL INTERVENTION: Tamoxifen and raloxifene.

OUTCOME: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefits.

EVIDENCE: A comprehensive, formal literature review was conducted for tamoxifen and raloxifene on the following topics: breast cancer risk reduction; tamoxifen side effects and toxicity, including endometrial cancer risk; tamoxifen influences on nonmalignant diseases, including coronary heart disease and osteoporosis; and decision making by women at risk for breast cancer. Testimony was collected from invited experts and interested parties.

VALUES: More weight was given to publications that described randomized trials.

BENEFITS/HARMS/COSTS: The American Society of Clinical Oncology (ASCO) Working Group acknowledges that a woman's decision regarding breast cancer risk-reduction strategies will depend on the importance and weight attributed to the information provided regarding both cancer and non–cancer-related risks.

CONCLUSIONS: For women with a defined 5-year projected risk of breast cancer of ≥ 1.66%, tamoxifen (at 20 mg/d for up to 5 years) may be offered to reduce their risk. It is premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting. On the basis of available information, use of raloxifene should currently be reserved for its approved indication to prevent bone loss in postmenopausal women. Conclusions are based on single-agent use of the drugs. At the present time, the effect of using tamoxifen or raloxifene with other medications (such as hormone replacement therapy), or using tamoxifen and raloxifene in combination or sequentially, has not been studied adequately. The continuing use of placebo-controlled trials in other risk-reduction trials highlights the current unanswered issues concerning the use of such interventions, especially when the influence on net health benefit remains to be determined. Breast cancer risk reduction is a rapidly evolving area. This technology assessment represents an ongoing process with existing plans to monitor and review data and to update recommendations in a timely matter. (See Table 1 for a summary of conclusions.)

VALIDATION: The conclusions of the Working Group were evaluated by the ASCO Health Services Research Committee and by the ASCO Board of Directors.

SPONSOR: American Society of Clinical Oncology.
Specificity of HercepTest in Determining HER-2/neu Status of Breast Cancers Using the United States Food and Drug Administration–Approved Scoring System
Authors: Jacobs Timothy W. , Gown Allen M. , Yaziji Hadi , Barnes Melissa J. , Schnitt Stuart J.
Published: February 2017

PURPOSE: To evaluate the specificity of the HercepTest for Immunoenzymatic Staining (Dako Corp, Carpinteria, CA) for determining HER-2/neu protein expression in breast cancer.

MATERIALS AND METHODS: Forty-eight invasive breast cancers previously found to be HER-2/neu–negative by two different immunohistochemical (IHC) assays and not amplified for the HER-2/neu gene by fluorescence in situ hybridization were studied using the HercepTest kit. HercepTest was performed according to the manufacturer's guidelines, and the results were scored on a 0 to 3+ scale using the United States Food and Drug Administration (FDA)–approved grading system. In this system, cases scored as 2+ or 3+ are considered HER-2/neu–positive.

RESULTS: Among these 48 cases, the IHC score using the FDA-approved scoring system was 0 in four cases (8.3%), 1+ in 16 (33.3%), 2+ in 21 (43.8%), and 3+ in seven (14.6%). Therefore, 58.4% of these cases were categorized as HER-2/neu–positive, and the specificity of the HercepTest kit for HER-2/neu expression was 41.6%. However, with the use of a modified scoring system that took into account the level of staining of nonneoplastic epithelium, the specificity increased to 93.2%.

