bluuebunny/crossref_metadata_2025 huggingface dataset:
Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.
Authors: Matthay K K , Sather H N , Seeger R C , Haase G M , Hammond G D
Published: February 2017

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.
Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer.
Authors: Jakubowski A A , Casper E S , Gabrilove J L , Templeton M A , Sherwin S A , Oettgen H F
Published: February 2017

A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses.
Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group.
Authors: Hong W K , Nicaise C , Lawson R , Maroun J A , Comis R , Speer J , Luedke D , Hurtubise M , Lanzotti V , Goodlow J
Published: February 2017

A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multicenter trial. Patients were randomly assigned to receive one of the following three regimens: cyclophosphamide 1,000 mg/m2 intravenously (IV) day 1, vincristine 1.4 mg/m2 IV day 1, and etoposide 50 mg/m2 IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclophosphamide 1,000 mg/m2 IV day 1, vincristine 1.4 mg/m2 IV day 1, and doxorubicin 50 mg/m2 IV day 1 (CAV); cyclophosphamide 2,000 mg/m2 day 1 and vincristine 1.4 mg/m2 IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with respect to extent of disease, age, sex, performance status, and metastatic sites. No significant differences in response rates, response duration, or survival could be detected in limited disease, although there appeared to be a trend favoring CEV. Among extensive-disease patients, response duration on the CEV regimen was longer than on the CV regimen or the CAV program (P less than .001). The superiority of the CEV regimen was also demonstrated in the survival analysis in which differences attained statistical significance (P = .01). In this group the median survival was increased from 29 weeks on CV to 31 weeks on CAV and 39 weeks on CEV. Myelosuppression was the most frequent toxicity. It was more severe with CV than CEV or CAV. Most nonhematologic side effects were comparable among the three treatment groups. However, the high doses of cyclophosphamide in the CV regimen produced a higher incidence of hemorrhagic cystitis than in the CEV or CAV programs (P less than .001). Cardiotoxicity only occurred in the CAV group (P = .05). The addition of etoposide to the CV regimen resulted in significantly longer response duration and survival without increased toxicity. Similarly, the substitution of etoposide for the doxorubicin in the CAV regimen was associated with prolonged survival and reduced cardiotoxicity.
Small lymphocytic lymphoma.
Authors: Morrison W H , Hoppe R T , Weiss L M , Picozzi V J , Horning S J
Published: February 2017

The clinical course of 54 patients with small lymphocytic lymphoma (SL) was reviewed. The majority of patients had disseminated lymphoma at the time of diagnosis; 14 patients (26%) presented with Ann Arbor stage I and II disease. Five- and 10-year survival for all patients was 76% and 49%. The only clinicopathologic features identified that predicted a shortened survival were the presence or absence of systemic (B) symptoms (15% v 63% at 10 years, P = .01) and a diffuse rather than pseudofollicular nodal architecture (47% v 87% at 10 years, P = .04). Initial bone marrow involvement was not an adverse prognostic factor for patients who presented with stage III and IV disease. Ten patients developed a marked lymphocytosis consistent with progression to a leukemic phase (chronic lymphocytic leukemia [CLL]). These ten patients had a median initial lymphocyte count of 2,790, compared with 1,580 for those patients who did not progress to CLL (P = .0001). Developing CLL did not adversely affect survival (P = .48). Thirty-seven patients were treated with various combinations of radiation and chemotherapy; 17 patients received no initial therapy. Ten-year freedom from relapse (FFR) for stage I and II patients treated with irradiation was 80% and 62%; FFR for stage III and IV treated patients was 11%. Despite the marked differences in FFR, no statistically significant difference in survival could be demonstrated between the various stages. Selected patients with advanced SL received no initial therapy; these patients had a 10-year survival that was not statistically different from the immediately treated stage III and IV patients. Patients with stage I and II SL should be treated with irradiation; prolonged FFR and possibly cure of the disease can be achieved in these patients.
Combined small-cell and non-small-cell lung cancer.
Authors: Mangum M D , Greco F A , Hainsworth J D , Hande K R , Johnson D H
Published: February 2017

