bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical castration produced by the GnRH analogue leuprolide to treat metastatic breast cancer.
Authors: Harvey H A , Lipton A , Max D T , Pearlman H G , Diaz-Perches R , de la Garza J
Published: February 2017

Leuprolide (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered to 26 premenopausal women with metastatic breast cancer. Of 25 evaluable patients, 11 (44%) had a partial response with a median duration of 39 weeks and five (20%) remained stable. Six patients showed early rapid progression of their disease. Toxicity was mild and included hot flashes, nausea, vomiting, and headache. Leuprolide induced amenorrhea in all patients who received treatment for ten weeks or longer. We conclude that this GnRH analogue provides a safe and effective means of producing medical castration in premenopausal patients with metastatic breast carcinoma.
Follicular and diffuse mixed small-cleaved and large-cell lymphoma--a clinicopathologic study.
Authors: Hu E , Weiss L M , Hoppe R T , Horning S J
Published: February 2017

The clinical records and initial biopsy materials from 76 patients with mixed small-cleaved and large-cell lymphoma containing both a follicular and diffuse architectural pattern were reviewed. The characteristics of this group, treated at Stanford University Medical Center (SUMC) between 1963 and 1983, are described. The 5-year actuarial survival and freedom from progression are 70% and 27.5%, respectively. Classification according to the degree of follicularity indicated that patients with focally follicular areas (ie, less than 25% of the histologic section) have a significantly worse freedom from progression and overall survival at 5 years compared with those patients with a predominantly follicular architecture (ie, greater than 50% follicular areas). Based on our analysis, we feel that the degree of follicularity is an important prognostic factor and that mixed lymphoma patients with only focally follicular areas behave more like an intermediate-grade lymphoma and should be treated aggressively.
Lack of antiemetic effect of high-dose metoclopramide.
Authors: Roemeling R V , Christiansen N P , Hrushesky W J
Published: February 2017

Sixteen of 26 patients given 51 courses of treatment of the doxorubicin and cisplatin combination with no antiemetic therapy suffered the same number of vomiting episodes and had the same duration of vomiting as did the remaining ten patients given 20 cycles of this chemotherapy plus the standard high-dose metoclopramide regimen. This antiemetic regimen caused significant side effects in one fifth of the patients receiving it.
A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer.
Authors: Ruckdeschel J C , Finkelstein D M , Ettinger D S , Creech R H , Mason B A , Joss R A , Vogl S
Published: February 2017

Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.
Doxorubicin-induced skin necrosis in the swine model: protection with a novel radical dimer.
Authors: Averbuch S D , Gaudiano G , Koch T H , Bachur N R
Published: February 2017

The treatment of doxorubicin (DOX) extravasation tissue injury is poorly defined. A swine model has been developed to study DOX skin toxicity and potential pharmacologic antidotes. Intradermal injections of DOX in miniature female weanling swine produced predictable and dose-dependent ulcerations that closely resemble lesions observed in humans following extravasation of DOX. The ulcers reached maximal size at 3 weeks following DOX administration and were completely healed by 7 weeks. Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) is a radical dimer that can react with DOX in vitro to produce deoxydoxorubicin aglycone, an inactive anthracycline metabolite. When DHM3 was administered into the same intradermal injection site 15 minutes after DOX, the maximum ulcer size was reduced 80%, and the healing time was reduced to 5 weeks. The protection from toxicity was highly dependent on the time interval between DOX and DHM3 injections, with no protection noted after a 60-minute interval. Our data verify the swine model as a useful tool to study DOX-induced extravasation injury. Furthermore, DHM3 is an effective antidote for DOX-induced skin necrosis and has potential for clinical use.
Treatment of lymphoblastic lymphoma in adults.
Authors: Coleman C N , Picozzi V J , Cox R S , McWhirter K , Weiss L M , Cohen J R , Yu K P , Rosenberg S A
Published: February 2017

Forty-four adult patients with lymphoblastic lymphoma (LBL) were treated according to one of two protocols. Both included (1) induction with cyclophosphamide, doxorubicin, vincristine, prednisone, and L-asparaginase; (2) CNS prophylaxis; and (3) maintenance therapy with methotrexate (MTX) and 6-mercaptopurine. In the second protocol, CNS prophylaxis began earlier than in the first protocol and included cranial irradiation and intrathecal (IT) MTX rather than simultaneous high-dose systemic and IT MTX. The overall response rate was 100% (95% complete). With a 26-month median follow-up, the 1-and 3-year actuarial freedom from relapse (FFR) for the composite patient group was 70% and 56%, respectively. The incidence of CNS relapse was reduced from 31% in the first protocol to 3% in the second protocol (P = .04, Gehan). Patients can be assigned retrospectively to low (n = 19) and high (n = 25) risk prognostic groups, as indicated by a multivariate analysis of pretreatment prognostic factors. High-risk is defined by Ann Arbor stage IV disease with bone marrow or CNS involvement or initial serum lactate dehydrogenase (LDH) concentration of greater than 300 IU/L (normal, less than 200). FFR of low- and high-risk groups at 5 years are 94% and 19%, respectively (P = .0006). Low-risk patients are highly curable using this approach to adult LBL. More intensive treatment for high-risk patients is warranted.
High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in non-small-cell lung cancer.
Authors: Gandara D R , DeGregorio M W , Wold H , Wilbur B J , Kohler M , Lawrence H J , Deisseroth A B , George C B
Published: February 2017

