bluuebunny/crossref_metadata_2025 huggingface dataset:
Routine use of granulocyte colony-stimulating factor is not cost-effective and does not increase patient comfort in the treatment of small-cell lung cancer: an analysis using a Markov model.
Authors: Chouaid C , Bassinet L , Fuhrman C , Monnet I , Housset B
Published: February 2017

PURPOSE

The clinical indications and economic consequences of human granulocyte colony-stimulating factor (G-CSF) prescription during small-cell lung cancer (SCLC) chemotherapy remain controversial. The aim of this study, based on a Markov model, was to assess the impact of routine G-CSF use in the treatment of SCLC on costs and patient comfort. Markov models allow the modeling SCLC chemotherapy, in which the risk of febrile neutropenia (FN) is continuous over time and may occur more than once.

PATIENTS AND METHODS

We used a Markov model to compare three strategies: a chemotherapy dose reduction after FN and nonuse of G-CSF ("never" strategy), secondary use of G-CSF ("CSF if FN" strategy) and primary use of G-CSF ("systematic CSF" strategy). Model baseline probabilities were based on a review of medical records for all patients (n = 39) treated for SCLC in our unit during 1993 (when G-CSF was not used) and on published reductions in the incidence of FN obtained by using G-CSF. Two different types of rewards were used: a cost-utility scale that took into account the costs of FN (CFN) episodes and G-CSF (CCSF) courses; and a comfort-utility scale that took into account the discomfort of FN and G-CSF therapy. Costs were analyzed from the health care payer's perspective and utilities were assessed prospectively in standardized interviews with treated SCLC patients.

RESULTS

The never strategy was the least costly ($4,875 [United States] versus $5,816 and $7,690 for CSF if FN and systematic CSF) and gave the highest comfort value (378 U v 365 and 327 for CSF if FN and systematic CSF). Sensitivity analyses showed that the never strategy remains the less costly when the probability of a first FN episode was less than 49%, the probability of FN recurrence was less than 60%, or the CFN was less than $6,077, or the CCSF was greater than $863. In terms of patient comfort, the never strategy was the best choice, except for patients who considered that a course of G-CSF caused little or no discomfort, whether or not it prevented FN.

CONCLUSION

Routine use of G-CSF during SCLC chemotherapy is not justified by clinical benefits, improved patient comfort, or economic considerations.
Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival.
Authors: Kies M S , Haraf D J , Athanasiadis I , Kozloff M , Mittal B , Pelzer H , Rademaker A W , Wenig B , Weichselbaum R R , Vokes E E
Published: February 2017

PURPOSE

To determine tumor response rate, patterns of failure, toxicity, and survival in advanced squamous head and neck cancer after a combined treatment program that consists of induction chemotherapy, organ-sparing surgery, and concurrent chemoradiation. Long-term outcome data are presented.

PATIENTS AND METHODS

Between July 1991 and March 1993, 93 patients received three cycles of induction chemotherapy that consisted of cisplatin, fluorouracil (5-FU), l-leucovorin, and alpha-interferon2b (PFLl-alpha) followed by optional limited surgery and six to eight cycles of 5-FU, hydroxyurea, and concurrent radiation (FHX) to a total radiation dose of 65 to 75 Gy.

RESULTS

Ninety-three patients were entered onto this study and 97% had stage IV disease, with 66 patients who were N2 or N3. Sixty-one patients (66%) achieved a clinical complete remission (CR) after induction therapy. Thirty-four patients underwent surgery. Seventy-nine patients proceeded to FHX. With a median follow-up time of 43 months for surviving patients, 20 patients have had disease progression (13 local, two distant, five both), and there have been 35 deaths (18 from disease, six treatment-related, two from a second primary, and nine for other medical reasons). At 5 years, progression-free survival is 68%, and overall survival is 62%. Surgery was organ-preserving, as only a single laryngectomy and no glossectomies were performed in primary management. Acute toxicity related to PFLl-alpha consisted of severe or life-threatening mucositis in 57% and leucopenia in 65% of patients. During FHX, 81% of patients had grade 3 or 4 mucositis.

