bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions.
Authors: Creekmore S P , Harris J E , Ellis T M , Braun D P , Cohen I I , Bhoopalam N , Jassak P F , Cahill M A , Canzoneri C L , Fisher R I
Published: February 2017

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.
Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.
Authors: Margolin K A , Rayner A A , Hawkins M J , Atkins M B , Dutcher J P , Fisher R I , Weiss G R , Doroshow J H , Jaffe H S , Roper M
Published: February 2017

The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.
The prognostic significance of residual pigmentation following radiotherapy of epidemic Kaposi's sarcoma.
Authors: Cooper J S , Steinfeld A D , Lerch I A
Published: February 2017

The response to radiotherapy of epidemic Kaposi's sarcoma (EKS) is unusual in that irradiated regions are frequently left with a persistent purple stain, reminiscent of the color of the original tumor, but with no tumor mass. To date there are no published data to indicate whether the persistence of pigmentation can be predicted beforehand or if it has any prognostic import. We reviewed the response to treatment of 118 EKS lesions that were irradiated at New York University (NYU) Medical Center between 1981 and 1986. A total of 86 responded to treatment by complete clearance of the mass. Of these, 29 left residual purple pigmentation within the treatment portal, while 57 did not. Complete response (CR; without residual pigmentation) occurred more often in patients who had higher Karnofsky scores at the time of treatment. However, in terms of ultimate local control or survival, there were no differences between patients whose lesions cleared completely v those in whom pigmentation remained. We conclude that persistent pigmentation represents only a benign remnant of irradiated EKS and has no prognostic import.
An evaluation of outpatient bone marrow harvesting.
Authors: Brandwein J M , Callum J , Rubinger M , Scott J G , Keating A
Published: February 2017

In order to avoid the difficulties in scheduling and cost involved in admitting patients to hospital to undergo bone marrow harvests, we assessed outpatient marrow harvesting for autologous bone marrow transplant (BMT) candidates. Over a 13-month period, 39 consecutive patients with hematologic malignancies underwent bone marrow harvests as outpatients. For comparison we also evaluated 20 consecutive patients with similar disease status who had undergone bone marrow harvests as inpatients over the preceding 6 months. The mean hemoglobin value prior to harvest the mean volume of marrow harvested, and the mean nucleated cell count in the outpatient group were not significantly different from those of the inpatient group. There were no intraoperative complications. Of these 39 patients, 36 were discharged later the same day on oral iron supplements, with no adverse sequelae. Local pain was well controlled at home with mild oral analgesics. Two patients required admission due to postoperative hypotension--both responded promptly to intravenous (IV) fluids and blood and were discharged the following day. One patient was admitted postoperatively due to fever. There was a trend for the outpatients to receive less intra- and postoperative blood transfusions, but this did not reach statistical significance. The results suggest that most candidates for autologous BMT can safely undergo bone marrow harvesting as outpatients, thereby relieving pressure for hospital beds, potentially reducing costs and improving bed utilization. The study also raises the possibility of safely performing outpatient harvests on allogeneic BMT donors.
A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract.
Authors: Hillcoat B L , Raghavan D , Matthews J , Kefford R , Yuen K , Woods R , Olver I , Bishop J , Pearson B , Coorey G
Published: February 2017

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.
Direct comparisons of peripheral T-cell lymphoma with diffuse B-cell lymphoma of comparable histological grades--should peripheral T-cell lymphoma be considered separately?
Authors: Cheng A L , Chen Y C , Wang C H , Su I J , Hsieh H C , Chang J Y , Hwang W S , Su W C , Liu T W , Tien H F
Published: February 2017

