bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.
Authors: Ayash L J , Wheeler C , Fairclough D , Schwartz G , Reich E , Warren D , Schnipper L , Antman K , Frei E , Elias A
Published: February 2017

PURPOSE

With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS).

METHODS

From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS.

RESULTS

The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066).

CONCLUSION

We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.
Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay.
Authors: Hoon D S , Wang Y , Dale P S , Conrad A J , Schmid P , Garrison D , Kuo C , Foshag L J , Nizze A J , Morton D L
Published: February 2017

PURPOSE

The objective of the study was to develop a sensitive multimarker polymerase chain reaction (PCR) assay to detect circulating melanoma cells in patient blood. The rationale was that malignant melanoma is heterogeneous in regards to antigen expression.

PATIENTS AND METHODS

A PCR assay that uses four melanoma-associated gene markers (tyrosinase, p97, MUC18, and MAGE-3) was developed. Sensitivity and specificity of the PCR assay for individual markers were assessed using 10 melanoma cell lines and peripheral-blood lymphocytes (PBL) from 39 normal volunteers as controls. The assay's sensitivity and specificity were improved using nested primers and Southern blot analysis. Patients (N = 119) with American Joint Committee on Cancer (AJCC) stages I to IV disease were evaluated for circulating melanoma cells using the four gene markers under optimal conditions.

RESULTS

All melanoma-associated gene markers were expressed in at least 80% of the melanoma lines, whereas 37 of 39 normal PBL tested negative for all markers; the remaining two PBL were positive for MUC18. Using four markers in the PCR assay was significantly better than using tyrosinase alone. There was a significant correlation between the number of positive PCR markers, AJCC stage of disease, and progression of disease. In all AJCC stages, there were more PCR-positive patients with disease than without disease.

CONCLUSION

A multimarker PCR assay is more reliable and sensitive than a single-marker assay for detection of melanoma cells in blood of patients. This assay can provide important insight into tumor progression kinetics without major surgical or conventional radiologic diagnostic procedures.
Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer.
Authors: Kobayashi K , Vokes E E , Vogelzang N J , Janish L , Soliven B , Ratain M J
Published: February 2017

PURPOSE

Suramin is a promising agent for the treatment of hormone-refractory metastatic prostate cancer. However, questions about the relationship of severe neurotoxicity to sustained peak plasma concentrations greater than 300 micrograms/mL raised concerns that this drug could not be safely administered without adaptive control. To test the adaptive-control hypothesis, we designed a phase I study that relied on clinical end points, using a fixed dosing scheme that did not rely on adaptive control.

PATIENTS AND METHODS

In a phase I dose-escalation study using fixed dosing without adaptive control, gradually decreasing doses of suramin were administered to 63 patients on days 1 (loading dose), 2, 8, and 9 of a 28-day cycle. Fifty-four patients with hormone-refractory metastatic prostate cancer and nine patients with other solid tumors have been treated.

RESULTS

Doses of 400 mg/m2 to 2,080 mg/m2 on the first day have been administered. The mean peak plasma concentration following the loading dose at a dose level of 1,730 mg/m2 was 933 micrograms/mL (26% coefficient of variation), and the mean trough concentration was 139 micrograms/mL (40% CV) on day 1 of cycle 2 [corrected]. At 1,730 mg/m2, five of 13 patients experienced dose-limiting toxicity (DLT), including malaise, neurotoxicity, pericardial effusion, and coagulopathy. At 2,080 mg/m2, three of five patients experienced DLT. Two patients treated at this dose level died while on study. One of these patients died of a subdural hematoma sustained after a fall and had a prolonged prothrombin time at the time of his death. One patient developed classic suramin neurotoxicity, which led to respiratory failure, for which the patient refused intubation. No significant associations were noted between peak or trough concentrations during either cycles 1 or 2 and the occurrence of neurotoxicity.

