bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of care for women with ovarian cancer in the United States.
Authors: Muñoz K A , Harlan L C , Trimble E L
Published: February 2017

PURPOSE

To characterize treatments for ovarian cancer, to determine if recommended staging and treatment were provided, and to determine factors that influence receipt of recommended staging and treatment.

METHODS

A total of 785 women diagnosed with ovarian cancer in 1991 were selected from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program. Type and receipt of recommended staging and treatment were examined using data on surgery and physician-verified chemotherapy.

RESULTS

Most women with presumptive stage I and II ovarian cancer were treated with surgery alone (58%), while women with stage III or IV disease were treated with surgery plus platinum-based chemotherapy (75% stage III, 56% stage IV). Approximately 10% of women with presumptive stage I and II, 71% with stage III, and 53% with stage IV disease received recommended staging and treatment. The absence of lymphadenectomy and assignment of histologic grade were the primary reasons women with presumptive stage I and II cancer did not receive recommended staging and treatment, whereas for stages III and IV, it was due to older women not receiving surgery plus platinum-based adjuvant chemotherapy. Age, stage, comorbidity, "other" race/ethnicity, and treatment at a facility with an approved residency training program were associated with whether recommended staging and therapy were received.

CONCLUSION

Older women with late-stage disease did not receive recommended treatment. The majority of women with early-stage disease did not receive recommended staging and treatment.
NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology.
Authors: Coze C , Hartmann O , Michon J , Frappaz D , Dusol F , Rubie H , Plouvier E , Leverger G , Bordigoni P , Béhar C , Beck D , Mechinaud F , Bergeron C , Plantaz D , Otten J , Zucker J M , Philip T , Bernard J L
Published: February 2017

PURPOSE

NB87 was designed to test the efficacy of a short, non cross-resistant, induction protocol for unselected patients over 1 year of age with stage 4 neuroblastoma. A secondary objective was to compare in a randomized study the toxicity of two modalities of cisplatin administration.

PATIENTS AND METHODS

A total of 183 patients received two cycles of alternating sequences: cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1 and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary tumor (126 patients). Ninety-one were randomized to receive cisplatin either as bolus (BO; n = 48) or continuous infusion (CI; n = 43). International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with emphasis on skeletal evaluation by meta-iodobenzylguanidine (MIBG).

RESULTS

Hematotoxicity was predominant, with a higher incidence of neutropenia (P = .01) for CADO and of thrombocytopenia for CVP (P < .001). Severe infections, as well as nonhematologic toxicities, occurred more often after the first sequence. Gastrointestinal complications were predominant during both courses of CVP. The toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%). Combining all metastatic sites resulted in a 39% CR rate. After surgery, the final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000 Hz was reported equally in both arms (n = 6 for CI v n = 5 for BO).

CONCLUSION

Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter induction duration. However, the rate of MIBG normalization remains unsatisfactory and could be raised through the dose-intensive use of agents such as cyclophosphamide.
Retinoblastoma protein and proliferating-cell nuclear antigen expression as predictors of recurrence in well-differentiated papillary thyroid carcinoma.
Authors: Omura K , Nagasato A , Kanehira E , Kinsen H , Amaya S , Kimura K , Kajita T , Nozaki Y , Mizukami Y , Nonomura A , Watanabe Y
Published: February 2017

PURPOSE

We analyzed retinoblastoma protein (pRB) and proliferating-cell nuclear antigen (PCNA) expression in primary tumors and recurrent lesions of well-differentiated papillary thyroid carcinoma (PTC) to clarify the relationship between their expression and recurrent disease.

PATIENTS AND METHODS

The study included 93 patients with PTC. No recurrent disease had developed in 60 patients within 10 years after surgery (group N). Thirty patients in whom recurrent disease had developed after surgery were enrolled in group R. Levels of pRB and PCNA expression were quantified using the CAS 200 system (Cell Analysis Systems, Elmhurst, IL) following immunohistochemical staining.

RESULTS

Mean pRB expression level in the primary tumors in group R was significantly lower than that in group N (P < .0001). pRB expression in the tumors with a diameter up to 20 mm was significantly lower than that in tumors larger than 20 mm in group R (P < .01). There were no significant differences in the levels of expression of PCNA in the primary tumors between group N and group R. Univariate analysis demonstrated that the disease-free survival was significantly correlated with pN category, pRB, and PCNA expression level. The subgroup with high-level expression of pRB (> 25%) showed significantly long disease-free survival (P < .001). Furthermore, the subgroup with low-level expression of PCNA (< 35%) showed significantly longer disease-free survival (P < .05). Multivariate analysis showed pRB expression and pN category to be independent prognostic factors for disease-free survival in PTC.

