bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report.
Authors: Perez C A , Einhorn L , Oldham R K , Greco F A , Cohen H J , Silberman H , Krauss S , Hornback N , Comas F , Omura G
Published: February 2017

A total of 304 patients with limited small-cell carcinoma of the lung were treated with a combination of cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine (CAV) and elective brain irradiation (3,600 rad TD in 14 fractions). The patients were randomized to either receive or not receive thoracic irradiation (4,000 rad TD, split course). Of the 304 patients, 291 were eligible for the study. Two hundred eighteen (75%) were completely evaluable. In each group, 81% of the patients had a Karnofsky index of 80% or higher and 14% had supraclavicular or scalene lymph nodes. Patients treated with CAV and no thoracic irradiation had a complete response (CR) of 48%, in contrast to 63% for those receiving chest irradiation (P = .05). In the first group, the complete and partial response rate was 70%; in the second, 80%. The median survival for the eligible patients treated with CAV and brain radiation therapy was 49 weeks; for those treated with the same regimen plus thoracic irradiation, the median survival was 60 weeks. The actuarial two-year tumor-free survival is 19% in the first group and 28% in the second group. The median survival for the responders in the CAV plus brain irradiation group was 57 weeks and for those receiving thoracic irradiation, 78 weeks (P = .12). Thoracic failure was 52% in patients not treated with thoracic radiation therapy v 36% in those receiving it (P = .06). The distant metastases incidence was 23% in patients not treated with thoracic radiation and 35% in patients treated with thoracic radiation. Hematologic toxicity was comparable in both groups; 30% of the patients had moderate to severe granulocytopenia and 6%, low homoglobin. Two toxicity-related deaths occurred (one in each group). Moderate gastrointestinal toxicity was noted in 41% and severe in 16% of the patients receiving CAV and brain irradiation without thoracic radiotherapy v 44% and 20% in those irradiated in the thorax. Disease-free survival is enhanced in the patients receiving thoracic irradiation. More effective chemotherapy is critically needed to significantly improve overall survival. These preliminary results suggest that thoracic irradiation should be a primary component in the therapy of these patients, although this combined therapy is moderately toxic.(ABSTRACT TRUNCATED AT 400 WORDS)
The treatment of localized non-Hodgkin's lymphoma in children: a report from the Children's Cancer Study Group.
Authors: Jenkin R D , Anderson J R , Chilcote R R , Coccia P F , Exelby P R , Kersey J H , Kushner J H , Meadows A T , Siegel S E , Sposto R
Published: February 2017

Investigators of the Children's Cancer Study Group entered 73 children with previously untreated localized non-Hodgkin's lymphoma on a prospective randomized trial of systemic treatment with either a four-drug program (cyclophosphamide, vincristine, methotrexate, prednisone [COMP]) or a 10-drug (LSA2-L2 modified) program of 18 months duration. All patients received central nervous system prophylaxis with intrathecal methotrexate and most received local or regional radiation treatment. The three-year relapse-free survival rate for all patients (N = 73) was 84%; for COMP (N = 42) was 85%, and for LSA2-L2 (N = 31) was 84%. Of the 12 patients who suffered adverse events eight relapsed and four died of toxicity. Histopathology was reviewed centrally. Of 32 patients with nonlymphoblastic disease treated with COMP only one relapsed. Of 26 patients treated with LSA2-L2, four relapsed. Patients with localized lymphoblastic disease were uncommon. None of three patients treated with LSA2-L2 relapsed compared with three of nine treated with COMP. COMP is an excellent treatment for patients with localized disease of nonlymphoblastic type, but the relative value of the two regimens for patients with localized lymphoblastic disease is uncertain.
A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma.
Authors: Edmonson J H , Green S J , Ivins J C , Gilchrist G S , Creagan E T , Pritchard D J , Smithson W A , Dahlin D C , Taylor W F
Published: February 2017