CONCLUSION

(1) Suramin can be safely administered without adaptive control, (2) suramin on this schedule may exhibit significant activity against hormone-refractory metastatic prostate cancer, and (3) based strictly on toxicity considerations, we recommended that a day-1 dose of 1,440 mg/m2 be used in subsequent clinical trials, with a maximum of three cycles. Further studies to establish the optimal empiric dosing regimen are needed.
Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin.
Authors: Bitton R J , Figg W D , Venzon D J , Dalakas M C , Bowden C , Headlee D , Reed E , Myers C E , Cooper M R
Published: February 2017

PURPOSE

To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin.

METHODS

Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks).

RESULTS

Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL.

CONCLUSION

Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.
Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.
Authors: Valone F H , Kaufman P A , Guyre P M , Lewis L D , Memoli V , Deo Y , Graziano R , Fisher J L , Meyer L , Mrozek-Orlowski M
Published: February 2017

PURPOSE

MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210.

PATIENTS AND METHODS

Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2.

RESULTS

Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients.

CONCLUSION

MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.
p53 mutations in benign breast tissue.
Authors: Millikan R , Hulka B , Thor A , Zhang Y , Edgerton S , Zhang X , Pei H , He M , Wold L , Melton L J
Published: February 2017

PURPOSE

Patients with benign breast biopsies that exhibit atypical epithelial proliferation or fibroadenoma may be at increased risk for invasive breast cancer. We hypothesized that molecular markers might also be useful to evaluate the malignant potential of nonneoplastic breast tissue.

PATIENTS AND METHODS

Study subjects belonged to a cohort of 6,805 women who underwent biopsy for nonmalignant breast disease at the Mayo Clinic and Rochester-affiliated hospitals between 1967 and 1981. As part of a nested case-control study that compared subjects who developed invasive breast cancer with those who did not, we analyzed a sample of 60 benign breast biopsies for the following markers: HER-2/neu and p53 over-expression by immunohistochemistry, HER-2/neu and PRAD-1 amplification using differential polymerase chain reaction (PCR), and p53 mutation using single-strand conformation analysis (SSCA) and direct DNA sequencing by asymmetric PCR.

RESULTS

None of 60 biopsies showed amplification of HER-2/neu or PRAD-1. Five samples exhibited low-level immunoreactivity to the HER-2/neu protein product. Fourteen samples exhibited focal or diffuse immunoreactivity to the p53 protein. Point mutations in the p53 gene were found in five samples: three of these samples exhibited mutations that altered the amino acid sequence. Only two of five samples with p53 mutation exhibited p53 overexpression. Histologic diagnoses on three samples with nonconservative p53 mutation were, respectively, nonproliferative fibrocystic change, papillomatous hyperplasia, and fibroadenoma.

CONCLUSION

The clinical significance of p53 mutation, p53 overexpression, and low-level HER-2/neu expression in benign breast tissue remains to be determined. Further research will be necessary to evaluate whether these markers could serve as useful adjuncts to histology in evaluation of the malignant potential of benign breast tissue.
Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.
Authors: Browman G P , Bergsagel D , Sicheri D , O'Reilly S , Wilson K S , Rubin S , Belch A , Shustik C , Barr R , Walker I
Published: February 2017

PURPOSE

To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone.

PATIENTS AND METHODS

In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors.

RESULTS

Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment.

CONCLUSION

Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.
Survival of patients with resistant Hodgkin's disease after polyclonal yttrium 90-labeled antiferritin treatment.
Authors: Herpst J M , Klein J L , Leichner P K , Quadri S M , Vriesendorp H M
Published: February 2017

PURPOSE

A follow-up study was initiated of patients with Hodgkin's disease who were treated with yttrium 90-labeled antiferritin. Prescription method, pharmacokinetics, acute and late side effects, and survival were evaluated.

