bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of limited-stage small-cell lung cancer with cyclophosphamide, doxorubicin, and vincristine with or without etoposide: a randomized trial of the North Central Cancer Treatment Group.
Authors: Jett J R , Everson L , Therneau T M , Krook J E , Dalton R J , Marschke R F , Veeder M H , Brunk S F , Mailliard J A , Twito D I
Published: February 2017

In this randomized study involving patients with limited-stage small-cell lung cancer (LD-SCC), we compared treatment with either cyclophosphamide; doxorubicin, and vincristine (CAV) or CAV plus etoposide (CAVE). All patients received identical thoracic radiation consisting of 3,750 cGy in 15 fractions and prophylactic cranial radiation (3,000 cGy in 10 fractions). Among 231 evaluable patients, the two treatment arms were well matched with respect to sex, age, performance score, and presence or absence of heart disease. A major regression (REGR) was observed in 83% of all patients and a complete response (CR) in 60%. There was no difference in the response rate between the two treatment regimens. The median time to progression is 10.4 months (95% confidence interval [Cl], 8.9 to 12 months) for CAVE versus 8.9 months (95% Cl, 7.9 to 10.4 months) for CAV (P = .04). The median survival is 15.1 months (95% Cl, 11.7 to 17.8 months) for CAVE versus 12.4 months (95% Cl, 11 to 14.4 months) for CAV. This difference is not significantly different (P = .13). Toxicity was primarily myelosuppression and was significantly greater for the four-drug regimen. Fatal treatment-related toxicity was observed in two patients on the CAVE regimen and no treatment-related deaths were observed on the CAV treatment. In conclusion, the addition of etoposide to the CAV regimen resulted in increased toxicity but did not lead to a meaningful improvement in survival.
Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity.
Authors: Steis R G , Urba W J , VanderMolen L A , Bookman M A , Smith J W , Clark J W , Miller R L , Crum E D , Beckner S K , McKnight J E
Published: February 2017

Autologous lymphokine-activated killer (LAK) cells and recombinant human interleukin-2 (rIL-2) were administered intraperitoneally (IP) to 24 patients with malignancies limited to the peritoneal space. Ten patients had ovarian cancer, 12 had colorectal cancer, and one patient each had endometrial carcinoma and primary small-bowel adenocarcinoma. All ovarian cancer patients, three of twelve colorectal cancer patients, and one patient with endometrial carcinoma had received prior therapy. Patients received IL-2 100,000 U/kg every 8 hours intravenously (IV) for 3 days, and 2 days later underwent daily leukapheresis for 5 days. LAK cells were generated in vitro by incubating the peripheral blood mononuclear cells in IL-2 for 7 days and were then administered IP daily for 5 days through a Tenckhoff catheter (Davol, Inc, Cranston, RI) together with IL-2 25,000 U/kg IP every 8 hours. All but one patient completed at least one cycle of therapy. Toxic side effects included minor to moderate hypotension, fever, chills, rash, nausea, vomiting, abdominal pain and distension, diarrhea, oliguria, fluid retention, thrombocytopenia, and minor elevations of liver function tests; all of these rapidly improved after discontinuation of IL-2. One patient had a grand mal seizure, and one suffered a colonic perforation; these were felt to be treatment-related. IP fibrosis developed in 14 patients and limited repeated cyclic administration of this therapy in five patients. Two of 10 (20%) ovarian cancer patients and five of 12 (42%) colorectal cancer patients had laparoscopy- or laparotomy-documented partial responses. We conclude that LAK cells and rIL-2 can be administered IP to cancer patients, resulting in moderate to severe short-term toxicity and modest therapeutic efficacy. Further investigation of this form of adoptive immunotherapy modified to address the problem of IP fibrosis and with lower IP IL-2 doses is justified by these initial results.
A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.
Authors: Ernstoff M S , Nair S , Bahnson R R , Miketic L M , Banner B , Gooding W , Day R , Whiteside T , Hakala T , Kirkwood J M
Published: February 2017

