bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support.
Authors: Dunphy F R , Spitzer G , Buzdar A U , Hortobagyi G N , Horwitz L J , Yau J C , Spinolo J A , Jagannath S , Holmes F , Wallerstein R O
Published: February 2017

We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.
A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer.
Authors: Levine M N , Gent M , Hryniuk W M , Bramwell V , Abu-Zahra H , DePauw S , Arnold A , Findlay B , Levin L , Skillings J
Published: February 2017

A randomized trial has been performed in which women with axillary node-positive breast cancer were allocated to either a short intensive 12-week chemohormonal treatment consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and tamoxifen (CMFVP plus AT) or 36 weeks of CMFVP. The median follow-up is 37 months. Of the 222 women randomized to the 12-week treatment, 113 (50.9%) have experienced either recurrence or death as compared with 90 patients (41.9%) in the 36-week treatment group. The corresponding 3-year relapse-free survivals are 55% and 64%, respectively, P = .003. Fifty-nine (26.6%) of the patients in the 12-week group have died compared with 46 (21.4%) of the 36-week group. The corresponding 3-year survival rates are 78% and 85%, respectively, P = .04. A Cox regression analysis showed an associated increased risk ratio for recurrence or death of 1.7, P = .003, and for death of 1.8, P = .017 in the 12-week treatment group compared with the 36-week group. Thus, this 12-week regimen of adjuvant chemohormonal therapy is inadequate treatment for women with axillary node-positive breast cancer; possible explanations for this inferiority are its shorter duration and/or a negative interaction of tamoxifen on the chemotherapy.
The effect of right atrial catheters on infectious complications of chemotherapy in children.
Authors: van Hoff J , Berg A T , Seashore J H
Published: February 2017

Rates of infections and catheter complications in children with right atrial catheters (RACs) receiving chemotherapy were compared with those without RACs in a retrospective cohort study. One hundred sixty-five children presenting to Yale-New Haven Hospital with a malignancy diagnosed between January 1, 1981 and December 31, 1985 were followed through June 30, 1986 for the number of treatment-related complications resulting in hospitalization. The time on therapy totaled 80,089 person-days that were divided into 510 periods of observation defined by the presence or absence of a RAC, disease status (remission, partial remission, or relapse), intensity of chemotherapy (using a 0 to 4 scale), and use of radiation therapy. Children with RACs experienced markedly higher rates of sepsis (14-fold higher, P less than .0001) and catheter-site infection or other catheter complications requiring hospitalization (both greater than 30-fold higher, P less than .0001). These effects persisted after controlling for other risk factors, ie, disease status, chemotherapy intensity, and age. Children with RACs also had higher rates of fever and neutropenia and other infections requiring hospitalization that were more strongly influenced by the other risk factors. The association of RACs with sepsis, fever and neutropenia, and days hospitalized for treatment-related complications was assessed using multivariable analysis methods to control for disease status, intensity of chemotherapy, radiation therapy, type of cancer, age, and sex. The presence of a RAC (rate ratio [RR], 6.39; P less than .0001) and the disease status (RR, 2.45; P = .0004) were the only factors that predicted sepsis. Fever and neutropenia rates were most influenced by chemotherapy intensity (RR, 2.31; P = .0001) and age (RR, 0.94; P = .013 per year of age) and less by the presence of a RAC (RR, 1.56; P = .053). Controlling for other risk factors, children with RACs experienced a 6.4-times higher rate of sepsis and spent an average of 15.4 more days per year in the hospital for treatment-related complications.
3H-thymidine-labeling index as a prognostic indicator in node-positive breast cancer.
Authors: Silvestrini R , Daidone M G , Valagussa P , Di Fronzo G , Mezzanotte G , Mariani L , Bonadonna G
Published: February 2017