Although increased efficacy has been described with a five-day schedule of high-dose cisplatin (CDDP) in hypertonic saline, severe myelosuppression and cumulative neurotoxicity have limited the usefulness of this therapy. In order to evaluate a possible dose-response relationship in non-small-cell lung cancer (NSCLC), 17 patients with metastatic disease were treated with a modified dose schedule delivering the same total dose (200 mg/m2) in a divided day 1 and 8 schedule. During a pilot study, a total of 47 cycles of therapy were administered, with a median of three cycles per patient and a median total cumulative dose of 600 mg/m2. Nine of 17 patients received at least 600 mg/m2. While nephrotoxicity was similar to previous reports of the five-day schedule, the incidence and severity of myelosuppression and peripheral neuropathy were markedly reduced. Using this modified schedule, severe myelosuppression did not occur. Clinically severe peripheral neuropathy developed in only one patient (6%). The overall response rate was 47% (eight of 17 patients). Plasma platinum pharmacokinetics during five cycles of the modified day 1 and 8 schedule were compared with pharmacokinetics of the five-day schedule. Accumulation of plasma ultrafiltrate platinum occurred in the five-day schedule, but not in the day 1 and 8 schedule. This difference in pharmacokinetics is one possible explanation for the reduced toxicity of this modified schedule. Although the degree of activity seen in this pilot study is encouraging, the efficacy of high-dose CDDP in NSCLC remains to be defined. In view of reduced myelosuppression and neurotoxicity, further trials with this modified schedule are indicated.
Medical oncology manpower training: a position statement of the American Society of Clinical Oncology.
Authors: Kennedy B J , Calabresi P , Clarkson B , Frenkel E
Published: February 2017

The evolution of Medical Oncology is facing its first major crisis, that of oversupply of trained oncologists. The tabulated number of certified medical oncologists does not constitute all of the physicians practicing Medical Oncology in the United States. Because of the adequate supply of medical oncologists in clinical practice, but a deficiency of academic oncologists dedicated to research careers, a reduction in training programs should emphasize those programs that lack research opportunities. These recommendations are in keeping with the report of the Long-Range Planning Committee of the American Society of Clinical Oncology of March 21, 1984. Plans to expedite these goals are being established.
First repeated bone scan in the observation of patients with operable breast cancer.
Authors: Pedrazzini A , Gelber R , Isley M , Castiglione M , Goldhirsch A
Published: February 2017

Data on 1,601 patients with node-positive operable breast cancer who were randomized in four different prospective adjuvant therapy trials were analyzed to evaluate the role of routine bone scans and the alkaline phosphatase value at regular intervals in screening for bone involvement. Bone scan was a prerequisite for randomization and was repeated within the first 12 months in 90% (1,441) of the patients. Abnormal or doubtful scan findings had to be verified by x-ray examination. The repeated scan results were normal in 1,263 (87.8%) patients, doubtful but with no radiologic evidence of bone metastasis in 161 (11%), and abnormal (radiologically confirmed) in 17 (1.2%). After a median observation of 4 years bone metastases as the first relapse developed in 136 (8.5%) patients. This occurred in 87 of 1,263 (6.9%) of the patients with normal repeated scan results and in 18 of 161 (11.2%) of those with doubtful repeated scan findings. Based on the results of the first repeated scan, early detection of a first recurrence in bone might have been possible for 2.4% of the population. Serum alkaline phosphatase levels were also without clinical use. Bone scan in the observation of patients with operable breast cancer should be performed only as dictated by the clinical situation.
Phase I study of recombinant leukocyte A human interferon combined with BCNU in selected patients with advanced cancer.
Authors: Creagan E T , Kovach J S , Long H J , Richardson R L
Published: February 2017