CONCLUSION: Our results indicate that the HercepTest kit, when used in accordance with the manufacturer's guidelines and the FDA-approved scoring system, results in a large proportion of breast cancers being categorized as positive for HER-2/neu protein expression and that many of these seem to be false-positives. Consideration of the level of staining of nonneoplastic epithelium resulted in improved specificity. The current FDA-approved scoring system for HercepTest results should be reevaluated before its widespread use in clinical practice.
Bicalutamide Monotherapy Versus Flutamide Plus Goserelin in Prostate Cancer Patients: Results of an Italian Prostate Cancer Project Study
Authors: Boccardo Francesco , Rubagotti Alessandra , Barichello Mario , Battaglia Michele , Carmignani Giorgio , Comeri Giancarlo , Conti Giario , Cruciani Giorgio , Dammino Sandro , Delliponti Umberto , Ditonno Pasquale , Ferraris Valentino , Lilliu Sergio , Montefiore Franco , Portoghese Filippo , Spano Giovanni
Published: February 2017

PURPOSE: To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade (MAB) in the treatment of advanced prostatic cancer.

PATIENTS AND METHODS: Previously untreated patients with histologically proven stage C or D disease (American Urological Association Staging System) were randomly allocated to receive either bicalutamide or MAB. After disease progression, patients treated with bicalutamide were assigned to castration. The primary end point for this trial was overall survival. Secondary end points included response to treatment, disease progression, treatment safety, quality-of-life (QOL), and sexual function.

RESULTS: A total of 108 patients received bicalutamide and 112 received MAB. There was no difference in the percentage of patients whose prostate-specific antigen returned to normal levels. At the time of the present analysis (median follow-up time, 38 months; range, 1 to 60 months), 129 patients progressed and 89 died. There was no difference in the duration of either progression-free survival or overall survival. However, a survival trend favored bicalutamide in stage C disease but MAB in stage D disease. Overall and subgroup trends were confirmed by multivariate analysis. Serious adverse events and treatment discontinuations were more common in patients receiving MAB (P = .08 and P = .04, respectively). Fewer patients in the bicalutamide group complained of loss of libido (P = .01) and of erectile dysfunction (P = .002). Significant trends favored bicalutamide-treated patients also with respect to their QOL, namely relative to social functioning, vitality, emotional well-being, and physical capacity.

CONCLUSION: Bicalutamide monotherapy yielded comparable results relative to standard treatment with MAB, induced fewer side effects, and produced a better QOL.
Docetaxel and Cisplatin in Combination as First-Line Chemotherapy for Advanced Epithelial Ovarian Cancer
Authors: Vasey P. A. , Paul J. , Birt A. , Junor E. J. , Reed N. S. , Symonds R. P. , Atkinson R. , Graham J. , Crawford S. M. , Coleman R. , Thomas H. , Davis J. , Eggleton S. P.H. , Kaye S. B.
Published: February 2017

PURPOSE: A prospective, nonrandomized, multicenter, open feasibility study of cisplatin and docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV epithelial ovarian cancer was conducted. The primary end point was the incidence of severe fluid retention that necessitated treatment withdrawal.

PATIENTS AND METHODS: Cisplatin and docetaxel were administered every 3 weeks for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg two times per day). One hundred patients (median age, 53 years; range, 24 to 71 years) received a total of 512 cycles of chemotherapy in two cohorts: cohort 1, 49 patients, 258 cycles (cisplatin 75 mg/m2 and docetaxel 75 mg/m2); cohort 2, 51 patients, 254 cycles (cisplatin 75 mg/m2 and docetaxel 85 mg/m2).

RESULTS: No patients were taken off study because of fluid retention. Sixty-six patients completed six cycles of protocol therapy; 16 stopped early because of toxicity (neurotoxicity in six patients, nephrotoxicity in three, neutropenia in two, and hypersensitivity, diarrhea and vomiting, skin rash, clinical deterioration, and patient's wishes in one patient each). Grade 3/4 neutropenia was observed in more than 75% of patients and seemed to be cumulative. Patients in cohort 2 had significantly more severe neutropenia and lethargy than those in cohort 1. In addition, there were five treatment-related deaths in cohort 2 (three neutropenia and two upper gastrointestinal hemorrhage). Neurotoxicity (mainly sensory, > grade 1) was observed in 23 patients. The overall clinical response rate was 69% (complete response, 38%; partial response, 31%); CA-125 response rate was 73%. Median progression-free survival for the group was 12 months.