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.
Treatment of small-cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group pilot study.
Authors: Taylor C W , Crowley J , Williamson S K , Miller T P , Taylor S A , Giri T G , Stephens R L , Livingston R B
Published: February 2017

We designed an intensive, weekly treatment regimen for patients with small-cell lung cancer (SCLC) using six of the most active chemotherapeutic agents for this disease (doxorubicin [DOX], cyclophosphamide [CTX], vincristine [VCR], etoposide [VP-16], cisplatin [CDDP], and methotrexate [MTX]). The goal of this program was to gain rapid, repetitive exposure to multiple, active drugs. Treatment was administered weekly for a total of 16 weeks. Seventy-six SCLC patients (limited disease, 34; extensive disease, 42) were treated. The overall complete plus partial response rate was 82%. Complete response rates of 47% and 38% were observed in patients with limited (LD) and extensive disease (ED), respectively. The median survivals for patients with LD and ED were 16.6 and 11.4 months, respectively. Toxicities were tolerable and were primarily hematologic. Twenty-six patients had one or more transient life-threatening toxicities, but only one patient developed a fatal toxicity. Eighty-four percent of the patients received 80% or greater of the intended protocol dosages over the entire 16-week treatment period. We conclude that this intensive, short-duration treatment regimen is at least as good as other "standard" regimens, and we are encouraged aged by the complete response rate and median survival in patients with ED SCLC.
Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension.
Authors: Gasparini M , Lombardi F , Gianni M C , Massimino M , Gandola L , Fossati-Bellani F
Published: February 2017

A series of 15 consecutive children with head and neck nonorbital rhabdomyosarcoma (RMSA) with meningeal extension were prospectively treated with chemotherapy consisting of Adriamycin (doxorubicin; Adria Laboratory, Columbus, OH) (ADM), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) followed by radiotherapy (60 Gy) to the primary tumor volume, along with intrathecal methotrexate (IT MTX). Thirteen of 15 responded to preradiation chemotherapy. Four of 13 relapsed. Relapse occurred at the level of the primary tumor in three of four. The 3-year progression-free survival (PFS) was 59%, similar to that achieved in a previous series treated with a comparable therapeutic approach that also included whole-brain radiotherapy as a prophylaxis of possible occult meningeal seeding. It is concluded that CNS prophylaxis with radiotherapy is questionable in the management of childhood RMSA with meningeal extension.
Quantitative analysis of antibody localization in human metastatic colon cancer: a phase I study of monoclonal antibody A33.
Authors: Welt S , Divgi C R , Real F X , Yeh S D , Garin-Chesa P , Finstad C L , Sakamoto J , Cohen A , Sigurdson E R , Kemeny N
Published: February 2017

A33 is a mouse immunoglobulin G2a (IgG2a) monoclonal antibody (mAb) that detects a heat-stable, protease- and neuraminidase-resistant epitope. The antigen is homogeneously expressed by virtually all colon cancers and in the colon mucosa but not other epithelial tissues. The biodistribution and imaging characteristics of iodine-131 (131I)-mAbA33 were studied in colorectal carcinoma patients with hepatic metastases. Antibody labeled with 2 to 5 mCi of 131I was administered intravenously (IV) 7 to 8 days before surgery at five dose levels, ranging from 0.2 mg to 50 mg, with three or more patients entered at each dose level. In addition, three patients received 2 mg 131I-mAbTA99 (an isotype-matched control mAb) together with 125I-mAbA33. Evaluation included whole-body imaging with a gamma camera, technetium-99 (99mTc)-human serum albumin blood pool scans, liver/spleen scans, abdominal computed tomographic (CT) scans, hepatic arteriograms, antibody pharmacokinetics, and assessment of antibody distribution in biopsied malignant and normal tissues. Selective mAbA33 localization to tumor tissue was demonstrated in 19 of 20 patients, and external imaging correlated with surgical inspection, pathologic examination, and tissue radioactivity. One week after antibody administration, tumor:liver ratios ranged from 6.9:1 to 100:1 and tumor:serum ratios from 4.1:1 to 25.2:1. 99mTc-albumin blood pool studies showed that liver metastases were hypovascular, emphasizing the selective localization of mAbA33 despite poor tumor-blood flow. Control mAbTA99 studies showed mAbA33 localization was antigen-specific; tumor:liver ratios were 2.3- to 45-fold higher for specific antibody. In metastatic lesions, radioisotope was localized primarily in the viable periphery; however, even the necrotic tumor core concentrated specific antibody. External imaging showed isotope visualization in some patients' large bowel; whether this represents specific antibody uptake or gastric iodine secretion is unclear.
Phase II trial of interferon gamma and monoclonal antibody 17-1A in pancreatic cancer: biologic and clinical effects.
Authors: Tempero M A , Sivinski C , Steplewski Z , Harvey E , Klassen L , Kay H D
Published: February 2017

