bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.
Authors: Gertz M A , Kyle R A , Noel P
Published: February 2017

PURPOSE

To determine the natural history of amyloidosis associated with Waldenström's macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy.

PATIENTS AND METHODS

From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years).

RESULTS

Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenström's macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure.

CONCLUSION

The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.
Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor.
Authors: Tournade M F , Com-Nougué C , Voûte P A , Lemerle J , de Kraker J , Delemarre J F , Burgers M , Habrand J L , Moorman C G , Bürger D
Published: February 2017

PURPOSE

The Sixth International Society of Pediatric Oncology study (SIOP6) concerned Wilms' tumor with favorable histology, preoperatively treated to obtain a high rate of stage I patients, and sought to reduce treatment for patients with stage I and stage II negative nodes (IIN0) tumors and to find better therapy to prevent relapses in stage II positive nodes (IIN1) and stage III patients.

PATIENTS AND METHODS

Eligible patients (N = 509) had received four weekly doses of vincristine (VCR) and two courses of dactinomycin (AMD) preoperatively and were assigned after surgery, according to stage and lymph node involvement, to three different prognostic groups, which were to be randomized. Stage I patients (n = 303) received VCR and AMD either for 17 weeks (S) or 38 weeks (L). Stage IIN0 patients (n = 123) received either 20 Gy irradiation (R+) or no irradiation (R-) and received VCR and AMD for 38 weeks. Stage IIN1 and III patients (n = 83) received intensified VCR and AMD (INTVCR) versus VCR, AMD, and Adriamycin (ADRIA; Doxorubicin Farmitalia Carbo Erba, Rueil, Malmaison, France; doxorubicin). Assessment criteria were 2-year disease-free survival (DFS) and 5-year survival (SURV) percentages. A stopping rule was added that took into account abdominal recurrences for the stage IIN0 trial.

RESULT

A 52% rate of stage I tumors was obtained, with a low rate of ruptures (7%). The 2-year DFS and 5-year SURV rates according to the different therapeutic groups were stage I, 92% versus 88% (equivalent) and 95% versus 92% for S and L, respectively; stage IIN0, 72% versus 78% (stage equivalent) and 88% versus 85% for R+ and R-, respectively; and stage IIN1 and stage III, 49% versus 74% (P < .029) and 77% versus 80% for INTVCR and ADRIA, respectively, which results in an 82% DFS and 89% SURV rate for the entire trial population. However, six abdominal metastases observed during the first year of follow-up (FU) in the R- group versus none in the R+ group resulted in discontinuation of the stage IIN0 trial.

CONCLUSION

Risk-adapted therapy to limit risk of sequelae is possible. More intensive chemotherapy is necessary to prevent abdominal recurrences in nonirradiated stage IIN0 patients treated preoperatively. A three-drug protocol is necessary in stage IIN1 and stage III patients.
Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies.
Authors: Estorch M , Carrió I , Martínez-Duncker D , Berná L , Torres G , Alonso C , Ojeda B
Published: February 2017

PURPOSE

To compare myocyte cell damage induced by doxorubicin or mitoxantrone, we performed left ventricular ejection fraction (LVEF) measurements and indium 111 antimyosin antibody studies in a group of patients with advanced breast cancer who had been treated with these anthracycline derivatives.

PATIENTS AND METHODS

We studied 35 patients eligible to receive chemotherapy including the anthracyclines: doxorubicin or mitoxantrone (cumulative dose of doxorubicin, 500 mg/m2; or mitoxantrone, 120 mg/m2). LVEF was measured before and after 10 cycles of chemotherapy. Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR).

RESULTS

Patients treated with doxorubicin presented with a significant decrease in LVEF after chemotherapy (before, 60.4% +/- 8.92%; after, 49.8% +/- 9.71%; P = .001). Antimyosin uptake was observed in all patients with a HLR of 2.03 +/- 0.25. Seven of eight patients with a HLR greater than 2.03 had a greater than 10% decrease in LVEF. Patients treated with mitoxantrone did not present with a decrease in LVEF after chemotherapy (before, 55.4% +/- 6.25%; after, 55.8% +/- 7.25%; not significant). Antimyosin uptake was observed in 14 of 17 patients with a HLR of 1.77 +/- 0.18 (P < .05).