CONCLUSION: Cisplatin and docetaxel can be administered at doses of 75 mg/m2 and 75 mg/m2, respectively, every 3 weeks, and the utility of this regimen is not limited by fluid retention. However, 33 of 100 patients were unable to complete the planned six cycles, which may explain, in part, the poor overall progression-free survival. Increasing the docetaxel dose to 85 mg/m2 adds unacceptable hematologic toxicity and potential risks to the patient.
Complete Surgical Excision Is Effective Treatment for Children With Immature Teratomas With or Without Malignant Elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study
Authors: Marina Neyssa M. , Cushing Barbara , Giller Roger , Cohen Lewis , Lauer Stephen J. , Ablin Arthur , Weetman Robert , Cullen John , Rogers Paul , Vinocur Charles , Stolar Charles , Rescorla Fred , Hawkins Edith , Heifetz Stephen , Rao Pejaver V. , Krailo Mark , Castleberry Robert P.
Published: February 2017

PURPOSE: To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%.

PATIENTS AND METHODS: Patients with immature teratomas treated at Pediatric Oncology Group or Children's Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death.

RESULTS: Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy.

CONCLUSION: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.
Genetic Prodrug Activation Therapy for Breast Cancer: A Phase I Clinical Trial oferbB-2–Directed Suicide Gene Expression
Authors: Pandha Hardev S. , Martin Lesley-Ann , Rigg Anne , Hurst Helen C. , Stamp Gordon W.H. , Sikora Karol , Lemoine Nicholas R.
Published: February 2017

PURPOSE: This trial was designed to test the safety and efficacy of a tumor-specific genetic prodrug activation therapy targeted by use of the human erbB-2 gene promoter. The erbB-2 oncogene is overexpressed in approximately 20% of cases of breast cancer and is associated with poor prognosis.

PATIENTS AND METHODS: Twelve breast cancer patients received transcriptionally targeted gene therapy in a phase I clinical trial using direct intratumoral injection of plasmid construct combined with systemic administration of prodrug. The genetic prodrug activation therapy is specifically targeted to erbB-2–overexpressing breast cancer cells by use of a therapeutic cassette that contains the Escherichia coli cytosine deaminase gene driven by the tumor-specific erbB-2 promoter, thus allowing activation of fluorocytosine to the active cytotoxic fluorouracil only within tumor cells that express the oncogene.

RESULTS: The approach was shown to be safe and to result in targeted gene expression in up to 90% of cases. Using a number of different assays, we demonstrated that significant levels of expression of the suicide gene were specifically restricted to erbB-2–positive tumor cells, confirming the selectivity of the approach.

CONCLUSION: The results of this study, the first targeted gene therapy for breast cancer and the first to use the cytosine deaminase system in human subjects, are encouraging for the development of genetic prodrug activation therapies that exploit the transcriptional profile of cancer cells.
Phase I Clinical/Pharmacokinetic and Pharmacodynamic Trial of the c-raf-1 Antisense Oligonucleotide ISIS 5132 (CGP 69846A)
Authors: Stevenson James P. , Yao Kang-Shen , Gallagher Maryann , Friedland David , Mitchell Edith P. , Cassella Amy , Monia Brett , Kwoh T. Jesse , Yu Rosie , Holmlund Jon , Dorr F. Andrew , O'Dwyer Peter J.
Published: February 2017

PURPOSE: Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay.

PATIENTS AND METHODS: Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter.

RESULTS: Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P < .05) at doses ≥ 2.5 mg/kg.

CONCLUSION: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.
Associations Between Community Income and Cancer Survival in Ontario, Canada, and the United States
Authors: Boyd Chris , Zhang-Salomons Jina Y. , Groome Patti A. , Mackillop William J.
Published: February 2017

PURPOSE: The objectives of this study were as follows: (1) to compare the magnitude of the association between socioeconomic status (SES) and cancer survival in the Canadian province of Ontario with that in the United States (U.S.), and (2) to compare cancer survival in communities with similar SES in Ontario and in the U.S.