The prognostic relevance of 3H-thymidine-labeling index (3H-TdR-LI) was retrospectively evaluated in 523 women with resectable node-positive breast cancer given adjuvant combination chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil (CMF) +/- Adriamycin (doxorubicin; Farmitalia, Carlo Ezba, Italy). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were significantly higher for patients with slowly proliferating tumors (3H-TdR-LI less than or equal to 2.8%) compared with rapidly proliferating tumors (RFS, 66% v 50%, P = .0007; OS, 85% v 73%, P = .0012). In the analysis of RFS, 3H-TdR-LI provided prognostic information independent of axillary node involvement, tumor size, and estrogen receptor (ER) status, with an estimated lower hazard ratio compared with the degree of nodal involvement, but equivalent to that of the other indicators. Conversely, nodal involvement was found to interact with 3H-TdR-LI and receptors on survival. Present findings confirm that tumor cell kinetics represents a prognostic indicator also in an adjuvant situation. 3H-TdR-LI can substantially contribute to a more precise definition of high-risk patients within subsets having the traditionally favorable prognostic characteristics.
A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group.
Authors: Coombes R C , Schein P S , Chilvers C E , Wils J , Beretta G , Bliss J M , Rutten A , Amadori D , Cortes-Funes H , Villar-Grimalt A
Published: February 2017

Three hundred fifteen patients with operable gastric cancer were randomized to receive fluorouracil, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and mitomycin (FAM) or no adjuvant treatment between September 1981 and July 1984. After excluding ineligible patients, 281 patients are included in this analysis. Treatment was moderately well tolerated by the majority of patients, the common side effects being nausea and vomiting (58%) and alopecia (57%). Three possible treatment-related deaths were seen, all due to cardiac failure. At median follow-up of 68 months, 164 patients have died, 73 in the treated arm and 91 in the control arm. There was no significant difference in disease-free or overall survival between the two arms of the study (P = 0.21). There is some evidence that patients with more advanced carcinoma (T3-T4) derived some benefit from treatment (P = 0.04). The interpretation of this finding must take into account that all subgroups were defined retrospectively, and this could, therefore, be a chance finding. We conclude that adjuvant chemotherapy as given in this trial is not indicated as routine treatment in operable gastric cancer, but that further evaluation in stage T3-T4 patients is warranted.
A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861.
Authors: Klastersky J , Sculier J P , Lacroix H , Dabouis G , Bureau G , Libert P , Richez M , Ravez P , Vandermoten G , Thiriaux J
Published: February 2017

The European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Working Party conducted a randomized trial comparing cisplatin (CDDP; 120 mg/m2, day 1) and carboplatin (CBDCA; 325 mg/m2, day 1) in combination with etoposide (VP16; 100 mg/m2, days 1, 2, and 3) in advanced non-small-cell lung cancer (NSCLC). Two hundred twenty-eight patients were eligible for survival and 202 assessable for response. We obtained 27 of 100 objective responses (ORs; 27%) in the CDDP arm and 16 of 102 (16%) in the CBDCA arm (P = .07). There was no significant difference in survival. Toxicity, consisting mainly of myelosuppression and renal function impairment, was significantly increased in the patients receiving the CDDP treatment. We conclude that CDDP plus VP16 was more active but also more toxic than CBDCA plus VP16 in advanced NSCLC.
Prevention of bacteremia attributed to luminal colonization of tunneled central venous catheters with vancomycin-susceptible organisms.
Authors: Schwartz C , Henrickson K J , Roghmann K , Powell K
Published: February 2017

Forty-five children with oncologic or hematologic disorders requiring tunneled central venous catheters (TCVC) for the administration of immunosuppressive therapy were randomized to receive either 10 U/mL heparin (H) (24 patients) or a solution of 10 U/mL H and 25 micrograms/mL vancomycin (H-V) (21 patients) for all catheter flushes. Episodes of fever or suspected sepsis were evaluated to determine whether the addition of vancomycin to the flush solution would alter the incidence of symptomatic bacteremia attributed to luminal colonization of TCVC with vancomycin-susceptible bacteria. Patients were enrolled for 247 +/- 150 days, accounting for a total of 11,095 days of catheter use. Bacteremia attributed to luminal colonization with vancomycin-susceptible organisms occurred in five patients (six infections) receiving H alone compared with zero patients receiving H-V (P = .035). The time to the first episode of bacteremia with vancomycin-susceptible organisms, analyzed by Kaplan-Meier survival curves, was significantly longer in patients receiving H-V (P = .04). There were no differences in the incidence of other infections including bacteremia attributed to luminal colonization with vancomycin-resistant organisms, other bacteremias (including those arising from the catheter exit site), exit-site cellulitis, or fungal infections. No organisms resistant to vancomycin were identified. Vancomycin could not be detected in the peripheral blood of patients receiving vancomycin in the flush solution. No vancomycin-related toxicities were noted. We conclude that the use of an H-V flush solution in immunocompromised patients with TCVC can decrease the frequency of bacteremia attributed to luminal colonization with vancomycin-susceptible bacteria.
Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: a prospective study.
Authors: Ochs J , Mulhern R , Fairclough D , Parvey L , Whitaker J , Ch'ien L , Mauer A , Simone J
Published: February 2017