CONCLUSION

111In antimyosin monoclonal antibodies defect myocardial cell damage produced by doxorubicin and mitoxantrone. In patients with advanced breast cancer, cumulative doses of 120 mg/m2 of mitoxantrone produce less myocardial cell damage than cumulative doses of 500 mg/m2 of doxorubicin. 111In antimyosin uptake without decrease in LVEF after treatment with mitoxantrone indicates the presence of myocyte cell damage, but not to the extent necessary to deteriorate function. These results indicate that 111In antimyosin antibody studies are useful in the noninvasive comparative assessment of cardiotoxicity produced by different anthracycline derivatives.
Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma.
Authors: Dinapoli R P , Brown L D , Arusell R M , Earle J D , O'Fallon J R , Buckner J C , Scheithauer B W , Krook J E , Tschetter L K , Maier J A
Published: February 2017

PURPOSE

We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and PCNU with those of RT and carmustine (BCNU) in patients with malignant glioma.

PATIENTS AND METHODS

A total of 346 patients with histologically verified supratentorial grade 3 and grade 4 astrocytoma were studied. After surgery, patients were randomly assigned to receive RT 60 Gy in 30 fractions and either PCNU 100 mg/m2 or BCNU 200 mg/m2 every 7 weeks for 1 year and every 10 weeks for the second year. RT and chemotherapy were started within 72 hours of randomization and usually on the same day. Of 334 assessable patients, 72% had partial or radical resection and 71% had grade 4 tumors. Median age was 59 years, and 85% had performance scores of 0 to 2 (Eastern Cooperative Oncology Group [ECOG]). The follow-up duration of 51 living patients ranged from 10.3 to 63.2 months, with a median of 36.2 months.

RESULTS

The median survival duration in each group was 47 weeks, and median time to progression was 28 weeks. PCNU produced significantly more leukopenia and thrombocytopenia, whereas BCNU produced significantly more nausea, vomiting, and irritation.

CONCLUSION

PCNU has no therapeutic advantage at this dose and schedule and does not warrant further study as a single agent for patients with high-grade glioma.
Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients.
Authors: Kirn D , Mauch P , Shaffer K , Pinkus G , Shipp M A , Kaplan W D , Tung N , Wheeler C , Beard C J , Canellos G P
Published: February 2017

PURPOSE

A retrospective study was performed to define clinical characteristics and therapeutic outcome for patients with large-cell and immunoblastic lymphoma of the mediastinum.

PATIENTS AND METHODS

Fifty-seven patients who presented with primary, mediastinal large-cell and immunoblastic lymphoma were retrospectively studied to determine initial sites of disease, radiologic characteristics, treatment, outcome, and factors that have prognostic significance for progression-free and overall survival.

RESULTS

Fifty-six of the 57 patients had disease that was confined to sites above the diaphragm. Bulky disease and extensive intrathoracic infiltration were common in these patients. All patients were treated with intensive chemotherapy regimens, and 44% of patients received chest irradiation. The overall 5-year survival by Kaplan-Meier estimation was 50% with a freedom-from-relapse rate of 45%. Predictors of disease relapse after chemotherapy included the presence of a pleural effusion (P = .015), a number of involved extranodal sites (P < .01), and a lactic dehydrogenase (LDH) ratio > 3.0 (LDH value/upper limit of assay; P = .04) as well as an incomplete treatment response as evidenced by residual mass on chest radiograph (P = .02) or persistent gallium 67 avidity (P = .01) after chemotherapy. Predictors of decreased survival included the presence of pleural effusion (P = .001), the number of involved extranodal sites (P = .022), and a positive posttreatment 67Ga scan (P = .027).

CONCLUSION

Patients with primary mediastinal large-cell and immunoblastic lymphoma have an approximate 50% chance of surviving disease-free after initial therapy. The presence of pleural effusion at presentation was associated with an extremely poor outcome. Bulk disease per se was a negative predictive factor only in patients without pleural effusions when compared with patients who did not have bulk disease. In addition, all patients with involvement of two or more extranodal sites relapsed when treated with standard chemotherapy.
Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.
Authors: Minasian L M , Motzer R J , Gluck L , Mazumdar M , Vlamis V , Krown S E
Published: February 2017

PURPOSE

Three trials were conducted to define the efficacy and toxicity of interferon alfa-2a in the treatment of metastatic renal cell cancer. Univariate and multivariate analyses were performed to identify prognostic factors for survival.

