bluuebunny/crossref_metadata_2025 huggingface dataset:
Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors.
Authors: Vokes E E , Weichselbaum R R
Published: February 2017

Concomitant chemoradiotherapy can be used in order to increase both the local and systemic control of solid tumors. The rationale for its use and experimental data for selected chemotherapy drugs are reviewed. Clinical trials have focused on increasing complete response (CR) and survival rates; in addition, improved quality of life by decreasing the use of conventional surgical procedures is being pursued. Both of these goals may have been achieved for some tumors, most notably for anal cell carcinoma. Improved survival with concomitant chemoradiotherapy has also been shown for patients treated on randomized studies for pancreatic, colorectal, small-cell lung, head and neck, and cervical cancer. These results call for the continued investigation of this approach in the laboratory and in the clinic.
Phase I trial of murine monoclonal antibody L6 in breast, colon, ovarian, and lung cancer.
Authors: Goodman G E , Hellström I , Brodzinsky L , Nicaise C , Kulander B , Hummel D , Hellström K E
Published: February 2017

Murine monoclonal antibody (MAb) L6 binds to an antigen expressed on the surface of breast, colon, ovary, and nonsmall-cell lung cancer. This antibody effects antibody-dependent cellular cytotoxicity (ADCC) with human mononuclear cells and complement-dependent cytotoxicity (CDC) with human complement. Because of these activities, we conducted a phase I trial of MAb L6 in patients with advanced cancer. Nineteen patients whose tumors highly expressed antigen were selected for this trial. Eighteen were evaluable. MAb L6 was administered at dose levels ranging from 5 mg/m2/d to 400 mg/m2/d for 7 days and was well tolerated. The only side effects detected were fever and headaches at the highest dose levels. The serum half-life of L6 was directly related to dose and ranged from a mean of 7.7 hours at 5 mg/m2/d to 29.1 hours at 400 mg/m2/d. Peak serum concentrations ranged from 0.22 micrograms/mL to 362 micrograms/mL. Biopsies at the end of treatment showed L6 to localize well to tumor cells with apparent in vivo saturation occurring at dose levels above 100 mg/m2/d. Thirteen patients formed human antimouse antibodies (HAMA), some as early as day 13. One patient with recurrent breast cancer on the chest wall achieved a complete remission. The response was first noted at 5 weeks and a pathologic complete remission occurred at 14 weeks. Because of its favorable binding properties and the encouraging clinical effect observed, future evaluation of this MAb appears warranted.
Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin's disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy.
Authors: Straus D J , Gaynor J J , Myers J , Merke D P , Caravelli J , Chapman D , Yahalom J , Clarkson B D
Published: February 2017

The initial promising results with alternating chemotherapy regimens (mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine [MOPP/ABVD]; lomustine, melphalan, and vindesine [CAD] plus MOPP plus ABV) combined with intermediate-dose radiation therapy (RT) have been sustained with further follow-up; 82.2% of patients (152 of 185) achieved a complete remission (CR), and overall survival is 71.7% +/- 4.4% at 8 years (median follow-up is 55 months among the survivors). No statistically significant differences were found in CR percentage, CR duration, or survival between stages IIB, IIIB, and IV patients. For that reason, stepwise Cox regression analyses to identify the important prognostic factors were performed on overall survival, tumor mortality, freedom from disease progression, and survival following disease progression. Pretreatment characteristics were also tested for association with the probability of achieving CR, CR duration, and death due to other causes. Characteristics that were consistently associated with an independently unfavorable prognosis were low hematocrit, high serum lactic acid dehydrogenase (LDH), age more than 45 years, inguinal node involvement, mediastinal mass greater than .45 of the thoracic diameter, and bone marrow involvement. Patients with two or more unfavorable characteristics were much more likely to fail treatment (median survival, 62.4 months) than those with none or only one unfavorable factor (greater than 95% survival). This striking difference between the low- and high-risk groups remained even if the comparison was restricted to patients less than or equal to 45 years of age. These results provide a basis for selecting the young patients at high risk of failure for more intensive initial treatment with either autologous bone marrow rescue or hematopoietic growth factors.
Evaluation of pre- and postoperative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction.
Authors: Ajani J A , Roth J A , Ryan B , McMurtrey M , Rich T A , Jackson D E , Abbruzzese J L , Levin B , DeCaro L , Mountain C
Published: February 2017