We prospectively compared neuropsychologic functioning and clinical indicators of neurotoxicity in 49 consecutive childhood leukemia patients in long-term continuous complete remission (CR) who had received two different regimens of CNS prophylaxis by random assignment. Twenty-three patients were treated with 1,800 cGy cranial radiation and intrathecal methotrexate (RT group) and 26 with parenteral methotrexate only (MTX group). Over half of the RT group had somnolence syndrome, and four developed cerebral calcifications late in their clinical course. Abnormal electroencephalograms (EEGs) were seen in 15 patients in the MTX group, and six had early, transient white-matter hypodensities apparent on computed tomographic (CT) scans. Mean scores on standard tests of intelligence and academic achievement, administered after remission induction and again at a median of 6 years after treatment cessation, did not differ significantly between the two groups. However, statistically significant decreases in overall and verbal intelligence quotients (IQs) and in arithmetic achievement were found within both treatment groups. Sixteen of 26 in the MTX group and 14 of the 23 in the RT group had clinically important decreases (greater than or equal to 15 points) on one or more neuropsychologic measures. These changes did not correlate with findings on CT scans, EEGs, or other clinical signs of neurotoxicity. We conclude that 1,800 cGy cranial radiation and parenteral methotrexate, as used in this study, are associated with comparable decreases in neuropsychologic function.
Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma.
Authors: Shapiro D N , Parham D M , Douglass E C , Ashmun R , Webber B L , Newton W A , Hancock M L , Maurer H M , Look A T
Published: February 2017

Clinical and histopathologic features are often inadequate for accurate prediction of relapse or survival of individual patients with rhabdomyosarcoma (RMS). We therefore studied the cellular DNA content (ploidy) of RMS cells in relation to histology and response to therapy in 37 patients with unresectable tumors. Using flow cytometric techniques, we found that about one third of patients had diploid tumor stem lines, regardless of the histologic subtype. In the group with abnormal ploidy, a hyperdiploid classification (1.10 to 1.80 times the DNA content of normal diploid cells) was exclusively associated with embryonal histology (P = .001). By contrast, near-tetraploidy (1.80 to 2.60 times the DNA content of normal cells) was strongly associated with alveolar histology (P = .001). Thus, in these histologic subtypes of RMS, abnormal ploidy appears to arise through different mechanisms. Tumor-cell ploidy had a significant impact on survival that was especially apparent in patients with unresectable, nonmetastatic (group III) tumors. In this subgroup, hyperdiploidy conferred the best prognosis and diploidy the worst (P less than .0001). None of the eight patients with diploid tumors survived for more than 18 months. Tumor-cell ploidy was the best predictor of treatment outcome for patients with either embryonal (P less than .001; relative risk, 25.5) or alveolar (P = .073; relative risk 7.1) RMS and contributed significantly after adjustment for disease stage and anatomic site. Patients with unresectable diploid RMS have an unacceptably high risk of treatment failure, justifying new therapeutic approaches for this distinct subgroup.
Extrarenal Wilms' tumor: staging, treatment, and prognosis.
Authors: Coppes M J , Wilson P C , Weitzman S
Published: February 2017