PATIENTS AND METHODS

Prospectively, 159 patients were treated with interferon alfa-2a. In the first trial, 42 patients received 50 x 10(6) U/m2 intramuscularly three times per week. In the second trial, 64 patients received gradually escalating doses of interferon alfa-2a from 3 to 36 x 10(6) U subcutaneously administered daily. The third trial was randomized; 25 patients received daily interferon alfa-2a alone and 28 were treated with daily interferon alfa-2a and 0.15 mg/kg vinblastine every 3 weeks.

RESULTS

The overall response proportion was 10% (two complete and 14 partial responses). The median response duration was 12.2 months. The median survival duration was 11.4 months, with 3% of patients alive at 5 or more years. A univariate statistical analysis showed that a Karnofsky performance status > or = 80, prior nephrectomy, and interval from diagnosis to treatment of longer than 365 days were significant prognostic factors for survival. In a multivariate analysis, only prior nephrectomy and Karnofsky performance status > or = 80 were shown to be independent predictors of survival.

CONCLUSION

Interferon alfa-2a had minimal antitumor activity in patients with advanced renal cell carcinoma and long-term survival was achieved in a small proportion of patients. The need for continued investigation and the identification of more effective therapy for advanced renal cell carcinoma is evident from the poor overall survival rate observed in these 159 patients. The investigation of new agents and of interferon alfa-2a in combination with other agents remains a priority.
Etoposide in relapsed or refractory Wilms' tumor: a phase II study by the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group.
Authors: Pein F , Pinkerton R , Tournade M F , Brunat-Mentigny M , Levitt G , Margueritte G , Rubie H , Sommelet D , Thyss A , Zücker J M
Published: February 2017

PURPOSE

Despite a high cure rate of approximately 85% in Wilms' tumor by multimodality therapy, to date only four drugs are known to be active against such tumors. There is a clear need for new active drugs.

PATIENTS AND METHODS

Thirty-one patients with relapsed or refractory Wilms' tumor from three British and 14 French centers were treated with intravenous (IV) etoposide 200 mg/m2 daily for 5 days. Original stage was I (n = 3), II (n = 7), III (n = 9), IV (n = 10), and V (n = 2). Prior chemotherapy, administered initially or at relapse, included vincristine and dactinomycin in all cases, doxorubicin or epirubicin in 30, and ifosfamide in 20. Sites of relapse or resistant disease were lung in 13, abdomen or pelvis in six, liver in one, and multiple in 11. When entered onto the study, 12 patients were in first relapse, 10 in second relapse, and four in third or more relapse. Five had never obtained a complete remission. All but two (progressing) patients received two courses of etoposide, the second course being administered at day 21.

RESULTS

A complete response (CR) was documented in two patients, partial response (PR) in 11, stable disease in 10, and progressive disease (PD) in eight. The duration of response could not be evaluated, because all responding patients were subsequently treated with multimodality therapy. The major toxicities observed were neutropenia and thrombocytopenia, but most patients had been heavily pretreated. No toxic death clearly associated with etoposide was noted.

CONCLUSION

It is concluded that etoposide in this schedule is an active agent in Wilms' tumor and should be considered for inclusion in regimens for high-risk patients, such as those with metastatic disease at diagnosis and those who relapse after multiagent chemotherapy.
Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects.
Authors: Sosman J A , Weiss G R , Margolin K A , Aronson F R , Sznol M , Atkins M B , O'Boyle K , Fisher R I , Boldt D H , Doroshow J
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2.

PATIENTS AND METHODS

We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2.

RESULTS

A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response).

CONCLUSION

The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.
Prognostic factors in Waldenström's macroglobulinemia: a report of 167 cases.
Authors: Facon T , Brouillard M , Duhamel A , Morel P , Simon M , Jouet J P , Bauters F , Fenaux P
Published: February 2017

PURPOSE

A single-center retrospective analysis was conducted in 167 patients with Waldenström's macroglobulinemia (WM) to delineate prognostic factors.