Peripheral T-cell lymphoma (PTCL) forms a morphologically heterogeneous group of non-Hodgkin's lymphomas (NHL) with distinct immunophenotypes of mature T cells. Progress has been slow in defining specific clinicopathological entities to this particular group of NHL. In order to elucidate the specific characteristics of PTCL, a direct comparison of PTCL with a group of diffuse B-cell lymphomas (DBCL) was performed. Between June 1983 and December 1987, we studied 114 adults with NHL, using a battery of immunophenotyping markers. Adult T-cell leukemia/lymphoma, lymphoblastic lymphoma, mycosis fungoides/Sézary syndrome, follicular lymphoma, well-differentiated lymphocytic lymphoma, and true histiocytic lymphoma were excluded from this study since these are distinct clinicopathologic entities with well-recognized immunophenotypes. Of the remaining 75 patients, 70 who had adequate clinical information were analyzed, and of these, 34 were PTCL and 36 were DBCL. Classified according to the National Cancer Institute (NCI) Working Formulation (WF), 68% of PTCL and 31% of DBCL were high-grade lymphomas. Clinical and laboratory features were similar, except PTCL had a characteristic skin involvement and tended to present in more advanced stages with more constitutional symptoms. Induction chemotherapy was homogeneous in both groups, and complete remission rates were 62% for PTCL and 67% for DBCL. Patients with DBCL had a better overall survival than patients with PTCL, but the survival benefit disappeared after patients were stratified according to intermediate- or high-grade lymphoma. A subgroup of PTCL patients who had received less intensive induction chemotherapy was found to have a very unfavorable outcome. We conclude that (1) PTCL follows the general grading concept proposed in WF classification; (2) within a given intermediate or high grade, PTCL and DBCL respond comparably to treatment; (3) the intensity of induction chemotherapy has a crucial impact on the outcome of PTCL patients; and (4) with a few exceptions, the clinical and laboratory features of PTCL and DBCL are comparable.
Multivariate analysis of prognostic factors in acute myeloid leukemia: value of clonogenic leukemic cell properties.
Authors: Delmer A , Marie J P , Thevenin D , Cadiou M , Viguié F , Zittoun R
Published: February 2017

The initial clinical and biological parameters, including clonogenic leukemic cell (CFU-L) assay, were reviewed for their prognostic significance in a cohort of 188 adult patients with newly diagnosed untreated acute myeloid leukemia (AML). Almost all patients received induction therapy with daunorubicin (DNR) and cytarabine (Ara-C) according to the European Organization for Research and Treatment of Cancer (EORTC) AML 5 to AML 9 trials. Bone marrow samples from 116 representative patients were obtained for CFU-L assay with an efficiency percentage of 89.6%; 76 patients had a measurement of the CFU-L self-renewal capacity (second plating efficiency [PE2]) and 91 patients had CFU-L inhibition test after exposure to DNR and/or Ara-C. The prognostic significance of parameters such as age, hematological antecedent, WBC count, liver enlargement, and Auer rods is confirmed in the present study. Moreover, high platelet and polymorphonuclear counts appeared to be related to resistance to induction course. However, through multivariate analysis, CFU-L sensitivity to drugs and self-renewal capacity appeared to be major independent prognostic factors in AML. A low CFU-L inhibition in the presence of the DNR and Ara-C combination correlates with a poorer complete remission (CR) rate, but not with CR duration. Patients with the lower PE2 values experienced both higher CR rate and longer CR duration. The practical interest of CFU-L study remains to be defined but, at least, PE2 measurement could be considered in the future as a major variable in determining therapeutic aggressiveness.
Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.
Authors: Vokes E E , Panje W R , Schilsky R L , Mick R , Awan A M , Moran W J , Goldman M D , Tybor A G , Weichselbaum R R
Published: February 2017

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.
Prognostic factors and staging classification of patients with epidemic Kaposi's sarcoma.
Authors: Chachoua A , Krigel R , Lafleur F , Ostreicher R , Speer M , Laubenstein L , Wernz J , Rubenstein P , Zang E , Friedman-Kien A
Published: February 2017

Two hundred twelve patients with acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) were followed prospectively. Univariate and multivariate analyses were performed to determine significant predictors of survival and development of opportunistic infection (OI) from the time of diagnosis of KS. Clinical variables analyzed were age at onset, presence of systemic symptoms, prior or coexistent OI, development of OI greater than 3 months following KS diagnosis, and extent of disease. Laboratory variables analyzed were absolute number of peripheral T-helper lymphocytes (T4), helper/suppressor ratio (T4/T8), serum beta-2-microglobulin, and serum acid labile alfa interferon. Three independent variables were predictive of shorter survival: (1) prior or coexistent OI (P = .02), (2) presence of systemic symptoms (P = .001), and (3) absolute T4 count less than 300 cells/microL (P = .002). Based on survival, patients with AIDS-related KS can be divided into four groups: (1) those with no prior or coexistent OI, no systemic symptoms, T4 greater than or equal to 300 cells/microL (median survival, 31 months): (2) those with no prior or coexistent OI, no systemic symptoms, and T4 less than 300 cells/microL (median survival, 20 months); (3) those with no prior or coexistent OI and presence of systemic symptoms (median survival, 15 months); and (4) those with prior or coexistent OI (median survival, 7 months).
Hypertension in long-term survivors of childhood renal cancers.
Authors: Kantor A F , Li F P , Janov A J , Tarbell N J , Sallan S E
Published: February 2017