Extrarenal Wilms' tumors are rare and have mainly been the subject of isolated case reports. This retrospective evaluation of 34 patients suggests a clinical course very similar to that of renal Wilms' tumor. While clinical presentation varies according to the extrarenal localization, investigations to determine the size of the primary tumor (T), regional lymph node involvement (N), and the occurrence of distant metastasis (M) are very similar, ie, chest x-ray, abdominal ultrasound (US), and computed axial tomographic (CAT) scan of the abdomen and chest. Stage grouping according to the pathologic TNM classification showed stage I in 30%, stage II in 10%, stage IIIa in 34%, stage IIIb in 23%, and stage IVa in 3%; four patients could not be staged. Evaluation of therapy and survival indicate the need for postoperative chemotherapy (CT) to all patients, while the same data suggest that the drugs used for renal Wilms' tumor are equally effective for extrarenal Wilms' tumor. Radiotherapy (RT) probably should be reserved for those patients with unresectable gross residual disease and for metastatic disease. The radiation dose used in the reviewed cases varied from 2,000 to 5,000 cGy. However, recent experience suggests that high doses are not justified in renal Wilms' tumor. The estimated overall 2-year survival of the 34 patients is 82% (95% confidence interval, 63% to 92%).
P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.
Authors: Miller T P , Grogan T M , Dalton W S , Spier C M , Scheper R J , Salmon S E
Published: February 2017

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.
Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.
Authors: Keating M J , Kantarjian H , O'Brien S , Koller C , Talpaz M , Schachner J , Childs C C , Freireich E J , McCredie K B
Published: February 2017

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.
Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer.
Authors: Hainsworth J D , Andrews M B , Johnson D H , Greco F A
Published: February 2017

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.
Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases.
Authors: Cote R J , Rosen P P , Lesser M L , Old L J , Osborne M P
Published: February 2017

We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.
Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma.
Authors: Rydholm A , Gustafson P , Rööser B , Willén H , Akerman M , Herrlin K , Alvegård T
Published: February 2017

From 1980 through 1986, 119 patients with soft tissue sarcomas of the extremities were referred to our tumor center either before surgery (n = 78) or immediately after incisional biopsy or marginal excision (n = 41). The tumors were classified according to anatomic location at admittance as subcutaneous (n = 40), intramuscular (n = 30), and extramuscular tumors (n = 49). Open biopsy was omitted in 75 of the 78 patients referred before surgery; the preoperative diagnosis was based on physical and radiographic findings and fine-needle aspiration cytology. The surgical intention for subcutaneous tumor was to obtain a wide margin, which required a cuff of fat tissue around the tumor and inclusion of the deep fascia beneath the tumor. A wide margin for an intramuscular tumor implied no open biopsy and an unbroken muscle fascia or thick muscle cuff around the tumor (primary myectomy). The 70 patients with subcutaneous and intramuscular tumors were all treated by local surgery. A wide margin was obtained in 56 patients who were not given radiotherapy. During a median follow-up of 5 years (range, 3.5 to 10 years), four of these 56 patients--47 of whom had high-grade malignant tumors--had a local recurrence. We conclude that routine combination of limb-sparing surgery with adjuvant radiotherapy is not necessary in patients with soft tissue sarcoma. Two thirds of soft tissue sarcomas of the extremities are primarily subcutaneous or intramuscular tumors, the majority of which can be treated by local surgery without local adjuvant therapy with a local recurrence rate of less than 10%, irrespective of malignancy grade.
Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: the British autograft group experience.
Authors: Chopra R , Goldstone A H , McMillan A K , Powles R , Smith A G , Prentice H G , Reid C , Marcus R , Bell A , Milligan D
Published: February 2017

The results in 34 adult patients with acute myeloid leukemia (AML) who have undergone autologous bone marrow transplantation (ABMT) using busulfan and cyclophosphamide (Bu/Cy) in 12 United Kingdom (UK) centers have been analyzed. There were 19 females and 15 males; median age was 40 years (range, 21 to 62 years). Nine patients were in first relapse; 25 were in second remission. The median time of first remission for the whole group was 11.5 months (range, 1 to 56 months). All the patients in first relapse and six patients in second remission received first remission marrow. The leukemia-free survival (LFS) for the patients in first relapse was 33%, with a median follow-up of 20 months. The LFS for the patients in second remission was 48% with a median follow-up of 26 months. The length of second remission exceeds the length of first remission in 14 patients. Considerable toxicity with hemorrhagic cystitis (four patients; none fatal), venoocclusive disease (four patients; one fatal), pneumonitis (four patients; one fatal), intracranial hemorrhage (two patients; two fatal) has occurred. There have been four procedure-related deaths (12%). Hematologic recovery was satisfactory for neutrophils (median time to 0.5 x 10(9)/L, 22 days [range, 11 to 101 days]), but very slow for platelets (median time to 50 x 10(9)/L, 62 days [range, 15 to 1,080 days]). This study suggests that the use of Bu/Cy with ABMT for patients beyond first remission in AML compares favorably with chemotherapy, and although the procedure-related mortality is acceptable, it is associated with protracted platelet recovery.
Herpes simplex virus infection in the immunocompromised cancer patient.
Authors: Bustamante C I , Wade J C
Published: February 2017