PATIENTS AND METHODS

One hundred sixty-seven patients diagnosed between January 1969 and December 1988, fulfilling diagnostic criteria of WM, were entered onto this study. One hundred twenty-eight patients were treated with chlorambucil (0.1 mg/kg/d): 117 at diagnosis and 11 during the disease course. Seventeen variables were analyzed in all patients and in treated patients for their prognostic value on survival using the Kaplan-Meier method and a Cox multivariate regression analysis.

RESULTS

Median survival duration for all patients was 60 months. Pretreatment factors associated with shorter survival in the entire population were age > or = 60 years (P = .006), male sex (P = .0001), general symptoms (P = .01), hemoglobin less than 10 g/dL (P = .008), leukocytes less than 4 X 10(9)/L (P = .02), neutrophils less than 1.7 X 10(9)/L (P = .02), and platelets less than 150 X 10(9)/L (P = .0006). Organomegaly, signs of hyperviscosity, renal failure, monoclonal immunoglobulin M (M IgM) level, blood lymphocytosis, and percentage of marrow lymphoid cells were not significantly correlated with survival. In a Cox multivariate regression analysis, the combination of factors that gave the best prognostic value was the association of sex (P = .0002), neutrophils (P = .002), age (P = .008), and hemoglobin (P = .02).

CONCLUSION

Our findings suggest that some pretreatment parameters, including older age, male sex, general symptoms, and cytopenias, carry a poor prognosis in WM. By contrast, high initial tumor burden (indicated by organomegaly, high IgM level, and high percentage of marrow lymphoid cells) does not seem to be significantly associated with short survival. Our results help define a high-risk population that could perhaps benefit from newer therapeutic approaches.
Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation.
Authors: Sparano J A , Wadler S , Diasio R B , Zhang R , Lu Z , Schwartz E L , Einzig A , Wiernik P H
Published: February 2017

PURPOSE

To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-alpha) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-alpha on 5-FU pharmacokinetics.

PATIENTS AND METHODS

Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-alpha, 5 x 10(6) IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-alpha administration using the paired t test.

RESULTS

The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-alpha 2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-alpha was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-alpha on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-alpha administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1).

CONCLUSION

IFN-alpha substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-alpha-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-alpha to enhance the toxic effects of 5-FU.
Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Childrens Cancer Group.
Authors: Nesbit M E , Buckley J D , Feig S A , Anderson J R , Lampkin B , Bernstein I D , Kim T H , Piomelli S , Kersey J H , Coccia P F
Published: February 2017

PURPOSE

In an effort to evaluate the usefulness of bone marrow transplantation, the Childrens Cancer Group (CCG) initiated a multiinstitutional study comparing bone marrow transplantation versus chemotherapy after successful induction of remission for previously untreated children and young adults with acute myeloid leukemia.

PATIENTS AND METHODS

From 1979 to 1983, 508 patients were entered onto this study and 490 were treated. After induction, patients with an HLA mixed leukocyte culture (MLC)-compatible sibling underwent bone marrow transplantation. Patients not eligible for bone marrow transplantation were eligible for randomization to two chemotherapy maintenance regimens. All patients undergoing bone marrow transplantation were conditioned with cyclophosphamide and total-body irradiation (TBI). Methotrexate was used to prevent or modify graft-versus-host disease (GVHD).

RESULTS

Three hundred eighty-one patients achieved bone marrow remission (78%). Eighty-nine patients had an HLA/MLC-compatible sibling donor and were eligible for bone marrow transplantation, and 252 had no match. Comparison of survival estimates for patients eligible for transplantation versus not eligible at 3 years (52% v 41%), 5 years (50% v 36%), and 8 years (47% v 34%) showed a significant difference in favor of bone marrow transplantation (P < .05). Disease-free survival (DFS) demonstrated similar results. Application of a cure model to the results showed a better outcome for those eligible for transplantation (P = .04). Patients randomized between the two chemotherapy regimens did not show any significant difference between those treated with a continuous maintenance versus a cyclic regimen (P = .16).