METHODS: The Ontario Cancer Registry provided information about all cases of invasive cancer diagnosed in Ontario from 1987 to 1992, and the Surveillance, Epidemiology and End Results Registry (SEER) provided information about all cases diagnosed in the SEER regions of the U.S. during the same time period. Census data provided information about SES at the community level. The product-limit method was used to describe cause-specific survival. Cox proportional hazards models were used to describe the association between SES and the risk of death from cancer.

RESULTS: There were significant associations between SES and survival for most cancer sites in both the U.S. and Ontario, but the magnitude of the association was usually larger in the U.S. In the poorest communities, there were significant survival advantages in favor of cancer patients in Ontario for many disease groups, including cancers of the lung, head and neck region, cervix, and uterus. However, in upper- and middle-income communities, there were significant survival advantages in favor of the U.S. for all cases combined and for several individual diseases, including cancers of the breast, colon and rectum, prostate, and bladder.

CONCLUSION: The association between SES and cancer survival is weaker in Ontario than it is in the U.S. This is due to a combination of better survival among patients in the poorest communities and worse survival among patients in the wealthier communities of Ontario relative to those in the U.S.
Treatment of Multifocal Primary Cutaneous B-Cell Lymphoma: A Clinical Follow-Up Study of 29 Patients
Authors: Bekkenk Marcel W. , Vermeer Maarten H. , Geerts Marie-Louise , Noordijk Ed M. , Heule Freerk , van Voorst Vader Pieter C. , van Vloten Willem A. , Meijer Chris J.L.M. , Willemze Rein
Published: February 2017

PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines.

PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg).

RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis.

CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.
Lack of Effect of Adjuvant Chemotherapy on the Elimination of Single Dormant Tumor Cells in Bone Marrow of High-Risk Breast Cancer Patients
Authors: Braun Stephan , Kentenich Christina , Janni Wolfgang , Hepp Florian , de Waal Johann , Willgeroth Fritz , Sommer Harald , Pantel Klaus
Published: February 2017

PURPOSE: There is an urgent need for markers that can predict the efficacy of adjuvant chemotherapy in patients with solid tumors. This study was designed to evaluate whether monitoring of micrometastases in bone marrow can predict the response to systemic chemotherapy in breast cancer.

PATIENTS AND METHODS: Bone marrow aspirates of 59 newly diagnosed breast cancer patients with either inflammatory (n = 23) or advanced (> four nodes involved) disease (n = 36) were examined immunocytochemically with the monoclonal anticytokeratin (CK) antibody A45-B/B3 (murine immunoglobulin G1; Micromet, Munich, Germany) before and after chemotherapy with taxanes and anthracyclines.

RESULTS: Of 59 patients, 29 (49.2%) and 26 (44.1%) presented with CK-positive tumor cells in bone marrow before and after chemotherapy, respectively. After chemotherapy, less than half of the previously CK-positive patients (14 of 29 patients; 48.3%) had a CK-negative bone marrow finding, and 11 (36.7%) of 30 previously CK-negative patients were CK-positive. At a median follow-up of 19 months (range, 6 to 39 months), Kaplan-Meier analysis of 55 assessable patients revealed a significantly reduced overall survival (P = .011; log-rank test) if CK-positive cells were detected after chemotherapy. In multivariate analysis, the presence of CK-positive tumor cells in bone marrow after chemotherapy was an independent predictor for reduced overall survival (relative risk = 5.0; P = .016).