CONCLUSION

pRB expression level can be used as a reliable predictor for recurrence of PTC.
Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: long-term results from a single institution.
Authors: Pisters P W , Patel S R , Varma D G , Cheng S C , Chen N P , Nguyen H T , Feig B W , Pollack A , Pollock R E , Benjamin R S
Published: February 2017

PURPOSE

To review a single institution's long-term results with doxorubicin-based preoperative chemotherapy for American Joint Committee on Cancer (AJCC) stage IIIB extremity soft tissue sarcoma (STS).

PATIENTS AND METHODS

The records of all patients with AJCC stage IIIB extremity STS treated with preoperative chemotherapy between 1986 and 1990 at The University of Texas M.D. Anderson Cancer Center were reviewed to assess rates of response, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS).

RESULTS

Seventy-six patients with stage IIIB disease received preoperative chemotherapy. The median sarcoma size was 10 cm. Seventy-two patients (95%) had tumors located deep to the muscular fascia. Most patients received a median of three preoperative cycles of doxorubicin and dacarbazine (ADIC), cyclophosphamide and ADIC (CyADIC), or other doxorubicin-based regimens. Radiographic response rates were as follows: complete response (CR), 9%; partial response (PR), 19%; minor response, 13%; stable disease, 30%; and progression, 30%. The overall objective major response rate (CRs plus PRs) was 27%. At a median follow-up time of 85 months, 5-year actuarial rates of LRFS, DMFS, DFS, and OS with 95% confidence intervals (CIs) were 83% (CI, 73% to 94%), 52% (CI, 41% to 66%), 46% (CI, 35% to 60%), and 59% (CI, 48% to 72%), respectively. Comparison of responding patients (CRs plus PRs) and nonresponding patients did not show any significant differences in LRFS, DMFS, DFS, or OS.

CONCLUSION

Preoperative doxorubicin-based chemotherapy was associated with response, DFS, and OS rates similar to those observed in randomized postoperative chemotherapy trials. Responding patients had rates of LRFS, DMFS, DFS, and OS comparable to those of nonresponders.
Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Français d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer.
Authors: Thiesse P , Ollivier L , Di Stefano-Louineau D , Négrier S , Savary J , Pignard K , Lasset C , Escudier B
Published: February 2017

PURPOSE

We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC.

MATERIALS AND METHODS

The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC.

RESULTS

Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed.

CONCLUSION

We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.
High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma.
Authors: Bierman P J , Vose J M , Anderson J R , Bishop M R , Kessinger A , Armitage J O
Published: February 2017

PURPOSE

This study evaluated the results of high-dose therapy followed by autologous bone marrow or peripheral-blood stem-cell transplantation for patients with follicular low-grade non-Hodgkin's lymphoma.

PATIENTS AND METHODS

We performed a retrospective review of 100 patients undergoing autologous transplantation for follicular low-grade lymphoma between April 22, 1983 and December 31, 1993.

RESULTS

Sixty-seven patients remained alive and 48 were failure-free. The median follow-up duration of surviving patients was 2.6 years (range, 1.0 to 11.7). There were eight (8%) deaths within 100 days of transplantation. Six additional patients died of nonrelapse causes up to 912 days after transplantation. Overall survival at 4 years was estimated to be 65% (95% confidence interval [CI], 54% to 75%) and failure-free survival was estimated to be 44% (95% CI, 33% to 55%). There was no definite evidence of a plateau in the failure-free survival curve. The only factor significantly associated with overall survival and failure-free survival was the number of chemotherapy regimen received before transplantation. No significant differences in outcome were observed between patients with follicular small cleaved-cell lymphoma and follicular mixed lymphoma, or between patients who received peripheral-blood stem-cell transplants and unpurged autologous bone marrow transplants.

CONCLUSION

Prolonged failure-free survival is possible following high-dose therapy and autologous hematopoietic rescue for follicular low-grade lymphoma. It is unclear whether patients are cured with this therapy or if survival is prolonged.
Gallium scans in the management of patients with Hodgkin's disease: a study of 101 patients.
Authors: Salloum E , Brandt D S , Caride V J , Cornelius E , Zelterman D , Schubert W , Mannino T , Cooper D L
Published: February 2017

PURPOSE

To evaluate the utility of periodic gallium (67Ga) scans in the management of patients with Hodgkin's disease.