Thirty-five consecutive patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative and three or four postoperative chemotherapy courses consisting of etoposide, fluorouracil, and cisplatin (EFP) to evaluate the rate of curative resection, clinical and pathologic response, toxic effects, and survival. One hundred thirty-seven courses with a median number of five courses (range, one to six) were administered. Preoperative EFP resulted in 17 (49%) major responses, including six patients who did not have carcinoma cells in the repeat endoscopic biopsy specimens and cytologic brushings. Among 32 patients who had surgery, 25 (78%) had curative resection, one patient had a complete pathologic response, and one had microscopic carcinoma in the resected specimen. Six patients had microscopic carcinoma at the resection margins and received postoperative radiotherapy. At a median follow-up of 20 months, the projected survival of 35 patients is 23 months (range, 6 to 33+). Fifteen patients died of their carcinomas, and 15 patients were alive (median follow-up, 20+ months; range, 15+ to 33+ months) with no evidence of relapse. There were no deaths related to chemotherapy, surgery, or radiotherapy. EFP-induced toxic reactions were moderate. Our data suggest that multiple courses of EFP are feasible. Future strategies for this disease should consider prolonged chemotherapy with regimens that result frequently in pathologic complete responses.
Chemotherapy of invasive thymoma.
Authors: Fornasiero A , Daniele O , Ghiotto C , Sartori F , Rea F , Piazza M , Fiore-Donati L , Morandi P , Aversa S M , Paccagnella A
Published: February 2017

Thirty-two patients with stage III or IV invasive thymoma (14 women and 18 men; median age, 40 years) were treated at the Padua Medical Oncology Department from 1977 to 1988. All patients received the following chemotherapy in 4-day courses: 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1; 0.6 mg/m2 of vincristine IV on day 3; and 700 mg/m2 of cyclophosphamide IV on day 4 (ADOC). The courses were repeated every 3 weeks, and toxic effects were tolerable. The radiologically defined overall clinical response rate (complete plus partial response) was 91% with 47% clinical complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates.
Concomitant Chemoradiotherapy
Authors: Vokes Everett E. , Weichselbaum Ralph R.
Published: February 2017

The title of Table 4 in the review article "Concomitant Chemoradiotherapy: Rationale and Clinical Experience in Patients With Solid Tumors" by Vokes and Weichselbaum published in the May 1990 issue (J Clin Oncol 8:911–934, 1990) was incorrect. It should have read "Table 4: Selected Randomized Trials in Head and Neck Cancer."
Effect of patients' expectations of benefit with standard breast cancer adjuvant chemotherapy on participation in a randomized clinical trial: a clinical vignette study.
Authors: Fetting J H , Siminoff L A , Piantadosi S , Abeloff M D , Damron D J , Sarsfield A M
Published: February 2017