CONCLUSION: The cytotoxic agents currently used for chemotherapy in high-risk breast cancer patients do not completely eliminate CK-positive tumor cells in bone marrow. The presence of these tumor cells after chemotherapy is associated with poor prognosis. Thus, bone marrow monitoring might help predict the response to systemic chemotherapy.
Outcome Of CNS Disease At Diagnosis in Disseminated Small Noncleaved-Cell Lymphoma and B-Cell Leukemia: A Children’s Cancer Group Study
Authors: Gururangan Sridharan , Sposto Richard , Cairo Mitchell S. , Meadows Anna T. , Finlay Jonathan L.
Published: February 2017

PURPOSE: To examine the impact of initial CNS involvement on outcome and patterns of failure in patients with disseminated small noncleaved-cell lymphoma and B-cell leukemia who were treated in four successive Children’s Cancer Group trials.

PATIENTS AND METHODS: Of 462 patients with disseminated disease, 49 (10.6%) had CNS disease at diagnosis (CNS+). CNS disease included meningeal disease or CNS parenchymal masses with or without cranial neuropathies (CSF+/Mass; CNPs) in 36 patients and isolated CNPs in 13. Of the CNS+ patients, 28 had M2 (5% to 25% blasts) or M3 (> 25% blasts) bone marrow involvement. All patients received protocol-based systemic and intrathecal chemotherapy. Thirty-six patients also received CNS irradiation.

RESULTS: Relapses occurred in 21 (43%) of 49 patients, predominantly in the CNS (71%) and bone marrow (52%). The 3-year event-free survival ± SE for all patients with CNS+ disease was 45% ± 7%. Patients with CSF+/Mass had a nominally higher treatment failure rate compared with patients with CNS− after adjusting for marrow status and lactate dehydrogenase (LDH) diagnosis, with a relative failure rate (RFR) of 1.52 (95% confidence interval [CI], 0.88 to 2.6; P = .15). In comparison, the RFRs for patients with M2 or M3 marrow and for those with LDH levels greater than 500 IU/L after adjusting for CNS disease were 1.4 (95% CI, 0.96 to 2.0; P = .029) and 2.2 (95% CI, 1.5 to 3.0; P < .001), respectively. The RFR for patients with isolated CNPs was 0.87 (95% CI, 0.36 to 2.1; P = .76).

CONCLUSION: We conclude that, with the treatments used during the period covered by these studies, the presence of CSF+/Mass CNS disease at diagnosis was associated with a nominally worse outcome independent of initial bone marrow status and LDH level, but the effect was not statistically significant.
Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects
Authors: de Jonge Maja J. A. , Loos Walter J. , Gelderblom Hans , Planting André S. Th. , van der Burg Maria E. L. , Sparreboom Alex , Brouwer Eric , van Beurden Vera , Mantel Marijke A. , Doyle Eddie , Hearn Solange , Ross Graham , Verweij Jaap
Published: February 2017

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects.

PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m2 either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design.

RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m2/d × 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m2/d × 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence.

CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m2/d PO × 5 preceded by cisplatin 75 mg/m2 IV day 1 once every 3 weeks, and topotecan 2.0 mg/m2/d PO followed by cisplatin 75 mg/m2 IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.
Evaluation of Tumor Measurements in Oncology: Use of Film-Based and Electronic Techniques
Authors: Schwartz Lawrence H. , Ginsberg Michelle S. , DeCorato Douglas , Rothenberg Lawrence N. , Einstein Steven , Kijewski Peter , Panicek David M.
Published: February 2017

PURPOSE: To evaluate the variability in bidimensional computed tomography (CT) measurements obtained of actual tumors and of tumor phantoms by use of three measurement techniques: hand-held calipers on film, electronic calipers on a workstation, and an autocontour technique on a workstation.

MATERIALS AND METHODS: Three radiologists measured 45 actual tumors (in the lung, liver, and lymph nodes) on CT images, using each of the three techniques. Bidimensional measurements were recorded, and their cross-products calculated. The coefficient of variation was calculated to assess interobserver variability. CT images of 48 phantoms were measured by three radiologists with each of the techniques. In addition to the coefficient of variation, the differences between the cross-product measurements of tumor phantoms themselves and the measurements obtained with each of the techniques were calculated.