Interferons manifest diverse immunomodulatory and antiproliferative characteristics. Since their spectrum of toxicities includes primarily fatigue and anorexia rather than the myelosuppression concomitant with cytotoxic therapies, it is conceptually appealing to combine both modalities. We conducted a phase I trial among 18 patients using the combination of leukocyte A recombinant interferon (IFN-rA) and BCNU. The intramuscular (IM) IFN-rA dose for the initial 12 patients was 12 X 10(6) U/m2 three times a week for an anticipated duration of 12 weeks. Among these patients, we escalated the monthly intravenous (IV) BCNU dose from 50 mg/m2 to 150 mg/m2. Six subsequent patients received IFN-rA 12 X 10(6) U/m2, days 1 to 3, and BCNU 150 mg IV on day 3 of each monthly cycle. Dose-limiting toxicities from both regimens were fatigue and myelosuppression. We recognize the limitation of small sample sizes. Nevertheless, in the absence of a significant number of life-threatening toxicities, it appears that near maximal doses of BCNU and concomitant IFN-rA can be administered with safety in an outpatient setting.
Gonadotropin hormone-releasing hormone analogues: a new therapeutic approach for prostatic carcinoma.
Authors: Eisenberger M A , O'Dwyer P J , Friedman M A
Published: February 2017

The introduction of potent analogues of gonadotropin hormone-releasing hormone (GnRH) into clinical practice and their use in patients with metastatic prostatic carcinoma provides an effective alternative to the exogenous administration of pharmacologic doses of estrogens or surgical castration. Their advantages over estrogens are primarily related to a lower incidence of cardiovascular toxicity and gynecomastia. Their choice over orchiectomy is based on cosmetic and psychologic factors since their endocrine effects and clinical benefits are virtually the same. In this review, we describe the current experience with GnRH analogues in the treatment of prostatic carcinoma and discuss their use in the context of other endocrine manipulations. GnRH analogues act on the pituitary and indirectly affect gonadal function, and represent an opportunity for combination with other compounds capable of suppressing or interfering with the effects of circulating and androgens. The availability of several new compounds affecting different aspects of androgen metabolism provides promise for rational drug selection and testing.
Prognostic significance of terminal deoxynucleotidyl transferase activity in acute nonlymphoblastic leukemia.
Authors: Benedetto P , Mertelsmann R , Szatrowski T H , Andreeff M , Gee T , Arlin Z , Kempin S , Clarkson B
Published: February 2017

Bone marrow and/or peripheral blood samples from 133 (75%) of a total of 177 consecutive previously untreated protocol patients with acute nonlymphoblastic leukemia (ANLL) were analyzed for terminal deoxynucleotidyl transferase (TdT) activity at the time of presentation. Twenty-nine (22%) were found to exhibit TdT activity (greater than or equal to 0.10 U/10(8) cells, TdT+) as measured in a biochemical microassay. There were no differences between TdT+ as compared with TdT-negative (TdT-) patients with respect to age, sex, French-American-British (FAB) classification, or the presence of Auer's rods. Remission induction rates were higher for the TdT- patients, with 68% v 48% for the TdT+ patients (P = .05). TdT- patients also experienced longer remissions (P = .003) than TdT+ patients, especially in the Auer's rod-positive subgroup (P = .002). None of five patients with TdT+ ANLL treated with vincristine and prednisone as initial therapy achieved complete remission; all required induction regimens containing daunorubicin or amsacrine in combination with cytosine arabinoside and 6-thioguanine. It is concluded that TdT activity in ANLL indicates biphenotypia or lineage infidelity and is associated with a poor prognosis on chemotherapy protocols currently used for the treatment of ANLL.
Human T-lymphotropic virus type III infection in previously immunocompromised hosts.
Authors: Groopman J E , Hammer S M , Sallan S E , Allan J D
Published: February 2017

The human T-lymphotropic virus type III (HTLV-III) is the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). HTLV-III infection in patients with prior underlying immune deficiency states such as cancer has not yet been studied. We report on the occurrence of clinically atypical opportunistic infections in previously immunocompromised patients that resulted from transfusion-acquired HTLV-III infection. Development of unusual infectious diseases in patients with neoplasms and other underlying immune deficiency disorders should lead to consideration of HTLV-III infection. Surveillance data should be obtained on these patients to accurately define the scope of HTLV-III infection.
Therapy for childhood soft-tissue sarcomas other than rhabdomyosarcoma: a review of 62 cases treated at a single institution.
Authors: Horowitz M E , Pratt C B , Webber B L , Hustu H O , Etcubanas E , Miliauskas J , Rao B N , Fleming I D , Mahesh Kumar A P , Green A A
Published: February 2017