The prevalence of hypertension was investigated in 119 adults who have survived for up to 53 years following the diagnosis of renal cancer in childhood (Wilms' tumor, 116 patients; renal carcinoma, three patients). Twenty-four (20%) have developed definite or borderline hypertension, as compared with 18.1 cases expected based on US population rates (relative risk [RR], 1.3; 95% confidence interval [CI], 0.9 to 2.0; P = .20). This nonsignificant excess is due to the heightened prevalence of definite hypertension among one subgroup of male patients. The findings are not explained by cigarette smoking, obesity, age, and stage at diagnosis of Wilms' tumor, or family history of hypertension. A case-comparison analysis within the cohort showed no consistent hypertensive effect associated with radiation therapy dose, radiotherapy concurrent with dactinomycin chemotherapy, or extent of renal surgery. Hypertension is not a common late complication of Wilms' tumor in our patients.
Lack of relationship between in vitro tumor cell growth and prognosis in extensive-stage small-cell lung cancer.
Authors: Stevenson H C , Gazdar A F , Linnoila R I , Russell E K , Oie H K , Steinberg S M , Ihde D C
Published: February 2017

The ability to establish a continuously growing tumor cell line from fresh tumor specimens has been associated with shortened survival in some human malignancies. Therefore, we assessed the relationship between survival and in vitro tumor cell growth from specimens obtained during routine staging procedures in 68 consecutive patients with untreated, extensive-stage small-cell lung cancer (SCLC) who received etoposide/cisplatin chemotherapy. Three groups of SCLC patients could be distinguished: (1) 23 patients in whom a tumor cell line was established in vitro; (2) 28 patients in whom tumor-containing specimens were cultured but in vitro growth did not occur; and (3) 17 patients in whom no tumor-containing specimen could be procured. No significant difference in response rates to chemotherapy of the three groups was noted. Poor performance status (P2 = .001), male gender (P2 = .0008), liver metastases (P2 = .0033), brain metastases (P2 = .0152), and the ability to obtain a tumor-containing specimen from the patient for laboratory culture (P2 = .0005) were all significant independent predictors of decreased survival in this patient population. While the ability to obtain a tumor cell specimen for cell culture using routine staging and diagnostic procedures identified patients with shortened survival, we found no significant survival differences between patients whose tumor cell specimens grew in cell culture v those that did not (median survival of 7 months v 11 months, P2 = .72). Our study indicates that the clinical outcome of extensive-stage SCLC patients from whom tumor cell lines can be established is not significantly different than in those cases from whom tumor-containing specimens could not be grown in vitro.
Numbers of host "helper" T cells and proliferating cells predict survival in diffuse small-cell lymphomas.
Authors: Medeiros L J , Picker L J , Gelb A B , Strickler J G , Brain S W , Weiss L M , Horning S J , Warnke R A
Published: February 2017

Diffuse small-cell lymphomas of B-lineage comprise a group of immunophenotypically related lymphoid malignancies that display variable clinical aggressiveness. We compared a variety of clinical, pathologic, and immunologic characteristics of 64 B-lineage diffuse small-cell lymphomas to patient survival in an effort to define prognostically relevant subtypes of these neoplasms. Neither clinical parameters nor histological subclassification correlated with patient outcome. In contrast, three immunologic features of these lymphomas showed a statistically significant relationship with actuarial survival. Neoplasms that manifested greater than or equal to 25% Ki-67+ cells (proliferation-associated antigen), less than 25% Leu 4+ cells (pan-T antigen), or less than 15% Leu 3+ cells (helper/inducer T-subset antigen) were associated with significantly decreased patient survival as compared to neoplasms with the reverse phenotype (P = .02, P = .003, P = .0005, respectively). Leu 3 findings were of particular importance in initial biopsies (P = .0007), while the Ki-67 findings were significant regardless of time of biopsy (P = .01 for biopsies at diagnosis and P = .004 for other biopsies). These data indicate that immunologic analysis can demonstrate subsets of diffuse small-cell lymphoma with different biologic potential, and suggest that such analysis be included in the routine work-up of patients with this type of neoplasm.
Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease.
Authors: van Leeuwen F E , Somers R , Taal B G , van Heerde P , Coster B , Dozeman T , Huisman S J , Hart A A
Published: February 2017