Thirty patients with advanced measurable pancreatic adenocarcinoma were entered onto a phase II trial with recombinant interferon gamma (Biogen, Cambridge, MA; 10(6) U/m2 daily for 4 days) and monoclonal antibody (Mab) 17-1A (Centocor, Malvern, PA; 150 mg in autologous leukocytes on days 2, 3, and 4 following interferon infusion). The effect of a single interferon gamma treatment on natural and antibody-dependent cellular cytotoxicity (ADCC), Fc receptor occupancy by antibody, and human leukocyte antigen-DR (HLA-DR) expression on monocytes and lymphocytes was also studied. Toxicity was modest and generally limited to grade I to II fever, nausea and vomiting, and hepatotoxicity. Five patients were considered to be nonassessable for response. Of the 25 assessable patients, one objective response (complete remission for a duration of 4 months) was observed. Stable disease for 2 months or greater was noted in nine patients. The median survival for the group was 5 months. Analysis of cytotoxicity data obtained prior to treatment showed reduced natural cytotoxic activity in these patients compared with normal volunteers. A significant improvement in natural cytotoxic activity to normal levels occurred within 24 hours following the interferon gamma infusion. This was also associated with augmented antibody-dependent cellular cytotoxicity. Although HLA-DR expression was not increased on either monocytes or lymphocytes, an increased capacity of both lymphocytes and monocytes to bind Mab 17-1A was observed. In all in vitro assays of ADCC, the presence of antibody excess was associated with improved cytolytic activity. In spite of the favorable modulation of cytolytic activity and improved ability of effector cells to bind Mab, we failed to demonstrated adequate clinical efficacy in the treatment of patients with pancreatic adenocarcinoma using this dose and schedule of interferon gamma and Mab 17-1A. Future trials will focus on alternate schedules of Mab 17-1A with the hope of improving tumor antigen saturation and circulating levels of infused antibody.
Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: a multivariate analysis of risk factors.
Authors: Wiley J M , Smith N , Leventhal B G , Graham M L , Strauss L C , Hurwitz C A , Modlin J , Mellits D , Baumgardner R , Corden B J
Published: February 2017

We evaluated the courses of 115 consecutive cases of pediatric acute leukemia treated with induction chemotherapy. Seventy-two patients developed fever associated with neutropenia; 15 developed systemic fungal infections. We reviewed multiple demographic and treatment characteristics of these patients in an attempt to identify potential risk factors for the development of invasive fungal disease (IFD). Risk factors identified in a univariate analysis included duration of neutropenia after first fever (P less than .0001), diagnosis of acute nonlymphocytic leukemia (ANLL) (P = .003), onset of fever and neutropenia within 5 days of starting induction chemotherapy (P = .009), and multiple (greater than one) surveillance culture sites positive for fungal organisms (P = .02). In a multiple logistic regression analysis, duration of neutropenia (P less than .001) remained a significant risk factor. The study group of patients had a significantly higher risk of fungal infections than a matched group of leukemia patients developing fever with neutropenia due to postremission consolidation chemotherapy (P = .003). In the first 48 patients, 14 (29%) developed IFD. In the subsequent patients (n = 24), intravenous miconazole (5 mg/kg every 8 hours) was begun at the time of the first fever. One of the 24 patients (4%) given miconazole developed IFD. The use of miconazole was a negative risk factor for the development of IFD in univariate (P = .01) and multivariate (P = .05) analysis. We conclude that pediatric leukemia patients who develop fever associated with neutropenia during induction chemotherapy are at high risk for developing IFD. The role of intravenous miconazole at the time of the first fever in this group deserves further study.
Splenic versus hepatic artery infusion of interleukin-2 in patients with liver metastases.
Authors: Mavligit G M , Zukiwski A A , Gutterman J U , Salem P , Charnsangavej C , Wallace S
Published: February 2017