PATIENTS AND METHODS

From 1990 to 1994, 101 patients treated for Hodgkin's disease (stage I to II, n = 67; stage III to IV, n = 34) had a positive 67Ga scan at the time of diagnosis. Treatment included chemotherapy in 27 patients, radiation therapy in 28, and combined modality therapy in 46. All patients underwent 67Ga scans at the time of diagnosis, near the end or just after treatment, and at periodic follow-up evaluation.

RESULTS

After treatment, the 67Ga scan remained positive in four patients and was interpreted as negative in 97. Among the four patients with positive scans, two died of progressive disease and two relapsed. Among the remaining 97 patients with negative 67Ga scans, 16 patients relapsed, including five with stage I to II (7.5%) and 11 with stage III to IV (34.4%) disease. The negative predictive value of posttherapy 67Ga scan was 83.5% for all patients; however, when calculated according to stage, it was 92.4% for patients with stage I to II disease and 64.5% for patients with stage III to IV disease (P < .01).

CONCLUSION

A positive 67Ga scan at the end of therapy is rarely seen in patients with Hodgkin's disease and should be considered a manifestation of gross residual disease. However, a negative 67Ga scan after therapy had a significantly lower predictive value in patients with stage III to IV disease compared with stage I to II disease. The predictive value of 67Ga scans, as well as newer imaging studies, should be analyzed according to pretreatment stage.
Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood.
Authors: Locatelli F , Niemeyer C , Angelucci E , Bender-Götze C , Burdach S , Ebell W , Friedrich W , Hasle H , Hermann J , Jacobsen N , Klingebiel T , Kremens B , Mann G , Pession A , Peters C , Schmid H J , Stary J , Suttorp M , Uderzo C , van't Veer-Korthof E T , Vossen J , Zecca M , Zimmermann M
Published: February 2017

PURPOSE

To evaluate the role of allogeneic bone marrow transplantation (BMT) in children with chronic myelomonocytic leukemia (CMML).

PATIENTS AND METHODS

Forty-three children with CMML given BMT and reported to the European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) data base were evaluated. In 25 cases, the donor was a human leukocyte antigen (HLA)-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 a matched unrelated donor (MUD). Conditioning regimens consisted of total-body irradiation (TBI) and chemotherapy in 22 patients, whereas busulfan (Bu) with other cytotoxic drugs was used in the remaining patients.

RESULTS

Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. There was a significant difference in the incidences of chronic graft-versus-host disease (GVHD) between children transplanted from compatible/one-antigen-mismatched relatives and from alternative donors (23% and 87%, respectively; P < .005). Probabilities of transplant-related mortality for children given BMT from HLA-identical/one-antigen-disparate relatives or from MUD/ mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%, whereas the 5-year event-free survival (EFS) rate was 31%. The EFS rate for children given BMT from an HLA-identical sibling or one-antigen-disparate relative was 38%. In this latter group, patients who received Bu had a better EFS compared with those given TBI (62% v 11%, P < .01).

CONCLUSION

Children with CMML and an HLA-compatible relative should be transplanted as early as possible. Improvement of donor selection, GVHD prophylaxis, and supportive care are needed to ameliorate results of BMT from alternative donors.
Detection of circulating tumor cells in patients with Ewing's sarcoma and peripheral primitive neuroectodermal tumor.
Authors: West D C , Grier H E , Swallow M M , Demetri G D , Granowetter L , Sklar J
Published: February 2017

PURPOSE

To determine the feasibility of detecting Ewing's sarcoma (ES) or peripheral primitive neuroectodermal tumor (PNET) through a reverse-transcriptase polymerase chain reaction (RT-PCR) of the t(11;22)(q24;q12) fusion transcript in blood and bone marrow samples from patients with these neoplasms.

PATIENTS AND METHODS

Peripheral-blood (PB) and/or bone marrow aspirate (BM) samples were obtained from 28 patients with ES or PNET at initial presentation or at relapse. Patients were divided into two groups: newly diagnosed patients with nonmetastatic disease and those with metastatic/relapsed disease. RNA was extracted from fractionated BM and PB samples, and RT-PCR was performed for the EWS/HumFLI1 fusion mRNA was transcribed across the t(11;22) breakpoint.

RESULTS

Among the 16 patients with nonmetastatic disease, three of 16 were RT-PCR positive for EWS/HumFLI1 RNA in BM and three of 10 were positive in PB. The total number of nonmetastatic patients who were positive in either PB or BM was four of 16 (25%). Among patients with metastatic/relapsed disease, two of six were positive in BM and five of 10 were positive in PB. The total fraction of patients with metastatic/relapsed disease that was positive in either BM or PB was six of 12 (50%).