The risk of second cancers (SCs) was assessed in 744 patients with Hodgkin's disease (HD) admitted to The Netherlands Cancer Institute from 1966 to 1983. Sixty-nine SCs were observed one month or more after start of first treatment. These included 14 cases of lung cancer, nine cases of non-Hodgkin's lymphoma (NHL), 16 cases of leukemia, and six cases of the myelodysplastic syndrome (MDS). The median interval between the diagnosis of HD and that of second lung cancer, NHL, and leukemia was 8.1, 13.3, and 5.7 years, respectively. The overall relative risks (RR) (observed/expected [O/E] ratios) of developing lung cancer, NHL, and leukemia were 4.9 (95% confidence limit [CL], 2.7 to 8.2), 31.0 (95% CL, 14.2 to 58.9) and 45.7 (95% CL, 26.1 to 74.2), respectively. At 15 years the cumulative risk of developing an SC amounted to 20.6% +/- 2.9%. The 15-year estimates of lung cancer, NHL, and leukemia were 6.2% +/- 1.9%, 5.9% +/- 2.1% and 6.3% +/- 1.7%, respectively. Increased lung cancer risk following HD has not frequently been clearly demonstrated before; that we were able to demonstrate such risk may be due to the completeness of follow-up over long periods that could be achieved in this study. Excess lung cancer risk was only noted in treatment regimens with radiotherapy (RT); also, all lung cancers arose in irradiation fields. Excess risk of leukemia was only found in treatment regimens involving chemotherapy (CT). For NHL, combined modality treatment was shown to be the most important risk factor. Risk of lung cancer and NHL increased with time since diagnosis. A time-dependent covariate analysis (Cox model) performed on leukemia and MDS showed an increasing risk with intensity of CT, age (greater than 40 years), and a splenectomy.
Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee.
Authors: Krown S E , Metroka C , Wernz J C
Published: February 2017

The availability of uniform and precise criteria for disease evaluation, response to treatment, and clinical staging of Kaposi's sarcoma (KS) in individuals with the acquired immune deficiency syndrome (AIDS) would facilitate therapeutic trials in patients with this neoplasm. Recently, a group of oncologists conducting clinical trials in patients with AIDS-associated KS as part of a cooperative group established by the National Institute of Allergy and Infectious Diseases (NIAID) drafted such criteria. The criteria take into account the unique problems associated with the evaluation of patients with a disseminated cutaneous neoplasm in the setting of a systemic virus infection associated with immune deficiency. The recommendations include a standardized format for documenting the extent of KS on initial and subsequent evaluations, response definitions that include assessments of lesion nodularity and tumor-associated edema in addition to more traditional methods for evaluating tumor response, and a new staging system that includes extent of tumor, immune status, and other AIDS-related disease manifestations, akin to the tumor-node-metastasis (TNM) system used to stage other tumors. The adoption of standardized criteria for the evaluation of KS should prove useful for group trials and for other investigators involved in the treatment of this disease.
Intraperitoneal cisplatin and etoposide in the treatment of refractory/recurrent ovarian carcinoma.
Authors: Reichman B , Markman M , Hakes T , Hoskins W , Rubin S , Jones W , Almadrones L , Ochoa M , Chapman D , Saigo P
Published: February 2017

To determine the efficacy of a 6-month course of combination intraperitoneal (IP) chemotherapy with cisplatin and etoposide in patients with refractory or recurrent advanced ovarian carcinoma, 67 patients were entered into this prospective, nonrandomized, single-institution trial. Cisplatin at 100 mg/m2 and etoposide at 200 mg/m2 were administered IP on day 1 every month for 6 months. Exploratory laparotomy was performed before protocol entry and was planned after the completion of 6 months of IP therapy to surgically document response. All patients had received prior intravenous (IV) chemotherapy with a cisplatin-based regimen. At protocol entry, 18 (27%) patients had surgically defined residual tumor (maximal tumor diameter) greater than 2.0 cm, 17 (25%) patients greater than 0.5 cm - less than or equal to 2.0 cm, and 32 (48%) patients less than or equal to 0.5 cm. Sixteen patients (24%) who had experienced a treatment-free interval of more than 1 year prior to study entry were considered as having recurrent disease and the remaining 51 (76%) patients were considered as having refractory disease. Toxicity was tolerable: four patients (6%) had nadir fever, three (4%) had culture-documented bacterial peritonitis, five (7%) had IP catheter-related complications, and 27 (40%) had an increase in serum creatinine greater than 1.5 mg/dL. Among the 57 patients who are fully evaluable for response, the overall surgically defined response rate, complete (CR), and partial response (PR), was 40% (23/57), and the CR rate was 21% (12/57). Among the patients with recurrent disease, eight of 13 (62%) responded, with responses seen among all categories of residual disease. Among the patients with refractory disease, 15 of 44 (34%) had surgically documented responses. However, responses were more frequent in patients with residual disease less than 0.5 cm; 11 of 20 (55%) versus four of 24 (17%) with residual greater than 0.5 cm, P = .019 (chi 2, one degree of freedom, Yates correction). The duration of the CRs ranges from 4 to 18+ months. Longer follow-up is needed to determine if there is any impact on survival.
Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial.
Authors: Johnson D H , Greco F A , Strupp J , Hande K R , Hainsworth J D
Published: February 2017