In an attempt to improve the therapeutic index of recombinant interleukin-2 (rIL-2) by generating or activating lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) regionally and/or in situ, we randomly assigned 28 patients with liver metastases to receive rIL-2 by continuous infusion for 5 days via either the splenic artery or the hepatic artery. Clinically significant and lasting tumor regression was observed only in two of 28 patients (7%), one in each of the two treatment arms. The maximum-tolerated daily dosage of rIL-2 was 3 x 10(6) U/m2; beyond this dosage, toxicity was excessive. Peripheral LAK cell activity measured in vitro and clinical tumor regression did not correlate. This observation, coupled with the equal distribution of regressions between the two treatment arms, raises the possibility that tumor regression, rare though it may be in response to rIL-2 administration, is largely mediated by TIL activation and not by LAK cell generation.
Effect of tumor necrosis factor on the human fibrinolytic system.
Authors: Silverman P , Goldsmith G H , Spitzer T R , Rehmus E H , Berger N A
Published: February 2017

We report the effects on the fibrinolytic system of intravenous (IV) recombinant tumor necrosis factor-alpha (rTNF-alpha) infusions in patients with advanced cancers. During a phase I clinical trial of rTNF-alpha, the plasma fibrinolytic system was closely monitored, measuring tissue-type plasminogen activator (tPA) antigen, plasminogen activator (PA) inhibitor activity, and plasma fibrinolytic activity. Thirteen patients with refractory malignancies received 40, 80, or 160 micrograms/m2 rTNF-alpha as 2-hour IV infusions. After a 1-week rest, the same dose was repeated daily for 5 days every 3 weeks for a maximum of four courses. The serum rTNF-alpha levels peaked at the completion of the IV infusion and rapidly declined thereafter, becoming unmeasurable within 1 hour in all patients. rTNF-alpha infusion markedly alters the plasma fibrinolytic system. During the 2-hour infusion, significant increases in the tPA antigen and plasma fibrinolytic activity were seen. After the infusion, PA inhibitor activity increased, neutralizing the plasma fibrinolytic activity. The increase in PA inhibitor activity was maximal 6 hours after the onset of the rTNF-alpha infusion. Fibrinolytic properties returned to pretreatment values within 24 hours. Daily rTNF-alpha infusions caused changes in plasma tPA antigen and PA inhibitor similar to those of single infusions. We conclude from these observations that the administration of rTNF-alpha in vivo to cancer patients causes profound alterations of endothelial cell-derived components of the fibrinolytic system.
Bone marrow transplantation for childhood Ki-1 lymphoma.
Authors: Chakravarti V , Kamani N R , Bayever E , Lange B , Herzog P , Sanders J E , August C S
Published: February 2017