Patients frequently overestimate the benefit of standard breast cancer adjuvant therapy. This is due in part to vague doctor-patient communication. To examine how the doctor's description and patient's expectations of the benefit of standard therapy affect clinical trial participation, we randomized 282 female cancer patients to one of two versions of a clinical vignette describing a choice between standard cyclophosphamide, methotrexate, and fluorouracil (5FU) (CMF) and a randomized trial comparing CMF with cyclophosphamide, doxorubicin, and 5FU (CAF). The vignettes differed only on whether results with CMF were described verbally or numerically in terms of disease-free survival (DFS). After selecting CMF or the trial, patients estimated their 10-year DFS with CMF. Patients were randomized 3:1 to the verbal vignette. The trial was selected by 110 of 210 (52.4%) verbal vignette patients versus 25 of 72 (34.7%) numeric vignette patients (P = .01). Estimates of 10-year DFS with CMF varied considerably; many were inaccurate. When patients in the verbal vignette group were divided into thirds according to DFS estimate, 22 of 64 (34.4%) in the top third selected the trial versus 38 of 64 (59.4%) and 38 of 65 (58.5%) in the middle and bottom third, respectively (P = .005). Younger age, college education, and previous participation in a trial also predicted trial selection. Multivariate logistic regression suggested that the benefit expected from CMF was more important than how benefit was described in treatment selection. Assuring realistic patient expectations of standard adjuvant therapy benefit is likely to be important during discussion of clinical trials.
When to randomize?
Authors: Durrleman S , Simon R
Published: February 2017

Many clinical trials address the question of the duration of therapy or whether initial therapy can be improved by the addition of a consolidation or maintenance regimen. For such clinical trials, the question of when to perform the randomization is often difficult. Conventional statistical wisdom prescribes that randomization should take place as late as possible before treatment is effected. This is not always possible or desirable, however. In this report, we describe the factors that are influenced by the timing of randomization, quantify how timing affects these factors, and attempt to provide a tool to help investigators and statisticians determine the appropriate time to randomize for individual studies and particular circumstances.
Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.
Authors: Ablin A R , Krailo M D , Ramsay N K , Malogolowkin M H , Isaacs H , Raney R B , Adkins J , Hays D M , Benjamin D R , Grosfeld J L
Published: February 2017

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.
Allogeneic bone marrow transplantation for relapsed and refractory lymphoma using genotypically HLA-identical and alternative donors.
Authors: Lundberg J H , Hansen R M , Chitambar C R , Lawton C A , Gottlieb M , Anderson T , Ash R C
Published: February 2017

Twenty-two patients, ages 16.6 to 43.9 years (median age, 30 years), with relapsed or refractory lymphoma were treated by allogeneic bone marrow transplantation after high-dose chemotherapy with or without total body irradiation (TBI). Seven patients had Hodgkin's disease, four had low-grade histology non-Hodgkin's lymphoma (NHL), seven had intermediate-grade NHL, and four had high-grade NHL. Of the 22 patients, 17 received T-cell (CD-3)-depleted marrow after intensive pretransplant chemoradiotherapy, and five received T-cell-replete grafts after chemotherapy-based preparative regimens. Five patients were transplanted from donors other than genotypically HLA-identical siblings: four from partially HLA-matched relatives, and one from a phenotypically HLA-identical unrelated donor. Acute graft-versus-host disease (GVHD) was less than or equal to grade II in all patients, and chronic GVHD was limited or absent in all but one patient. Of the 21 assessable patients, 17 (80.9%) achieved complete remissions. Death due to transplant-associated complications occurred in five patients, and five patients have relapsed. Thirteen patients are alive, and 12 are continuously relapse-free at a median follow-up of longer than 28 months (range, greater than 10 to greater than 58 months) from transplant. The cumulative probability of treatment failure from relapse or progression of lymphoma was 29% (95% confidence interval [CI], 12% to 51%), while the actuarial lymphoma-free (ie, event-free) survival plateau is 54.6% (95% CI, 34% to 76%). For young patients with advanced malignant lymphoma, allogeneic bone marrow transplantation appears superior to salvage chemotherapy for achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.
Transfusion-associated graft-versus-host disease: historical perspectives, incidence, and current use of irradiated blood products.
Authors: Greenbaum B H
Published: February 2017