Twenty-two patients with recurrent small-cell lung cancer (SCLC) were treated with single-agent etoposide 50 mg/m2/d by mouth for 21 consecutive days. Eleven patients had received previous chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of the latter patients also received salvage treatment with cisplatin and etoposide (EP). Nine patients had been treated with EP as induction therapy, while two patients had received high-dose cyclophosphamide, etoposide and cisplatin (HDCEP). Altogether, 18 patients had received previous intravenous etoposide. The median time off chemotherapy was 4.5 months (range, 1 to 28.9 months). Ten patients (45.5%; 95% confidence interval [CI], 27% to 65%) achieved a complete or partial response. Responses were most common in patients who had responded to previous chemotherapy and who had not received any treatment in the 90 days before initiation of oral etoposide. Median response duration was 4 months (range, 1.5 to 9.5 months) and median survival was 3.5+ months (range, 1.0 to 15+ months). Leukocyte and platelet nadirs were 1,800/microL and 160,000/microL, respectively, during cycle 1 of treatment and occurred between days 21 and 28. Overall, total leukocyte count decreased to less than 1,000/microL during 10 of 56 cycles (18%). Five patients required six hospitalizations for neutropenia and fever. There were two toxic deaths due to sepsis. Platelet counts less than 50,000/microL occurred in 14 cycles (25%). Alopecia developed in all patients; gastrointestinal toxicity was uncommon. This schedule of etoposide administration warrants further study in combination with other active agents in previously untreated patients with SCLC.
Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.
Authors: Ayash L J , Hunt M , Antman K , Nadler L , Wheeler C , Takvorian T , Elias A , Antin J H , Greenough T , Eder J P
Published: February 2017

Retrospective review of 291 solid tumor and lymphoma patients undergoing autologous bone marrow transplantation (BMT) was performed to determine the influence of pretransplant characteristics and preparative regimen to the development of hepatic venoocclusive disease (VOD). Twelve patients (4.1%) developed a clinical syndrome of right upper quadrant (RUQ) tenderness or hepatomegaly, jaundice, and ascites, with or without encephalopathy, within 40 days of marrow reinfusion. Evidence of metastatic liver disease was the only pretransplant characteristic predictive for VOD (P = .0002). Sex, age, histology, hepatitis B serology, and elevated liver function tests were not predictive. No individual preparative agent had a significant effect on the development of VOD. However, a single 2-hour infusion of carmustine (BCNU) (greater than or equal to 450 mg/m2) led to an increased incidence of VOD when compared with the same dose administered in a fractionated schedule (P = .0258) when given with two other chemotherapeutic agents. Seven of eight autopsy specimens confirmed the clinical diagnosis of VOD. The four patients in whom clinical VOD resolved had lower median peak bilirubins (7.3 v 15.9 mg/dL), lower median peak creatinines (2.1 v 4.1 mg/dL), and relatively quick engraftment of neutrophils (mean, 18.7 days). One of the four patients in whom VOD resolved had other grade 4 (life-threatening) toxicities in contrast to eight of eight who succumbed. In summary, VOD is an uncommon complication in autotransplantation of solid tumors and lymphomas. Our data suggest caution in selecting patients with known metastatic liver disease and consideration of a fractionated BCNU schedule especially in combination with other alkylating agents.
Bone marrow transplantation for myelodysplasia and secondary acute nonlymphoblastic leukemia.
Authors: Longmore G , Guinan E C , Weinstein H J , Gelber R D , Rappeport J M , Antin J H
Published: February 2017