Nine (2%) of 429 small-cell lung cancer (SCLC) patients seen at Vanderbilt University between 1977 and 1983 had a combined subtype SCLC at diagnosis (ie, small-cell carcinoma plus squamous cell or adenocarcinoma). Staging procedures and chemotherapy treatment were uniform for all 429 patients. The diagnosis of combined histology was established via bronchoscopy (six patients), needle aspiration biopsy (one), lymph node biopsy (one), and thoracotomy (one). The clinical characteristics of the combined subtype patients were similar to patients with other subtypes of SCLC (ie, there were no differences in median age, sex, performance status, and stage of disease). However, patients with a combined subtype histology had a higher incidence of peripheral lesions on chest x-ray (56% v 14%, P less than .001) and a lower median lactate dehydrogenase (LDH) (301 IU/L v 341 IU/L, P = .0002) at diagnosis. The overall response to chemotherapy (57% v 78; P = .5) and the median survival (8 months v 10 months; P = .4) of the combined subtype patients were similar to patients with other subtypes of SCLC. Two (22%) combined histology patients survived greater than or equal to 5 years. Both had had surgical resection in addition to chemotherapy. These data suggest that the combined subtype of SCLC is clinically similar to pure SCLCs and that surgery may play a prominent role in the management of these tumors. The possibility of a combined histology tumor should be considered in patients thought to have SCLC on the basis of limited biopsy material, such as a needle aspiration or bronchial biopsy, and when the primary lesion is peripherally located on chest x-ray.
Patterns of relapse in large-cell lymphoma patients with bulk disease: implications for the use of adjuvant radiation therapy.
Authors: Shipp M A , Klatt M M , Yeap B , Jochelson M S , Mauch P M , Rosenthal D S , Skarin A T , Canellos G P
Published: February 2017

In patients with large-cell lymphoma (LCL) treated with combination chemotherapy, the presence of bulk disease has consistently been associated with a poorer response rate and a shortened survival. The optimal therapy for patients with bulk disease (greater than or equal to 10 cm) will depend on whether treatment failures result from inadequate tumor eradication in prior bulk sites or from distant dissemination. To address this issue, we have evaluated patterns of relapse in patients with bulk disease who relapsed after achieving a complete remission with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M- or m-BACOD). Eighty-one II, III, or IV patients with disease greater than or equal to 10 cm were identified; 45 of the 81 patients achieved a confirmed complete response (CR) and are included in the analysis. The 45 complete responders included 21 patients with localized (stage II) disease and 24 patients with advanced (stage III/IV) disease. Six of the 21 stage II complete responders and three of the 24 stage II/IV complete responders also received adjuvant radiation therapy following completion of M- or m-BACOD. Only one of the 21 patients with stage II disease relapsed, doing so in the site of prior bulk involvement. In contrast, nine of 24 patients with stage III/IV disease relapsed, although no patient failed solely in the site of prior bulk disease. Stage III/IV patients recurred in either a new site (one patient), a new and old site (five), an old non-bulk site (two), or both old non-bulk and bulk sites (one). These results indicate that advanced-stage bulk-disease patients do not consistently relapse in sites of prior bulk disease; therefore, this group of patients is unlikely to benefit from adjuvant radiation therapy administered following completion of combination chemotherapy. Although the low relapse rate and the addition of adjuvant radiation therapy in a subgroup of the stage II bulk-disease patients precludes a definitive analysis, our results further suggest that these patients may be effectively treated with combination chemotherapy alone.
Prognostic factors for chemotherapy response and survival using combination chemotherapy as initial treatment of advanced head and neck squamous cell cancer.
Authors: Cognetti F , Pinnarö P , Ruggeri E M , Carlini P , Perrino A , Impiombato F A , Calabresi F , Chilelli M G , Giannarelli D
Published: February 2017