The development of infection remains a significant source of morbidity and mortality in the oncology patient. This patient population is at increased risk for infection because of alterations in cell-mediated immunity generated by the underlying neoplastic process and/or immunosuppressive therapy. Viral infection, particularly that attributable to herpes simplex virus (HSV), is being seen with increased frequency in the oncology patient. Because effective therapy is available with the early use of antiviral agents, it is important to be aware of the potential for viral infection and to recognize the signs and symptoms that are evident early in its course. An overview of HSV infection is provided here, including discussion of the virus itself, its pathogenesis, its clinical spectrum, and current prophylactic and therapeutic approaches.
Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: a phase I/II study.
Authors: Yung W K , Prados M , Levin V A , Fetell M R , Bennett J , Mahaley M S , Salcman M , Etcubanas E
Published: February 2017

A multicenter phase I/II trial of a human recombinant interferon beta (Betaseron; Triton Biosciences, Alameda, CA) was conducted in patients with recurrent glioblastoma and anaplastic astrocytoma in six centers between 1986 and 1988. Betaseron was given intravenously three times per week, starting at 90 x 10(6) IU per dose and escalating by 90 x 10(6) IU every 2 weeks up to a maximum dose of 540 x 10(6) per treatment. All patients had failed prior radiotherapy, and most had failed one or more courses of chemotherapy. Of the 72 patients entered into the protocol, 65 were considered assessable. Of 65 patients, 41 had glioblastoma, and 24 had anaplastic astrocytoma. Of the 65 assessable patients, 15 (23%) had an objective response (R), and 18 (28%) had stable disease (S), with a combined R and S rate of 51%. The Kaplan-Meier median time to progression was 24 weeks for the responders, 10 weeks for the nonresponders, and 23 weeks for the whole group. These results suggest that Betaseron has definite activity in recurrent gliomas, with an R + S rate of 51%. The maximum-tolerated dose (MTD) is between 180 and 360 x 10(6) IU, with neurotoxicity being the most troublesome toxicity at higher doses. Two patients died of treatment-related complication. Since most responders showed responses at the 180 x 10(6 IU dose range, further studies using a lower dose of Betaseron aimed at decreasing toxicity and allowing chronic maintenance therapy are merited.
Chemotherapy of advanced dysgerminoma: trials of the Gynecologic Oncology Group.
Authors: Williams S D , Blessing J A , Hatch K D , Homesley H D
Published: February 2017

Between 1984 and 1989, 20 assessable patients with incompletely resected ovarian dysgerminoma were treated on two protocols of the Gynecologic Oncology Group (GOG). All patients received cisplatin, bleomycin, and either vinblastine or etoposide. More recent patients also received consolidation chemotherapy with vincristine, dactinomycin, and cyclophosphamide (VAC). Eleven patients had clinically measurable disease, and 10 responded completely. Fourteen second-look procedures were done, and all were negative. Currently, 19 of 20 patients are disease-free with median follow-up of 26 months. Cisplatin-based chemotherapy is highly effective in patients with advanced dysgerminoma.
Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation.
Authors: Shepherd J D , Pringle L E , Barnett M J , Klingemann H G , Reece D E , Phillips G L
Published: February 2017

Hemorrhagic cystitis is a major complication of high-dose cyclophosphamide therapy used in preparation for allogeneic or autologous bone marrow transplantation. Although previous reports had suggested that the sulfhydryl-containing compound mesna might be superior to forced diuresis in preventing hemorrhagic cystitis, there were concerns about the effect of mesna on engraftment in these studies. To address these concerns, 100 patients were randomized to receive mesna or forced saline diuresis while undergoing bone marrow transplant conditioning with regimens that included high-dose cyclophosphamide. To try to minimize the likelihood of graft rejection, patients who were being transplanted with cyclophosphamide as a sole agent were excluded from the study. After randomization and administration of therapy, patients were monitored by microscopic and dip-stick urinalyses; they were also followed for effects of therapy on engraftment. The incidence of consistent or severe hematuria was 33% in the mesna arm and 20% in the hyperhydration arm (P = .31). Severe bleeding occurred in 12.5% of mesna patients and 7.5% of hyperhydration patients (P = .71). No unexpected toxicities were encountered, and engraftment times did not differ. Based on this randomized trial of 100 patients, we conclude that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation patients.
Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole.
Authors: Trump D L , Egorin M J , Forrest A , Willson J K , Remick S , Tutsch K D
Published: February 2017