CONCLUSION

Children and young adults who successfully achieved a remission with multiple-agent chemotherapy who had an HLA/MLC-compatible donor and were thus eligible for an allogeneic bone marrow transplant had better survival than those not eligible for transplantation.
Reinduction with the same cytostatic treatment in patients with metastatic breast cancer: an Eastern Cooperative Oncology Group study.
Authors: Falkson G , Gelman R , Glick J , Falkson C I , Harris J
Published: February 2017

PURPOSE

To investigate the therapeutic value of reinduction with the same cytostatic treatment that had been used in induction treatment for women with metastatic breast cancer.

MATERIALS AND METHODS

One hundred six women with metastatic breast cancer were given dibromodulcitol (mitolactol), doxorubicin, vincristine, tamoxifen, and fluoxymesterone (DAVTH) for 6 months of induction treatment, then randomized to receive one of two chemotherapy regimens if they had obtained an induction partial response (PR) or no change (NC), or to receive observation versus chemotherapy if they had obtained an induction complete response (CR). Patients were then retreated with DAVTH reinduction after relapse.

RESULTS

Seventy-four patients were eligible or had minor reasons for ineligibility. Severe or life-threatening toxicity was documented in 46%, and lethal toxicity in 4%. Eighteen percent had a response on reinduction (zero of 16 induction nonresponders, 15% induction PR, 44% induction CR). The median time to treatment failure (TTF) from reinduction was 3 months, and the median survival duration from reinduction was 14 months. In a logistic model, factors associated with more reinduction responses were observation after induction CR (P = .002) and age greater than 55 years (P = .04). Time since induction was not significant.

CONCLUSION

Reinduction of response after treatment failure remains a therapeutic problem. The need for better salvage treatment underlines the importance of developing new regimens.
Prognostic significance of p53 immunostaining in epithelial ovarian cancer.
Authors: Hartmann L C , Podratz K C , Keeney G L , Kamel N A , Edmonson J H , Grill J P , Su J Q , Katzmann J A , Roche P C
Published: February 2017

PURPOSE

To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase.

PATIENTS AND METHODS

We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease.

RESULTS

p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis.

CONCLUSION

Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.
Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.
Authors: Miles D W , Fogarty O , Ash C M , Rudd R M , Trask C W , Spiro S G , Gregory W M , Ledermann J A , Souhami R L , Harper P G
Published: February 2017

PURPOSE

A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC).

PATIENTS AND METHODS

Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria.

RESULTS

Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant).

CONCLUSION

In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.
Thymidylate synthase inhibition after administration of fluorouracil with or without leucovorin in colon cancer patients: implications for treatment with fluorouracil.
Authors: Peters G J , van der Wilt C L , van Groeningen C J , Smid K , Meijer S , Pinedo H M
Published: February 2017

PURPOSE

To determine the time-dependence of fluorouracil (5FU)-induced thymidylate synthase (TS) inhibition in colon cancer patients, the effect of leucovorin (LV), and the relation to response.

PATIENTS AND METHODS

A 5FU injection (500 mg/m2) was given to 47 patients with advanced colorectal cancer; tumor biopsy specimens were obtained 1 to 72 hours after laparotomy. Eleven patients received LV (2-hour infusion of 500 mg/m2) with 5FU midinfusion; biopsies were obtained after 45 hours. TS inhibition was evaluated by comparing the number of total and free 5-fluoro-2'-deoxy-uridine-5'- monophosphate (UMP) (FdUMP) binding sites and the total and residual catalytic activity of TS.

RESULTS

The total catalytic TS activity varied from 0 to 621 pmol/h/mg protein and the total number of FdUMP binding sites varied from 0 to 976 fmol/mg protein. The residual catalytic TS activity after 2, 23, and 45 hours was 41%, 65%, and 74% of the total catalytic activity; the number of free FdUMP binding sites was 12%, 27%, and 49% of the total number, respectively. LV enhanced TS inhibition after 45 hours; the residual catalytic activity decreased from 74% to 49%, and the number of free FdUMP binding sites from 49% to 24%. Eleven of 19 patients treated with hepatic arterial infusion of 5FU had a partial response (PR). In the nonresponding patients, total TS activity was significantly higher (P < .05) than in responding patients. A high TS activity with a poor inhibition correlated with no response.