CONCLUSION

PFLl-alpha is a highly active regimen that induced clinical CR in two thirds of patients. When followed by limited surgery and FHX, resultant local and distant disease control, organ preservation, and overall 5-year survival are very promising in high-risk stage IV patients. Based on these local control and survival data, further evaluation of this treatment sequence, induction chemotherapy followed by concurrent chemoradiation, is warranted. Identification of similarly active but less toxic regimens is a high priority.
Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.
Authors: Koops H S , Vaglini M , Suciu S , Kroon B B , Thompson J F , Göhl J , Eggermont A M , Di Filippo F , Krementz E T , Ruiter D , Lejeune F J
Published: February 2017

PURPOSE

Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival.

PATIENTS AND METHODS

A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm.

RESULTS

Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP.

CONCLUSION

Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.
Local Failure Is Responsible for the Decrease in Survival for Patients With Breast Cancer Treated With Conservative Surgery and Postoperative Radiotherapy
Authors: Fortin André , Larochelle Marie , Laverdière Jacques , Lavertu Sophie , Tremblay Daniel
Published: February 2017

PURPOSE: The aim of the present study was to evaluate the role of local failure (LF) in the survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis (DM) but also a cause.

METHODS: Charts of patients treated with breast conservative surgery between 1969 and 1991 were reviewed retrospectively. There were 2,030 patients available for analysis. The median duration of follow-up was 6 years. A Cox regression multivariate analysis was performed using LF as a time-dependent covariate.

RESULTS: Local control (LC) was 87% at 10 years. Local failure led to poorer survival at 10 years than local control (55% v 75%, P < .00). In a Cox model, local failure was a powerful predictor of mortality. The relative risk associated with LF was 3.6 for mortality and 5.1 for DM (P < .00). In patients with LF, the rate of DM peaked at 5 to 6 years, whereas it peaked at 2 years for patients with LC. The mean time between surgery and DM was 1,050 days for patients without LF and 1,650 days for patients with LF (P < .00).

CONCLUSION: Our results show that local failure is associated with an increase in mortality. The difference in the time distribution of distant metastasis for LF and LC could imply distinct mechanisms of dissemination. Local failure should be considered not only as a marker of occult circulating distant metastases but also as a source for new distant metastases and subsequent mortality.
Disseminated Tumor Cells in Lymph Nodes as a Determinant for Survival in Surgically Resected Non–Small-Cell Lung Cancer
Authors: Kubuschok B. , Passlick B. , Izbicki J. R. , Thetter O. , Pantel K.
Published: February 2017

PURPOSE: In recent years, the detection of even a few tumor cells in lymph nodes of patients with surgically resected non–small-cell lung cancer (NSCLC) became possible with immunohistochemical staining procedures. Tumor cells in lymph nodes have been shown to be associated with an increased rate of early recurrence. However, the prognostic significance of this minimal tumor cell spread for overall survival remains unclear.

PATIENTS AND METHODS: We used the epithelium-specific monoclonal antibody Ber-EP4, which recognizes the 17-1A antigen (also called EGP40 or Ep-CAM), to discover small tumor cell deposits (≤ three cells) in 565 regional lymph nodes judged as tumor-free by conventional histopathology in patients with NSCLC staged as pT1-4, pN0-2, M0, R0. In a prospective analysis, we studied the influence of the detected tumor cells on the cancer recurrence rate and survival of 117 patients.

RESULTS: Ber-EP4-positive cells were found in 27 of 125 patients (21.6%). After an observation period of 64 months, patients with disseminated tumor cells had reduced disease-free survival (P < .0001) and overall survival (P = .0001) rates in univariate analyses (log-rank test). Multivariate analysis (Cox model) showed a 2.7 times increased risk for tumor relapse and a 2.5 times increased risk for shorter survival in patients with disseminated tumor cells compared with patients without such cells. Patients without any evidence of histopathologic and immunohistochemical lymph node involvement had an overall survival rate of 78%.