Thirty-eight patients whose primary extremity or limb girdle osteosarcomas had been completely excised (37 amputations, one limb sparing procedure) were allocated at random to two treatment groups receiving respectively regular follow-up examinations plus a high-dose methotrexate (HDMTX) regimen or regular follow-up without primary adjuvant chemotherapy. Although the vincristine, HDMTX, leucovorin regimen was generally quite tolerable when given at three-week intervals for one year and most of the chemotherapy patients followed the planned HDMTX dose escalations from 3 to 6 to 7.5 g/m2, delayed methotrexate excretion limited dosage escalations in 25%. An estimated 52% of the 38 patients were surviving five years after randomization and an estimated 42% remained continuously relapse-free after five years. No significant differences between the outcomes of the 20 treated and the 18 untreated patients were apparent; however, power to detect differences was low. Furthermore, no significant differences in postmetastasis survival were apparent between the 12 treated and 10 untreated patients who relapsed. Approximately 20% of these failing patients appear to have been salvaged for long-term survival. This pilot study of HDMTX confirms the continuing need for controlled clinical trials in determining the therapeutic value of adjuvant chemotherapy programs for patients with primary osteosarcoma.
Prognostic factors influencing survival of patients with advanced colorectal cancer: hepatic-artery infusion versus systemic intravenous chemotherapy for liver metastases.
Authors: Bedikian A Y , Chen T T , Malahy M A , Patt Y Z , Bodey G P
Published: February 2017

In this study of 232 patients with histologically confirmed large bowel carcinoma, patient- and tumor-related characteristics were examined and their effect on prognosis was determined. Serum alkaline phosphatase and albumin concentrations, symptom duration prior to diagnosis of the primary tumor, and the status of the primary tumor showed the strongest relationship to survival after diagnosis of surgically noncurable disease. Patients who had normal serum alkaline phosphatase and albumin concentrations, patients whose symptoms lasted over 12 months before diagnosis, and patients whose primary tumor had been resected before diagnosis of noncurable disease had a good prognosis. Performance status, weight loss, sex, presence of liver metastasis, hemoglobin concentration, and absolute lymphocyte or monocyte counts in the peripheral blood, at time of diagnosis of surgically noncurable disease, were significant factors when examined individually. One hundred seventy-nine patients with metastatic colorectal cancer confined to the liver were selected from 601 patients who received chemotherapy for advanced colorectal cancer over 10-year periods to compare the efficacy of hepatic-artery infusion therapy with that of intravenous 5-fluoropyrimidine--containing chemotherapy. The two groups were similar with respect to prognostic factors. The hepatic-artery infusion chemotherapy produced a higher response rate than intravenous chemotherapy, but did not result in significant prolongation of survival.
Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study.
Authors: Valdivieso M , Burgess M A , Ewer M S , Mackay B , Wallace S , Benjamin R S , Ali M K , Bodey G P , Freireich E J
Published: February 2017

One hundred patients with non-small cell lung cancer were entered into a randomized evaluation of two schedules of doxorubicin combined with ftorafur, cyclophosphamide, and cisplatin (FACP). Doxorubicin was given either weekly at 20 mg/m2, or every three weeks (standard) at 60 mg/m2. Fifty-two patients were randomized to the FACP/weekly doxorubicin arm and 48 patients to the FACP/standard doxorubicin arm. The FACP/weekly doxorubicin regimen was associated with higher complete and partial remission rates (31% versus 19%), longer response duration (median, 33 versus 21 weeks), and longer survival duration for responders (median, 58 versus 50 weeks). These differences were not significant. Less neutropenia (p = 0.01) and less infectious morbidity (p = 0.05) were observed in the FACP/weekly doxorubicin arm. Twenty-eight patients underwent 35 endomyocardial biopsies to assess doxorubicin-induced cardiotoxicity. Sixteen biopsies were performed in 12 patients receiving cumulative doxorubicin doses ranging from 250 to 1,190 mg/m2 within the FACP/weekly doxorubicin arm. Nineteen biopsies were performed in 16 patients receiving cumulative doxorubicin doses ranging from 250 to 540 mg/m2 within the FACP/standard doxorubicin regimen. The FACP/weekly doxorubicin regimen was associated with significantly lower cardiotoxicity scores (p = 0.01). This study indicates that weekly administered doxorubicin is as effective and less cardiotoxic than the standard schedule.
Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.
Authors: Salmon S E , Young L , Soehnlen B , Liu R
Published: February 2017

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.
Plasma clearance of carcinoembryonic antigen following hepatic metastatectomy.
Authors: Lokich J , Ellenberg S , Gerson B , Knox W E , Zamcheck N
Published: February 2017