METHODS

Patients had measurable disease and failed > or = two multiagent chemotherapy regimens previously (N = 44). All patients received 5-mCi indium 111-labeled antiferritin 2 mg intravenously and were scanned repeatedly by gamma camera. In five patients, polyclonal antiferritin (rabbit, pig, or baboon) failed to target the tumor. Thirty-nine patients were injected intravenously with 10-, 20-, 30-, 40-, or 50-mCi yttrium 90-labeled antiferritin 2 to 5 mg. Patients received between one and five cycles. Some patients were supported with 5 x 10(7) autologous bone marrow cells per kilogram.

RESULTS

Yttrium 90-labeled polyclonal antiferritin does not produce immunologic, pharmacologic, or microbiologic complications in vivo. Bone marrow toxicity is the only side effect observed. Overall response rate is 20 of 39, or 51%. Two patients had stable disease. A significant positive correlation is found between blood radioactivity level 1 hour after radioimmunoconjugate administration and subsequent response of Hodgkin's disease. A dosage in millicuries per kilogram provides a higher positive correlation with blood radioactivity levels 1 hour after administration than a dosage in millicuries per square meter of body-surface area or in total millicuries. Fifty percent of patients survive for > or = 6 months.

CONCLUSION

The low-dose protein used (2 to 5 mg) indicates that the high response rate is due to radiation and not to immunologic effects of the antibody. High-activity administrations followed by bone marrow transplantation are not required for tumor response. The therapeutic ratio of radiolabeled antiferritin is higher than the therapeutic ratio observed in most phase I studies of chemotherapeutic agents. This analysis does not identify a superior mode of treatment for patients with end-stage Hodgkin's disease. However, in a heavily pretreated patient population, prolonged survival is observed after relatively inexpensive treatment. Preclinical research with yttrium 90-labeled antiferritin indicates that significant increases in tumor dose can be obtained in the future without an increase in normal tissue toxicity.
Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo.
Authors: Navari R M , Madajewicz S , Anderson N , Tchekmedyian N S , Whaley W , Garewal H , Beck T M , Chang A Y , Greenberg B , Caldwell K C
Published: February 2017

PURPOSE

To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis.

PATIENTS AND METHODS

Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy.

RESULTS

Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066).

CONCLUSION

Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.
Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study.
Authors: Robertson A G , Reed N S , Ralston S H
Published: February 2017

PURPOSE

To study the effects of oral clodronate on bone pain in patients with advanced metastatic bone disease.

PATIENTS AND METHODS

Fifty-five patients with progressing bone metastases were randomized to receive oral clodronate 1,600 mg/d (n = 27) or matching placebo (n = 28). The main outcome measures were bone pain (visual analog score), analgesic use, and compliance with therapy.

RESULTS

Visual analog pain score (median [interquartile range]) decreased from the pretreatment value in the clodronate group (-0.9 [-2.6 to -0.4]), but increased in the placebo group (+0.4 [-1.0 to +4.0]) (P = .03 between groups). Analgesic use increased with disease progression to a similar extent in both groups (59% increased use in the clodronate group v 64% of placebo group; difference not significant). Ten patients (37%) in the clodronate group and 12 (46%) in the placebo group withdrew from the study prematurely, most often because of difficulty with swallowing the capsules.

CONCLUSION

Clodronate improved control of bone pain to a modest degree in patients with advanced metastatic cancer, but did not reduce analgesic requirement significantly. Perhaps as a result of these factors, it proved difficult to maintain patients on therapy. Further studies will be needed to define the role of bisphosphonates such as clodronate in this situation, in comparison with established treatments such as radiotherapy and analgesics.
Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.
Authors: Bajetta E , Di Leo A , Biganzoli L , Mariani L , Cappuzzo F , Di Bartolomeo M , Zilembo N , Artale S , Magnani E , Celio L , Buzzoni R , Carnaghi C
Published: February 2017

PURPOSE

The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease.

PATIENTS AND METHODS

Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases).

RESULTS

The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred.