CONCLUSION

In this study, we show that it is possible to amplify the EWS/HumFLI1 RNA by RT-PCR from the BM and PB of a subset of patients with both nonmetastatic and metastatic ES or PNET, which implies that occult tumor cells are present at these sites. The true biologic and clinical meaning of this information is unknown. However, it does suggest a possible application of RT-PCR for the monitoring of residual disease in patients who are undergoing therapy for ES or PNET. This approach may permit early identification of patients who may benefit from alternative therapy or who may be spared possible overtreatment.
Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma.
Authors: Witte R S , Elson P , Bono B , Knop R , Richardson R R , Dreicer R , Loehrer P J
Published: February 2017

PURPOSE

Alkylating agents have modest activity in advanced urothelial carcinoma. Ifosfamide (IFX) is an agent as yet unstudied in advanced urothelial carcinoma. Despite recent advances in the treatment of this disease, there continues to be a need to identify new active agents and their toxicity spectra. Here we report results from the use of IFX in this population.

PATIENTS AND METHODS

Ambulatory patients with advanced urothelial carcinoma were treated with IFX 3,750 mg/m2 and mesna 2250 mg/m2 both intravenously (IV) daily for 2 days every 3 weeks. Significant renal and CNS toxicity required a dose change of IFX to 1,500 mg/m2 IV with mesna 750 mg/m2 IV for 5 days every 3 weeks. Doses were modified for hematologic, renal, and CNS toxicity.

RESULTS

Of 56 eligible patients entered onto the study, 26 received the 2-day schedule and 30 were treated on the 5-day regimen. All patients had progressive disease following prior systemic chemotherapy. There were five complete responses (CRs) and six partial responses (PRs) for an overall response rate of 20% (exact 95% confidence interval [CI], 10% to 32%). Renal and CNS toxicity was severe before the change in schedule, but manageable after the change. Major identified toxicities were gastrointestinal, myelosuppressive, renal, and CNS. There were four early deaths to which treatment probably contributed, but were multifactorial in etiology.

CONCLUSION

IFX has significant activity, but also major toxicity in a heavily cisplatin-pretreated cohort with advanced urothelial carcinoma. A modification of dose and/or schedule from that described should be considered in future trials. Combination regimens using this agent should be explored.
Analysis of the cost-effectiveness of paclitaxel as alternative combination therapy for advanced ovarian cancer.
Authors: McGuire W , Neugut A I , Arikian S , Doyle J , Dezii C M
Published: February 2017

PURPOSE

A phase III trial by the Gynecologic Oncology Group (GOG) provides strong evidence that a new alternative therapy--paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in combination with cisplatin (Platinol; Bristol-Myers Squibb Co)--is clinically more effective than the standard therapy using cyclophosphamide (Cytoxan; Bristol-Myers Squibb Co) in combination with cisplatin in the treatment of advanced ovarian cancer. We conducted a pharmacoeconomic analysis to determine whether the alternative paclitaxel-cisplatin (TP) therapy is cost-effective (CE) in comparison to standard cyclophosphamide-cisplatin (CP) therapy.

METHODS

Using an economic model, we applied cost data figures to resource utilization data derived from the two arms of the GOG trial. We examined paclitaxel benefits in terms of increased mean survival time, as well as median survival time. Estimates of the cumulative proportion surviving in the trial were based on Kaplan-Meier procedures.

RESULTS

Per year of life gained (YLG), TP therapy costs more ($19,820 more for inpatient treatment; $21,222 outpatient) than CP treatment.

CONCLUSION

The TP regimen's increased mean survival cost per YLG (inpatient and outpatient settings) adds a substantial benefit at an acceptable cost compared with CP therapy.
Repetitive cycles of cyclophosphamide, thiotepa, and carboplatin intensification with peripheral-blood progenitor cells and filgrastim in advanced breast cancer patients.
Authors: Shapiro C L , Ayash L , Webb I J , Gelman R , Keating J , Williams L , Demetri G , Clark P , Elias A , Duggan D , Hayes D , Hurd D , Henderson I C
Published: February 2017

PURPOSE

As an alternative to single-cycle cyclophosphamide, thiotepa, and carboplatin (CTCb) intensification, we evaluated the feasibility of administering one-quarter dose CTCb for four cycles with peripheral-blood progenitor-cell (PBPC) and filgrastim (granulocyte colony-stimulating factor [G-CSF]) in advanced-stage breast cancer patients.