CONCLUSION: The immunohistochemical detection of disseminated tumor cells in lymph nodes of patients with completely resected NSCLC is an independent prognostic factor for overall survival.
Molecular and Clinical Remissions in Multiple Myeloma: Role of Autologous and Allogeneic Transplantation of Hematopoietic Cells
Authors: Corradini Paolo , Voena Claudia , Tarella Corrado , Astolfi Monica , Ladetto Marco , Palumbo Antonio , Van Lint Maria Teresa , Bacigalupo Andrea , Santoro Alessandra , Musso Maurizio , Majolino Ignazio , Boccadoro Mario , Pileri Alessandro
Published: February 2017

PURPOSE: To describe molecular monitoring of minimal residual disease in patients with myeloma who have achieved complete remission (CR) after autologous or allogeneic transplantation of hematopoietic cells.

MATERIALS AND METHODS: Clonal markers based upon the rearrangement of immunoglobulin heavy-chain genes were generated for each patient and used for polymerase chain reaction (PCR) detection of residual myeloma cells. Fifty-one patients entered the program and 36 achieved CR. After transplantation, molecular monitoring was performed on 29 patients (15 autologous and 14 allogeneic transplants) who had molecular markers.

RESULTS: Our data show that molecular remissions are rarely achieved (7%) with high-dose chemotherapy followed by single or double autografting. In addition, virtually all peripheral blood progenitor cell and bone marrow samples contained residual myeloma cells, even when sample collection was scheduled after repeated courses of high-dose chemotherapy. All patients autografted with PCR-positive cells remain positive, and eight of 15 have relapsed. Two patients were autografted with PCR-negative cells: one is in clinical and molecular remission, and one relapsed 25 months after the transplant. In the allografting setting, a higher proportion of patients (50%) achieved molecular remission; there were two relapses, one in the PCR-positive group and one in the PCR-negative group.

CONCLUSION: This is the first large study of molecular remissions in myeloma patients to use a PCR-based approach utilizing patient-specific tumor markers. The sizeable fraction of patients who achieved molecular remission after allografting with peripheral blood progenitor cells represents a promising finding in an incurable disease.
Mantle Irradiation Alone for Clinical Stage I-II Hodgkin's Disease: Long-Term Follow-Up and Analysis of Prognostic Factors in 261 Patients
Authors: Wirth A. , Chao M. , Corry J. , Laidlaw C. , Yuen K. , Ryan G. , Byram D. , Davis S. , Kiffer J. , Quong G. , Liew K.
Published: February 2017

PURPOSE: To evaluate mantle radiotherapy (MRT) alone as the initial therapy of patients with clinical stage (CS) I-II Hodgkin's disease (HD).

PATIENTS AND METHODS: We performed a retrospective study of patients treated with MRT alone for CS I-II supradiaphragmatic HD between 1969 and 1994. Prognostic factor analysis was performed for progression-free survival (PFS) and overall survival (OS). Outcome was also assessed in favorable cohorts defined in the literature.

RESULTS: There were 261 eligible patients. The median follow-up period for surviving patients was 8.4 years (range, 1.8 to 27.4 years). The 10-year OS rate was 73%. Multifactor analysis for OS showed that age was the only important prognostic factor. The 10-year PFS rate was 58%. On multifactor analysis for PFS, the most important prognostic factors were clinical stage, B symptoms, histology, number of sites, and tumor bulk. The 10-year PFS rate for lymphocyte-predominant disease was 81% for stage I and 78% for stage II. In favorable patient cohorts defined in the literature, the 10-year PFS rate ranged from 70% to 73% for the whole group and from 71% to 90% in patients with favorable stage I disease, but only from 48% to 57% in patients with favorable stage II disease. On competing-risks analysis, the cumulative 10-year incidence of first site of failure in the para-aortic/splenic region alone was 10.5%. Sixty percent of relapsed patients remain progression-free at 10 years after chemotherapy salvage.