Four patients with isolated hepatic metastases from primary colonic cancer presented with elevated plasma carcinoembryonic antigen (CEA) levels and underwent surgical metastatectomy . Plasma levels were monitored at two to six hour intervals in the immediate postoperative period and daily measurements were obtained for an extended period thereafter, up to 34 days. CEA clearance demonstrated a two-phase decrement with an initial rapid decay followed by a logarithmic decline with plasma half-lives of 66, 75, 150, and 208 hours. The first phase decline of 63% to 89% in circulating CEA levels immediately following tumor removal may reflect the fact that the plasma CEA is in dynamic equilibrium with the tumor CEA. The kinetics of the second-phase decline of CEA is variable and may be related to the quantitative circulating pool or to pathophysiologic processes influencing CEA metabolism or secretion in the liver. Quantitative assessment of tumor CEA content by immunoperoxidase techniques suggests a direct relationship between tissue levels and circulating plasma levels. The study of CEA kinetics may help in understanding the biology of tumor marker production and improve the capacity for clinical monitoring of plasma levels in conjunction with tumor therapy.
Neocarzinostatin versus m-AMSA or doxorubicin in hepatocellular carcinoma.
Authors: Falkson G , MacIntyre J M , Schutt A J , Coetzer B , Johnson L A , Simson I W , Douglass H O
Published: February 2017

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).
Intrapericardial tetracycline sclerosis in the treatment of malignant pericardial effusion: an analysis of thirty-three cases.
Authors: Davis S , Rambotti P , Grignani F
Published: February 2017

Thirty-three unselected patients with cardiac tamponade secondary to malignant pericardial effusion were treated by intrapericardial instillation of tetracycline hydrochloride. Complete control of the initial signs and symptoms of tamponade was obtained in 30 patients without concomitant chemotherapy or radiotherapy. The procedure did not result in clinically significant complications. Failure of the technique was related to premature removal of the catheter by the patient (one patient) or the inability to totally remove hemorrhagic, clot-filled pericardial fluid (two patients). Survival ranged between 28-704 days and extended survival was related to the performance status and/or chemoradiosensitivity of the primary cancer. No patient successfully treated subsequently developed recurrent cardiac tamponade or alternatively, constrictive pericarditis. Tetracycline pericardial instillation remains a safe, simple, and efficacious treatment of tamponade secondary to malignant disease.
Relationship between sex hormone binding globulin and estrogen receptors in breast cancer.
Authors: Plymate S R , Stutz F H , Fariss B L
Published: February 2017

It has been suggested that the level of sex hormone binding globulin (SHBG) is a better predictor of response of breast cancer to hormone treatment than the measurement of estrogen receptor (ER). However, no correlation of SHBG with ER status has been shown. To define the relationship between SHBG and the ER, the following study was undertaken. Fifty women with breast cancer and known ER status had SHBG measured by dextran-coated charcoal saturation analysis. The mean SHBG in all ER-positive patients was 20.7 +/- 2.4 (ng DHT bound/mL) and in all ER-negative patients was 11.5 +/- 2.0 (p less than 0.01). The mean premenopausal level of SHBG was 22.2 +/- 3.8 ng/mL and postmenopausal level was 20.0 +/- 5.7 ng/mL. There was no significant difference between these groups. ER-positive patients on tamoxifen had a SHBG of 29.8 +/- 9 ng/mL and ER-negative subjects on tamoxifen had a mean SHBG level of 8.3 +/- 3.4 ng/mL, p less than 0.01. ER-positive patients have a higher SHBG level than ER-negative patients; furthermore, this difference between ER-positive and ER-negative subjects was further demarcated by changes in SHBG after the subjects had been placed on tamoxifen.
The effectiveness of behavioral intervention for reduction of nausea and vomiting in children and adolescents receiving chemotherapy.
Authors: Zeltzer L , LeBaron S , Zeltzer P M
Published: February 2017