CONCLUSION

Residual and total TS activity are predictive for response to 5FU. The findings may be applicable for treatment of patients with advanced disease and TS should be evaluated as a prognostic factor in adjuvant chemotherapy studies.
Renal tolerance of cisplatin in patients more than 80 years old.
Authors: Thyss A , Saudes L , Otto J , Creisson A , Gaspard M H , Dassonville O , Schneider M
Published: February 2017

PURPOSE

Assessment of cisplatin (CDDP) tolerance in patients more than 80 years old in good general condition who may benefit from CDDP-based treatment.

PATIENTS AND METHODS

Data on 35 patients older than 80 years who received one to six chemotherapy cycles (median, three cycles; total number of cycles, 98) including CDDP (60 to 100 mg/m2) were analyzed retrospectively. Before treatment, all patients had normal renal function as defined by serum creatinine (SC) levels below 132 mumol/L. Renal function was evaluated by measurement of SC and creatinine clearance (CC) before and after each course of chemotherapy. CC was calculated according to the Cockroft and Gault formula, where CC = (140 - age) x weight kg/0.814 x SC mumol/L. Renal toxicity was evaluated by the difference between prechemotherapy SC and the maximum SC level observed (delta SC) and by the difference between prechemotherapy CC and the minimal CC observed after treatment with CDDP (delta CC). The evolution of SC and CC during repeated courses of CDDP was analyzed, as were any extrarenal toxicities.

RESULTS

Renal function remained stable in 19 patients (54%) with delta SC less than 18 mumol/L and 18 of 35 patients (51%) with delta CC less than 9 mL/min. A slight deterioration in renal function was observed in 13 patients (37%) with delta SC greater than 18 mumol/L and less than 60 mumol/L, and with a delta CC greater than 11 mL/min and less than 21 mL/min. In three patients (9%), delta SC was greater than 60 mumol/L (71, 73, 115 mumol/L) and delta CC was greater than 21 mL/min (25, 26, 36 mL/min). There were no cases of severe renal insufficiency, clinical ototoxicity, or neurotoxicity > or = grade 2. Treatment was terminated after one or two courses in three patients because of grade 2 or 3 hematologic toxicity and in two patients for grade 3 nausea or vomiting.

CONCLUSION

CDDP at moderate doses can reasonably be administered to patients older than 80 years who may benefit from antineoplastic chemotherapy.
Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia.
Authors: Reinisch W , Willheim M , Hilgarth M , Gasché C , Mader R , Szepfalusi S , Steger G , Berger R , Lechner K , Boltz-Nitulescu G
Published: February 2017

PURPOSE

This study was initiated to evaluate whether soluble CD23 (sCD23) reflects disease activity and tumor load in B-cell chronic lymphocytic leukemia (B-CLL) and to determine its prognostic potential for this disease.

PATIENTS AND METHODS

The concentration of sCD23 was measured in the serum of 45 B-CLL patients, 50 patients with other lymphoproliferative disorders, and 41 healthy donors (HD). sCD23 serum levels from B-CLL patients were correlated with parameters of disease activity and total tumor mass (TTM) score. In selected cases, sCD23 was measured repeatedly over a 24-month period. Expression, density, and calculated total amount of membrane CD23 on peripheral-blood B-CLL cells, as well as its correlation to sCD23 levels in serum and supernatants, were determined.

RESULTS

sCD23 in B-CLL patients serum was highly elevated as compared with other lymphoproliferative disorders, with the exception of immunocytoma (IC). Both advanced Rai stages and active forms of B-CLL were associated with higher levels of sCD23. There was a highly significant reciprocal relationship between sCD23 and lymphocyte count doubling time (LCDT). Serum sCD23 correlated positively with serum deoxythymidine kinase activity and TTM score, but not with absolute lymphocyte counts. The repetitive measurement of serum sCD23 showed the usefulness of this marker in monitoring disease progression in B-CLL. The total amount of membrane CD23 on in vitro-cultured B-CLL cells correlated significantly with sCD23 levels in the supernatant, whereas correlation between serum sCD23 and membrane CD23 on freshly isolated B-CLL cells was absent.