CONCLUSION

VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.
Evaluation of HER-2/neu Gene Amplification and Overexpression: Comparison of Frequently Used Assay Methods in a Molecularly Characterized Cohort of Breast Cancer Specimens
Authors: Press Michael F. , Slamon Dennis J. , Flom Kerry J. , Park Jinha , Zhou Jian-Yuan , Bernstein Leslie
Published: February 2017

PURPOSE: To compare and evaluate HER-2/neu clinical assay methods.

MATERIALS AND METHODS: One hundred seventeen breast cancer specimens with known HER-2/neu amplification and overexpression status were assayed with four different immunohistochemical assays and two different fluorescence in situ hybridization (FISH) assays.

RESULTS: The accuracy of the FISH assays for HER-2/neu gene amplification was high, 97.4% for the Vysis PathVision assay (Vysis, Inc, Downers Grove, IL) and 95.7% for the the Ventana INFORM assay (Ventana, Medical Systems, Inc, Tucson, AZ). The immunohistochemical assay with the highest accuracy for HER-2/neu overexpression was obtained with R60 polyclonal antibody (96.6%), followed by immunohistochemical assays performed with 10H8 monoclonal antibody (95.7%), the Ventana CB11 monoclonal antibody (89.7%), and the DAKO HercepTest (88.9%; Dako, Corp, Carpinteria, CA). Only the sensitivities, and therefore, overall accuracy, of the DAKO Herceptest and Ventana CB11 immunohistochemical assays were significantly different from the more sensitive FISH assay.

CONCLUSION: Based on these findings, the FISH assays were highly accurate, with immunohistochemical assays performed with R60 and 10H8 nearly as accurate. The DAKO HercepTest and the Ventana CB11 immunohistochemical assay were statistically significantly different from the Vysis FISH assay in evaluating these previously molecularly characterized breast cancer specimens.
Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women's Health Initiative randomized clinical trial
Authors: Chlebowski R. T. , Schwartz A. , Wakelee H. , Anderson G. L. , Stefanick M. L. , Manson J. E. , Chien J. W. , Chen C. , Wactawski-Wende J. , Gass M.
Published: February 2017

CRA1500

Background: Sex differences in lung cancer outcome suggest a potential hormonal influence; however, observational studies provide mixed findings regarding menopausal hormone therapy (HT) and lung cancer. Methods: Secondary analyses of the WHI randomized, placebo-controlled trial of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) in 16,608 multi-ethnic postmenopausal women, aged 50–79 were conducted on lung cancer incidence and mortality. Lung cancers were confirmed by medical record review. Results: Groups were balanced for age, race/ethnicity, and prior HT. Smoking status was also comparable (never 50%, past 40%, current 10% in both groups). Cumulative risk for lung cancer was highest in current (0.51%), compared to past (0.14%) and never (0.04%) smokers. After 5.6 years on trial intervention and 2.4 years additional follow-up (median), small cell lung cancer incidence was comparable between randomization groups (total n=26), as was subsequent small cell lung cancer mortality. Although a trend for more non-small cell lung cancer (NSCLC) diagnoses in the active hormone group was not significant (p=0.12), an apparent divergence emerged after five years, with more diagnoses in the CEE+MPA group. In addition, mortality after NSCLC diagnosis was significantly higher for the CEE+MPA group (46.3% vs 27.0%, respectively, hazard ratio (HR) 1.59, 95% CI 1.03–2.46, p=0.04). As a result, CEE+MPA group women were more likely to die from NSCLC than those on placebo (p=0.02). Conclusions: Use of CEE + MPA for over 5 years increases a woman's risk for NSCLC mortality, the leading cause of cancer death in women. These data, together with recent results indicating higher breast cancer risk (Cancer Res 2009;69(2):78s), suggest cancer impact should influence risk-to-benefit consideration for combined HT use.