The rarity and diverse characteristics of the nonrhabdomyosarcomatous soft-tissue sarcomas (NRSTS) in children have hindered study of their clinical presentations and response to therapy. Here we describe the findings of a retrospective analysis of 62 cases of NRSTS seen in a single institution from 1962 through 1983. The most common histopathologic diagnosis was synovial sarcoma, occurring in 18 patients, followed by malignant schwannoma in 12. The median age at diagnosis was 11 years (range, 2 months to 20 years). Anatomic sites of primary tumors were the trunk (28), extremity (24), and head and neck (10). Of the 31 patients whose tumors were completely resected, 26 (84%) survive with no evidence of disease. Postoperative chemotherapy, administered to nearly one half of this group, did not produce any demonstrable gains in survival. Only one of the 26 patients with local or metastatic gross tumor after resection survives. We conclude that an aggressive surgical approach is imperative in patients with NRSTS and that the contribution of other treatment modalities needs to be defined in a collaborative group trial.
Long-term survivors in metastatic non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study.
Authors: Finkelstein D M , Ettinger D S , Ruckdeschel J C
Published: February 2017

Between December 1979 and June 1983 the Eastern Cooperative Oncology Group (ECOG) treated 893 good-performance status patients with metastatic non-small-cell lung cancer (NSCLC) on one of seven phase III combination chemotherapies. The overall median survival was 23.5 weeks with no significant differences between treatments. One hundred sixty-eight patients (19%) survived greater than 1 year and 36 (4%) for greater than 2 years. The etoposide-platinum combination had the highest proportion of 1-year survivors (25%). Mitomycin-vinblastine-platinum (MVP), which had demonstrated the highest response rate, had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Analysis of pretreatment characteristics that distinguished patients who survived greater than 1 year from those who did not demonstrated that an initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large-cell histology, less than 5% prior weight loss, no symptoms of shoulder or arm pain, and no liver metastases were predictors of longer survival. Of particular interest was the finding that response duration was significantly longer (P = .002) for those patients who experienced a longer time to best response. In addition, patients who survived greater than 1 year experienced greater degrees of nonlethal toxicity, in particular, gastrointestinal and hematologic, than patients who did not survive 1 year, (P = .006). A detailed chart review of 32 2-year survivors and 32 matched controls demonstrated that maintenance or improvement of performance status and maintenance of serum albumin levels at 3 months from the initiation of treatment were both important predictors of longer survival.
Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma.
Authors: Holmes E C , Gail M
Published: February 2017

The Lung Cancer Study Group randomized 141 patients with resected stage II and III adenocarcinoma and large-cell undifferentiated carcinoma to receive postoperative Cytoxan (Bristol-Meyers, Syracuse, NY), Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) chemotherapy or bacillus Calmette-Guerin (BCG) and levamisole immunotherapy. Careful intraoperative staging was performed on all patients. Before randomization, patients were stratified by stage, weight loss, cardiac arrhythmia, and institution. Prognostic variables such as stage, age, weight loss, and nodal involvement were equally distributed between the two groups. Disease-free survival was significantly prolonged in the group receiving chemotherapy. There was no evidence of a deleterious effect of the immunotherapy. This study indicates that postoperative CAP chemotherapy is effective in prolonging disease-free survival in these patients.
Emergency prebiopsy radiation for mediastinal masses: impact on subsequent pathologic diagnosis and outcome.
Authors: Loeffler J S , Leopold K A , Recht A , Weinstein H J , Tarbell N J
Published: February 2017

From 1968 to 1983, 19 patients were treated at the Joint Center for Radiation Therapy for symptomatic mediastinal masses before a biopsy was obtained. This study evaluates the impact of radiation on the ability to establish a pathologic diagnosis and the results of subsequent empirical therapy if no diagnosis was established. Eight of the 19 (42%) patients were not able to have a histologic diagnosis established at the time of biopsy. Seven of these eight patients went on to receive empiric therapy for what was thought to be the most likely diagnosis on clinical grounds. Four of the seven have not relapsed; three who have relapsed were found to have the diagnosis for which they were empirically treated. The untreated patient relapsed with seminoma. Thus, the use of emergency irradiation for mediastinal masses is sometimes associated with the loss of pathologic diagnosis. These patients likely have a radioresponsive disease (ie, lymphoma or seminoma) that may be treated successfully on the presumed clinical diagnosis even when the histologic diagnosis is lost secondary to prebiopsy irradiation.
Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen--a new intensive therapy protocol: a report from the Childrens Cancer Study Group.
Authors: Steinherz P G , Gaynon P , Miller D R , Reaman G , Bleyer A , Finklestein J , Evans R G , Meyers P , Steinherz L J , Sather H
Published: February 2017

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.
Gastrointestinal involvement and multiple lymphomatous polyposis in mantle-zone lymphoma.
Authors: Triozzi P L , Borowitz M J , Gockerman J P
Published: February 2017