Between May 1981 and December 1987, 152 consecutive patients with locally advanced and previously untreated head and neck squamous cell cancer (HNSCC) received two or three courses of neoadjuvant chemotherapy (NAC) prior to surgery and/or radiotherapy. Eighteen percent of patients achieved a complete response and 45% a partial response (PR), for an overall response rate of 63%. A variety of pretreatment patient and tumor characteristics were analyzed for both the tumor response to NAC and survival rate. Significantly higher CR rates were found in patients with a World Health Organization (WHO) performance status (PS) of 0 to 1 than in those patients with a PS of 2 (P = .03). Patients with stage III disease were significantly more likely to respond than those with stage IV (P = .006). Evaluation of all parameters through multivariate analysis identifies the tumor classification (P = .001) and the primary site (P = .006) as the most significant in predicting CR. The overall 5-year survival rate of the entire group of patients was 18% (median survival, 14.3 months). Analysis by PS (P = .001), stage (P = .002), and tumor (P = .001), and node (P = .01) classes showed significant differences. Patients achieving a CR after NAC had a significantly improved survival rate as compared with those with residual disease at assessment (P = .0003). With the multistep regression analysis, the tumor (P = .005) and node (P = .007) classifications, and the sex (P = .03) were significant factors, but CR (P = .0004) remained the most important and independent predictive factor. Randomized prospective trials are requested to clearly establish the role of NAC on survival rates.
Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma.
Authors: Friedman H S , Schold S C , Mahaley M S , Colvin O M , Oakes W J , Vick N A , Burger P C , Bigner S H , Borowitz M , Halperin E C
Published: February 2017

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.
Cardiac morphologic and functional changes induced by epirubicin chemotherapy.
Authors: Dardir M D , Ferrans V J , Mikhael Y S , el-Grindy M S , el-Aasar A B , el-Zawahry H M , Alling D W , Banks S M , el-Mawla N G
Published: February 2017

Cardiac toxicity was evaluated in 24 patients who received epirubicin as a single chemotherapeutic agent, in doses of either 30 mg/m2 every week (11 patients) or 90 mg/m2 every 3 weeks (13 patients). The total doses of epirubicin ranged from 180 mg/m2 to 918 mg/m2 (mean, 491 +/- 187). No patient had prior heart disease, hypertension, mediastinal irradiation, or chemotherapy with other anthracycline agents. None of the patients developed overt heart failure, significant arrhythmias, ECG alterations, or roentgenographic changes in heart size. There was no significant change in the mean value of echocardiographic percent fractional shortening before and after epirubicin therapy. Patients receiving epirubicin doses less than 450 mg/m2 had minimal hemodynamic disturbances; however, no cut-off point separating two significantly different subpopulations could be demonstrated. Endomyocardial biopsy was performed on all patients; 20 biopsies were evaluable. Histologic and ultrastructural changes were similar to those caused by other anthracycline agents. A strong correlation was demonstrated between total dose of epirubicin and pathologic change as quantified using the Billingham scale (r = .7, P = .0006). A cut-off point beyond which there was a probability of increased pathologic damage was statistically defined at 450 mg/m2 of epirubicin. Severe pathologic alterations and moderate hemodynamic changes were observed in only one patient, who received 918 mg/m2 of epirubicin. Patients who are expected to receive epirubicin in excess of 450 mg/m2 should be monitored for cardiac toxicity, and continuation of epirubicin therapy beyond 900 mg/m2 should be based on the results of monitoring.
Analyzing the same data in two ways: a demonstration model to illustrate the reporting and misreporting of clinical trials.
Authors: Baar J , Tannock I
Published: February 2017

The methods used to analyze and interpret clinical trials of chemotherapy may have a major impact on the conclusions that are drawn in papers reporting them. To illustrate this problem, we constructed a hypothetical clinical trial in which patients with metastatic cancer were treated with chemotherapy. The following two articles provide reports of this trial, analyzed by methods that we would interpret as being of low and high quality, respectively. In the present report, we describe briefly the methodological differences that led to the opposite conclusions based on this single set of data. The errors of reporting and omissions of the first article (A) are similar to those that have been extracted from recent issues of the Journal of Clinical Oncology and other leading cancer journals, although they have not all appeared within a single report. This demonstration model illustrates problems in the reporting of clinical trials and suggests guidelines for improved reporting.
Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy.
Authors: Longo D L , Glatstein E , Duffey P L , Ihde D C , Hubbard S M , Fisher R I , Jaffe E S , Gilliom M , Young R C , DeVita V T
Published: February 2017