PATIENTS AND METHODS

From June 1992 to August 1993, 20 stage IIIB (n = 7) and IV (n = 13) breast cancer patients received 78 cycles of induction with doxorubicin 90 mg/m2 by intravenous (IV) bolus with G-CSF 5 microg/kg/d by subcutaneous injection (SC) repeated every 14 to 21 days for four cycles. PBPC were collected by 2-hour single-blood volume leukapheresis on 2 consecutive days at the time of hematologic recovery from each cycle of doxorubicin. Eighteen patients received 61 cycles of intensification with cyclophosphamide 1,500 mg/m2, thiotepa 125 mg/m2, and carboplatin 200 mg/m2 by IV continuous infusion with G-CSF 10 microg/kg/d SC and PBPC support repeated every 21 to 42 days for four cycles.

RESULTS

Twelve of 20 patients (60%) completed all four planned cycles of doxorubicin induction followed by four cycles of one-quarter dose CTCb intensification. Statistically significantly decreases in the yield of mononuclear cells (MNC) (median slope per day, -0.032; P = .03), granulocyte-macrophage colony-forming unit (CFU-GM) (median slope per day, -0.57; P = .0008), and burst-forming unit-erythroid (BFU-E) (median slope per day, -1.18; P = .006) were observed over the course of the eight leukaphereses. Of 18 patients who began CTCb, 12 (67%) completed four cycles. Six patients were removed from study during intensification: two for progressive disease (PD), one refused further treatment, and three for dose-limiting hematologic toxicity. A fourth patient fulfilled the criteria for dose-limiting hematologic toxicity after cycle 4. The toxicity of the multiple cycle CTCb intensification regimen consisted of grade IV leukopenia, grade IV thrombocytopenia, and febrile neutropenia in 100%, 100%, and 26% of cycles, respectively. The median duration of each CTCb cycle was 24 days (range, 18 to 63), and the median duration of an absolute neutrophil count (ANC) < or = 500/microL and platelet count < or = 20,000/microL during each cycle was 6 days (range, 2 to 15) and 4 days (range, 0 to 38), respectively.

CONCLUSION

It is feasible to administer repetitive cycles of one-quarter dose CTCb intensification with PBPC and G-CSF. Additional studies are required to determine whether multiple cycles of CTCb intensification might offer a therapeutic advantage over a single high-dose cycle.
Reappraisal of the role of axillary lymph node dissection in the conservative treatment of breast cancer.
Authors: Haffty B G , Ward B , Pathare P , Salem R , McKhann C , Beinfield M , Fischer D , Reiss M
Published: February 2017

PURPOSE

The purpose of this study was (1) to review systemic therapy practice patterns to assess how information regarding nodal status currently influences systemic therapy decisions, and (2) to review long-term outcome of patients who do not undergo axillary dissection compared with patients who do.

METHODS AND MATERIALS

For the current practice patterns portion of the study, the records of 292 patients who presented in the past 3 years with invasive breast cancer and underwent conservative surgery were reviewed to determine systemic therapy administered with respect to patient age, primary tumor size, clinical nodal status, and presenting symptoms. For the long-term outcome portion of the study, the records of 955 patients with invasive breast cancer who underwent conservative surgery and radiation therapy before December 1989 were reviewed. Patient characteristics and outcome of those patients who underwent axillary dissection (n = 565, 59%) were compared with a cohort of patients treated during the same era who did not undergo axillary dissection (n = 390, 41%).

RESULTS

For the current practice-patterns cohort, information regarding nodal status appeared to influence adjuvant systemic therapy for those patients less than 50 years of age and for those patients with palpable masses who were older than 50. Patients older than 50 with nonpalpable mammographically detected tumors have a low probability of nodal involvement and information regarding nodal status rarely changed therapy in this group of patients. In the long-term outcome study, there were no significant differences in the rates of distant metastasis, disease-free survival, or overall survival between those patients who underwent lymph node dissection and those who did not.

CONCLUSION

For selected patients, axillary lymph node dissection appears to have little influence on subsequent management and long-term outcome. These data suggest that it is time to reassess the role of axillary lymph node dissection in patients who undergo conservative surgery and radiation therapy.
Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.
Authors: Johnson C A , Kilpatrick D , von Roemeling R , Langer C , Graham M A , Greenslade D , Kennedy G , Keenan E , O'Dwyer P J
Published: February 2017

PURPOSE AND METHODS

Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer.