Fifty-one children 6-17 years of age rated the severity of nausea, vomiting, and the extent to which chemotherapy bothered them during each course of chemotherapy. Sixteen patients had no symptoms and the doses administered to 16 others were not constant so that matched courses could not be assessed. After baseline measurement of two matched courses, the remaining 19 patients were randomized to receive hypnosis or supportive counseling during two more matched courses. An additional course with no intervention was assessed in half of the patients. No significant reduction of symptoms was demonstrated prior to intervention. However, intervention with both hypnosis and supportive counseling was associated with significant reductions in nausea, vomiting, and the extent to which these symptoms bothered patients (all p less than 0.001). Also, after termination of intervention, symptom ratings remained significantly lower than baseline. The data indicate that chemotherapy-related nausea and emesis in children can be reduced with behavioral intervention and that reductions are maintained after intervention has been discontinued.
Lorazepam: a randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine.
Authors: Bishop J F , Olver I N , Wolf M M , Matthews J P , Long M , Bingham J , Hillcoat B L , Cooper I A
Published: February 2017

Lorazepam was compared to placebo to assess its control of nausea and vomiting in patients receiving cytotoxic chemotherapy and prochlorperazine. The study design was a randomized, double-blind crossover in which three consecutive chemotherapy courses were compared so that each patient acted as his or her own control. Of 107 patients entered, 80 were evaluable for analysis. Lorazepam significantly reduced the severity and duration of nausea, the severity of vomiting, and the number of vomiting episodes when compared to placebo. Anxiety was reduced during lorazepam courses but not significantly when compared to placebo. There was significantly more sedation with lorazepam courses. Overall, patients preferred lorazepam courses although this preference was significant only in the patient subset receiving doxorubicin and cyclophosphamide. Lorazepam is a useful adjunct to prochlorperazine in patients receiving cytotoxic chemotherapy.
Neuroblastoma: the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children's Hospital experience.
Authors: Rosen E M , Cassady J R , Frantz C N , Kretschmar C , Levey R , Sallan S E
Published: February 2017

The treatment results for 118 patients with neuroblastoma seen at the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children's Hospital from 1970 to 1980 were analyzed. Patients were treated with a combination of surgery, radiation therapy, and chemotherapy depending on stage and age. Disease-free survival was excellent in all patient groups except those over one year of age with stage IV disease, a group for which currently available therapy cures only a small proportion of patients. Patients with stage III disease and older patients with stage II disease did extremely well (survival of 81% and 89%, respectively) and may have benefited from intensive treatment with all three modalities. Survival for infants (under one year) with stage IV neuroblastoma (90%) has clearly improved with intensive combination chemotherapy. With combination approaches and newer, more effective systemic regimens, a real impact on survival appears to have been made in the last decade. Better approaches will be necessary to cure more than an occasional older patient with stage IV disease.
The effects of prior radiation therapy and age on the frequency and duration of complete remission among various four-drug treatments for advanced Hodgkin's disease.
Authors: Cooper M R , Pajak T F , Gottlieb A J , Glicksman A S , Nissen N , Richards F , Bloomfield C , Holland J F
Published: February 2017

The current report examines the clinical response observed in 137 patients with advanced Hodgkin's disease who had relapsed from an initial complete response following radiation therapy (RTF) in comparison to 280 patients with no prior therapy (NPT). Patients were prospectively randomized to therapy with a four-drug combination chemotherapy program to determine whether CCNU and/or vinblastine are more effective than mechlorethamine and/or vincristine when combined with procarbazine and prednisone. The frequency of complete remission (CR) was 75% for the RTF group compared to 60% of those with NPT (P = .005). In the RTF group, those patients receiving a nitrosourea (CCNU) had a significantly greater CR frequency than those receiving mechlorethamine (P = .006). Significant risk factors favoring longer duration of remission were age less than 40 (P = .005), the absence of splenic involvement (P = .007), and the use of CCNU-containing programs (P = .015). The advantage for CCNU-containing programs was seen only in patients less than 40 years of age. In this study, the strongest factors favorably affecting response to therapy were prior RTF, age less than 40 years, and treatment with a nitrosourea (CCNU).
Combination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration.
Authors: Coates A S , Tattersall M H , Swanson C , Hedley D , Fox R M , Raghavan D
Published: February 2017

Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate (MTX) followed by 5-fluorouracil (5-FU), a randomized controlled clinical trial was conducted in 108 patients with advanced cancer, including 70 with squamous cell carcinoma (SCC) of the head and neck, nine with SCC of other primary sites, 24 with colorectal, and five with gastric adenocarcinomas. Patients were randomized to receive weekly therapy consisting of MTX followed one hour later by 5-FU, or 5-FU followed one hour later by MTX. There was a trend to higher tumor response rates in patients treated with MTX before 5-FU (45% v 33% overall; 65% v 39% in patients with previously untreated head and neck cancer), but these differences were not significant, either by chi-square test or by multivariate stepwise logistic regression. The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses. Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival (P less than 0.001), but among the 70 patients with head and neck cancer, the sequence of drug administration was the only other significant prognostic factor for survival, and favored the sequence of 5-FU followed by MTX (P less than 0.025).
The treatment of extragonadal seminoma.
Authors: Jain K K , Bosl G J , Bains M S , Whitmore W F , Golbey R B
Published: February 2017

Primary extragonadal seminoma (EGS) is a rare tumor of young adults that often presents with bulky primary tumors and metastatic disease. Long-term survival is inadequate with conventional therapy consisting of radiotherapy with or without surgery. The charts of 21 patients with EGS treated initially either with conventional therapy (group I) or with multimodality therapy including initial chemotherapy with high doses of cisplatin followed by either radiotherapy or surgery or both (group II) were reviewed. Five of the ten patients in group I developed recurrent disease and four of them eventually died of disease. Only one of 11 patients in group II died of metastatic disease and the remaining patients are free of disease with 19+ to 46+ months of follow-up. Of the six patients from group II who underwent surgical resection of apparently residual disease after chemotherapy but prior to radiotherapy, five were found to have completely necrotic tumor and one had microscopic disease on histologic examination, proving the efficacy of chemotherapy. Combined modality therapy including initial chemotherapy containing high doses of cisplatin provided rapid reduction in tumor burden and the results appeared superior to treatment that did not include initial chemotherapy.
Electron microscopy in small cell lung carcinomas: clinical correlation.
Authors: Copple B , Wright S E , Moatamed F
Published: February 2017

In order to investigate the relationship of subcellular differentiation of small cell lung carcinomas (SCLC) and clinical response, we reviewed the electron microscopic (EM) features of tumor biopsy specimens from 33 patients with SCLC diagnosed by light microscopy (LM). These tumors were divided by EM into four groups according to the ultrastructural features. Group I (13 patients) had tumors with only neurosecretory granules on EM. Group II (11 patients) had tumors with neurosecretory granules and other subcellular features of non-SCLC. Group III (five patients) had tumors that lacked neurosecretory granules but contained subcellular features of non-SCLC. Group IV (four patients) had tumors that lacked all of these features. The complete and partial response rate to systemic chemotherapy with or without radiation therapy was 88% in the total population studied. The response rates were not statistically different in any of the four groups based on EM findings. The results of this study suggest that the LM diagnosis of SCLC alone adequately identifies lung cancer patients with a high response rate to systemic therapy.
A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer.
Authors: Taylor S G , McGuire W P , Hauck W W , Showel J L , Lad T E
Published: February 2017

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.
Toxic deaths in the Second National Wilms' Tumor Study.
Authors: Jones B , Breslow N E , Takashima J
Published: February 2017

There were 122 deaths among 803 children registered, randomized, and followed in the second National Wilms' Tumor Study; 17 occurred in children apparently free of disease and were attributable to causes other than tumor progression. Seven deaths were attributed to infection during periods of drug-induced leukopenia; four were due to liver failure; and one each was attributable to radiation pneumonopathy, intestinal obstruction, renal failure, myocardial disease, and encephalopathy. The cause of one death was unexplained. Of particular concern were four (of 47) infants under one year of age with group I or II disease who had toxic deaths. Subsequent to these experiences the doses of all chemotherapeutic agents were reduced by 50% for infants under one year of age. No deaths from toxicity were observed thereafter in infants. An analysis of the therapeutic effect of this dose reduction showed three of 47 relapsed on full dose and five of 54 on half dose. The difference is not statistically significant. This report is a further demonstration of the potentially serious vulnerability of infants to standard doses of anticancer drugs even when they are calculated on a per kilogram basis.
Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin's disease.
Authors: Appelbaum F R , Sullivan K M , Thomas E D , Buckner C D , Clift R A , Deeg H J , Neiman P E , Sanders J E , Stewart P , Storb R
Published: February 2017