Two children with Ki-1 antigen-positive, non-Hodgkin's lymphoma received high-dose chemotherapy, fractionated total body irradiation (TBI), and allogeneic bone marrow transplantation. Both patients had relapsed multiple times on conventional chemotherapy and radiation therapy. Following transplantation, there was successful engraftment with disappearance of clinical signs and symptoms of their disease. As of June 1, 1989 they are in continuous unmaintained complete remission, 56 and 40 months, respectively, after bone marrow transplantation.
Treatment of isolated testicular relapse in childhood acute lymphoblastic leukemia: an Italian multicenter study. Associazione Italiana Ematologia ed Oncologia Pediatrica.
Authors: Uderzo C , Grazia Zurlo M , Adamoli L , Zanesco L , Aricò M , Calculli G , Comelli A , Cordero di Montezemolo L , Di Tullio M T , Guazzelli C
Published: February 2017

Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARA-C), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Patients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR.
Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity.
Authors: Lévi F , Benavides M , Chevelle C , Le Saunier F , Bailleul F , Misset J L , Regensberg C , Vannetzel J M , Reinberg A , Mathé G
Published: February 2017

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.
Detection of neuroblastoma cells in blood.
Authors: Moss T J , Sanders D G
Published: February 2017

Tumor surveillance tests are used to detect relapse and to guide the clinician in making therapeutic changes. Identification of relapse early in the course of disease may improve long-term survival. For patients with neuroblastoma, current conventional surveillance methods include radiologic testing, bone marrow analysis, physical examination, and measurement of urinary catecholamine metabolites. Immunocytologic analysis of blood for the detection of circulating tumor cells is a highly specific and sensitive method, which may prove useful in monitoring patients with neuroblastoma. In our study, circulating tumor cells were detected in seven of 10 patients with known disseminated disease at diagnosis and in six of 13 patients during therapy. In some patients, as few as two tumor cells were identified among 100,000 normal hematopoietic cells. The presence or absence of circulating neuroblasts in the 13 patients evaluated during therapy was significantly correlated with tumor relapse (P = .002). We conclude that immunocytologic analysis of blood is a sensitive method for the detection of circulating neuroblasts. We recommend that this technique be used in conjunction with other conventional methods for improved tumor detection and subsequent monitoring of neuroblastoma patients.
Mediastinal large-B-cell lymphoma with sclerosis: a clinical study of 21 patients.
Authors: Todeschini G , Ambrosetti A , Meneghini V , Pizzolo G , Menestrina F , Chilosi M , Benedetti F , Veneri D , Cetto G L , Perona G
Published: February 2017

We report the clinical findings of 21 consecutive patients affected by mediastinal large B-cell lymphoma with sclerosis. This type of lymphoma is a recently described histopathologic entity characterized on clinical grounds by distinctive features, which, according to our series, can be summarized as follows: young age (median, 30 years; range, 15 to 42 years), prevalence of females over males (15 v six), rare occurrence of superficial lymph node enlargement (three of 21 patients), and involvement of unusual extranodal sites (kidney six, adrenal cortex two patients). The clinical course appears to be closely related to treatment. In fact, complete remission (CR) was not obtained in the six patients submitted to conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus bleomycin (CHOP-Bleo) regimens until 1985, as opposed to 13 CRs reached in the 15 patients subsequently treated with more aggressive regimens after 1985 (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B], 12 patients; methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone [M-BACOD], two patients; and vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate, and prednisone [F-MACHOP], one patient; plus involved-field radiotherapy, 10 patients). Among the 13 patients who achieved a CR, only one relapse was observed at 10 months. The median overall survival of complete responders after an observation period of 11 to 69 months has not yet been reached, and the event-free survival curve indicates that 90% of patients who achieve CR may be potentially cured.
Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16.
Authors: Fisher B , Redmond C , Legault-Poisson S , Dimitrov N V , Brown A M , Wickerham D L , Wolmark N , Margolese R G , Bowman D , Glass A G
Published: February 2017

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.
Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis.
Authors: Kwak L W , Halpern J , Olshen R A , Horning S J
Published: February 2017