RESULTS

The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine.

CONCLUSION

This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.
Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.
Authors: Miller V A , Benedetti F M , Rigas J R , Verret A L , Pfister D G , Straus D , Kris M G , Crisp M , Heyman R , Loewen G R , Truglia J A , Warrell R P
Published: February 2017

PURPOSE

The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer.

PATIENTS AND METHODS

Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29.

RESULTS

Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism.

CONCLUSION

LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.
Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.
Authors: de Gramont A , Bosset J F , Milan C , Rougier P , Bouché O , Etienne P L , Morvan F , Louvet C , Guillot T , François E , Bedenne L
Published: February 2017

PURPOSE

This multicenter study compared the therapeutic ratio of a monthly schedule of low-dose leucovorin (LV) and fluorouracil (5-FU) bolus with a bimonthly schedule of high-dose LV and 5-FU bolus plus continuous infusion in patients with advanced colorectal cancer.

PATIENTS AND METHODS

Of the 448 patients randomly assigned to treatment, 433 were assessable. Treatment A was a monthly regimen of intravenous (IV) LV 20 mg/m2 plus bolus 5-FU 425 mg/m2 for 5 days every 4 weeks. Treatment B was a bimonthly regimen of IV LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and 22-hour infusion 5-FU 600 mg/m2 for 2 consecutive days every 2 weeks. Therapy was continued until disease progression. Second-line chemotherapy, which included 5-FU continuous infusion, was allowed in both arms.

RESULTS

The response rates in 348 patients with measurable lesions were 14.4% (monthly regimen) and 32.6% (bimonthly regimen) (P = .0004). The median progression-free survival times were 22 weeks (monthly regimen) and 27.6 weeks (bimonthly regimen) (P = .0012). The median survival times were 56.8 weeks (monthly regimen) and 62 weeks (bimonthly regimen) (P = .067). Grade 3-4 toxicities occurred in 23.9% of patients in the monthly arm compared with 11.1% of those in the bimonthly arm (P = .0004). Patients in arm A more frequently experienced severe granulocytopenia (7.3% v 1.9%), diarrhea (7.3% v 2.9%), and mucositis (7.3% v 1.9%) than patients in arm B.

CONCLUSION

The bimonthly regimen was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival.
Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma.
Authors: Tanigawa N , Amaya H , Matsumura M , Shimomatsuya T
Published: February 2017

PURPOSE

The relationship between the expression of vascular endothelial growth factor (VEGF) and its receptor, KDR, in human gastric carcinoma tissues and tumor angiogenesis, as well as patient outcome, were investigated.

MATERIALS AND METHODS

One hundred sixty-three primary tumor specimens were investigated by immunohistochemical studies with anti-VEGF, anti-KDR, and anti-CD34 antibodies and by monitoring patients for at least 2 years after surgery.

RESULTS

For intensity of VEGF staining, 48 tumors were graded as 0, 36 as 1+, 63 as 2+, and 16 as 3+. Tumors with strong VEGF staining, assessed as 2+ and 3+, had significantly higher vascularity than those with weak VEGF. Eighty-eight tumors (54%) were positive for KDR. There was no association between KDR expression and tumor vascularity. No close correlation was found between VEGF and KDR expressions. The Cox proportional hazards model identified intratumoral vessel count as the most significant and independent prognostic factor among various clinicopathologic factors. In contrast, overall survival rates for 84 patients with weak VEGF staining tumors and 79 with strong VEGF staining tumors were not significantly different. Patients with tumors of either localized Borrmann types or well-differentiated histologies, which are found more frequently in tumors with strong VEGF staining, survived significantly longer than those with tumors of either infiltrative Borrmann types or poorly differentiated histologies.

CONCLUSION

We suggest that expression of VEGF is more frequently found in tumors with well-differentiated histology and plays a role in the promotion of angiogenesis in human gastric carcinomas.
Detection of human papillomavirus mRNA and cervical cancer cells in peripheral blood of cervical cancer patients with metastasis.
Authors: Pao C C , Hor J J , Yang F P , Lin C Y , Tseng C J
Published: February 2017

PURPOSE

To determine the presence of cervical cancer cells in circulating peripheral blood of stage IVb cervical cancer patients with metastasis to distant organs.