Transfusion-associated graft-versus-host disease (TGVHD) has been reported in 131 patients as a complication of supportive treatment with an overall 90% mortality. This study was undertaken to define the historical incidence of TGVHD, its symptomatology, and mortality among affected patients by age, diagnosis, and blood product transfused. Although the use of irradiated blood products (IBPs) virtually eliminates the risk of this highly lethal complication, the use of IBPs appears variable. To ascertain current use of IBPs, questionnaires were sent to 100 pediatric and adult hematologists, oncologists, and bone marrow transplant physicians asking their perceptions about and actual use of IBPs. The results of the questionnaire, information on irradiation effects on cellular blood products, and current recommendations for irradiation of blood products are discussed.
A Prospective Comparison of Neuropsychologic Performance of Children Surviving Leukemia Who Received 18-Gy, 24-Gy, or No Cranial Irradiation
Authors: Mulhern Raymond K. , Fairclough Diane , Ochs Judith
Published: February 2017

Table 1 of the report "A Prospective Comparison of Neuropsychologic Performance of Children Surviving Leukemia Who Received 18-Gy, 24-Gy, or No Cranial Irradiation" (J Clin Oncol 9:1348–1356, 1991) contained an error. lt is reprinted here correctly in its entirety:

Please see the PDF for Table.
Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.
Authors: Poon M A , O'Connell M J , Wieand H S , Krook J E , Gerstner J B , Tschetter L K , Levitt R , Kardinal C G , Mailliard J A
Published: February 2017

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.
CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?
Authors: Haddy T B , Adde M A , Magrath I T
Published: February 2017

Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).
Cutaneous lymphomas other than mycosis fungoides: follow-up study of 52 patients.
Authors: Joly P , Charlotte F , Leibowitch M , Haioun C , Wechsler J , Dreyfus F , Escande J P , Revuz J , Reyes F , Varet B
Published: February 2017

Cutaneous lymphomas other than mycosis fungoides (MF) represent a rare and heterogeneous group of lymphomas. Their clinical behavior remains largely unknown. In this study, the clinical and immunohistologic characteristics and follow-up data of 52 well-documented cases of cutaneous lymphomas other than MF, presenting with initial cutaneous lesions, were reviewed. Twenty-seven patients presented with skin disease alone (stage IE), and 25 patients had concurrent cutaneous and extracutaneous disease (stage IV). The tumors were grouped into high-grade lymphomas (HGLs; 21%), intermediate-grade lymphomas (IGLs; 58%), and low-grade lymphomas (LGLs; 21%). A B-cell phenotype was most often expressed by cutaneous lymphomas (73%), particularly by stage IE lymphomas (85%). Among 13 cases of T-cell lymphomas, loss of one of the pan-T-cell antigens was detected in all cases but one. The clinical course of cutaneous lymphoma was closely dependent on stage and histologic subtype but not on T-cell or B-cell phenotype. Of 20 patients with stage IV HGL or IGL, 13 were treated by polychemotherapy with curative potential. Their median survival was 37 months. Fourteen patients with stage IE HGL or IGL were treated by radiotherapy alone. Nine patients (69%) relapsed within 2 years posttreatment. Seven of them relapsed in the skin outside the initial site involved, suggesting that radiotherapy alone is not an adequate treatment for these patients. Preliminary results concerning seven other patients with stage IE IGL or HGL treated by an initial third-generation polychemotherapy regimen are presented.
The calculation of actual or received dose intensity: a comparison of published methods.
Authors: Longo D L , Duffey P L , DeVita V T , Wesley M N , Hubbard S M , Young R C
Published: February 2017

