bluuebunny/crossref_metadata_2025 huggingface dataset:
High-dose ifosfamide with mesna uroprotection: a phase I study.
Authors: Elias A D , Eder J P , Shea T , Begg C B , Frei E , Antman K H
Published: February 2017

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.
Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas.
Authors: Schneider A M , Straus D J , Schluger A E , Lowenthal D A , Koziner B , Lee B J , Wong G , Clarkson B D
Published: February 2017

Seventy previously untreated patients with stage II, III, and IV intermediate- or high-grade lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between September 1985 and November 1987. Forty-nine of these patients had diffuse large-cell lymphoma (DLCL), and eight of these patients were human immunodeficiency virus (HIV)-positive. Complete responses were achieved in 54% of all patients and 52% of those with DLCL. With follow-up extending to 36 months, 45% of all DLCL patients are alive, and 50% are still living, if the HIV-positive patients are excluded from the analysis. Chemotherapy was quite toxic. Seventy-five percent of patients had severe mucositis, 42% had peripheral neuropathy, 50% required hospitalization, and 54% experienced leukopenia with a WBC count below 1,000/microL. Seven percent (five patients) died of toxicity related to the chemotherapy. Our analysis of prognostic parameters indicated that B symptoms, a performance status below 80, and, to a lesser extent, elevation of serum lactic acid dehydrogenase (LDH) (in HIV-negative DLCL patients) were associated with an inferior survival. Advanced age, sex, and bulky disease were not found to have a statistically significant effect on survival. Our preliminary results indicate that MACOP-B chemotherapy is an effective regimen for high- and intermediate-grade lymphomas. However, the survival for patients with DLCL treated with MACOP-B is no different than that achieved with previous regimens at our institution.
Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance.
Authors: Hansen S W , Berthelsen J G , von der Maase H
Published: February 2017

Fertility and Leydig cell function were investigated in 31 patients previously treated for nonseminomatous testicular cancer. Twenty-two patients with metastatic cancer had received cisplatin-based chemotherapy, and the median follow-up was 64 months (range, 42 to 100 months). Nine patients without metastases were treated with orchiectomy alone, and follow-up in this group was a median of 61 months (range, 40 to 77 months). None of the patients have relapsed and retroperitoneal lymph node dissection was not performed in any patient. Both the concentration of spermatozoa and the volume of the remaining testis are significantly reduced in patients who had previously received chemotherapy when compared with patients treated with orchiectomy alone (P less than .05). There were no significant differences between groups when comparing morphology, motility, and penetration of the spermatozoa. Subclinical Leydig cell dysfunction with normal testosterone and elevated luteinizing hormone (LH) was observed in one patient (11%) treated with orchiectomy alone, while 59% of the patients who had received chemotherapy had elevated LH (P less than .05). We conclude that cisplatin-based chemotherapy leads to a persistent impairment of fertility and Leydig cell function in the majority of patients with testicular cancer.
A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer.
Authors: Wallerstein R , Spitzer G , Dunphy F , Huan S , Hortobagyi G , Yau J , Buzdar A , Holmes F , Theriault R , Ewer M
Published: February 2017

To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.
High- versus standard-dose megestrol acetate in women with advanced breast cancer: a phase III trial of the Piedmont Oncology Association.
Authors: Muss H B , Case L D , Capizzi R L , Cooper M R , Cruz J , Jackson D , Richards F , Powell B L , Spurr C L , White D
Published: February 2017

One hundred seventy-two patients with advanced breast cancer were randomized to receive oral standard-dose megestrol acetate (MA), 160 mg/d or high-dose MA, 800 mg/d. All but two patients had one prior trial of tamoxifen therapy for either metastatic disease (74%) or as adjuvant treatment (26%). Pretreatment characteristics were similar for both arms. High-dose MA resulted in a superior complete plus partial response rate (27% v 10%, P = .005), time to treatment failure (median, 8.0 v 3.2 months, P = .019), and survival (median, 22.4 v 16.5 months, P = .04) when compared with standard-dose therapy. These differences remained significant after adjustment for other covariates. Thirty-four patients were given high-dose MA after failure of standard-dose MA treatment, and none responded. Weight gain was the most distressing side effect, with 13% of standard-dose and 43% of high-dose patients gaining more than 20 lbs. Four major cardiovascular events occurred in patients receiving high-dose treatment and one in patients given standard doses. Other toxicity was modest. High-dose MA may represent a significant improvement in secondary endocrine therapy for advanced breast cancer patients refractory to initial endocrine treatment, but its use on a regular basis should be reserved until these results are confirmed by other clinical trials.
Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics.
Authors: Presant C A , Wolf W , Albright M J , Servis K L , Ring R , Atkinson D , Ong R L , Wiseman C , King M , Blayney D
Published: February 2017