During a phase I trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (Css) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The 5FUra was administered at doses ranging from 185 mg/m2/d times three to 3,600 mg/m2/d times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The Css of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra Css in cycles of 5FUra plus dipyridamole was 23% +/- 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% +/- 6.5%. When the occurrence of any degree of stomatitis was related to the Css 5FUra, with patients grouped in cohorts of 2-mumol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1-e-0.114Css), r2 = 0.88; for 5FUra alone, percentage frequency stomatitis = 100(1-e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, these relationships were as follows: percentage frequency of stomatitis = 100(1-e-0.00031 [dose]), r2 = 0.85; and percentage frequency of stomatitis = 100(1-e-0.00051 [dose]), r2 = 0.80. When the relationship between the percentage reduction in WBC and Css 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100(1-e-0.085Css), r2 = 0.46; for 5FUra alone, percentage reduction in WBC = 100(1-e-0.060Css), r2 = 0.61. When 5FUra dose was substituted for Css, these relatinships were as follows: percentage reduction in WBC = 100(1-e-0.00023 [dose]), r2 = 0.40; percentage reduction in WBC = 100(1-e-0.00024 [dose]), r2 = 0.65. The relationship between either Css 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted Css determined by the risk and severity of toxicity deemed acceptable.
Oncologists' reluctance to accrue patients onto clinical trials: an Illinois Cancer Center study.
Authors: Benson A B , Pregler J P , Bean J A , Rademaker A W , Eshler B , Anderson K
Published: February 2017

Clinical trials are recognized as the standard of care for the cancer patient, and the randomized, controlled trial represents the most definitive method to determine the effectiveness or ineffectiveness of a cancer treatment. However, less than 3% of all eligible patients enter a clinical trial. Of the 437 physician members of the Illinois Cancer Center (ICC), 244 responded to a survey designed to determine factors that present a significant barrier to entering patients on clinical trials. Rigid protocol design was the primary deterrent to accrual, especially for medical oncologists. Surgeons, radiation oncologists, and medical oncologists differed with respect to several factors, including willingness to seek a clinical trial, tendency to treat patients off study, quality-of-life issues, and the belief that trials were too excessive in time commitment (P less than .05). Compared with hospital-based physicians, community oncologists had fewer patients on trial, were more likely to enter patients on the basis of age, and were more concerned about aspects of informed consent and the financial burden of a trial (P less than .01). One third of the physicians never pursued a clinical trial because of conflict with the priorities of individual care and excessive follow-up time. Fourteen percent indicated that they discouraged patients from participating in a clinical trial due to the risk of a patient receiving a placebo and patient follow-up requirements (P less than .05). Subgroups of physicians differ in their reluctance to accrue patients, and there are clusters of beliefs expressed by physicians concerning their clinical trial activity. Current conduct of clinical trials needs to be reassessed, and intervention studies are required to determine the best methodology to alter physician reluctance to pursue clinical trials.
Intensive weekly combination chemotherapy for patients with intermediate-grade and high-grade non-Hodgkin's lymphoma.
Authors: Sweetenham J W , Mead G M , Whitehouse J M
Published: February 2017