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.
A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer.
Authors: Slevin M L , Clark P I , Joel S P , Malik S , Osborne R J , Gregory W M , Lowe D G , Reznek R H , Wrigley P F
Published: February 2017

Etoposide is an increasingly used and well-tolerated drug in cancer medicine. Its cytotoxic action is phase-specific and it has demonstrated schedule dependency in both in vitro and animal studies, but clinical evidence of the importance of drug scheduling is uncertain. The two administration schedules of etoposide that have been compared in this randomized study of 39 patients with previously untreated extensive small-cell lung cancer treated with single-agent etoposide were 500 mg/m2 as a continuous intravenous (IV) infusion over 24 hours or five consecutive daily 2-hour infusions each of 100 mg/m2. Both regimens were repeated every 3 weeks, for a maximum of six cycles. Patients received combination chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAC) or radiotherapy on failure to respond or at relapse, depending on their Karnofsky performance status. The same therapy was used in both arms of the study. All patients are evaluable for response to etoposide. In the 24-hour arm, two patients achieved a partial remission, resulting in an overall response rate of 10%. In the 5-day schedule, 16 patients had a partial response and one had a complete remission, producing an overall response rate of 89%, which was significantly superior to that in the 24-hour arm (P less than .001). The median duration of remission to etoposide in the 5-day arm was 4.5 months. Bone marrow toxicity was similar in both schedules. Etoposide pharmacokinetics were measured in all patients, and total areas under the concentration versus time curves (AUCs) were equivalent in both regimens. This study has clearly demonstrated the importance of etoposide scheduling in humans, and the superiority of five daily infusions over a 24-hour continuous infusion. The response rate to single-agent etoposide using an efficacious schedule in extensive small-cell lung cancer has been determined to be in excess of 80%.
Effects of granulocyte-macrophage colony-stimulating factor on in vitro growth of human solid tumors.
Authors: Salmon S E , Liu R
Published: February 2017

Solid tumor biopsies from 33 patients were tested in vitro to evaluate the growth modulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). In 29 of 33 studies (88%), addition of GM-CSF either had no effect on in vitro growth, or induced growth inhibition. While significant growth inhibition was observed in 10 studies, marked inhibition was only observed in three studies. However, all dose-response curves were usually flat, suggesting indirect effects. Moderate growth stimulation was observed in four instances, which may have been due to residual granulocyte-macrophage progenitors within the biopsies. We conclude that GM-CSF has little or no growth-modulatory effect on most nonhematopoietic neoplasms. The primary role of GM-CSF in patients with solid tumors appears to be in prevention or reversal of myelosuppression associated with therapy. Thus, while GM-CSF seems unlikely to have a role in monotherapy of cancer, it is also unlikely to have its utility compromised by enhancement of tumor growth.
Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.
Authors: Forastiere A A , Orringer M B , Perez-Tamayo C , Urba S G , Husted S , Takasugi B J , Zahurak M
Published: February 2017

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.
Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer.
Authors: Boyer M , Raghavan D , Harris P J , Lietch J , Bleasel A , Walsh J C , Anderson S , Tsang C S
Published: February 2017

To date, the prevalence and nature of the late toxicity of cisplatin-based combination chemotherapy for advanced testicular cancer has been poorly documented. Thirty men with a median age of 35 years (range, 23 to 63), who had undergone such treatment were assessed with detailed investigation to determine the type and frequency of chronic toxicity. The median follow-up from the time of commencement of chemotherapy was 75 months (range, 48 to 126). The most common late toxic effects were high tone hearing loss in 23 men (77%) and electrophysiological evidence of peripheral nerve damage in 15 (50%). Both the hearing and nerve abnormalities were predominantly asymptomatic. In addition, elevation of serum cholesterol, noted in 20 patients (67%), was significant (P = .014) when compared with a control population. Hyperuricemia was present in nine patients (30%). Only one patient, with other risk factors (smoking, family history), had evidence of ischaemic heart disease while 20% (all with a smoking history) had a diminished single breath diffusing capacity for carbon monoxide (DLCO). Cisplatin-based chemotherapy is relatively free of major long-term side effects and should not be withheld for fear of late toxicity.
Effective salvage chemotherapy with etoposide, dactinomycin, and methotrexate in refractory germ cell cancer. Australasian Germ Cell Trial Group.
Authors: Levi J A , Thomson D , Harvey V , Gill G , Raghavan D , Tattersall M , Snyder R , Burns I , Sandeman T , Byrne M
Published: February 2017