Two recent reports of the same combination chemotherapy program, cyclophosphamide, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, bleomycin, and prednisone (ProMACE-CytaBOM), in similar subsets of patients with advanced-stage aggressive-histology lymphoma used two different methods to report the actual dose-intensity (DI) data. One method treats DI as a property of a particular cycle of treatment within the entire population that received that cycle. The other treats DI as a characteristic of a particular patient's entire treatment course. We have applied both methods to the same set of data and provide evidence that the latter method is preferable for at least two reasons: (1) it more accurately reflects actual DI by clearly incorporating the duration of the actual treatment course and, thus, can be used to compare the administration of same or related regimens to distinct patient populations; and (2) it allows assignment of a numerical value to an individual patient's treatment course or a group of patients' treatment courses such that DI can be examined for its impact on treatment outcome just like any other prognostic factor. The observed differences in treatment outcome between the Southwest Oncology Group (SWOG) and National Cancer Institute (NCI) studies are not clearly related to differences in distribution of clinical prognostic factors in the two study populations. The differences in methods of reporting DI prohibit evaluation of the influence of dose-related variables on outcome in the two studies. Adoption of a standard method of calculating and reporting DI data would facilitate evaluation of the prognostic significance of DI.
Intensive Therapy for Small-Cell Lung Cancer Using Carboplatin Alternating With Cisplatin, Ifosfamide, Etoposide, Mid-Cycle Vincristine, and Radiotherapy
Authors: Prendiville Joseph , Radford John , Thatcher Nick , Steward Will , Ranson Malcolm , Burt Paul , Stout Ron
Published: February 2017

An error was made at the final printing stage of the report entitled "Intensive Therapy for Small-Cell Lung Cancer Using Carboplatin Alternating With Cisplatin, Ifosfamide, Etoposide, Mid-Cycle Vincristine, and Radiotherapy" by Prendiville et al (J Clin Oncol 9:1446–1452). Under the Treatment Regimens section, the first sentence of the second paragraph should read "On day 5 of the first cycle of chemotherapy, prophylactic cranial irradiation was given by opposing lateral fields in one fraction of 8 Gy."
A randomized prospective assessment of recombinant leukocyte A human interferon with or without aspirin in advanced renal adenocarcinoma.
Authors: Creagan E T , Twito D I , Johansson S L , Schaid D J , Johnson P S , Flaum M A , Buroker T R , Geeraerts L H , Veeder M H , Gesme D H
Published: February 2017

We performed a prospective, controlled trial of recombinant leukocyte A interferon (IFN-alpha 2A) with or without aspirin (ASA) in 176 patients with assessable advanced renal cell cancer in light of a 34% response rate (10 of 29 patients) from the two-agent regimen in an earlier nonrandomized trial. This encouraging result was substantially higher than the 15% response rate typically achieved with IFN therapy alone. Eighty-seven patients received IFN-alpha 2A 20 x 10(6) U/m2 intramuscularly three times a week, and 89 received the same IFN therapy with ASA 600 mg orally four times each day. Each group was balanced as to relevant prognostic discriminants. Response rates were 8% for the group receiving ASA in addition to IFN, and 13% for the group receiving IFN alone (P = .30). The median times to progression were 1.9 months for the group receiving IFN with ASA and 2.7 months for the group receiving IFN alone (log-rank P = .36). The median survival durations were 8.8 months for the IFN and ASA group and 8.0 months for the IFN-only group (log-rank P = .60). These figures are also inferior to those typically reported from other studies. Our findings reemphasize the crucial role of randomized trials, admittedly cumbersome and time-consuming, to determine accurately the value of apparently promising therapies. Although some patients may derive benefit from IFN therapy, our findings raise disturbing questions regarding the potential IFN-alpha 2A according to the dose and schedule used in this trial to have any substantive impact on the ultimate outcome of disseminated renal cell cancer.
Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity.
Authors: Caligiuri M A , Murray C , Soiffer R J , Klumpp T R , Seiden M , Cochran K , Cameron C , Ish C , Buchanan L , Perillo D
Published: February 2017