We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.
A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver.
Authors: Wagman L D , Kemeny M M , Leong L , Terz J J , Hill L R , Beatty J D , Kokal W A , Riihimaki D U
Published: February 2017

Over a 4-year period (1982 to 1986), 91 patients with solitary or multiple metastases from colorectal cancer were stratified, based on findings at laparotomy, to one of three groups and then prospectively randomized to one of two treatment arms within each group. Group A patients had solitary resectable metastases, group B patients had multiple, resectable metastases, and group C patients had multiple, unresectable metastases. Patients were randomized to one of two treatment arms within a group: group A-arm A1: resection only, arm A2: resection and continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUdR); group B-arm B1: resection and CHAI, arm B2: CHAI only; group C-arm C1: CHAI, arm C2: systemic fluorouracil followed by CHAI. Median time to failure (TTF) was 31.8, 11.1, and 8.8 months for groups A, B, and C, respectively. Arm A2 had an improved TTF when compared with arm A1 (P = .03). Median survival correlated with extent of disease and was 37.3, 22.4, and 13.8 months for groups A, B, and C, respectively. Survival was not changed by treatment variation (arms) within each group. Two- and 5-year cumulative survivals for groups A, B, and C were 72.7% and 45.4%; 45.8% and 16.7%; and 31.7% and 3.2%, respectively. In patients with multiple metastases (groups B and C), those patients whose original tumor was a Dukes' B had a significantly improved TTF and survival over those patients whose tumor was a Dukes' C (P less than or equal to .02).
The unique aspects of acute promyelocytic leukemia.
Authors: Stone R M , Mayer R J
Published: February 2017

Acute promyelocytic leukemia (APL) accounts for approximately 10% of cases of acute myeloid leukemia (AML). Distinctive features of this disorder at the time of diagnosis include leukopenia coexisting with a marrow replaced with granulated dysplastic promyelocytes, disseminated intravascular coagulopathy, lack of Ia (HLA-DR) antigen expression, and translocation between the long arms of chromosomes 15 and 17 (t[15;17]). Heparin is widely but not universally used to interfere with the coagulopathy during the initial phases of treatment. Serial bone marrow examinations during the induction period demonstrate the achievement of remission despite the persistence of malignant-appearing promyelocytes. Patients with APL are generally younger than those with other subtypes of AML, have a 70% to 80% likelihood of entering remission, and are thought to have a more favorable prognosis than other individuals with AML. Remission may be achieved with a conventional anthracycline-cytarabine combination, anthracycline alone, or, apparently, all-trans retinoic acid. Genes potentially important in myeloid differentiation such as granulocyte colony-stimulating factor (G-CSF) and myeloperoxidase are located close to the breakpoint in the t(15;17) but have not been conclusively shown to be rearranged in the translocation. A better understanding of the unique aspects of APL may well shed light on the pathogenetic processes of AML.
Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience.
Authors: Hudson M , Jaffe M R , Jaffe N , Ayala A , Raymond A K , Carrasco H , Wallace S , Murray J , Robertson R
Published: February 2017

Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I, II, and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF), Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.
Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma.
Authors: Pazdur R , Ajani J A , Patt Y Z , Winn R , Jackson D , Shepard B , DuBrow R , Campos L , Quaraishi M , Faintuch J
Published: February 2017

We conducted a phase II clinical trial of fluorouracil (5FU) and recombinant interferon alfa-2a (rIFN alpha-2a) in 52 previously untreated patients with bidimensionally measurable metastatic colorectal cancer. During week 1, 5FU was administered as a continuous intravenous infusion, 750 mg/m2/d for 5 consecutive days. Intravenous bolus administration of 5FU 750 mg/m2 was given weekly for 7 weeks starting on day 12. rIFN alpha-2a (Roferon; Hoffman-LaRoche, Nutley, NJ), 9 x 10(6) U, was administered subcutaneously three times weekly during weeks 1 to 8. Patients were evaluated for response on week 9. Of 52 patients enrolled in the study, 51 were assessable for toxicity, and 45 were assessable for response. Fifteen patients experienced partial response, and one patient achieved a clinical complete response for an overall response rate of 35% (95% confidence interval [CI], 22%, 50%). Median duration of response is 7.5 months (range, 4 to 11 months). Seventy percent of patients entered on the study are alive with a median follow-up duration of 7 months. Twenty-five percent of patients developed grade 4 toxicity, and 82% developed grade 3 toxicity. One drug-related death in the presence of sepsis was reported, and two treatment-related seizures occurred. Our experience with this schedule produced a lower response rate with greater toxicity than previously reported. Current randomized trials comparing this schedule of 5FU with rIFN alpha-2a to 5FU plus folinic acid (leucovorin) or single-agent 5FU may determine its role in the treatment of advanced colorectal carcinomas.
The relative value of conventional staging procedures for developing prognostic models in extensive-stage small-cell lung cancer.
Authors: Sheehan R G , Balaban E P , Cox J V , Frenkel E P
Published: February 2017