Fifty-one patients with advanced germ cell malignancy who had either failed to achieve complete remission with initial cisplatin, vinblastine, and bleomycin chemotherapy or who had relapsed after complete response (CR) to this therapy and then proven refractory on retreatment, were treated with etoposide (75 mg/m2 for 3 days), dactinomycin (1 mg/m2 day 1), and methotrexate (30 mg/m2 day 1) (EAM) every 3 weeks. Courses were continued until maximum response without empirical limit, and if complete remission was achieved, two courses of consolidation therapy were given before cessation of treatment. Thirteen patients (25%) were complete responders with residual masses containing fibrosis or benign teratoma being subsequently resected in seven patients. Two patients had persisting viable carcinoma within residual masses that were completely resected, leaving no evidence of disease (NED); the combined CR plus NED rate was 29%. The only pretreatment factor significantly influencing this response rate was tumor volume. Toxicities were moderate, with leukopenia being observed in 28% of patients, but it was severe in only 2%. There was one death from septicemia. Severe nausea and vomiting occurred in only 9% of patients and treatment-related stomatitis was observed in 42%. All patients achieving CR plus NED have been followed for a minimum of 5 years and no relapses have occurred, suggesting that these patients are cured. Unlike other regimens of salvage chemotherapy, this treatment program did not contain cisplatin and it is contended that a completely noncrossresistant drug regimen based on etoposide provides the opportunity to further improve the curability of patients with advanced germ cell cancer.
Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study.
Authors: Goodman G E , Crowley J J , Blasko J C , Livingston R B , Beck T M , Demattia M D , Bukowski R M
Published: February 2017

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.
Phase I study of interleukin-2 and interferon alfa-2a as outpatient therapy for patients with advanced malignancy.
Authors: Hirsh M , Lipton A , Harvey H , Givant E , Hopper K , Jones G , Zeffren J , Levitt D
Published: February 2017

Twenty-six patients were treated in this phase I study with the combination of interleukin-2 (IL2) administered as a continuous infusion and interferon alfa-2a (IFN alpha-2a) administered intramuscularly to patients in an outpatient setting. The maximum-tolerated dose of both agents given as outpatient therapy was 2 x 10(6) U/m2 days 1 to 5 of IL2 and 9 x 10(6) U/m2 days 1, 3, and 5 of IFN alpha-2a for 4 consecutive weeks. A 2- to 4-week rest period was permitted after each 4 weeks of treatment. Fatigue was the treatment-limiting toxicity, and serious clinical or laboratory abnormalities occurred infrequently during this study. Patients with colon cancer metastatic to the liver tolerated treatment worse than patients with other tumors. Twelve of the 15 patients with renal cell cancer were assessable for response determinations. Of these 12 patients, three exhibited complete tumor regression, three have had partial objective regression, and three patients experienced stabilization of rapidly progressive disease. This therapy appears to be well tolerated in an outpatient treatment setting and shows significant activity against advanced renal cell cancer.
Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study.
Authors: Miller T P , Dahlberg S , Weick J K , Files J C , Eyre H J , Pendergrass K B , Fisher R I
Published: February 2017