Eight patients with disseminated Hodgkin's disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy were treated with high-dose chemoradiotherapy and marrow transplantation from an HLA-identical sibling. Two patients remain alive in unmaintained complete remission (CR) at 38 and 39 months after transplant. In the other six patients, reasons for failure included relapse of lymphoma (two patients), or death due to complications of the transplant procedure, including Legionnaire's disease, disseminated zoster, graft-v-host disease, and aspiration pneumonia secondary to severe mucositis. These results demonstrate that some patients with MOPP-resistant Hodgkin's disease can obtain prolonged CR following intensive chemoradiotherapy and allogeneic marrow transplantation.
Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro.
Authors: Hug V , Hortobagyi G N , Drewinko B , Finders M
Published: February 2017

Hormones and cytotoxic drugs are often combined in the treatment of patients with breast carcinoma to broaden the antitumor spectrum of the therapy. We found that, in vitro, the most commonly used endocrine agent, tamoxifen citrate, attenuates the cytotoxic potential of 5-fluorouracil (5-FU) and of doxorubicin. The effect was observed on estrogen receptor positive and on estrogen receptor negative breast tumor cells. Combinations of growth inhibitory hormones and cytotoxic drugs may therefore be counter-productive. For the treatment of hormone-independent tumors they may even be harmful since in these tumors tamoxifen exerts no independent cell kill that compensates for its modifying effect on the cytotoxicity of drugs.
Extensive-stage small-cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose cyclophosphamide plus high-dose etoposide.
Authors: Johnson D H , Wolff S N , Hainsworth J D , Porter L L , Grosh W W , Hande K R , Greco F A
Published: February 2017

Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.
Reduction of fatal complications from combined modality therapy in Hodgkin's disease.
Authors: Mauch P M , Canellos G P , Rosenthal D S , Hellman S
Published: February 2017

A total of 464 pathologically staged IA through IIIB Hodgkin's disease patients were evaluated for the risk of developing acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, or a fatal infection after treatment with radiation therapy (RT) alone, initial combined radiation therapy and chemotherapy (CMT), or RT with MOPP administered at relapse. Patients received a standard six cycles of MOPP, and additional maintenance chemotherapy was not administered. Patients receiving total nodal irradiation (TNI) and MOPP chemotherapy have an 11.9% actuarial risk of developing a fatal complication at ten years, as compared to a 0.8% risk for lesser field irradiation and MOPP (P = .005). The risk with RT alone is 0.6%. Patients 40 years of age or older have a greater risk for complications. These data report a low risk for fatal complication with CMT when less than TNI is administered and when maintenance chemotherapy is not used.
Echocardiographic abnormalities following cardiac radiation.
Authors: Perrault D J , Levy M , Herman J D , Burns R J , Bar Shlomo B Z , Druck M N , Wu W Q , McLaughlin P R , Gilbert B W
Published: February 2017

Five years or more after receiving cardiac radiation, 41 patients with Hodgkin's disease and seminoma in remission were subjected to echocardiography. The abnormalities detected included pericardial thickening in 70%, thickening of the aortic and/or mitral valves in 28%, right ventricular dilatation or hypokinesis in 39%, and left ventricular dysfunction in 39%. In the 23 patients treated by an upper mantle technique with shielding, the incidence of right ventricular abnormalities and valvular thickening was significantly lower than in patients treated with modified techniques. Although no symptoms were attributable to the observed abnormalities, longer follow-up time may reveal important functional implications.
Ewing's sarcoma in bones of the hands and feet: a clinicopathologic study and review of the literature.
Authors: Shirley S K , Askin F B , Gilula L A , Vietti T J , Thomas P R , Siegal G P , Reinus W R , Kissane J M , Nesbit M E
Published: February 2017

Review of current data from the Intergroup Ewing's Sarcoma Study (IESS) shows that Ewing's sarcoma (ES) is rare in bones of the hands and feet. Only 12 of 377 evaluable patients in the first two IESS studies had a primary tumor in these small, distal bones. The age distribution was typical for that seen in patients with ES at other sites. Males were affected twice as often as females, and tumors in the bones of the feet were much more common than those in the hands. All signs and symptoms were local in distribution. As in other sites, the dominant histologic pattern was categorized as diffuse. With the exception of those patients with lesions in the calcaneus, the prognosis for disease-free survival was excellent. A literature review of cases of ES reported in bones of the hands and feet showed generally comparable results.
A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.
Authors: Jain K K , Casper E S , Geller N L , Hakes T B , Kaufman R J , Currie V , Schwartz W , Cassidy C , Petroni G R , Young C W
Published: February 2017