CONCLUSION: These results support the use of MRT alone in patients with favorable CS I HD and CS I-II HD with lymphocyte-predominant histology. The remainder of patients with CS I-II HD require more intensive treatment.
RET Proto-Oncogene in the Development of Human Cancer
Authors: Eng Charis
Published: February 2017

The RET proto-oncogene, located on chromosome subband 10q11.2, encodes a receptor tyrosine kinase expressed in tissues and tumors derived from neural crest. Germline (present in every cell of the body) mutations in RET cause multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PC), and hyperparathyroidism (HPT). This knowledge has allowed molecular diagnosis and presymptomatic DNA-based testing to become possible. RET testing is considered the standard of care in MEN 2 families because clinical decisions are made based on the results of such gene testing. There appears to be a correlation between specific RET mutation type and organ-specific tumor development. Such knowledge might be useful in tailoring targeted surveillance in the near future. Somatic (in the tumor only) RET mutations have been found in a proportion of sporadic MTCs and PCs. Whether the presence of somatic RET mutation is associated with a poor prognosis is currently being investigated as another tool for molecular medicine.
Dose-Response Trial of Megestrol Acetate in Advanced Breast Cancer: Cancer and Leukemia Group B Phase III Study 8741
Authors: Abrams Jeffrey , Aisner Joseph , Cirrincione Constance , Berry Donald A. , Muss Hyman B. , Cooper M. Robert , Henderson I. Craig , Panasci Lawrence , Kirshner Jeffrey , Ellerton John , Norton Larry
Published: February 2017

PURPOSE: To investigate whether dose escalation of megestrol acetate (MA) improves response rate and survival in comparison with standard doses of MA.

PATIENTS AND METHODS: Three hundred sixty-eight patients with metastatic breast cancer, positive and/or unknown estrogen and progesterone receptors, zero or one prior trial of hormonal therapy, and no prior chemotherapy for metastatic disease were prospectively randomized into three groups. The groups of patients received either MA 160 mg/d (one tablet per day), MA 800 mg/d (five tablets per day), or MA 1,600 mg/d (10 tablets per day).

RESULTS: Patient characteristics were well balanced in the three treatment groups. Three hundred sixty-six patients received treatment and were included in the analyses. The response rates were 23%, 27%, and 27% for the 160-mg, 800-mg, and 1,600-mg arms, respectively. Response duration correlated inversely with dose. Median durations of response were 17 months, 14 months, and 8 months for the 160-mg, 800-mg, and 1,600-mg arms, respectively. No significant differences in the treatment arms were noted for time to disease progression or for survival; survival medians were 28 months (low dose), 24 months (mid dose) and 29 months (high dose). The most frequent and troublesome toxicity, weight gain, was dose-related, with approximately 20% of patients on the two higher-dose arms reporting weight gain of more than 20% of their prestudy weight, compared with only 2% in the 160-mg dose arm.

CONCLUSION: With a median follow-up of 8 years, these results demonstrate no advantage for dose escalation of MA in the treatment of metastatic breast cancer.
Clinical and Pharmacokinetic Phase I Study of Multitargeted Antifolate (LY231514) in Combination With Cisplatin
Authors: Thödtmann R. , Depenbrock H. , Dumez H. , Blatter J. , Johnson R. D. , van Oosterom A. , Hanauske A.-R.
Published: February 2017

PURPOSE: Multitargeted antifolate (MTA; LY231514) has broad preclinical antitumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways. This study was designed to (1) determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin.

PATIENTS AND METHODS: Patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1, both agents were administered on day 1 starting with MTA 300 mg/m2 and cisplatin 60 mg/m2. In cohort 2, MTA (500 or 600 mg/m2) was administered on day 1, followed by cisplatin (75 mg/m2) on day 2.

RESULTS: In cohort 1, 40 assessable patients received 159 courses of treatment. The MTD was MTA 600 mg/m2/cisplatin 100 mg/m2. DLTs were reversible leukopenia/neutropenia and delayed fatigue. Hydration before cisplatin therapy did not influence MTA pharmacokinetics. Eleven objective remissions included one complete response in a patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epithelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment. The MTD was MTA 600 mg/m2 and cisplatin 75 mg/m2. DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient).