CONCLUSION

Our results indicate that sCD23 is a highly sensitive and specific parameter with prognostic potential for B-CLL, which may be used as a tumor marker and may help to assess disease activity.
Secondary malignancies after bone marrow transplantation in adults.
Authors: Lowsky R , Lipton J , Fyles G , Minden M , Meharchand J , Tejpar I , Atkins H , Sutcliffe S , Messner H
Published: February 2017

PURPOSE

The records of 557 consecutive adult recipients of allogeneic-related and -unrelated and syngeneic bone marrow transplants (BMTs) were reviewed to determine the incidence of secondary cancers.

PATIENTS AND METHODS

Four hundred fifty-six patients were transplanted for acute lymphocytic leukemia (ALL; n = 79), acute myelogenous leukemia (AML; n = 182), and chronic myelogenous leukemia (CML; n = 195); 42 patients were transplanted for aplastic anemia (AA) and 59 for a variety of other hematologic and nonhematologic disorders, malignant and nonmalignant. Conditioning regimens included high-dose chemotherapy with or without total-body irradiation (TBI). Statistical analyses determined the cumulative incidence of developing a secondary cancer and elucidated the associated risk factors. Complete records (1 to 24 years of follow-up) on all patients were available.

RESULTS

Nine patients developed 10 secondary cancers for a cumulative actuarial risk of 12% (95% confidence interval [CI], 4.3 to 23.0) 11 years after transplant. The age-adjusted incidence of secondary cancer was 4.2 times higher than that of primary cancer in the general population. Eight of the 10 were epithelial in origin and three were cutaneous. TBI and acute graft-versus-host disease (GVHD) with a severity > or = grade II were associated with the development of any secondary cancer. On the other hand, chronic GVHD was a risk factor only for the development of secondary skin neoplasms.

CONCLUSION

Adult recipients of BMT face a significant risk of developing a secondary malignancy. Their risk is similar to that of other patients with hematologic malignancies who are treated with chemoradiotherapy only. Epithelial tumors, rather than the more commonly reported Epstein-Barr virus (EBV)-associated lymphomas, were most common. The fact that we did not routinely use T-cell-depleted marrow grafts nor anti-T-cell immunoglobulin for the treatment of acute GVHD may explain this variance.
Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors.
Authors: Motzer R J , Bajorin D F , Schwartz L H , Hutter H S , Bosl G J , Scher H I , Lyn P , Fischer P
Published: February 2017

PURPOSE

A trial of paclitaxel was conducted in patients with previously treated germ cell tumors (GCT). As the identification of new agents in GCT may be compromised by restricting entry criteria to heavily pretreated patients, an alternative trial design was used in which eligibility was restricted to patients with limited prior therapy.

PATIENTS AND METHODS

Patients were eligible if their prior therapy was limited to one cisplatin-based regimen or < or = six cycles of prior cisplatin-based therapy. Paclitaxel 250 mg/m2 was administered by continuous infusion over 24 hours every 21 days. The dose of paclitaxel was modified for each patient based on toxicity. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg/d was administered during nadir periods.

RESULTS

Thirty-one patients were treated; eight patients (26%) achieved a partial (n = 5) or a complete (n = 3) response. Responses were achieved in patients who had failed to respond to treatment with cisplatin, ifosfamide, and etoposide, and in patients with poor prognostic features, ie, mediastinal primary tumor site and patients with a best prior response of an incomplete response to cisplatin therapy. One complete responder remains continuously free of disease at 13+ months and one of the five patients who achieved a partial response remains progression-free at 14+ months.