Twenty-three patients with primary myelodysplasia (MDS) or secondary myelodysplasia/acute nonlymphocytic leukemia (MDS/ANLL) were treated with allogeneic or syngeneic bone marrow transplantation (BMT). Only one patient was in a chemotherapy-induced hematologic remission. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, cyclosporine, or T-cell depletion using one of two anti-CD5 monoclonal antibodies. For patients with primary MDS, the median age was 19 years (range, 11 to 41 years) and the actuarial disease-free survival was 56% +/- 21% (median follow-up, 2 years; range, 0.8 to 5 years). There were three graft failures (two with autologous recovery) and two early deaths. Outcome appeared to be related to French-American-British (FAB) classification. For patients with secondary MDS/ANLL, the median age was 28 years (range, 3 to 16 years) and the actuarial disease-free survival was 27% +/- 13% (median follow-up, 5 years; range, 2.5 to 8.5 years). There were no graft failures, two relapses, and four early deaths. The presence of marrow fibrosis per se did not predict for graft failure (P = .21); however, the use of T-cell depleted marrow in patients with marrow fibrosis resulted in graft failure in three of five individuals. Our results suggest that in patients with primary MDS or secondary MDS/ANLL, BMT should be considered early in the course of the disease, and that attempts at inducing a remission prior to BMT appeared to be unnecessary. In MDS patients with marrow fibrosis, T-cell depletion should be avoided.
Acute renal dysfunction during interleukin-2 treatment: suggestion of an intrinsic renal lesion.
Authors: Shalmi C L , Dutcher J P , Feinfeld D A , Chun K J , Saleemi K R , Freeman L M , Lynn R I , Wiernik P H
Published: February 2017

Adoptive immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells has been effective in treating some advanced malignancies in animals and humans. One complication of this treatment is a reversible, oliguric, acute renal failure, which has been ascribed to renal hypoperfusion and resultant prerenal azotemia. We serially studied renal function in 10 patients receiving high-dose regimens of recombinant interleukin-2 (rIL-2) to attempt to delineate further the nature of the renal dysfunction caused by IL-2 treatment. Renal plasma flow was computed from iodine 131 (I-131 Hippuran; Mediphysics, Paramus, NJ) orthoiodohippurate, excretion curves, and glomerular filtration rate (GFR) was determined by creatinine clearance. Studies done prior to and on day 4 of treatment showed that GFR fell in nine of 10 patients, with a mean decrease of 43% +/- 8%, and renal plasma flow fell in five of the 10 patients with a mean decrease of 5% +/- 10%. The average pretherapy filtration fraction was calculated to be 23% +/- 1% and after 4 days of treatment, decreased to a mean value of 15 +/- 2%. The BUN to creatinine ratio also declined in all patients. These findings collectively suggest that IL-2 nephrotoxicity may result from an intrarenal defect in addition to the previously described prerenal azotemia. Additionally, radionuclide studies of renal function are a reliable and reproducible noninvasive method of assessing these changes in renal function.
A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group.
Authors: Ettinger D S , Finkelstein D M , Abeloff M D , Ruckdeschel J C , Aisner S C , Eggleston J C
Published: February 2017

The present randomized, prospective study was designed to assess whether alternating induction cyclophosphamide, doxorubicin, vincristine-altretamine (hexamethylmelamine), etoposide, and methotrexate (CAV-HEM) chemotherapy is better than standard chemotherapy (CAV) in improving response, survival, and remission time in 577 evaluable patients having extensive-disease small-cell lung cancer (SCLC). In addition, the study was designed to assess the impact of maintenance chemotherapy following a complete response (CR) on the time to progression and survival. The response rates (CR plus partial response [PR]) for CAV-HEM and CAV were 64% and 61%, respectively, but 23% of the patients on CAV-HEM achieved a CR compared with 16% for CAV alone (P = .03). Among complete responders, the continuation of therapy significantly increased the remission time for patients on CAV, while maintenance therapy for patients on CAV-HEM had no significant impact on remission time. However, the increased remission had little effect on survival. Patients on CAV maintenance therapy survived marginally longer than those patients on no maintenance therapy, whereas patients who received CAV-HEM and no maintenance therapy survived longer than those on maintenance therapy. CAV-HEM was associated with significantly higher severity of complications (ie, mainly myelosuppression) than CAV (P = .01). Maintenance chemotherapy was associated with significantly more complications than no maintenance therapy. Patients on CAV-HEM lived significantly longer than those on CAV alone (45.9 weeks v 42.7 weeks; P = .002). Ten percent of patients treated on CAV-HEM survived at least 2 years, compared with 4% on CAV alone. In our study involving patients with extensive-disease SCLC, the alternating induction chemotherapy significantly increased the CR rates and had a small impact on long-term survival compared with the results achieved with standard induction chemotherapy. Moreover, when the alternating induction chemotherapy was used, long-term maintenance chemotherapy was not needed.
Characterization of immunoglobulin and T-cell receptor gene patterns in B-cell precursor acute lymphoblastic leukemia of childhood.
Authors: Felix C A , Poplack D G , Reaman G H , Steinberg S M , Cole D E , Taylor B J , Begley C G , Kirsch I R
Published: February 2017