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.
Dose, Response, and Survival in Metastatic Mammary Cancer
Authors: Kagan A. Robert
Published: February 2017

To the Editor:

Congratulations to Hryniuk and Bush in their effort to make sense out of many different chemotherapy regimens. However, in my opinion, I think they interpret their results too narrowly. For example, in Fig 2 and especially Fig 4, a straight line parallel to the ordinate at 0.6 fits the data as well as a line with a slope. In Fig 5, I am led by the discussion to accept a line from a median survival time (MST) of 10 months to an MST of 20 months, as the CR plus PR percent is increased from 20% to 80%. A line parallel to the abscissa at an MST of 15 months fits the data as well.

If the lines drawn through the data have slopes, then the authors are correct in postulating increased dose intensity from 0.6 to 1.0+ indicates increased responses and increased survival. On the other hand, parallel lines drawn through the data give an alternate conclusion, namely that a threshold must be reached to achieve maximum benefit and doses above the threshold dose achieve very little.

Accepting the data points by Hryniuk and Bush without criticism, how do we know what line best fits their compilation of data, a straight line or a line with a slope?
Dose Intensity in Chemotherapy
Authors: Tonkin Katia , Tannock Ian
Published: February 2017

To the Editor:

In a recent article, Hryniuk and Bush have established a strong correlation between dose intensity of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy, and the rate of tumor response in patients with metastatic breast cancer.

They also observed a significant correlation between rate of tumor response and median survival time (r = .66, P < .001). The authors were careful to avoid the conclusion that there was a direct correlation between dose intensity and median survival, but it is surprising that they did not examine this more important relationship directly. We have used data provided in their paper to test for correlation between median survival time and dose intensity for patients receiving CMF chemotherapy, and find little evidence for a direct relationship (r = .25, P = .27—two-tailed Student's t test). Moreover, if the studies are weighted according to the number of patients in them, the correlation coefficient is even lower (r = .14, P = .50—two-tailed Student's t test).

Unfortunately, metastatic breast cancer is not cured by chemotherapy, and appropriate endpoints are those of palliation, namely quantity and quality of survival. Quality of survival cannot easily be addressed in a retrospective review, but increasing dose intensity has the capability both to improve quality of life by ameliorating symptoms of disease, and to decrease it by adding toxicity. Factors such as sites of metastases and performance status of patients are known to influence duration of survival and could mask a relationship with dose intensity. However, the data reviewed by Hryniuk and Bush do not provide evidence for a relationship between dose of chemotherapy and survival.

A prospective randomized trial is in progress at our institution that addresses the relationship between dose intensity of CMF chemotherapy and both quantity and quality of survival for patients with metastatic breast cancer. In the absence of results from this and other prospective trials that address the dose-response effect of chemotherapy in palliation, one should not assume that more is better.
Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study.
Authors: Maurer L H , Pajak T , Eaton W , Comis R , Chahinian P , Faulkner C , Silberfarb P M , Henderson E , Rege V B , Baldwin P E
Published: February 2017

Patients with limited-stage small-cell carcinoma of the lung (SCCL) were randomly assigned to a four-drug chemotherapy program consisting of methotrexate, doxorubicin, cyclophosphamide, and CCNU (MACC) or to a regimen consisting of cyclophosphamide, CCNU, and vincristine alternated with Adriamycin (Adria Laboratories, Columbus, Ohio) and vincristine (CCV/AV). All patients received 4,500 cGy, in a split course, to the primary tumor, mediastinum, and supraclavicular lymph node drainage areas and 3,000 cGy to the whole brain. After four cycles of chemotherapy, patients were randomly assigned to chemotherapy plus methanol extractable residue of BCG (MER-BCG) or no MER-BCG. The complete response frequencies were similar for the two regimens (54% and 48%) as were the median survivals (12.0 and 11.5 months) and the two-year survival rates (15% and 17%). Immunotherapy with MER-BCG did not prolong the time to disease progression or improve survival. Women had a greater chance of achieving a complete remission independent of performance status. There was a complex interaction between sex and the chemotherapy regimens that may have important implications for the design and stratification of future trials in SCCL.
Sequential therapy with methotrexate and 5-fluorouracil in the treatment of advanced colorectal carcinoma.
Authors: Leone B A , Romero A , Rabinovich M G , Perez J E , Macchiavelli M , Strauss E
Published: February 2017