PATIENTS AND METHODS

Cervical cancer tissue from 15 stage IVb cervical cancer patients with metastasis were analyzed for the presence of human papillomavirus (HPV) type 16 DNA by nested polymerase chain reaction (PCR). The presence of transcriptional products of the HPV type 16 E6-transforming gene in the peripheral blood of the same 15 cancer patients was analyzed by reverse transcription and PCR. Cervical tissues and peripheral-blood specimens from 12 normal healthy individuals served as controls.

RESULTS

Thirteen of 15 (86.7%) cervical cancer tissues from same number of patients were found to contain HPV type 16 DNA. Peripheral-blood specimens from 12 of 13 (92.3%) cervical HPV DNA-positive patients were found to contain HPV-specific mRNA detectable by reverse transcription (RT) and PCR. Cervical tissues from all 12 normal controls were HPV-free. None of the peripheral-blood specimens from two cervical HPV-negative cancer patients and 12 normal controls contained detectable amounts of mRNA of HPV type 16 E6-transforming gene.

CONCLUSION

The most likely source of the HPV-specific mRNA detected in the peripheral blood of cervical cancer patients with metastasis is the cervical cancer cells derived from or shed from the cervix. The presence of HPV E6 mRNAs in peripheral blood may be a sensitive indicator of circulating cervical cancer cells. If PCR positivity is proven to be able to predict disease progression reliably, these findings may have clinical applications in the treatment of cervical and many other cancers.
Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.
Authors: Buzaid A C , Ross M I , Balch C M , Soong S , McCarthy W H , Tinoco L , Mansfield P , Lee J E , Bedikian A , Eton O , Plager C , Papadopoulos N , Legha S S , Benjamin R S
Published: February 2017

PURPOSE

To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system.

METHODS

Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature.

RESULTS

Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size.

CONCLUSION

Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.
TPDC-FuHu chemotherapy for the treatment of recurrent metastatic brain tumors.
Authors: Kaba S E , Kyritsis A P , Hess K , Yung W K , Mercier R , Dakhil S , Jaeckle K A , Levin V A
Published: February 2017

PURPOSE

To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors.

PATIENTS AND METHODS

One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses.

RESULTS

Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients.

CONCLUSION

TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.
TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance.
Authors: Rubnitz J E , Downing J R , Pui C H , Shurtleff S A , Raimondi S C , Evans W E , Head D R , Crist W M , Rivera G K , Hancock M L , Boyett J M , Buijs A , Grosveld G , Behm F G
Published: February 2017

PURPOSE

TEL gene rearrangements due to the 12;21 chromosomal translocation are the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a B-precursor immunophenotype. The limited number of clinically useful genetic markers in this leukemia subtype prompted us to assess TEL status as a predictor of treatment outcome.

PATIENTS AND METHODS

We determined the status of the TEL gene (rearranged or germline) in 188 cases of B-precursor acute leukemia using Southern blot analysis and related the findings to event-free survival. All comparisons of outcome were stratified by treatment regimen, risk classification, age, and leukocyte count.

RESULTS

Forty-eight patients (26%) had a rearranged TEL gene. At 5 years of follow-up, an estimated 91% +/- 5% (SE) of this group were event-free survivors, compared with only 65% +/- 5% of the group with germline TEL (stratified log-rank P = .011). For nonhyperdiploid patients, the odds ratio of an adverse event in the germline TEL group to that for the rearranged TEL group was 4.06 (95% confidence interval, 1.86 to 8.84). The relationship of TEL rearrangement to a favorable prognosis was independent of recognized good-risk features in B-precursor leukemia, including age, initial leukocyte count, and hyperdiploidy.

CONCLUSION

Rearrangement of the TEL gene distinguishes a large subset of children with favorable-prognosis B-precursor leukemia who cannot be identified by standard prognostic features. It may be possible to treat these patients less aggressively without loss of therapeutic efficacy.
Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia.
Authors: Marks D I , Kurz B W , Link M P , Ng E , Shuster J J , Lauer S J , Carroll D , Brodsky I , Haines D S
Published: February 2017

PURPOSE

To determine whether potential alteration in p53 function through p53 gene mutation or mdm-2 overexpression correlates with early treatment failure in childhood acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS

Diagnostic marrow samples from 34 children were analyzed for p53 gene alterations by western blot and SSCP/DNA sequence analysis and for mdm-2 overexpression by western blot analysis. These samples were derived from two groups of children with ALL: 17 good outcome patients who are in long-term continuous complete remission and 17 poor outcome patients who did not achieve a complete remission or relapsed within 6 months of achieving remission.