RESULTS: The differences between the coefficients of variation were statistically significantly different for the autocontour technique, compared with the other techniques, both for actual tumors and for tumor phantoms. There was no statistically significant difference in the coefficient of variation between measurements obtained with hand-held calipers and electronic calipers. The cross-products for tumor phantoms were 12% less than the actual cross-product when calipers on film were used, 11% less using electronic calipers, and 1% greater using the autocontour technique.

CONCLUSION: Tumor size is obtained more accurately and consistently between readers using an automated autocontour technique than between those using hand-held or electronic calipers. This finding has substantial implications for monitoring tumor therapy in an individual patient, as well as for evaluating the effectiveness of new therapies under development.
Correlation Between Docetaxel Clearance and Estimated Cytochrome P450 Activity by Urinary Metabolite of Exogenous Cortisol
Authors: Yamamoto Noboru , Tamura Tomohide , Kamiya Yoshikazu , Sekine Ikuo , Kunitoh Hideo , Saijo Nagahiro
Published: February 2017

PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6β-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method.

PATIENTS AND METHODS: Thirty patients with advanced non–small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6β-OHF and FC were measured. More than 2 days later, 60 mg/m2 of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed.

RESULTS: After cortisol administration, the total amount of 24-hour urinary 6β-OHF (T6β-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 ± 4,076 μg/d (mean ± SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 ± 6.4 L/h/m2 and 2.66 ± 0.91 mg/L 8729· h, respectively. An excellent correlation between docetaxel CL and T6β-OHF was observed (r = .867). In multivariate analysis, T6β-OHF (P < .001), alpha-1-acid glycoprotein (P < .004), AST (P = .007), and age (P = .022) significantly correlated with docetaxel CL.

CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6β-OHF after cortisol administration.
Cost of Outpatient Blood Transfusion in Cancer Patients
Authors: Crémieux Pierre-Yves , Barrett Barbara , Anderson Kenneth , Slavin Mitchell B.
Published: February 2017

PURPOSE: To determine the cost of outpatient RBC transfusion from the provider’s perspective at a major urban, academic cancer center.

PATIENTS AND METHODS: We retrospectively studied 517 cancer patients with hematologic or solid tumors who received blood during fiscal year 1995 to 1996. A process-flow diagram was developed, and cost and utilization data for 12 months were collected and analyzed. A structured interview process was used to identify all direct and indirect costs from within the inpatient unit, blood bank, and outpatient clinic. Average costs were computed for the entire sample and for specific subgroups.

RESULTS: In 1998 dollars, the average cost per RBC unit was $469 for adults and $568 for pediatric cancer patients. Adults and children generally received two and one RBC units per transfusion, respectively. Therefore, the average cost of a two-unit transfusion was $938 for adults. Patients with hematologic tumors required more RBC units (7.1 RBC units per year) at a higher average cost ($512 per RBC unit) than patients with solid tumors (4.7 RBC units per year, $474 per RBC unit). Further variations across tumor types were observed. Overhead, direct material, and direct labor represented 46%, 19%, and 35% of total costs respectively.

CONCLUSION: The cost of outpatient RBC transfusions in cancer patients is higher than previously reported, in part because overhead costs and fixed costs might have been underestimated in previous studies. Furthermore, age, tumor type, and geographic variations in the cost of fixed assets and labor have a substantial impact on the cost of blood. The results indicate that the cost-effectiveness of alternatives to transfusions in the management of cancer patients may have been underestimated in the existing literature.
Increased Risk of Acute Leukemia After Adjuvant Chemotherapy for Breast Cancer: A Population-Based Study
Authors: Chaplain Gilles , Milan Chantal , Sgro Catherine , Carli Paule-Marie , Bonithon-Kopp Claire
Published: February 2017

PURPOSE: To quantify the risk of acute leukemia after adjuvant therapy, especially chemotherapy with topoisomerase II inhibitors.