[Table: see text]

[Table: see text]
Impact of sentinel lymph node biopsy on staging of early cervical cancer: Results of a prospective, multicenter study
Authors: Lecuru F. , Bats A. , Mathevet P. , Querleu D. , Leblanc E. , Morice P. , Darai E. , Marret H. , Collin C. , Chatellier G. , Gilaizeau F.
Published: February 2017

CRA5506

Background: 10% to 15% of patients with pN0 early cervical cancer experience recurrences. This may be related either to nodes missed by the dissection or located outside the dissection field or to failed diagnosis of node metastases. The objective of this study was to measure the benefits from sentinel node (SN) detection in terms of nodes collected from unusual territories and of detected micrometastases and isolated tumor cells (ITCs). Methods: 145 patients who had stage Ia1-Ib1 epidermoid cancer or adenocarcinoma or adenosquamous cancer were included in a multicenter study (January 2005 - June 2007). Noninclusion criteria were age<18 years, pregnancy, and previous treatment. SNs were identified by combined technetium and blue-dye labeling in the pelvic and para-aortic territories. Slices were cut 200 μm apart. At each level, HES staining and labeling with anti-cytokeratin antibodies (AE1-AE3) were performed. SNs in an unusual territory were defined as SNs outside the ilio-obturator region. ITC was defined as size <0.2 mm, micrometastasis as size 0.2 to 2mm, and macrometastases as size >2 mm. The study was funded by the French National Institute of Cancer and reviewed by an IRB. Results: 17 patients were excluded for major protocol deviations, leaving 128 patients for the per protocol analysis. One or more SNs were detected in 98.4% of patients (95%CI, 94.4 to 99.9%). The 430 detected SNs were located as follows: external iliac, 80.5 %; common iliac, 8.6%; presacral and paraaortic, 5.5%; and parametrial, 4.9 %. SN detection identified at least one SN in an unusual territory in 48/128 (37.5%) patients. There were 26 positive SNs in 21(16.4%) patients of whom 8 (38%) had macrometastases, 7 (33%) micrometastases, and 6 (29%) ITCs. Of these 26 nodes, 7 (27%) were detected only by immunohistochemistry (6/128 patients: 4.6%). There was no false-negative No node metastases were found in 104/128 (81.2%) patients. Conclusions: SN detection supplied additional information in 39.8% of patients (51/128), either showing that drainage occurred via unusual pathways or detecting cancer spread via immunohistochemistry. Node dissection could have been avoided in the 104/128 patients with negative nodes, potentially decreasing treatment-associated morbidity.

No significant financial relationships to disclose.
Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC)
Authors: Belani C. P. , Brodowicz T. , Ciuleanu T. , Kim J. H. , Krzakowski M. , Laack E. , Wu Y. L. , Peterson P. , Krejcy K. , Zielinski C.
Published: February 2017

CRA8000

Background: Pemetrexed's efficacy, favorable tolerability profile, and ease of administration provided a strong rationale for evaluation as maintenance therapy in patients (pts) with advanced NSCLC. We present the final analyses for all outcomes, including overall survival (OS), from a phase III study of Pem vs. Plac (Ciuleanu, J Clin Oncol 26, 2008, A 8011) in pts with stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based chemotherapy. Methods: In this double-blind trial, pts were randomized 2:1 to receive Pem (500 mg/m2, day 1) plus BSC or Plac plus BSC in 21-day cycles until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. The final OS analysis was performed using an unadjusted Cox model. Overall α = 0.05 for PFS and OS. Results: In the 663 randomized pts (Pem 441: Plac 222), Pem resulted in significantly better OS (13.4 vs. 10.6 mos [HR 0.79, 95% CI: 0.65–0.95, P = 0.012]). As reported earlier, Pem also had better PFS (P <0.00001) and response (P <0.001) ( Table ). The improvements in PFS and OS were observed primarily in patients with non-squamous histology (PFS HR = 0.47 and OS HR = 0.70). Treatment by histology interaction for OS was significant (P = 0.038). Drug-related grade 3/4 toxicities were higher for Pem (16% vs 4%; P <0.001); specifically, fatigue (5% vs 0.5%) and neutropenia (2.9% vs. 0%). Grade 3/4 toxicities did not increase significantly in pts who received ≥6 and ≥10 cycles of Pem. There were no Pem-related deaths. Fewer pts in the Pem arm (51.5% vs 67.1%; P <0.001) received systemic post-discontinuation therapy. Conclusions: Pem maintenance therapy is well tolerated and offers superior OS and PFS compared with Plac, making it a new treatment paradigm for patients with advanced NSCLC who respond to initial therapy. This trial further validates that Pem has greater efficacy in patients with non-squamous histology.