CONCLUSION: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.
Dissemination Risk Index Based on Plasminogen Activator System Components in Primary Breast Cancer
Authors: Bouchet Cécile , Hacène Kamel , Martin Pierre-Marie , Becette Véronique , Tubiana-Hulin Michèle , Lasry Serge , Oglobine Jean , Spyratos Frédérique
Published: February 2017

PURPOSE: To study interactions between disease-free survival (DFS) and four components of the plasminogen activator system: urokinase-type plasminogen activator (uPA), its two inhibitors (PAI-1 and PAI-2), and its membrane receptor uPAR.

PATIENTS AND METHODS: We conducted a retrospective study of 499 primary breast cancer patients (median follow-up, 6 years). uPA, PAI-1, and PAI-2 were determined on cytosols and uPAR on solubilized pellets, using enzyme-linked immunoadsorbent assay kits (American Diagnostica, Greenwich, CT). Classical univariate and multivariate statistical methods were used together with multiple correspondence analysis to graphically examine interactions between the variables and outcome.

RESULTS: By univariate analysis, higher uPA and PAI-1 values were significantly related to shorter DFS (P = .002; P < .00002). PAI-2 was not significantly related to DFS, although patients with high and very low PAI-2 values had a longer DFS. Multiple correspondence analysis showed the parallel impact of uPA and PAI-1 on outcome, and the clearly different behavior of PAI-2 compared with PAI-1. The prognostic contribution of uPAR seemed weak by both methods. A dissemination risk index [uPA × PAI-1/(PAI-2 + 1)], taking into account the modulation of uPA proteolytic activity by the ratio of its two inhibitors, was then tested. Dissemination risk index was selected as an independent variable in the Cox model in the overall population (P < .000001) and in node-positive patients (P < .00001). It was the only variable selected in node-negative patients (P = .003).

CONCLUSION: A dissemination risk index determined on primary tumor and taking into account the different effects of PAI-1 and PAI-2 on uPA can be of major help in clinical management of breast cancer, particularly in node-negative patients.
Prognostic and Predictive Factors for Patients With Metastatic Breast Cancer Undergoing Aggressive Induction Therapy Followed by High-Dose Chemotherapy With Autologous Stem-Cell Support
Authors: Rizzieri D. A. , Vredenburgh J. J. , Jones R. , Ross M. , Shpall E. J. , Hussein A. , Broadwater G. , Berry D. , Petros W. P. , Gilbert C. , Affronti M. L. , Coniglio D. , Rubin P. , Elkordy M. , Long G. D. , Chao N. J. , Peters W. P.
Published: February 2017

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy.

PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses.

RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P = .0041), smaller metastatic foci (≤ 2 v > 2 cm) (P = .0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases (≤ 2 v > 2 years) (P = .0051), and prior treatment with tamoxifen (P = .0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P = .0001) and those who developed liver metastases (P = .0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P = .0006), as did patients who had received prior adjuvant therapy (P = .0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P = .0143).

CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive–patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.
Cost-Utility Analysis of Chemotherapy Using Paclitaxel, Docetaxel, or Vinorelbine for Patients With Anthracycline-Resistant Breast Cancer
Authors: Leung P. P. , Tannock I. F. , Oza A. M. , Puodziunas A. , Dranitsaris G.
Published: February 2017

PURPOSE: Paclitaxel, docetaxel, and vinorelbine have been approved for chemotherapy in patients with advanced breast cancer that is resistant to anthracyclines. Selecting which agent to use is difficult because each possesses advantages and disadvantages related to clinical response, toxicity, method of administration, and cost. A cost-utility analysis was therefore performed to create a rank order on the basis of effectiveness, quality of life, and economic considerations.