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytoBOM) for patients with intermediate- and high-grade non-Hodgkin's lymphomas was tested by the Southwest Oncology Group (SWOG) to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimens in a cooperative group setting. On day 1, cyclophosphamide, doxorubicin, and etoposide were administered, followed by cytarabine, bleomycin, vincristine and methotrexate with leucovorin given on day 8. There were 51 complete remissions (CRs) among 78 previously untreated patients (65%) having clinical stage II-IV disease. The median length of follow-up is 37.9 months with 57% of patients alive at 3 years and 50% of CR patients free of disease at 3 years. Patients with diffuse large-cell lymphoma have the best survival (63% at 3 years) and relapse-free survival (RFS; 68% at 3 years with no relapses seen after 14 months). Administration of ProMACE-CytoBOM is feasible and safe in a cooperative group setting with 84% of 537 courses of treatment given exactly according to schedule and fatal toxicities seen in five patients (6%). ProMACE-CytaBOM may represent improved treatment for diffuse large-cell lymphoma, but the modest differences compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) indicate the need for a prospective randomized comparative trial.
Early hospital discharge of children with cancer treated for fever and neutropenia: identification and management of the low-risk patient.
Authors: Mullen C A , Buchanan G R
Published: February 2017

Children with leukemia and solid tumors are often hospitalized for empiric broad-spectrum antibiotic therapy because of fever during periods of chemotherapy-induced neutropenia. Conventional practice dictates that parenteral antibiotics be continued until the patient is afebrile and has recovered from neutropenia, ie, until the absolute neutrophil count (ANC) exceeds 500 cells per cubic millimeter. However, the practice in our center has been to discontinue parenteral antibiotic therapy and discharge many such patients before resolution of neutropenia. Since the feasibility and safety of this approach has not been studied, we reviewed the records of 114 consecutive hospitalizations for fever and neutropenia in 61 patients during a 13-month period. Seventy-seven children (68%) were discharged to their homes while still neutropenic after they had been afebrile for 1 to 2 days on parenteral antibiotics, had negative blood cultures, appeared well, and usually had some evidence of bone marrow recovery. Five patients (4.4%) developed recurrent fever and required rehospitalization within 7 days of discharge. Only three of the 77 patients (3.9%) who were sent home with neutropenia had recurrent fever. Each had a brief and uneventful second hospitalization. Two of the 37 children discharged with an ANC over 500 cells per cubic millimeter required rehospitalization. A declining ANC and advanced malignancy were risk factors in predicting recurrence of fever following discharge. A rising monocyte count was a predictor of imminent recovery from neutropenia. These results suggest that "early" discharge of an afebrile yet still neutropenic patient is safe when the patient is in remission, has no evidence of serious infection, appears clinically stable, and has indications of bone marrow recovery. The conventional approach of routinely continuing the hospitalization until resolution of neutropenia may be unnecessary in such low-risk patients.
Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry.
Authors: O'Reilly S M , Camplejohn R S , Barnes D M , Millis R R , Rubens R D , Richards M A
Published: February 2017

Adjuvant systemic therapy for women with node-negative breast cancer is most easily justified for those patients at highest risk of relapse. We have examined the impact of tumor size, histologic grade, estrogen receptor (ER) status, tumor ploidy, and S-phase fraction (SPF) on relapse-free survival (RFS) for 169 patients with node-negative breast cancer in order to identify groups of patients at high and low risk of relapse. Patients with small tumors (less than or equal to 1.0 cm) had a significantly better RFS than those with larger tumors (P = .005), with 96% remaining relapse-free at 5 years. Patients with tumors less than or equal to 1.0 cm were thus excluded from analysis when attempting to define a group with a poor prognosis. Within the group of patients with tumors greater than 1.0 cm, tumor ploidy (P = .63), ER status (P = .3), or progesterone receptor (PgR) status (P = .24) did not predict for RFS. Patients with grade 1 or 2 infiltrating ductal tumors had a significantly better prognosis than those with grade 3 tumors (P = .04). The prognostic factor that gave the widest separation between subgroups, however, was SPF. Patients whose tumors were greater than 1.0 cm with an SPF less than or equal to 10% had a 5-year RFS of 78% compared with a 5-year RFS of 52% for those with an SPF greater than 10% (P = .006). We have combined tumor size and SPF to identify three prognostic groups: (1) tumor less than or equal to 1.0 cm, 5-year RFS 96%; (2) tumor greater than 1.0 cm plus SPF less than or equal to 10%, 5-year RFS 78%; 3) tumor greater than 1.0 cm plus SPF greater than 10%, 5-year RFS 52%. These prognostic groupings may help identify patients most suitable for adjuvant therapy.
Drug-induced DNA damage and tumor chemosensitivity.
Authors: Epstein R J
Published: February 2017