[Table: see text]

[Table: see text]
Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM)
Authors: Hauschild A. , Eggermont A. M. , Jacobson E. , O'Day S. J.
Published: February 2017

LBA9012

Background: Elesclomol is an investigational first-in-class oxidative stress inducer that increases oxidative stress in cancer cells leading to mitochondria-induced apoptosis. Methods: Patients (pts) with Stage IV MM, no prior chemotherapy, LDH μ 2× ULN were randomized (1:1) to either 213 mg/m2 elesclomol in combination with 80 mg/m2 paclitaxel (ELPAC) or 80 mg/m2 paclitaxel alone (P); both were given weekly ×3 followed by 1 week rest until disease progression. Pts were stratified by prior non-cytotoxic treatment, M1 grade, and LDH. The primary endpoint was PFS with >90% power to detect a 2-month improvement. The primary PFS analysis was planned once all pts had been enrolled and at least 164 PFS events had occurred. Results: 651 pts were enrolled between September 2007 and February 2009. Prognostic factors were generally well balanced. PFS analysis was based on investigator assessment of 411 pts (219 events). Median PFS was 3.5 m (95% CI 2.7–3.7) in ELPAC and 1.9 m (95% CI 1.9–3.3) in P [HR 0.88; 95% CI 0.67–1.16, p=0.3695]. The median number of cycles was 3 in ELPAC and 2 in P. Safety analysis showed increased signals on ELPAC including increased ≥Gr 3 AEs (N=405, 32.8% vs. 23.5%), increased AEs leading to death (N=405, 3.5% vs <1%) and increased overall deaths (N=651, 80 vs 53; 80% censored). Most common AEs in ELPAC were fatigue (32.8%), alopecia (31.3%) and nausea (27.9%). Conclusions: There was an improvement in PFS in the ELPAC arm, but it did not achieve statistical significance. In February 2009, the study was halted based on the recommendation of the DMC to unblind the study after the DMC observed increased deaths on the ELPAC arm. The DMC could not determine whether the observed increased deaths were treatment related or not. Of note, in this analysis there were no specific target organ toxicities attributable to ELPAC that could explain the imbalance of deaths. OS data continues to be collected to determine if the observed imbalance in OS persists as the data mature.

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ACOSOG Z0010: A multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer.
Authors: Cote R. , Giuliano A. E. , Hawes D. , Ballman K. V. , Whitworth P. W. , Blumencranz P. W. , Reintgen D. S. , Morrow M. , Leitch A. M. , Hunt K.
Published: February 2017

CRA504

Background: SN biopsy (SNB) with immunohistochemistry (IHC) of histologically negative SN identifies metastases (mets) not seen by standard histology. The impact of IHC-detected BM mets has been reported in several large single-institution studies. 5,539 patients (pts) were entered into this prospective multicenter observational study to determine the clinical significance of SN and BM mets.

Methods: Patients underwent lumpectomy and SNB with bilateral iliac crest BM aspiration. BM and histologically negative SN were evaluated with IHC in a central laboratory (results not clinically reported). Overall survival (OS), disease-free survival, and locoregional recurrence were determined. Results with OS (the primary endpoint) are reported here.