While diffuse large-cell lymphoma (DLCL) is considered to be highly curable with current therapy, treatment failures are observed even with intensive combination chemotherapy regimens. In order to study the prognostic significance of actual dose intensity of chemotherapy in DLCL, we retrospectively analyzed 115 previously untreated patients treated as Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclosphosphamide, vincristine, prednisone, and bleomycin (MACOP-B). The actual relative dose intensity (RDI), the amount of drug actually administered to each patient during the first 12 weeks of therapy, was calculated as standardized to CHOP and analyzed in addition to clinical factors prognostic for survival by univariate analysis. Multivariate recursive partitioning (tree-structured) survival analysis identified the actual RDI of Adriamycin greater than 75% as the single most important predictor of survival. A model incorporating the actual RDI of Adriamycin and performance status, in combination with serum lactate dehydrogenase (LDH) and extranodal disease, defined three overall prognostic groups of patients with respective 3-year survival rates of 89%, 63%, and 18%. The three prognostic groups remained distinct, even when restricted to complete responders. This model was also predictive of survival when dose intensity was analyzed relative to the optimum dose defined for each of the three regimens and when applied to a subgroup of patients aged 50 years or younger. We conclude that actual RDI is an important prognostic factor for survival in DLCL and that analysis of RDI early in the course of treatment may allow modification of the treatment plan.
Immunobiologic factors predictive of clinical outcome in diffuse large-cell lymphoma.
Authors: Slymen D J , Miller T P , Lippman S M , Spier C M , Kerrigan D P , Rybski J A , Rangel C S , Richter L C , Grogan T M
Published: February 2017

The prognostic importance of immunobiologic factors in diffuse large-cell lymphoma (DLCL) is studied in 105 consecutive DLCL patients. Multivariate results using the Cox proportional hazards model clearly indicate that the Ki-67 index (P = .002), a marker of cell proliferation activity, and the presence or absence of human leukocyte antigen-DR (HLA-DR) (P = .007) are strong predictors of survival even in the presence of established clinical factors of stage (P = .015) and symptoms (P = .050). Using these four variables, prognostic groups were formed identifying patient groups with varying degrees of risk. The group of patients with three or four risk factors present at the time of diagnosis had a median survival of 4 months compared with a median survival of 59 months for the group with no risk factors. Similarly, prognostic groups for disease-free survival (DFS) were constructed based on the proportional hazards model that involved B versus T phenotype (P = .035) and HLA-DR (P = .054). Median DFS for the patient group with one or two risk factors present was 11 months compared with 43 months with no risk factors present. This study suggests immunobiologic parameters are important predictors of clinical outcome in DLCL patients and are of value in identifying subgroups of patients who have not responded to currently available therapy. The practical significance of this study is to identify parameters that may suggest specific changes in therapy of patient subgroups.
Combined high-dose carboplatin and cisplatin, and ifosfamide in previously untreated ovarian cancer patients with residual disease.
Authors: Lund B , Hansen M , Hansen O P , Hansen H H
Published: February 2017

Carboplatin 200 mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3, ifosfamide 1,500 mg/m2 days 1 to 3, and mesna 900 mg/m2 days 1 to 3 every 4 weeks for six cycles were given to 37 previously untreated ovarian cancer patients with residual disease after the primary laparotomy. The median observation time was 17+ months (range, 9+ to 24+ months). Of all the patients, 81% had primary residual disease larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 36 assessable patients was 58%, PCR was 42%. Of the PCR patients, 53% had primary residual tumor larger than 5 cm. The substantial hematologic toxicity was manageable, but also the main reason for dose modifications. During treatment, 92% and 100% of the patients developed WBC and platelet nadir values corresponding to World Health Organization (WHO) grades 3 to 4. Dose-limiting encephalopathy, nephro- and neurotoxicity each occurred in 6% of the patients. The high PCR rate warrants further investigations of combined high-dose platinum and ifosfamide.
Hypersensitivity reactions from taxol.
Authors: Weiss R B , Donehower R C , Wiernik P H , Ohnuma T , Gralla R J , Trump D L , Baker J R , Van Echo D A , Von Hoff D D , Leyland-Jones B
Published: February 2017

Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.
Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy.
Authors: Kelsen D P , Minsky B , Smith M , Beitler J , Niedzwiecki D , Chapman D , Bains M , Burt M , Heelan R , Hilaris B
Published: February 2017

Ninety-six patients with operable epidermoid cancer of the esophagus were entered into a phase III, random assignment study designed to compare the efficacy of two preoperative approaches (chemotherapy [CT] or radiation therapy [RT]). Major study end points were objective response rates, surgical outcome, and recurrence pattern. Patients were randomly assigned to receive either two cycles of cisplatin, vindesine, and bleomycin or 55 Gy of radiation before a planned surgical procedure. Postoperative crossover therapy (radiation to those receiving preoperative CT and vice versa) was given to patients with T3Nany or unresectable tumors. Objective response rates of the primary tumor to preoperative therapy were similar (RT 64%, CT 55%), as were operability rates (RT 77%, CT 75%), resection rates (RT 65%, CT 58%), and operative mortality (RT 13.5%, CT 11.1%). Significantly higher doses of CT could be administered when CT was given as initial therapy, rather than after RT/surgery. Local failure or persistence occurred in 33% of operable patients. The median survival for all patients was 11 months; 20% remain alive without disease (median follow-up, 34 months). Because of the crossover design, it was not possible to analyze survival according to the preoperative therapy arm alone. This study suggests that since CT is as effective in treating local tumor as RT, but can also potentially treat systemic disease, investigational programs using CT before surgery as part of initial treatment for localized esophageal cancer should continue. However, if a significant impact on overall survival is to be achieved, more effective chemotherapy regimens or schedules need to be identified. Outside of carefully designed clinical trials, surgery alone or radiation alone remain standard therapy.
Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19).
Authors: Raimondi S C , Behm F G , Roberson P K , Williams D L , Pui C H , Crist W M , Look A T , Rivera G K
Published: February 2017

In earlier studies of the cytogenetic characteristics of leukemic lymphoblasts from children with pre-B-cell acute lymphoblastic leukemia (ALL), we concluded that certain chromosomal abnormalities explain, in part, the increased presence of high-risk features at diagnosis and the less favorable response to therapy among patients with this immunologic subclass of ALL. With extended follow-up and a larger patient population, we have further evaluated the biologic and clinical aspects of pre-B leukemia. Of 686 cases of ALL with adequate immunophenotyping, 150 were classified as pre-B cell. Seventy-seven (69%) of the 112 pre-B cases with fully banded karyotypes had a translocation. The t(1;19) accounted for 28 (25%) of these pre-B cases and 31 (6.5%) of all 480 consecutively banded ALL cases. Three (2.6%) of the pre-B cases had a novel dicentric (7;9)(p1?3;p11) translocation. A t(9;22)(q34;q11) and a t(4;11)(q21;q23) were observed in seven (6%) and three (2.6%) of the cases, respectively. Within the pre-B subgroup, comparison of t(1;19) cases (n = 28) with those having other translocations (n = 49) or no identifiable translocations (n = 35) indicated that higher leukocyte counts (P = .002), absence of DNA indexes greater than 1.16 (P = .02), higher serum lactate dehydrogenase levels (P less than .0001), and a higher frequency of nonwhite race (P = .006) were significantly related to the t(1;19). Both the t(1;19) and other chromosomal translocations were associated with an adverse prognosis in the subset of patients treated from 1979 to 1984 (Total Therapy study X). In a more recent and more intensive chemotherapy program (Total Therapy study XI), neither the t(1;19) nor other chromosomal translocations has conferred an inferior outcome, suggesting that effective treatment can offset the negative impact of chromosomal rearrangements in cases of childhood pre-B ALL.
The myelodysplastic syndromes: biology and implications for management.
Authors: List A F , Garewal H S , Sandberg A A
Published: February 2017