Immunoglobulin (Ig) and T-cell receptor (TCR) genes were examined in the lymphoblasts of 70 children with immunophenotypically defined B-cell precursor acute lymphoblastic leukemia (ALL). The most frequent genes to rearrange were Ig heavy (H) chain (93%) and TCR delta (79%), followed by TCR gamma (49%), Ig kappa and/or lambda light (L) chain (46%), TCR alpha (46%), and TCR beta (29%). Thus, despite their putative "B-cell precursor" lineage, these leukemias manifest a remarkably high incidence of TCR gene rearrangements. While certain patterns predominate, there is considerable heterogeneity in Ig and TCR genotypes in this disease. No significant associations were found between Ig and TCR genotype and commonly used prognostic factors including age, sex, race, WBC, French-American-British (FAB) subtype, or cytogenetics. However, the lymphoblasts of three of six patients who failed to achieve initial remission had germline patterns of every Ig and TCR gene, a genotype not observed in the leukemic cells from any of the 64 patients who achieved complete remission (p2 = .0007). This study suggests that particular Ig and TCR genotypes may be of clinical relevance in childhood B-cell precursor ALL. The finding of rearranged TCR genes in a large proportion of cases raises fundamental questions about early lineage commitment and lymphocyte differentiation along B-cell and T-cell pathways.
High-dose cisplatin combination chemotherapy in the treatment of advanced epithelial ovarian carcinoma.
Authors: Hainsworth J D , Burnett L S , Jones H W , Grosh W W , Johnson D H , Greco F A
Published: February 2017

We treated 25 newly diagnosed patients with advanced epithelial ovarian cancer with an intensive induction chemotherapy regimen using high-dose cisplatin in combination with cyclophosphamide and doxorubicin. All patients had either stage IIIC or stage IV disease. Two intensive induction courses of chemotherapy were administered at 28-day intervals, which consisted of cisplatin 40 mg/m2 daily for 5 days, cyclophosphamide 500 mg/m2 day 1, and doxorubicin 40 mg/m2 day 1. Four courses of chemotherapy using cisplatin 60 mg/m2, doxorubicin 40 mg/m2, and cyclophosphamide 500 mg/m2 followed the high-dose induction therapy. Two of the first six patients died during high-dose induction therapy (one died of neutropenia and sepsis, one of intercurrent intracerebral hemorrhage). Doxorubicin was subsequently omitted from the induction therapy due to unacceptable myelosuppression; no deaths occurred in the remaining 19 patients, and myelosuppression was manageable. Peripheral neuropathy was the most severe side effect with this regimen. This complication was unpredictable, developed during the third or fourth month of treatment, and was disabling in five patients. Other toxicity included prolonged nausea and vomiting (eight patients), ototoxicity (five patients), and nephrotoxicity (two patients), but these did not compromise therapy. All 23 assessable patients had objective response to therapy. Four of 12 patients who underwent second-look laparotomy had pathologic complete response, while four additional patients had only microscopic residual disease. The median survival for the entire group was 25 months. Four patients remain continuously disease-free 23 to 48 months following completion of therapy. Although this regimen was tolerated by most patients, the unpredictable occurrence of disabling neuropathy may limit its usefulness.(ABSTRACT TRUNCATED AT 250 WORDS)
Cellular DNA content and prognosis of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience.
Authors: Alvegard T A , Berg N O , Baldetorp B , Fernö M , Killander D , Ranstam J , Rydholm A , Akerman M
Published: February 2017

The nuclear DNA content of 148 high-grade soft tissue sarcomas of the extremities and trunk was determined by flow cytometry, using tumor material from paraffin-embedded tissue. The patients were part of a prospective randomized clinical trial on the efficacy of adjuvant single-agent chemotherapy with doxorubicin. Chemotherapy did not improve the metastasis-free survival (MFS). After a median follow-up time of 48 months (range, 2 to 97), a multivariate analysis of prognostic factors for developing metastatic disease was performed. DNA aneuploidy was found to be an independent prognostic risk factor in addition to histologic malignancy grade IV, intratumoral vascular invasion, tumor size over 10 cm, and male sex. Patients with none or one risk factor had a 5-year MFS of 79%, with two risk factors 65%, with three risk factors 43%, and with four and five risk factors 0%. About one half (78 of 148) of the patients with three factors or less belonged to a group with a MFS over 60%. The combination of different risk factors, including DNA aneuploidy, seems to be a useful prognostic model for soft tissue sarcomas, which could be of value to select high-risk patients for further trials with adjunctive therapy.
Improved methodology for analyzing local and distant recurrence.
Authors: Gelman R , Gelber R , Henderson I C , Coleman C N , Harris J R
Published: February 2017