High response and overall survival rates have been reported for second- and third-generation combination chemotherapy regimens used in the treatment of advanced intermediate- and high-grade non-Hodgkin's lymphoma (NHL). Results with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy have been particularly impressive, although this regimen produces considerable toxicity. We have devised a similar regimen, which differs from previously reported weekly regimens in that it includes etoposide given at 14-day intervals. The doses of methotrexate and prednisolone were lower in our regimen than those used in MACOP-B. Alternating cycles of cyclophosphamide, doxorubicin, and etoposide (week 1) and methotrexate, bleomycin, and vincristine (week 2) were given for a total of 12 weeks, with continuous oral prednisolone and prophylactic antibiotics. We report here the first 61 patients entered onto this study. The overall response rate is 84% (57% complete remission [CR], 27% partial remission [PR]). With a median follow-up of 32 months for surviving patients, the actuarial overall survival at 3 years is 47%, and the failure-free survival is 45%. The dose-limiting toxicity of this regimen was mucositis. Five deaths occurred during chemotherapy, two of which were due to sepsis. The dose intensities of cyclophosphamide and doxorubicin in this regimen are considerably lower than those in MACOP-B. However, because of the inclusion of etoposide, the projected average relative dose intensity for our regimen is higher than that for MACOP-B. Our regimen has produced inferior results to those reported for MACOP-B. This may be because the addition of etoposide has failed to compensate for the lower doses of doxorubicin and cyclophosphamide. Alternatively, it may reflect differences in the presenting features of the patient populations.
Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.
Authors: Miles D W , Earl H M , Souhami R L , Harper P G , Rudd R , Ash C M , James L , Trask C W , Tobias J S , Spiro S G
Published: February 2017

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.
A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.
Authors: Elias A D , Ayash L J , Eder J P , Wheeler C , Deary J , Weissman L , Schryber S , Hunt M , Critchlow J , Schnipper L
Published: February 2017

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.
Sex or survival: trade-offs between quality and quantity of life.
Authors: Singer P A , Tasch E S , Stocking C , Rubin S , Siegler M , Weichselbaum R
Published: February 2017

Patients with localized prostate cancer may be treated with either surgery (radical prostatectomy) or radiotherapy. Although controversial, many physicians believe that surgery offers a higher survival rate. However, the surgical treatment may also produce a higher rate of sexual impotency. Our study assessed how men value survival and sexual potency when asked to trade off one for the other. Using the treatment-choice technique, we interviewed 50 men aged 45 to 70 years without known prostate cancer. At hypothetical rates of survival (90% at 5 years for surgery) and impotency (90% for surgery and 40% for radiotherapy) representing published estimates, 32% of respondents were unwilling to trade off any survival, but 68% were willing to trade off a 10% or greater advantage in 5-year survival (by choosing radiotherapy) to maintain sexual potency. The median 5-year survival traded off was 10% (range, 0% to 80%). Willingness to trade off survival for sexual potency was significantly related to level of education, but not to age, interest in sex, frequency of sexual intercourse, or ability to achieve erection. We conclude that some men may choose treatment with lower long-term survival to increase their chance of remaining sexually potent. Because these men may be difficult to identify in clinical practice, physicians should thoroughly discuss both surgery and radiotherapy options with patients who have localized prostate cancer.
When is a prognostic factor useful? A guide for the perplexed.
Authors: Levine M N , Browman G P , Gent M , Roberts R , Goodyear M
Published: February 2017

Traditionally, a number of variables have been used to predict outcome in patients with early-stage breast cancer. These tests are simple to perform and relatively inexpensive. Recently, a number of new factors, eg, tumor proliferative index, nuclear DNA content, and amplification or overexpression of growth-promoting genes or oncogenes have been identified as potential predictors of outcome in patients with breast cancer. There is now increasing pressure to introduce such tests into routine clinical practice. How does a clinical practitioner identify which test, or group of tests, best predicts adverse outcome and whether any more clinically useful information is provided than with the use of more traditional factors alone? The aim of a prognostic test in breast cancer is to predict which patients are destined to develop a recurrence of cancer and those who are not. The prognostic usefulness of a test can be expressed in terms of relative risk (RR), which is the ratio of the risk of breast cancer recurrence in patients who test positive to the risk in those who test negative. Methodologic guidelines that should be satisfied by a study evaluating the predictive ability of a test include the following: (1) Was an inception cohort assembled? (2) Was the referral pattern described? (3) Were laboratory and clinical outcomes assessed in a blinded fashion? (4) Was complete follow-up achieved? (5) Was adjustment for extraneous prognostic factors carried out? (6) Were appropriate statistical methods used? An approach is suggested to help the clinician choose the test, or combination of tests, likely to discriminate between "high-" and "low-risk" patients in his/her own practice. The decision regarding what particular threshold value (risk) defined by a prognostic test (or series of tests) warrants adjuvant therapy for an individual patient is a complex one but should be based on a clear presentation of the risks and benefits to the patient.