The clinical, histologic, and immunologic features of three cases of lymphoma presenting with gastrointestinal symptoms and involving the gastrointestinal tract were studied. Two of the cases had involvement of long segments of the bowel with polypoid lesions, a rare presentation of gastrointestinal lymphoma referred to as multiple lymphomatous polyposis (MLP). All cases were classified as mantle-zone lymphoma (MZL), a follicular variant of intermediate lymphocytic lymphoma (ILL) characterized by the proliferation of small atypical lymphoid cells as wide mantles surrounding benign-appearing germinal centers. The patients were typical of other patients with MZL in that they were male, middle age or older, and their clinical courses were not aggressive despite the presence of disease at an advanced stage. Our review of the literature suggests that there is an inordinate number of cases of MZL with gastrointestinal involvement. We also note that most reports of cases of MLP have described histologic lesions remarkably similar to what we have observed. We conclude that MZL may have predilection for involvement of the gastrointestinal tract, that this involvement is often in the manner of MLP, and that most cases of MLP probably have MZL or ILL.
Consolidation and maintenance therapy in multiple myeloma: randomized comparison of a new approach to therapy after initial response to treatment.
Authors: Cohen H J , Bartolucci A A , Forman W B , Silberman H R
Published: February 2017

A randomized, controlled trial was initiated in 1977 to evaluate the impact of three alternative approaches to consolidation and maintenance therapy after initial maximal response for multiple myeloma. All patients were treated initially with BCNU, cyclophosphamide, and prednisone (BCP) until a designated level of response was achieved. Responders were randomly assigned to either melphalan and prednisone (MP); prednisone, Adriamycin (Adria Laboratories, Columbus, Ohio), azathioprine, and vincristine (PAIV), or no therapy until relapse, then treatment with BCP. Initial response rates were comparable with previous trials. A small number of incremental responses were observed with both MP and PAIV. Survival was the same for all three maintenance approaches and the same as that observed in our previous continuous BCP or MP therapy. Additional or consolidation/maintenance therapy of the type administered here appears to offer little advantage once an initial response has been achieved.
Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients.
Authors: Golomb H M , Jacobs A , Fefer A , Ozer H , Thompson J , Portlock C , Ratain M , Golde D , Vardiman J , Burke J S
Published: February 2017

Sixty-four patients with hairy-cell leukemia (HCL) (61 had undergone prior splenectomy) were treated with alpha-2 interferon (Intron A, Schering Corp, Kenilworth, NJ) subcutaneously three times per week at a dosage of 2 X 10(6) U/m2. Three patients (5%) demonstrated a complete response (CR) with apparent eradication of hairy cells from the bone marrow, 45 patients (70%) showed a partial response (PR) defined as normalization of all three blood counts associated with decreased involvement in the bone marrow, and nine patients (14%) showed a minor response that included improvement in at least one blood count. Three patients had no response, three patients died before completing 1 month of therapy, and one patient refused further therapy after 1 month of therapy. The median platelet count returned to normal by the second month of treatment. The median hemoglobin returned to greater than 12 mg/dL by the fourth month of treatment, and the median granulocyte count to greater than 1,500/mu by the fifth month of treatment. Bone marrow biopsy analysis during interferon therapy demonstrated a decrease in median hairy-cell index by more than half. Transfusion of both RBCs and platelets were decreased within 4 months of initiating treatment. Serious infections, which averaged four per month in 16 of the 64 patients before interferon therapy, were rarely observed after the first month of treatment. Treatment-induced toxicity was mild, consisting primarily of influenza-like symptoms, fatigue, and minor skin disorders. Alpha-2 interferon therapy is highly effective in reversing the course of progressive HCL and should be considered the treatment of choice for a minimum of 12 months in patients who have progressive disease post-splenectomy.
Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer.
Authors: Fisher B , Fisher E R , Redmond C
Published: February 2017