In previous clinical trials, recombinant interleukin-2 (rIL-2) has been infused at high doses over short periods of time to generate lymphokine-activated killer (LAK) cells in vivo. These trials have been limited by severe toxicities, and the immunologic effects of rIL-2 have been transient. The present study was designed to assess the toxicity and immunologic effects of prolonged administration of low doses of rIL-2. In this phase I study, patients with advanced cancer were scheduled to receive intravenous (IV) infusion of rIL-2 without interruption for 3 months in an outpatient setting. Twenty-one patients received rIL-2 at doses ranging from 0.5 x 10(5) to 6.0 x 10(5) U/m2/d. Treatment was extremely well tolerated, and no patient experienced grade 3 or grade 4 toxicity. The lowest dose level (0.5 x 10(5) U/m2/d) did not have demonstrable immunologic activity. At doses of 1.5 x 10(5) and 4.5 x 10(5) U/m2/d, rIL-2 infusion resulted in the specific expansion of natural-killer (NK) cells (sixfold and ninefold increases, respectively, at these two dose levels) without any changes in B cells, T cells, neutrophils, or monocytes. Grade 2 toxicity was observed at the dose of 6.0 x 10(5) U/m2/d, as three patients required interruption of therapy and two patients who completed therapy developed transient hypothyroidism. In patients with increased NK cells, enhancement of non-major histocompatibility complex (MHC)-restricted cytotoxicity and increased generation of LAK cells in vitro were also demonstrated. Therapy with low-dose rIL-2 can be given safely in an uninterrupted fashion for prolonged periods of time in an outpatient setting. This results in selective expansion of NK cells in vivo with minimal toxicity. Further investigation of this schedule for immunomodulation in vivo should be pursued in phase II studies of both malignant and immunodeficient disease states.
Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.
Authors: Rubin C M , Le Beau M M , Mick R , Bitter M A , Nachman J , Rudinsky R , Appel H J , Morgan E , Suarez C R , Schumacher H R
Published: February 2017

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.
Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.
Authors: O'Shaughnessy J A , Wittes R E , Burke G , Friedman M A , Johnson J R , Niederhuber J E , Rothenberg M L , Woodcock J , Chabner B A , Temple R
Published: February 2017

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.
Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide phosphatidylethanolamine in children with osteosarcoma.
Authors: Kleinerman E S , Snyder J S , Jaffe N
Published: February 2017

The purpose of these studies was to determine whether chemotherapy interfered with the ability of peripheral blood monocytes from patients with osteosarcoma to respond to the liposome-encapsulated activating agent muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). This was done in preparation of designing an adjuvant therapy protocol that includes L-MTP-PE combined with chemotherapy postoperatively for the treatment of primary osteosarcoma. The majority of patients who fail current adjuvant chemotherapy do so while on chemotherapy. Therefore, we believe it is important to combine L-MTP-PE with chemotherapy early in the treatment course rather than waiting until all chemotherapy cycles are completed. The tumoricidal properties of monocytes from patients with osteosarcoma could be activated by L-MTP-PE to levels equal to or greater than those expressed by normal control monocytes. No intrinsic monocyte defect could be demonstrated. Single-agent chemotherapy consisting of cisplatin (CPD), high-dose methotrexate (MTX), Cytoxan (CTX, cyclophosphamide; Bristol-Myers Co, Evansville, IN), or Adriamycin (ADR, doxorubicin; Adria Laboratories, Columbus, OH) did not interfere with this activation process. There was even a suggestion of enhanced activation potential following the administration of ADR. However, when both ADR and CTX were administered together on the same day, profound suppression in monocyte activation was observed. This suppressed function returned to normal by 3 weeks postcombination therapy. We therefore conclude that L-MTP-PE can be combined with ADR, CPD, MTX, or CTX as single agents but recommend that ADR plus L-MTP-PE is the most effective combination. By contrast, we discourage the use of L-MTP-PE when ADR and CTX are given together.
Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.
Authors: Rusch V W , Figlin R , Godwin D , Piantadosi S
Published: February 2017

Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.
Developing a postgraduate medical oncology training program in Taipei, Taiwan, Republic of China.
Authors: Carbone P P
Published: February 2017