Results: SN were successfully identified in 5,184 of 5,485 pts (94.5%). Histologic SN mets were found in 1,239 pts (23.9%). IHC detected an additional 350 pts (10.5%) with SN mets. BM mets were identified by IHC in 105 of 3491 examined (3.0%). 5-yr overall survival is shown in the Table . BM IHC positivity significantly predicted decreased OS (p=0.015). A multivariable analysis that included SN and BM status, ER, PR, grade, size, and age showed that neither IHC detected mets in SN (p=0.66) or BM (p=0.08) were independent predictors of OS, although BM status showed a strong trend.

Conclusions: The detection of BM mets by IHC in pts with clinical T1/2 N0M0 breast cancer identifies those pts at significantly increased risk for death; the impact of BM mets on outcome supports and confirms prior studies. In this study, SN IHC-detected mets appear to have no significant impact on OS. The routine examination of SN by IHC is not supported in this patient population by this study.

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A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC).
Authors: Karp D. D. , Lee S. J. , Shaw Wright G. L. , Johnson D. H. , Johnston M. R. , Goodman G. E. , Clamon G. H. , Okawara G. S. , Marks R. , Ruckdeschel J. C. ,   MDACC Thoracic Chemoprevention Research Group
Published: February 2017

CRA7004

Background: Selenium was reported to have possible lung cancer chemopreventive benefits based on a large skin cancer trial secondary observation. (JAMA 1996; 276: 1957-1963). Since that time, research continued to suggest that Se could decrease risk of second primary tumor (SPT) in persons with resected NSCLC. In 2007, a publication from another group suggested an increased association of Se with type 2 diabetes (Annals Int Med 147:217-223).

Methods: From Oct 2000-Nov 2009, 6 groups, led by ECOG, carried out a double blind, placebo controlled trial using selenized yeast 200 micrograms daily in a 2:1 randomization vs. placebo for 48 mo in completely resected stage I NSCLC. Participation was 6–36 mo post-op and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, a negative chest x-ray, and no other evidence of recurrence. Planned size of 1,960 participants had been designed to detect a 40% decrease in SPTs with 80% power. Methylation studies of sputum and blood (S. Belinsky) add important biologic correlates to this project.

Results: Interim analysis occurred in Oct 2009 after 1,561/1,772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken). Endpoints included SPTs, recurrence, and toxicity. A total of 216 SPTs developed of which 84 (38.9%) were lung cancer. SPT (lung/overall) incidence was 1.36/3.66 per 100 person yrs for placebo vs. 1.91/4.11 for Se (p=.150). 5 yr progression free survival was 78% for placebo vs. 72% for Se. Study was stopped according to futility analysis. Grade 1 or 2 toxicity occurred in 38% of placebo and 39% Se. Grade 3 toxicity was 3% placebo vs. <1% Se. Compliance was excellent (>95% at 2 yrs).

Conclusions: No increase in diabetes mellitus or skin cancer was detected. Se was safe but conferred no benefit over placebo. Methylation studies are continuing.

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PRECEDENT: A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer.
Authors: Naumann R. W. , Symanowski J. T. , Ghamande S. A. , Gabrail N. Y. , Gilbert L. , Teneriello M. G. , Sutton G. , Lovejoy C. , Messmann R. A.
Published: February 2017

LBA5012b

Background: EC145, a conjugate of folic acid and desacetylvinblastine hydrazide binds with high affinity to the folate receptor (FR), found on > 90% of epithelial ovarian cancers. This abstract reports interim data on an international randomized, phase II study of EC145 + PLD compared with PLD alone, in women with platinum-resistant ovarian cancer. An independent Data Safety Monitoring Board (DSMB) has conducted a prespecified interim analysis on PFS and safety with results reported herein.

Methods: Women ≥ 18 with ECOG PS of 0-2 and ≤ 2 prior systemic cytotoxic regimens were randomized to receive EC145 (2.5 mg IV weeks 1 and 3) + PLD (50 mg/m2 IBW IV q 28 days) or PLD (50 mg/m2 IBW IV q 28 days) alone until progression or death.