Between 1972 and 1974, patients were entered into a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate L-phenylalanine mustard (L-PAM) as an adjuvant to mastectomy in patients with primary breast cancer and pathologically positive axillary nodes. Overall, findings through 10 years of observation indicate an 8% difference in disease-free survival (DFS) (P = .06) and a 5% difference in survival (P = .4). Women less than or equal to 49 years of age who received L-PAM demonstrate a significant (P = .03) prolongation of DFS and a significant (P = .05) survival benefit compared with those who received a placebo. There is a 37% reduction in their mortality and a cumulative odds of survival of 1.67. In that age group, both those with one to three and greater than or equal to 4 positive nodes benefited, but the advantage was greater when there were fewer positive nodes. There was a significant (P = .009) reduction in mortality (64%) and a cumulative odds of survival of 3.25 in patients less than or equal to 49 years old with one to three positive nodes. No advantage from L-PAM was observed in patients greater than or equal to 50 years old. When L-PAM response is related to nuclear grade, a marker of tumor differentiation, there is a highly significant improvement in DFS (less than .001), distant DFS (.001), and survival (.004) through 10 years of observation for all patients with tumors classified as nuclear grade poor (poorly differentiated), regardless of age and nodal status. Mortality was reduced by 32% and the cumulative odds of survival was 2.10 at 10 years. Of singular importance is the observation of a benefit in those greater than or equal to 50 years of age as well as in those less than or equal to 49 years of age with poorly differentiated tumors. There is a significant (P = .003) survival benefit for those in the older age group with a 37% reduction in mortality, and a cumulative odds of survival of 2.75. Patients in both age groups with well-differentiated tumors demonstrated no benefit from L-PAM. Those who are older seem to do less well following chemotherapy. We conclude that tumor differentiation is a better discriminant of response to chemotherapy than is age, and that both younger and older women are responsive to adjuvant chemotherapy when they have poorly differentiated tumors.
Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer.
Authors: Ingle J N , Green S J , Ahmann D L , Long H J , Edmonson J H , Rubin J , Chang M N , Creagan E T
Published: February 2017

A randomized clinical trial was performed to compare the efficacy of tamoxifen (TAM) alone with that of TAM plus aminoglutethimide (AG) and hydrocortisone (HC). Patients failing TAM could receive AG and HC. Objective responses to therapy were seen in 21 of 49 TAM patients (43%) and 25 of 51 TAM, AG and HC patients (49%). Time to disease progression and survival distributions were not significantly different between the treatment arms. Toxicity was greater for patients treated with TAM, AG, and HC and the trial was discontinued early for this reason. Twenty-four patients received AG and HC after TAM therapy and three (12%) achieved a response. We conclude that the combination of TAM, AG, and HC is not recommended over TAM alone because toxicity appears to outweigh any potential therapeutic advantage.
Etoposide (VP-16) and cisplatin in previously treated small-cell lung cancer: clinical trial and in vitro correlates.
Authors: Batist G , Carney D N , Cowan K H , Veach S R , Gilliom M , Bunn P A , Ihde D C
Published: February 2017

Treatment of patients with relapsed small-cell lung cancer (SCLC) has been uniformly unsuccessful. Recently, the combination of etoposide (VP-16) and cisplatin in this setting has been reported to result in up to 50% response rates. We treated 29 patients with relapsed SCLC with this combination and found only a 12% response rate. The discrepancy between our results and those of others is most likely due to differences in prior treatment of the patients, although the effect of dose and schedule modifications are considered. Our patients had received a six-drug regimen over a median of 7 months and had a median drug-free interval before this treatment of only 3 weeks. Evidence is presented that suggests that this aggressive initial therapy affected both host tolerance to further treatment and the development of tumor resistance at the cellular level.
Calmodulin: a potential target for cancer chemotherapeutic agents.
Authors: Hait W N , Lazo J S
Published: February 2017

Calmodulin is a ubiquitous, calcium-binding protein that is responsible for many of the intracellular actions of calcium. Recent evidence suggests that calmodulin may regulate cellular proliferation and that its function may be altered in malignancy. The discovery that drugs such as phenothiazines antagonize the action of calmodulin led to the study of these antagonists against tumor cells. It is now appreciated that calmodulin antagonists are cytotoxic, can restore the sensitivity of resistant cells to drugs such as doxorubicin and vincristine, and can augment the cytotoxicity of bleomycin. This report addresses the possibility of developing new forms of chemotherapeutic agents that work by disrupting the function of this intriguing molecule.
High-dose cytosine arabinoside: treatment and cellular pharmacology of chronic myelogenous leukemia blast crisis.
Authors: Iacoboni S J , Plunkett W , Kantarjian H M , Estey E , Keating M J , McCredie K B , Freireich E J
Published: February 2017