Since the initial efforts to characterize the myelodysplastic syndromes in 1976, an extensive body of information has accumulated defining biologic features and the relation to clinical aspects of disease. While the pathogenesis of these disorders remains incompletely understood, laboratory investigations indicate that they are clonal disorders affecting hematopoietic stem cells characterized by a progressive imbalance between self-renewal and differentiation. Despite karyotypic resemblance to acute myeloid leukemia, fundamental biologic differences may underly the disappointing results achieved to date with intensive chemotherapy. The recent availability of recombinant hematopoietic growth factors for use in clinical trials has shown that the maturation defect in many instances can be overcome with administration of lineage-restricted recombinant hematopoietins. Routine use of these promising agents must await results of randomized clinical trials to determine the impact of prolonged treatment on leukemic evolution and disease-related morbidity.
Phase II study of biochemical modulation of fluorouracil by low-dose PALA in patients with colorectal cancer.
Authors: O'Dwyer P J , Paul A R , Walczak J , Weiner L M , Litwin S , Comis R L
Published: February 2017

Higher response rates in colorectal cancer have been observed with regimens that increase the cytotoxicity of fluorouracil (5-FU) by altering the biochemical milieu at its site(s) of action. Phosphonacetyl-L-aspartate (PALA), which inhibits aspartate transcarbamylase and depletes uridine nucleotide pools in vitro and in vivo, selectively potentiates the antitumor activity of 5-FU in preclinical models. In a phase I/II study in patients with advanced colorectal cancer, PALA 250 mg/m2 was given on day 1, followed 24 hours later by 5-FU 2,600 mg/m2 by 24-hour infusion repeated weekly. Through the use of subcutaneous ports and portable infusion pumps, all patients were treated outside the hospital setting. Thirty-nine patients without prior chemotherapy received 884 courses of treatment. The primary site was colon in 31, rectum in eight. Toxicity was generally mild to moderate except among four patients who were escalated to 5-FU 3,250 mg/m2: two developed severe gastrointestinal toxicity and myelosuppression. Among the remaining 35 patients, gastrointestinal and neurologic toxicities predominated, but usually did not develop until the third or fourth month of treatment. Two patients were inevaluable for response. Among the 37 evaluable patients there were three complete and 13 partial remissions for a total response rate of 43% (95% confidence interval [Cl], 27% to 59%). The median duration of response was 5 months (range, 1.5 to 15 months). The projected mean survival is in excess of 17 months. This high response rate is comparable to the best results obtained with other means of modulation of 5-FU. Demonstration of a survival benefit will require larger phase III studies.
Effect of Tumor Necrosis Factor on the Human Fibrinolytic System
Authors: Silverman Paula , Goldsmith George H. , Spitzer Thomas R. , Rehmus Esther H. , Berger Nathan A.
Published: February 2017

At the request of the authors, the following is a correction of reference 4 cited in the report "Effect of Tumor Necrosis Factor on the Human Fibrinolytic System" by Silverman et al (J Clin Oncol 8:468–475, 1990): Reference 4. Helson L, Green S, Carswell EA, et al: Effect of tumor necrosis factor on cultured human melanoma cells. Science 258:731–732, 1975.
Cardiopulmonary resuscitation and the patient with cancer.
Authors: Vitelli C E , Cooper K , Rogatko A , Brennan M F
Published: February 2017

The records of 114 cancer patients suffering cardiopulmonary arrests (CPA) during a 3-year period at Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively reviewed to identify variables predicting final outcome in these patients. Although 65.7% of the patients were successfully resuscitated, only 12 (10.5%) were discharged alive from the hospital. Median survival after discharge was 150 days. By univariate and multivariate analysis, the only variable predicting the likelihood of a patient's being discharged alive after a CPA was the performance status of the patient at the time of admission to the hospital. Thus, a patient spending more than 50% of the time in bed at the time of admission had only a 2.3% chance of being discharged alive after CPA. A thorough discussion of these findings between physicians and patients and their families is strongly recommended at the time of admission to spare cancer patients unnecessary invasive resuscitative procedures.
Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies.
Authors: Chun H G , Leyland-Jones B , Cheson B D
Published: February 2017

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.