Because cancer is the number one cause of mortality in Taiwan, a governmental decision was made to develop an experiment in medical oncology education using a United States-style training program in medical oncology in three Taipei, Taiwan, university hospitals. In the past, trainees from developing countries came to the United States or other foreign countries to receive specialty training. In doing so, the training did not necessarily prepare the individuals with skills to treat the indigenous cancers, nor did they work with other related specialists or support staff such as nursing and pharmacy, so important to providing good cancer care. This program involved 13 fellows with significant laboratory experience working with American faculty on-site. The major benefits of this model for oncology training are that the trainees developed important interdisciplinary relationships with local staff at each of the hospitals; they were involved in the treatment of the major cancer diseases of Taiwan such as nasopharyngeal, hepatocellular, and cervical cancers as well as breast, lung, and colon cancers; and they completed a certification process involving written and oral tests by two senior American oncologist examiners. Oncology services have been established at each of the hospitals and most of the fellows have expressed an interest or made arrangements to come to the United States to get additional research experience.
Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin.
Authors: Markman M , Rothman R , Hakes T , Reichman B , Hoskins W , Rubin S , Jones W , Almadrones L , Lewis J L
Published: February 2017

In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program, a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease, and a laparotomy was not performed to assess response), 31 (43%) responded, including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate), based on duration of CFI, were 5 to 12 months, 27% (5%); 13 to 24 months, 33% (11%); and more than 24 months, 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion, secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.
The pattern of intrathoracic Hodgkin's disease assessed by computed tomography.
Authors: Diehl L F , Hopper K D , Giguere J , Granger E , Lesar M
Published: February 2017

Computed tomography (CT) was used to define the sites of intrathoracic abnormality in Hodgkin's disease, determine a pattern of progression of disease in the thorax, and establish the place of this pattern of spread in the differential diagnosis of thoracic abnormalities. One hundred eight patients with newly diagnosed Hodgkin's disease were studied by chest CT. Seventy-seven patients had intrathoracic abnormalities. The pattern seen was one of contiguous spread from the anterior mediastinal/paratracheal area to the other mediastinal lymph node groups (aortopulmonary, subcarinal, posterior mediastinal, and internal mammary), to the hila, and then into the lung by extension or as discrete nodules. Involvement of the pleura, pericardium, or chest wall occurred only after the anterior mediastinal/paratracheal mass had enlarged to greater than 30% of the thoracic diameter. The probability that this pattern of contiguous lymph node spread occurred by chance alone was very small. Hodgkin's disease spreads from the anterior mediastinal/paratracheal area in a contiguous manner. Exceptions are unusual enough that when they occur, diagnoses other than Hodgkin's disease are more likely.
Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.
Authors: Goldenberg D M , Horowitz J A , Sharkey R M , Hall T C , Murthy S , Goldenberg H , Lee R E , Stein R , Siegel J A , Izon D O
Published: February 2017

Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2, in order to study antibody distribution, pharmacokinetics, dosimetry, toxicity, tumor targeting, and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients, doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions, two mixed and minor responses, and one no response), while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted, and only myelotoxicity accompanied therapeutic doses, with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi, which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg), 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs, suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.
High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study.
Authors: Ravindranath Y , Steuber C P , Krischer J , Civin C I , Ducore J , Vega R , Pitel P , Inoue S , Bleher E , Sexauer C
Published: February 2017

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.
Superiority of ProMACE-CytaBOM Over ProMACE-MOPP in the Treatment of Advanced Diffuse Aggressive Lymphoma
Authors: Longo Dan L. , DeVita Vincent T. , Duffey Patricia L. , Wesley Margaret N. , Ihde Daniel C. , Hubbard Susan M. , Gilliom Mercedes , Jaffe Elaine S. , Cossman Jeffrey , Fisher Richard I. , Young Robert C.
Published: February 2017

Table of the report entitled "Superiority of ProMACE-CytaBOM Over ProMACE-MOPP in the Treatment of Advanced Diffuse Aggressive Lymphoma: Results of a Prospective Randomized Trial" by Longo et al (J Clin Oncol 9:25–38, 1991) contained several errors. It is reprinted here correctly in its entirety:

Please see the PDF for Table.