Twenty-one patients with chronic myelogenous leukemia (CML) in blastic transformation underwent 22 remission induction attempts with high-dose cytosine arabinoside (ara-C), administered as a two-hour infusion of 3 g/m2 for six to 12 doses. Ara-C doses were administered every 12 hours in 15 patients and every six to ten hours in six patients. Median patient age was 35 years (range, 20 to 62). The median duration of benign phase was 25 months (range, 0 to 167). Morphology of blast crisis blast cells was myeloid in 15 patients and lymphoid in six. Five patients achieved complete remission (CR), three had partial remission (PR), and one had hematologic improvement, for an overall response rate of 41%. Median remission duration was 2.5 months (range, 0.5 to 6 months). Survival duration was 6 months for responding patients and 1.5 months for those with resistant disease. The response rate was similar for patients with myeloid and lymphoid blast crisis (31% v 50%, respectively). The response rate was significantly higher for patients whose benign phase was less than 1 year (75% v 21%, P = .05) and who had prolonged marrow aplasia after ara-C (86% v 27%, P = .05). Myelosuppression was the major dose-limiting toxicity, and cerebellar toxicity occurred in two patients. Intracellular ara-C 5'-triphosphate (ara-CTP) levels were similar in blood and bone marrow leukemic cells and were slightly greater in the cells of responding patients compared to those with resistant disease. We conclude that high-dose ara-C is an effective regimen for CML blast crisis, resulting in a substantial response rate but modest remission duration. Its combination with other agents may further improve the prognosis of patients with this resistant disease.
Immunocytochemical assay for estrogen receptor in patients with breast cancer: relationship to a biochemical assay and to outcome of therapy.
Authors: McClelland R A , Berger U , Miller L S , Powles T J , Coombes R C
Published: February 2017

We developed an immunoperoxidase technique using a monoclonal antibody to the estradiol receptor (ER) to identify immunoreactive ER (iER) in breast carcinomas and compared this with the conventional dextran-coated charcoal (DCC) steroid binding assay. We also examined the relationship between the iER and response to therapy in patients with advanced breast cancer. We found iER-positive cells in 60 of 90 carcinomas (66.7%); this correlated with the DCC assay (r = 0.76; P less than .001). Of these, 56 patients were found to be assessable for response to endocrine therapy. Twenty-two showed an objective response to some form of endocrine manipulation, and all these had positively stained carcinomas. By deriving a staining intensity index (SII) we observed that 21 of 22 responders (95%) had an SII of greater than or equal to 0.5, whereas only 8 of 34 nonresponders (24%) had an SII of greater than or equal to 0.5. This difference is highly significant (P less than .001). None of the 17 patients with negatively stained carcinomas responded to endocrine therapy. We conclude that the monoclonal antibody to ER can help identify breast cancer patients who may respond to endocrine therapy.
Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.
Authors: Atkins M B , Gould J A , Allegretta M , Li J J , Dempsey R A , Rudders R A , Parkinson D R , Reichlin S , Mier J W
Published: February 2017

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.
Radiation therapy salvage of Hodgkin's disease following chemotherapy failure.
Authors: Fox K A , Lippman S M , Cassady J R , Heusinkveld R S , Miller T P
Published: February 2017

Between 1972 and 1984, 17 patients with advanced Hodgkin's disease failing intensive combination chemotherapy in previously unirradiated nodal and/or pulmonary sites were treated with salvage radiotherapy. Treatment consisted of comprehensive wide field radiotherapy to all known areas of disease. Doses administered to these fields ranged from 1,700 to 5,000 rad, with only three patients (18%) receiving less than 3,000 rad to any field. With a median follow-up of over 4 years, 88% achieved a complete response, with median actuarial disease-free survival (DFS) of 19 months (range, 4 to 61+). Actuarial median survival was 64 months, with a range of 4 to 134+ months. Nine patients (53%) are currently alive with three (18%) in continuous complete remission (CR) for 24, 30, and 61 months. In addition, four patients relapsing after salvage radiotherapy are now in CR following additional therapy. Patients younger than 35 years of age had a significantly increased overall survival when compared with older patients (P less than .005). An initial complete response to chemotherapy lasting 12 or more months appeared to be a favorable prognostic factor, although small patient numbers preclude statistical significance. Comprehensive salvage radiotherapy is of significant benefit in patients with advanced Hodgkin's disease relapsing after combination chemotherapy in nodal and/or pulmonary sites.
Phase II clinical trial of triazinate in combination with mitomycin C for patients with advanced gastric cancer.
Authors: O'Connell M J , Schutt A J , Moertel C G , Hahn R G
Published: February 2017

Thirty-three patients with advanced measurable gastric cancer were treated with a combination of mitomycin C and triazinate. Twenty-nine of these patients had failed prior chemotherapy. Nine patients (27%) had an objective tumor response (median duration, 10 weeks). Median survival of all patients treated was 21 weeks. This study demonstrates that carefully selected patients with advanced gastric cancer who have failed a trial of chemotherapy, but are still ambulatory and maintaining adequate nutrition are appropriate subjects for studies of new treatment regimens. Based on the observed objective tumor response rate and median patient survival, further studies of these drugs in combination for the treatment of advanced gastric cancer are indicated.
A phase I study of menogaril in patients with advanced cancer.
Authors: Brown T D , Donehower R C , Grochow L B , Rice A P , Ettinger D S
Published: February 2017