PATIENTS AND METHODS: We performed a population-based study in a cohort of 3,093 women younger than 85 years who resided in the French administrative area of the Côte d’Or, who were given a first diagnosis of primary breast cancer between 1982 and 1996, and who received a curative treatment. Information about therapy and follow-up events was obtained from records of cancer registries that covered this area.

RESULTS: Until December 1998, 10 cases of acute leukemia, including nonlymphoid acute leukemia and refractory anemia with excess of blasts, occurred in patients before any local or distant recurrence. All cases developed in the first 4 years of follow-up. Compared with the general female population, the incidence rate of leukemia was significantly increased in women who received radiotherapy and chemotherapy (standardized incidence ratio, 28.5; P < .0001). A dose-dependent increase in the risk of leukemia was observed in women treated with mitoxantrone. Cox regression analysis showed that the risk of leukemia was significantly lower in patients treated with anthracyclines than in those treated with mitoxantrone at cumulative doses ≥ 13 mg/m2.

CONCLUSION: The combination of adjuvant radiotherapy and chemotherapy with mitoxantrone induces a high risk of acute leukemia in patients with breast cancer. A leukemogenic effect of chemotherapy with anthracyclines cannot be ruled out with certainty. However, there are some suggestions that these topoisomerase II inhibitors might be less leukemogenic than mitoxantrone and could be preferred in an adjuvant setting.
Low-Stage Medulloblastoma: Final Analysis of Trial Comparing Standard-Dose With Reduced-Dose Neuraxis Irradiation
Authors: Thomas Patrick R. M. , Deutsch Melvin , Kepner James L. , Boyett James M. , Krischer Jeffrey , Aronin Patricia , Albright Leland , Allen Jeffrey C. , Packer Roger J. , Linggood Rita , Mulhern Raymond , Stehbens James A. , Langston James , Stanley Philip , Duffner Patricia , Rorke Lucy , Cherlow Joel , Friedman Henry S. , Finlay Jonathan L. , Vietti Teresa J. , Kun Larry E.
Published: February 2017

PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease.

PATIENTS AND METHODS: The Pediatric Oncology Group and Children’s Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible.

RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P = .080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P = .141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time.

CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.
Treatment for Primary CNS Lymphoma: The Next Step
Authors: Abrey Lauren E. , Yahalom Joachim , DeAngelis Lisa M.
Published: February 2017

PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved disease control and survival in patients with primary CNS lymphoma (PCNSL). The reported protocol was designed to optimize and enhance the chemotherapeutic component of treatment.

PATIENTS AND METHODS: Fifty-two patients were treated with five cycles of high-dose MTX 3.5 g/m2, procarbazine 100 mg/m2/d, and vincristine 1.4 mg/m2. Thirty patients received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to diminish the risk of delayed neurotoxicity; these patients are compared with 12 older patients who completed the entire treatment regimen. Most patients (n = 35) received high-dose cytarabine after RT.

RESULTS: Objective response rate to the induction chemotherapy regimen was 90%; overall median survival is 60 months. Grade 3 or 4 myelosuppression was seen in 30 patients, primarily in association with cytarabine; grade 3 nephrotoxicity due to MTX was seen in two patients. Older patients had similar median survival with or without the addition of RT: 32 versus 33 months, respectively. However, late neurotoxicity was significantly more common in those older patients who received RT (P = .00004). Patients younger than 60 years who received the complete treatment regimen have not reached median disease-free or overall survival.

CONCLUSION: Increasing the dose of MTX and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. Younger patients in particular fared extremely well with this treatment regimen. In older patients, deferring whole-brain RT did not compromise overall survival but did reduce treatment-related toxicity.