RESULTS

Two children within the poor outcome group were found to have p53 gene mutations. Furthermore, five poor outcome patients were shown to have greater than 10-fold overexpression of mdm-2 protein compared with the mean level of mdm-2 protein measured in the good outcome group. Aberrant p53 protein expression was found in only one good outcome patient, whereas no good outcome children were found to have elevated levels (> 10-fold) of mdm-2 protein.

CONCLUSION

We show for the first time that potential alteration in p53 function in childhood ALL is more common (P = .036) in cases of early treatment failure than in children who remain in long-term continuous remission.
Clinical relevance of DNA ploidy and proliferative activity in childhood rhabdomyosarcoma: a retrospective analysis of patients enrolled onto the Italian Cooperative Rhabdomyosarcoma Study RMS88.
Authors: De Zen L , Sommaggio A , d'Amore E S , Masiero L , di Montezemolo L C , Linari A , Madon E , Dominici C , Bosco S , Bisogno G , Carli M , Ninfo V , Basso G
Published: February 2017

PURPOSE

Evaluation of the possible clinical relevance of DNA ploidy and proliferative activity assessed as S-phase fraction (SPF) in childhood rhabdomyosarcoma (RMS).

PATIENTS AND METHODS

We conducted a retrospective study on 59 RMS patients enrolled onto the ICS-RMS88 protocol (seven botryoid, 35 embryonal, and 17 alveolar RMS), for which formalin-fixed paraffin-embedded (FFPE) tissue was available. Nuclear suspensions for cytometric investigation were obtained using a mechanical disaggregation. Tumors were distinguished according to their DNA index (DI) value as follows: diploid (0.9 < DI < 1.1), hyperdiploid (1.1 < or = DI < 1.8 or DI > or = 2.2), and tetraploid (1.8 < or = DI < 2.2); for analysis of SPF, a cutoff value of 14% was used.

RESULTS

DNA histograms were diploid in 19 (33%) cases, hyperdiploid in 29 (49%), and tetraploid in 10 (32%). One patient showed both a hyperdiploid and a tetraploid peak. The 5-year overall survival (OS) rate by ploidy status was 73% in hyperdiploid patients as compared with 33% and 25% in diploid and tetraploid patients, respectively (P = .0012). A striking difference emerged when the 5-year OS for the combined diploid and tetraploid RMS groups was compared with survival of the hyperdiploid RMS group: 30% versus 73%, respectively (P = .0006). In addition, the SPF was prognostically relevant: 5-year OS by SPF less than or greater than 14% was 70% and 36%, respectively (P = .009). Multivariate analysis confirmed the importance of DNA content (P = .0006) and SPF (P = .034) in predicting survival.

CONCLUSION

These findings confirm that ploidy and SPF are important new prognostic factors that are able to identify selected groups of patients at high risk of treatment failure, even if the tumor's presentation is favorable according to standard criteria.
Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients.
Authors: Rudoler S B , Shields C L , Corn B W , De Potter P , Hyslop T , Curran W J , Shields J A
Published: February 2017

PURPOSE

Metastatic deposits are the most common intraocular malignancies. We evaluated the efficacy of external-beam radiotherapy (EBRT) in the palliation of posterior uveal metastases in terms of clinically relevant outcomes: functional vision, tumor control, and globe preservation.

PATIENTS AND METHODS

Four hundred eighty-three consecutive patients (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972 and 1995. Of these, 233 eyes (188 patients) had lesions of the posterior uveal tract and received EBRT. Best-corrected visual acuity (VA) was documented pre- and post-EBRT. Visual function was considered excellent if VA < or = 20/50, navigational if 20/60 to 20/200, and legally blind if > or = 20/400. Most patients received 30 to 40 Gy in 2- to 3-Gy fractions to the posterior or entire globe.

RESULTS

Fifty-seven percent of all assessable eyes had improved visual function or maintained at least navigational vision following EBRT. Thirty-six percent of legally blind eyes regained useful vision. Ninety-three percent experienced no clinical evidence of tumor progression and the globe preservation rate was 98%. The following characteristics independently predicted improvement to or maintenance of excellent vision on multivariate analysis: excellent vision pre-EBRT (P = .001), age less than 55 years (P = .004), white race (v black/Hispanic) (P = .003), and tumor base diameter less than 15 mm (P < .001).

CONCLUSION

EBRT effectively restores and maintains useful vision in patients with choroid metastases, with a globe preservation rate of 98%. Patients less than 55 years with pretreatment VA better than 20/60 and tumor diameter less than 15 mm are most likely to benefit from this therapeutic intervention.