Twenty-nine patients with advanced colorectal carcinoma were entered in this study to evaluate the efficacy and toxicity of a sequential chemotherapeutic schedule with methotrexate (MTX), 200 mg/m2 intravenously (IV) (push injection) and 5-fluorouracil (5-FU), 1,200 mg/m2 in continuous IV infusion, using a 20-hour time interval. All patients received calcium leucovorin (LV), 25 mg, intramuscularly (IM) every six hours for eight doses beginning 24 hours after methotrexate administration. Courses were administered every 15 days. Of the 24 patients evaluable for response, 11 (46%) had major objective regressions (one complete remission [CR] and ten partial remissions [PR]). The survival rate of patients who responded to treatment was 60% at 16 months, whereas patients with no change and those in whom the disease progressed had a median survival of 9 months and 3 months, respectively. The median duration of response has not yet been reached in patients who presented objective tumor regression, and was 7.5 months in those with no change. Significant differences were found between objective regression and no change (P less than .0005) and between no change and tumor progression (P less than .05). All patients were evaluable for toxicity. There were three toxic-related deaths (10%) because of severe myelosuppresion, sepsis, and hemorrhage. These promising results, despite important toxicity, reveal the synergism between the two chemotherapeutic agents and also indicate that the response rate achieved could be a consequence of the 20-hour interval and high dose of 5-FU. Further studies are necessary to determine the optimal time interval and the adequate 5-FU dose.
Late intensive combined modality therapy followed by autologous bone marrow infusion in extensive-stage small-cell lung cancer.
Authors: Ihde D C , Deisseroth A B , Lichter A S , Bunn P A , Carney D N , Cohen M H , Veach S R , Makuch R W , Johnston-Early A , Abrams R A
Published: February 2017

To attempt to improve the poor prognosis of extensive-stage small-cell lung cancer (SCLC) patients, we tried to administer late intensive combined modality therapy (LICMRX) to patients with good tumor regression after 12 weeks of conventional chemotherapy. Twenty-nine consecutive extensive-stage SCLC patients received 6 weeks of cyclophosphamide, methotrexate, and lomustine (CMC) induction therapy, followed by 6 weeks of vincristine, doxorubicin, and procarbazine (VAP). After restaging for assessment of tumor response, autologous bone marrow (ABM) was collected in patients in good medical condition with complete response (CR) or partial response (PR) and no tumor on marrow examination. LICMRX consisted of irradiation with 2,000 rad in five fractions for five days to sites of initial tumor involvement, followed by cyclophosphamide, 60 mg/kg for 2 days, and etoposide, 200 mg/m2 for 3 days and then by ABM infusion. Prophylactic cranial irradiation (PCI) was administered thereafter, but no further chemotherapy was used. Due to lack of tumor regression or poor medical condition, only ten of the original 29 patients were eligible for LICMRX; two refused, so only eight (28%) received therapy. Three patients who began LICMRX in CR developed recurrence of SCLC after an additional 4, 8, and 15 months. Of five patients with PR, one attained CR but relapsed at 3 months, two remained in PR and progressed at 2 and 4 months, and two died of infection without recovery from LICMRX. Mean time from ABM infusion to recovery of granulocyte count to 500/microL was 15.8 days in the six surviving patients (range, 12-22). The major non-hematologic toxicity of LICMRX was severe esophagitis. Among all 29 patients, there were six CRs (21%) and no 2-year survivors, compared with a CR rate of 36% and 10% 2-year survivors in 78 extensive-stage patients previously treated with CMC plus VAP without LICMRX. We conclude that the LICMRX given in this study can be administered to only a minority of extensive-stage SCLC patients and is very unlikely to yield substantial improvement in the fraction of 2-year survivors (95% confidence limits for 2-year survival 0% to 10%).