PATIENTS AND METHODS: Eighty-eight anthracycline-resistant breast cancer patients who had received paclitaxel (n = 34), docetaxel (n = 29), or vinorelbine (n = 25) during the past 2 years were identified. Total resource consumption was collected, which included expenditures for chemotherapy, supportive care, laboratory tests, management of adverse effects, and all related physician fees. Utilities from 25 oncology care providers and 25 breast cancer patients were estimated using the time trade-off technique. The economic estimates from the chart review and clinical data from the literature were then modeled using the principles of decision analysis.

RESULTS: Each of the three drugs led to a similar duration of quality-adjusted progression-free survival (paclitaxel, 37.2 days; docetaxel, 33.6 days; vinorelbine, 38.0 days). Vinorelbine was the least costly strategy, with an overall treatment expenditure of Can $3,259 per patient, compared with Can $6,039 and Can $10,090 for paclitaxel and docetaxel, respectively.

CONCLUSION: Palliative chemotherapy with vinorelbine in anthracycline-resistant metastatic breast cancer patients has economic advantages over the taxanes and provides at least equivalent quality-adjusted progression-free survival. These benefits are largely related to its lower drug acquisition cost and better toxicity profile.
Comparison of CSF Cytology and Spinal Magnetic Resonance Imaging in the Detection of Leptomeningeal Disease in Pediatric Medulloblastoma or Primitive Neuroectodermal Tumor
Authors: Fouladi Maryam , Gajjar Amar , Boyett James M. , Walter Andrew W. , Thompson Stephen J. , Merchant Thomas E. , Jenkins Jesse J. , Langston James W. , Liu Aiyi , Kun Larry E. , Heideman Richard L.
Published: February 2017

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET.

PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD.

RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively.

CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.
Randomized Comparison of Megestrol Acetate Versus Dexamethasone Versus Fluoxymesterone for the Treatment of Cancer Anorexia/Cachexia
Authors: Loprinzi Charles L. , Kugler John W. , Sloan Jeff A. , Mailliard James A. , Krook James E. , Wilwerding Mary B. , Rowland Kendrith M. , Camoriano John K. , Novotny Paul J. , Christensen Bradley J.
Published: February 2017

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetites in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia.

PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetites and drug toxicities.

RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P = .03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P = .06).

CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.
Survival in Hereditary Breast Cancer Associated With Germline Mutations of BRCA2
Authors: Verhoog L. C. , Brekelmans C.T.M. , Seynaeve C. , Dahmen G. , van Geel A. N. , Bartels C.C.M. , Tilanus-Linthorst M.M.A. , Wagner A. , Devilee P. , Halley D.J.J. , van den Ouweland A.M.W. , Meijers-Heijboer E. J. , Klijn J.G.M.
Published: February 2017

PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients.

PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis.

RESULTS: The 5-year disease-free survival was 52% for each group (P = .91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P = .50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P = .05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52.8%, respectively; P = .34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P = .06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P = .61 and P = .19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P = .02).

CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.
Prospective Pilot Study of Sildenafil for Treatment of Postradiotherapy Erectile Dysfunction in Patients With Prostate Cancer
Authors: Weber Damien C. , Bieri Sabine , Kurtz John M. , Miralbell Raymond
Published: February 2017

PURPOSE: Erectile dysfunction is a common late complication patients may experience after external-beam radiotherapy for prostate cancer. The efficacy and safety of oral sildenafil to correct sexual dysfunction caused by external-beam radiotherapy was studied in patients participating in our prospective trial.

PATIENTS AND METHODS: Thirty-five assessable patients participated in this prospective pilot study. Using a 25-point scale based on the International Index of Sexual Function, erectile dysfunction was assessed weekly, during which time patients received sildenafil 100 mg orally once a week for 6 consecutive weeks. Response was defined as a score of 18 or more, corresponding to at least one successful attempt at sexual intercourse per week.