Menogaril (7-con-O-methylnogarol) is a semisynthetic anthracycline analogue of nogalamycin that has shown good activity against a variety of experimental tumor systems as well as decreased cardiac toxicity when compared with doxorubicin in preclinical studies. Forty-one patients with refractory solid tumors received menogaril during a phase I trial at The Johns Hopkins Oncology Center (Baltimore). Menogaril was administered as an intravenous (IV) infusion on days 1 and 8 of a 28-day cycle in doses of 8 to 140 mg/m2. Eastern Cooperative Oncology Group (ECOG) grade 3 and 4 leukopenia was the principle dose-limiting toxicity and was occasionally accompanied by thrombocytopenia. Both WBC and platelet nadirs occurred between days 15 and 22. Anemia requiring transfusion was occasionally seen. Nonhematologic toxicities observed included frequent anorexia and malaise that was not dose related and postinfusion phlebitis that was dose related and occasionally dose limiting. Gastrointestinal toxicity and alopecia were infrequent and mild in severity. Three patients with cumulative doses of menogaril greater than 1,400 mg/m2 had no significant changes in ejection fractions as determined by serial gated blood pool scans. Two patients had greater than 10% decrements in ejection fractions without clinical changes at total doses of 128 and 288 mg/m2. One patient with prior anthracycline therapy and chest irradiation decreased her left ventricular ejection fraction from 52% to 30% and developed respiratory failure after two cycles of therapy in the setting of disease progression. No responses to menogaril therapy were observed. The recommended phase II dose for menogaril on this day 1 and 8 schedule is 140 mg/m2. A starting dose of 90 mg/m2 should be considered for heavily pretreated patients. In comparing results of this phase I schedule with those of other schedules, evidence for schedule-dependent toxicity differences should be sought.
Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. Cancer and Leukemia Group B.
Authors: Aisner J , Weinberg V , Perloff M , Weiss R , Perry M , Korzun A , Ginsberg S , Holland J F
Published: February 2017

Three combination chemotherapy regimens each with or without the methanol-extracted residue of bacillus Calmette-Guérin (BCG) (MER) were compared for efficacy. After stratification for disease-free interval and dominant sites of disease, patients were randomized to either CMF (cyclophosphamide [CYC], 100 mg/m2 orally, days 1 through 14; methotrexate [MTX], 40 mg intravenously [IV], days 1 and 8; 5-fluorouracil [5-FU], 500 mg/m2 IV, days 1 and 8), or CAF (CYC, 100 mg/m2 orally, days 1 through 14; doxorubicin [DOX], 25 mg/m2 IV, days 1 and 8; 5-FU, 500 mg/m2 IV, days 1 and 8), or CAFVP (CAF as above plus vincristine [VCR], 1.0 mg/m2 IV, days 1 and 8; and prednisone [PRED], 40 mg/m2 orally, days 1 through 14). Nonspecific immunotherapy with MER was administered in five sites at 100 micrograms or at the lowest tenfold dilution that produced a 1-cm indurated lesion. A total of 432 patients were entered, but 37 were disqualified, leaving 395 evaluable for treatment results and toxicities. One hundred thirty-five evaluable patients were randomized to chemoimmunotherapy until October 28, 1978. One hundred twenty-six evaluable patients were randomized to chemotherapy alone in the same time period. For the entire study, a total of 260 evaluable patients were randomized to chemotherapy. Chemoimmunotherapy patients were compared with the initial 126 chemotherapy patients. Chemotherapy regimens were compared among all 260 patients. Patient characteristics were similar between regimens and between chemotherapy and chemoimmunotherapy treatment groups. For patients on chemotherapy plus MER, there was no significant differences between the regimens for response frequencies: 43%, 41%, and 32%, respectively for CMF, CAF, and CAFVP. The comparable chemotherapy alone group had 36%, 58%, and 63% response, respectively. The response rates, adjusted for chemotherapy regimen, were 52% and 38% (P = .02) for chemotherapy and chemoimmunotherapy, respectively. MER was associated with painful ulcers and fevers. Thus, MER produced toxicity without response or survival benefit and further randomization after October 28, 1978 was to chemotherapy alone. For 260 evaluable patients on chemotherapy alone, the complete (CR) and partial responses (PR) were 37%, 55%, and 58%, respectively for CMF, CAF, and CAFVP. These response rates for CAF and CAFVP were significantly better than CMF (P = .01 and P less than .01, respectively). These comparisons were consistent within subgroupings such as dominant sites of disease.(ABSTRACT TRUNCATED AT 400 WORDS)