Cytotoxic drugs act principally by damaging tumor-cell DNA. Quantitative analysis of this interaction provides a basis for understanding the biology of therapeutic cell kill as well as a rational strategy for optimizing and predicting tumor response. Recent advances have made it possible to correlate assayed DNA lesions with cytotoxicity in tumor cell lines, in animal models, and in patients with malignant disease. In addition, many of the complex interrelationships between DNA damage, DNA repair, and alterations of gene expression in response to DNA damage have been defined. Techniques for modulating DNA damage and cytotoxicity using schedule-specific cytotoxic combinations, DNA repair inhibitors, cell-cycle manipulations, and adjunctive noncytotoxic drug therapy are being developed, and critical therapeutic targets have been identified within tumor-cell subpopulations and genomic DNA alike. Most importantly, methods for predicting clinical response to cytotoxic therapy using both in vitro markers of tumor-cell sensitivity and in vivo measurements of drug-induced DNA damage are now becoming a reality. These advances can be expected to provide a strong foundation for the development of innovative cytotoxic drug strategies over the next decade.
Is prophylactic cranial irradiation indicated in small-cell lung cancer?
Authors: Fleck J F , Einhorn L H , Lauer R C , Schultz S M , Miller M E
Published: February 2017

Although prophylactic cranial irradiation (PCI) is frequently used in the treatment of patients with limited-extent small-cell lung cancer (SCLC), its role remains controversial. One hundred fourteen SCLC patients with limited disease treated at Indiana University were retrospectively reviewed. Fifty-eight of 114 (51%) patients achieved a complete remission (CR) and were analyzed. Thirty-eight of these 58 CR patients received PCI (+PCI) and 20 of 58 CR patients did not receive PCI (-PCI). Twenty-six of 38 patients who received PCI subsequently relapsed. No patient initially relapsed in the CNS, although one patient had a brain metastasis following recurrence in the chest. Eleven of 38 patients who were treated with PCI survived for longer than 30 months and were considered long-term survivors. Seven of these 11 patients (63%) developed clinically significant neurological toxicity. Sixteen of 20 patients who did not receive PCI relapsed, but there was only one initial relapse in the CNS. Three additional patients who relapsed in the chest subsequently developed CNS metastasis. All responded to palliative radiation with improvement in their symptoms. The high incidence of CNS toxicity in the long-term survivors and the relatively infrequent incidence of isolated CNS recurrent in patients not subjected to PCI raise serious questions concerning the role, if any, of PCI in limited SCLC.
Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma.
Authors: Dexeus F H , Logothetis C J , Sella A , Fitz K , Amato R , Reuben J M , Dozier N
Published: February 2017

Fifty patients with locally advanced or metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) at 100 mg orally daily starting on day 1 and cimetidine 300 mg orally four times a day starting on day 15. When disease progressed, coumarin was escalated to 100 mg orally four times a day. Three patients (6%; 95% confidence interval [Cl], 2% to 17%) achieved a partial response, one of those after dose escalation. In addition, one patient had a minor response, then progressing disease, and again had a minor response after dose escalation. All four responders had nonassessable primary tumors (three had had prior nephrectomy and one a renal angioinfarction). The only major toxicity was renal (37 patients had minor to moderate elevations in serum creatinine level). Immunologic studies (hypersensitivity skin testing, lymphocyte blastogenesis response, number of lymphocytes, T lymphocytes, T helper and T suppressor subsets, and T helper: suppressor ratio), performed before and after therapy, showed a relative lymphopenia and decreased hypersensitivity skin-testing results at baseline, and a general decline over time in the number of T cells and T helper and T suppressor subsets. There was no enhancement in any of the immunologic parameters tested. The response rate was 6%, lower than previously reported; a general immunodeficiency was noted at baseline, and the lymphopenia worsened with progressing disease, unaffected by therapy.
Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy.
Authors: Guthrie T H , Porubsky E S , Luxenberg M N , Shah K J , Wurtz K L , Watson P R
Published: February 2017