RESULTS: Thirty patients (86%) completed the 6-week study. Seventy-seven percent of these patients had significantly improved erectile function, allowing recovery of full capacity for sexual intercourse. Of 27 patients not receiving concomitant hormone treatment, failure to respond was observed in only four patients (15%) compared with four (50%) of eight patients receiving hormonal treatment during the study. The time course of response was gradual, with 40%, 57%, 66%, 69%, and 74% responding at weeks 1 through 5, respectively. Therapy was generally well tolerated. The most frequently reported side effects in patients were flushing (37%), transient headache (17%), and dyspepsia (9%). No patient reported priapism, and no cardiovascular event or death was observed. After response, 12 patients (34%) reported the ability to achieve and maintain an erection sufficient for intercourse in the absence of sildenafil (ie, 24 hours to 6 days after taking the medication).

CONCLUSION: This study suggests that oral sildenafil is well tolerated and can reverse erectile dysfunction after radiotherapy in a substantial proportion of prostate cancer patients.
Survival After Relapse in Children and Adolescents With Rhabdomyosarcoma: A Report From the Intergroup Rhabdomyosarcoma Study Group
Authors: Pappo Alberto S. , Anderson James R. , Crist William M. , Wharam Moody D. , Breitfeld Phillip P. , Hawkins Douglas , Raney R. Beverly , Womer Richard B. , Parham David M. , Qualman Steven J. , Grier Holcombe E.
Published: February 2017

BACKGROUND: Despite advances in therapy, nearly 30% of children with rhabdomyosarcoma experience progressive or relapsed disease, which is often fatal.

PATIENTS AND METHODS: To facilitate the development of a retrieval therapy protocol, we studied potential risk factors that were predictive of survival after first relapse in 605 children who were enrolled onto three consecutive Intergroup Rhabdomyosarcoma Study Group protocols.

RESULTS: The median survival time from first recurrence was 0.8 years; the estimated percentage of patients who survived 5 years from first recurrence was 17% ± 2% (mean ± SD). Univariate analysis showed that tumor histology was an important predictor of 5-year survival (P < .001): the 5-year survival rate was 64% for patients with botryoid tumors (n = 19), 26% for patients with embryonal tumors (n = 313), and 5% for patients with alveolar or undifferentiated sarcoma (n = 273). Further analysis identified prognostic factors within histologic subtypes (P < .001). For patients with embryonal tumors, the estimated 5-year survival rate was 52% for patients who initially presented with stage 1 or group I disease, 20% for those with stage 2/3 or group II/III disease, and 12% for those with group IV disease. For patients with stage 1/group I disease, estimated 5-year survival rates were higher for patients with local (72%) or regional (50%) recurrence than for those with distant (30%) recurrence. Among patients with alveolar or undifferentiated sarcoma, only the disease group predicted outcome: the 5-year survival estimate was 40% for group I versus 3% for groups II through IV. We identified a “favorable risk” group (approximately 20% of patients) whose 5-year estimated survival rate was near 50%; for all other patients, the estimated survival was near 10%.

CONCLUSION: This analysis demonstrates that the probability of 5-year survival after relapse for rhabdomyosarcoma is dependent on several factors at the time of initial diagnosis, including histologic subtype, disease group, and stage. These findings will form the basis of a multi-institutional risk-adapted relapse protocol for childhood rhabdomyosarcoma.
Phase II Study of Area Under the Plasma-Concentration-Versus-Time Curve–Based Carboplatin Plus Standard-Dose Intravenous Etoposide in Elderly Patients With Small-Cell Lung Cancer
Authors: Okamoto Hiroaki , Watanabe Koshiro , Nishiwaki Yutaka , Mori Kiyoshi , Kurita Yuzoh , Hayashi Izumi , Masutani Masayuki , Nakata Koichiro , Tsuchiya Satoshi , Isobe Hiroshi , Saijo Nagahiro
Published: February 2017

PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)–based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area–based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC.

PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 × (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m2 was given intravenously on days 1, 2, and 3. Patients aged ≥ 70 years old with a performance status of 0 to 2 were eligible.

RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%.

CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.
Prognostic Factors for Children and Adolescents With Surgically Resected Nonrhabdomyosarcoma Soft Tissue Sarcoma: An Analysis of 121 Patients Treated at St Jude Children's Research Hospital
Authors: Spunt Sheri L. , Poquette Catherine A. , Hurt Yasmeen S. , Cain Alvida M. , Rao Bhaskar N. , Merchant Thomas E. , Jenkins Jesse J. , Santana Victor M. , Pratt Charles B. , Pappo Alberto S.
Published: February 2017

PURPOSE: The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution.