Studies of radiation therapy and/or surgery in the treatment of cancer frequently use actuarial methods to estimate curves of time to local failure and compare two such curves with statistical methods originally developed for survival data. In such analyses, patients who fail first in distant sites or die before local failure are considered censored for time to local failure. While the arithmetic of these calculations is usually correct, the interpretation of the results is almost universally incorrect. For example, an actuarial Kaplan-Meier curve of time to breast recurrence after breast conserving treatment consistently overestimates the percentage of patients who would benefit from a subsequent mastectomy. Actuarial methods require the assumption that time to local failure and time to distant failure are statistically independent. For most human malignancies this is not a reasonable assumption, since there are always some patient subgroups at high risk of both local and distant failure and some patient subgroups at low risk for either type of failure. Without the assumption of independence, the time to local failure distribution is not well defined. The basic problem is that estimating time to local failure falls into the category of analyzing "competing risks," since the various causes of failure are competing for the same patient. For this reason, the effects of a particular treatment on local failure cannot be assessed separately from its effects on distant failure. This report explains the concepts of statistical independence, nonidentifiability, and competing risks and illustrates the pitfalls of using actuarial methods to assess local tumor control.(ABSTRACT TRUNCATED AT 250 WORDS)
Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle.
Authors: Petersen F B , Appelbaum F R , Hill R , Fisher L D , Bigelow C L , Sanders J E , Sullivan K M , Bensinger W I , Witherspoon R P , Storb R
Published: February 2017

Between October 1979 and January 1988, 101 patients with malignant lymphoma who failed initial induction treatment or relapsed received high-dose combination chemotherapy or chemoradiotherapy followed by infusion of autologous bone marrow. Twenty-eight of the 101 patients survive, 18 of whom are disease-free for a median of 26 (range, 12 to 66) months. The 5-year actuarial probabilities of survival, event-free survival (EFS), and relapse from transplantation were 20%, 11%, and 84%, respectively. Multivariate analysis showed that the likelihood of EFS was decreased among patients transplanted with a Karnofsky score of less than 80%. Recurrent lymphoma after transplant was the most important cause of treatment failure with 36 of 62 relapses occurring within 100 days from marrow infusion. Early, but not late relapse, was more frequent in patients transplanted for advanced lymphoma, and both early and late relapses were increased among patients with impaired pretransplant clinical performance or high-grade histology of lymphoma. Ten patients who relapsed post-transplant are alive, seven in remission. Further improvement of these results will require earlier transplantation, improved preparative regimens, or early posttransplant therapy.
Aromatase inhibition with 4-hydroxyandrostenedione in the treatment of postmenopausal patients with advanced breast cancer: a phase II study.
Authors: Höffken K , Jonat W , Possinger K , Kölbel M , Kunz T , Wagner H , Becher R , Callies R , Friederich P , Willmanns W
Published: February 2017

Estrogen deprivation by aromatase inhibition is an effective treatment in breast cancer. Between October 1986 and March 1988, 91 postmenopausal patients with advanced breast cancer entered a phase II study performed jointly in three center to investigate the new aromatase inhibitor 4-hydroxyandrostenedione. Patients received 500 mg 4-hydroxyandrostenedione intramuscularly (IM) every 2 weeks for 6 weeks, and 250 mg every 2 weeks thereafter. There were two complete (CRs) and 19 partial remissions (PRs) (response rate, 23%). Disease stabilization (no change; NC) was seen in 26 patients, and in 44 patients (48%), disease progression occurred. Duration of the CRs is 20+ months, median durations of PR and NC are 13+ and 8 months, respectively. Receptor status, relapse-free interval, and sites of metastatic lesions did not appear to influence treatment results. However, efficacy of previous tamoxifen treatment favorably predicted response to 4-hydroxyandrostenedione. Serum estradiol levels decreased significantly in patients after 2 weeks of treatment. Side effects were mostly nonspecific and of low degree, requiring discontinuation of treatment in only 3% of the patients. We conclude that aromatase inhibition with 4-hydroxyandrostenedione is efficacious in the treatment of postmenopausal breast cancer.