This study reports the results of cisplatin (CDDP)-based chemotherapy (CT) as sole therapy and as neoadjuvant (NA) therapy in 28 consecutive patients (pts) with advanced basal cell (BC) and squamous cell (SC) cancers of the skin. CT in 24 pts consisted of CDDP 75 mgm/m2 and doxorubicin (Dox) 50 mg/m2 intravenously (IV) every 3 weeks with Dox being omitted in four pts due to severe preexisting cardiac disease. Thirteen of the 28 pts received CT in the NA setting, five before surgery and eight before radiation therapy (RT). Response rates to CT were complete remission (CR) in eight of 28 (28%) pts, partial remission (PR) in 11 of 28 (40%) for an overall response rate of 68%. Thirteen pts received a second treatment modality with five of 13 pts having a CR to CT alone before the second modality and seven converting to CR postsecond modality for a total CR rate of 12 of 13 (92%) in the multimodality group. Duration of responses in the CT-only group ranged from 4 to 82 months; however, only two patients remain in remission in this group. Of the twelve CRs from the multimodality therapy group, 11 of 12 (91%) pts remain in CR with duration of response ranging from 3 to 81 months. Toxicities were manageable, with no toxic deaths and only five pts stopped CT secondary to side effects. This study suggests the combination of CDDP and Dox is highly effective in BC and SC cancers of the skin and by itself can produce long unmaintained remissions, but when combined with a second modality of therapy, it is capable of producing not only long unmaintained CRs but probable cures in the majority of pts.
The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.
Authors: Holoye P Y , McMurtrey M J , Mountain C F , Murphy W K , Dhingra H M , Umsawasdi T , Glisson B S , Lee J S , Carr D T , Valdivieso M
Published: February 2017

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.
Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia.
Authors: Schwarzinger I , Valent P , Köller U , Marosi C , Schneider B , Haas O , Knapp W , Lechner K , Bettelheim P
Published: February 2017

The prognostic significance of the expression of surface membrane antigens on the blasts of 123 consecutive patients with de novo acute myeloblastic leukemia (AML) was evaluated. For this purpose, reactivity of monoclonal antibodies (mAbs) CLB-ERY3 (antiblood-group H antigen), VIM-D5 (CD15), WT1 (CD7), MY7 (CD13), MY9 (CD33), VID-1 (antihuman leukocyte antigen locus DR [anti-HLA DR]), VIM-2 (CDw65L), VIM-13 (CD14), 63D3 (CD14) and anti-TdT with leukemic blast cell populations was prospectively analyzed with respect to the rates of complete remission (CR), continuous complete remission (CCR), and survival. The overall rate of CR was 65%, the 6-year rates of overall CCR and survival were 23% and 13%, respectively (median period of patient observation, 30 months). Of all Abs tested, four (CLB-ERY3, MY7, anti-TdT, and VIM-D5) were found to be of prognostic value. Reactivity of CLB-ERY3, MY7, and anti-TdT was predictive for CR (CLB-ERY3+, 43% v CLB-ERY3-, 73%, P less than .02; MY7+, 59% v MY7-, 91%, P less than .003; TdT+, 28% v TdT-, 71%, P less than .001, respectively) and probability of survival (significantly lower survival rates: CLB-ERY3+, P less than .02; MY7+, P less than .03; and TdT+ cases, P less than .001, respectively). Reactivity of VIM-D5 was significantly associated with a higher probability of CCR (P less than .01). Our results confirm earlier reports on the prognostic significance of expression of CD13 and TdT in AML and indicate CLB-ERY3 (antiblood-group H antibody) and VIM-D5 (CD15) as further markers predictive for the clinical outcome in patients with de novo AML.