PATIENTS AND METHODS: We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed.

RESULTS: At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% ± 3% and 77% ± 4%, respectively. In univariate models, positive surgical margins (P = .004), tumor size ≥ 5 cm (P < .001), invasiveness (P = .002), high grade (P = .028), and intra-abdominal primary tumor site (P = .055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P = .003), intra-abdominal primary tumor site (P = .028), and the omission of radiation therapy (P = .043) predicted local recurrence, whereas tumor size ≥ 5 cm (P < .001), invasiveness (P < .001), and high grade (P = .004) predicted distant recurrence.

CONCLUSION: In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.
Results of Treatment for Soft Tissue Sarcoma in Childhood and Adolescence: A Final Report of the German Cooperative Soft Tissue Sarcoma Study CWS-86
Authors: Koscielniak Ewa , Harms Dieter , Henze Günter , Jürgens Herbert , Gadner Helmut , Herbst Manfred , Klingebiel Thomas , Schmidt Bernhard F. , Morgan Mary , Knietig Robert , Treuner Jörn
Published: February 2017

PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy.

PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54.4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation).

RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% ± 3% and 69% ± 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% ± 5%; stage II, 69% ± 6%; stage III, 57% ± 4%; and stage IV, 19% ± 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% ± 5% v 44% ± 6%; P = .053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site.

CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.
High Cure Rates and Reduced Long-Term Toxicity in Pediatric Hodgkin's Disease: The German-Austrian Multicenter Trial DAL-HD-90
Authors: Schellong Günther , Pötter Richard , Brämswig Jürgen , Wagner Wolfgang , Prott Franz-Josef , Dörffel Wolfgang , Körholz Dieter , Mann Georg , Rath Bettina , Reiter Alfred , Weissbach Gerhard , Riepenhausen Marianne , Thiemann Markus , Schwarze Ernst-Wilhelm
Published: February 2017

PURPOSE: To further reduce therapy-related late effects in patients with pediatric Hodgkin's disease (HD) while maintaining the high cure rates achieved with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction was addressed by substituting etoposide for procarbazine (OEPA) in the induction therapy for boys. Radiation doses and fields were further reduced.

PATIENTS AND METHODS: Three hundred nineteen boys and 259 girls younger than 18 years with previously untreated HD, enrolled onto the study between 1990 and 1995, were allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or four cycles, respectively, of COPP. Low-dose radiotherapy was given to the initially involved sites, ie, reduced involved fields.

RESULTS: Initial response to OPPA or OEPA induction was virtually identical. Eight of 578 patients experienced early progression of HD. Thirty-seven relapses, three secondary tumors, and no secondary leukemias have been recorded, with a median follow-up duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The probability of 5-year event-free survival/overall survival is 91%/98% in the total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk factor analysis showed two significant prognostic factors: histologic subtype NS2 and “B” symptoms. OEPA induction therapy, large mediastinal tumor, and age were not significant. Preliminary studies of testicular function indicate a lower risk of germ cell damage than previously documented with OPPA.

CONCLUSION: OEPA is a satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a comprehensive treatment program for all stages of pediatric HD and offers a favorable benefit/risk ratio, combining excellent disease control, moderate acute toxicity, and reduced long-term toxicity.
Randomized Clinical Trial of Adjuvant Mitomycin Plus Tegafur in Patients With Resected Stage III Gastric Cancer
Authors: Cirera Lluís , Balil Anna , Batiste-Alentorn Eduard , Tusquets Ignasi , Cardona Teresa , Arcusa Àngels , Jolis Laura , Saigí Eugeni , Guasch Imma , Badia Anna , Boleda Montse
Published: February 2017

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer.

PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m2 intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model.

RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P = .04 for survival and P = .01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group.

CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.