Results: The interim analysis occurred after the 46th event out of a planned study total of 95 progressions or deaths. Demographic characteristics at screening such as age, cancer type, residual tumor after debulking, prior therapy, CA-125 and time from diagnosis were balanced between arms. RECIST mean sum tumor length was longer for the combination arm (122.7 mm vs. 81.3 mm). There was no statistical difference between study arms with regard to total adverse events, serious adverse events, or the number of subjects reporting at least one treatment-emergent drug-related serious adverse event resulting in discontinuation. The Table displays the results of the interim analysis of PFS. At the interim, there is also a trend toward benefit in overall survival for the combination arm with HR = 0.425 (p value of 0.064).

Conclusions: Results indicate a greater than doubling in median PFS for women with platinum-resistant ovarian cancer receiving EC145 and PLD over those receiving PLD alone. These interim data suggest that EC145 and PLD is the first combination to show a statistically significant delay in progression-free survival over standard therapy in women with platinum-resistant ovarian cancer.

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Carboplatin (C) plus paclitaxel (P) versus carboplatin plus pegylated liposomal doxorubicin (PLD) in patients with advanced ovarian cancer (AOC): Final analysis of the MITO-2 randomized multicenter trial.
Authors: Pignata S. , Scambia G. , Savarese A. , Sorio R. , Breda E. , Legge F. , Gebbia V. , Musso P. , Gallo C. , Perrone F. ,   on behalf of MITO Group
Published: February 2017

LBA5033

Background: CP is standard first-line chemotherapy for AOC. MITO-2 (Multicentre Italian Trials in Ovarian Cancer) is an academic multicenter randomized phase III study, testing whether C-PLD is more effective than CP.

Methods: AOC chemo-naïve patients (pts), stage IC-IV, aged≤75, ECOG PS≤2, were randomized to CP (C AUC5 + P 175 mg/m2,d1q3w) or to C-PLD (C AUC5 + PLD 30 mg/m2,d1q3w), both for 6 cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, toxicity and quality of life (QoL). To have 80% power in detecting a 0.80 HR in PFS, with 2-sided α error 0.05, 632 events were needed and 820 pts were planned. Response rate and toxicity have been reported at ASCO 2009 (abs #LBA5508). All analyses are based on intention to treat.

Results: From Jan ’03 to Nov ’07, 820 pts were randomized, 410 to each arm. Median age was 57 yrs (range 21-77). Stage III (60%) and IV (21%) were prevalent. A plateau in PFS events was reached before obtaining the planned number. Thus, following an IDMC recommendation, the final analysis was done with 556 events occurred as of December 31, 2009. This size is consistent with HR to be detected equal to 0.79, with 80% power. With a median follow-up of 40.2 months, median PFS was 19.0 and 16.8 months with C-PLD and CP, respectively (HR 0.95, 95%CI 0.81-1.13, log-rank p value=0.58). Lack of significant difference was confirmed (HR 0.96, 95%CI 0.81-1.14) at multivariable analysis adjusted by stage, PS, residual disease, age and size of the institution. There was no heterogeneity of treatment effect among major subgroups. With 313 deaths recorded, median OS was 61.6 and 53.2 months with C-PLD and CP, respectively (HR 0.89, 95%CI 0.72-1.12, log-rank p value=0.32). QoL data will be presented at the meeting.

Conclusions: In the MITO-2 trial, C-PLD was not found to be superior to CP, which remains the standard first-line chemotherapy for AOC.However, given the observed confidence interval and the different toxicity profile, C-PLD could be considered an alternative to standard therapy. Study was partially supported by Schering-Plough.

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A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinb in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19.
Authors: Goss G. D. , Lorimer I. , Tsao M. S. , O'Callaghan C. J. , Ding K. , Masters G. A. , Roberts P. , Jett J. R. , Edelman M. J. , Shepherd F. A.
Published: February 2017

LBA7005

Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC.

Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug.

Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size >4cm was predictive of poor DFS (p<0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib.

Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented.

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