CONCLUSION

Paclitaxel has antitumor activity in GCT and warrants continued study in combination chemotherapy. Phase I/II trials will address its role in combination with cisplatin and ifosfamide and as a part of dose-intensive therapy. Furthermore, the study showed that a trial design in which eligibility criteria limits prior therapy was feasible, resulted in the identification of antitumor activity in a new agent, and may be considered in future trials for other promising new agents in GCT.
Clinical impact of chemotherapy-induced thrombocytopenia in patients with gynecologic cancer.
Authors: Goldberg G L , Gibbon D G , Smith H O , DeVictoria C , Runowicz C D , Burns E R
Published: February 2017

PURPOSE AND METHODS

This retrospective analysis of 501 patients with gynecologic cancer treated with chemotherapy evaluates the relationship between platelet count and clinical bleeding, as well as the clinical effects of platelet transfusion therapy. Thrombocytopenic patients were divided into six groups according to platelet counts, and major or minor bleeding manifestations were documented. Thrombocytopenia was defined as a platelet count less than 100,000/microL.

RESULTS

Thrombocytopenia occurred in 182 (36.3%) patients over 808 of 1,546 chemotherapy cycles (52%). No intracranial or life-threatening bleeding occurred in any patient. The majority of patients (139 [76.4%]) had no clinical bleeding. Minor bleeding, such as purpura, occurred in 34 patients (18.7%) and 44 cycles (5.4%). Major bleeding occurred in nine patients (4.9%) and 10 cycles (1.3%). Five major bleeding events occurred in 49 patients with platelet counts between 0 and 10,000/microL. Forty-three of these patients received platelet transfusions. Thirty-eight of 43 transfused patients (88.3%) had no bleeding. Of the remaining five patients, two were transfused prophylactically with no effect. Three major bleeding events occurred in patients with platelet counts that ranged from 11,000 to 20,000/microL, but these were due to chronic instrumentation or trauma. In patients with platelet counts more than 20,000/microL, major bleeding occurred only from necrotic metastatic lesions. Random-donor platelet transfusions provided inconsistent increments in platelet counts. Overall, 27.5% of patients achieved the expected increase in platelet number based on units of platelet concentrate transfused. The use of single-donor or human leukocyte antigen (HLA)-matched platelets did not provide greater increments in those patients who were refractory to random-donor platelets.

CONCLUSION

Platelet counts > or = 10,000/microL are not associated with spontaneous major bleeding. Prophylactic platelet transfusions in patients with gynecologic malignancies and chemotherapy-induced thrombocytopenia should be limited to those with platelet counts < or = 10,000/microL, provided they are not bleeding and have no major anatomic or pathophysiologic precursors of bleeding.
Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.
Authors: Murray N , Coppin C , Coldman A , Pater J , Rapp E
Published: February 2017

PURPOSE

The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population.

PATIENTS AND METHODS

Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status.

RESULTS

Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01).

CONCLUSION

The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.
Randomized double-blind, placebo-controlled evaluation of oral ondansetron in the prevention of nausea and vomiting associated with fractionated total-body irradiation.
Authors: Spitzer T R , Bryson J C , Cirenza E , Foelber R , Wallerstadt M , Stout C , Kunka R L , Plagge P B , Dubois A
Published: February 2017

PURPOSE

To evaluate oral ondansetron in the prevention of total-body irradiation (TBI)-induced nausea and vomiting.

METHODS

Twenty patients who received 4 days of TBI as part of their preparative regimen before bone marrow transplantation were randomized to receive either 8-mg oral doses of ondansetron or placebo. Administration of drug was double-blinded. Initial rescue therapy consisted of intravenous (i.v.) ondansetron 0.15 mg/kg following two or more emetic episodes between successive fractions of TBI or five total emetic episodes during the 4 days of therapy. If, after receipt of i.v. ondansetron, patients had two or more emetic episodes between fractions of TBI or five total emetic episodes, additional antiemetics were administered.

RESULTS

Patients who received oral ondansetron had significantly fewer emetic episodes compared with those who received placebo (P = .005) over the entire 4-day study period. Oral ondansetron was also significantly superior to placebo with respect to the time of onset of emesis or rescue (P = .003). Six of 10 patients treated with oral ondansetron completed the study without additional antiemetic therapy, while none of 10 patients who received placebo completed the study without rescue antiemetic therapy. Six placebo patients who received initial rescue therapy with i.v. ondansetron required no additional antiemetics. No relationships were apparent between peak ondansetron concentration (Cmax) or area under the concentration versus time curve (AUC) and number of emetic episodes.

CONCLUSION

Oral ondansetron is an effective therapy for the prevention of emesis induced by TBI.