Published prognostic models for small-cell lung cancer (SCLC) have either combined limited- and extensive-stage patients or have not included standard anatomic staging information to assess the relative value of the knowledge of specific sites and number of sites of metastases in predicting survival in extensive-stage disease. We studied 136 extensive-stage patients in whom traditional staging procedures were performed and in whom other previously demonstrated significant pretreatment variables were determined. Using the Cox proportional hazards model, when all data were included, three variables were significant: performance status (PS) (P = .0001), number of sites of metastases (P = .0010), and age (P = .0029). A prognostic algorithm was developed using these variables, which divided the patients into three distinct groups. When the anatomic staging data were omitted, the serum albumin (P = .0313) was the only variable in addition to PS (P = .0001) and age (P = .0064) that was significant. An alternative algorithm using these three variables was nearly as predictive as the original. Therefore, in extensive-stage patients, reasonable pretreatment prognostic information can be obtained without using the number or specific sites of metastases as variables once the presence of distant metastases has been demonstrated.
Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma.
Authors: Maor M H , Velasquez W S , Fuller L M , Silvermintz K B
Published: February 2017

Thirty-four patients with stages IE and IIE gastric lymphoma were treated with chemotherapy and radiotherapy combinations without stomach resection. In 20 patients, the diagnosis was established by endoscopic biopsy only; the other 14 had laparotomy and biopsy. No patient had a gastrectomy before treatment. Nineteen patients had stage IE disease and 15 had stage IIE. Lymphoma diagnoses were: diffuse large-cell, 26; immunoblastic, three; diffuse well-differentiated, three; nodular mixed, one; and unclassified, one. The treatment plan was to deliver an initial four cycles of chemotherapy, followed by radiotherapy, and finally, more chemotherapy. Thirty-three patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo). Four patients with stage IIE disease received cyclophosphamide, methotrexate, etoposide, and dexamethasone (CMED). Twenty-three patients (68%) never had a relapse. Three patients had successful salvage therapy, one for local recurrence and two for tumor dissemination. Five patients died of recurrent abdominal disease, and one died of tumor dissemination. Two died of treatment-related complications, one of sepsis during treatment with CMED and one of bleomycin-induced lung fibrosis. No patient developed stomach perforation or bleeding as a result of chemotherapy or radiotherapy. Twenty-four of the 26 surviving patients were able to retain their stomachs. One patient required a gastrectomy for progressive disease during chemotherapy, and another required a subtotal gastrectomy for relief of an obstruction caused by cicatrization. These data show that surgery is not a necessary procedure in gastric lymphoma. Favorable results can be achieved by combining effective chemotherapy and local radiation.
Phase I/II trial of granisetron: a novel 5-hydroxytryptamine antagonist for the prevention of chemotherapy-induced nausea and vomiting.
Authors: Addelman M , Erlichman C , Fine S , Warr D , Murray C
Published: February 2017

A new class of antiemetic agents, the 5-hydroxytryptamine (5-HT3) antagonists, have been shown to possess potent antiemetic properties in the ferret model. We conducted a phase I/II trial of the 5-HT3 antagonist BRL43694 (granisetron) in 24 chemotherapy-naïve patients who were receiving any combination of doxorubicin and/or cisplatin. The first 12 patients received 40 micrograms/kg and the second 12 received 80 micrograms/kg of granisetron intravenously before beginning chemotherapy. Nausea was assessed by a patient-completed visual analogue scale and episodes of retching recorded by the patient and an independent observer. Fifty-two percent of the 22 evaluable patients had no retching or vomiting and 32% had no nausea during the first 24 hours after chemotherapy. Pharmacokinetic measurements were performed. The disposition of granisetron was best described using a two-compartment model. The area under the plasma concentration curve (AUC) was 277 +/- 226 ng.h/mL and 359 +/- 282 ng.h/mL at 40 and 80 micrograms/kg, respectively. The total body clearance was 0.319 +/- 0.315 L/kg/hr and 0.483 +/- 0.504 L/kg/hr at the 40 and 80 micrograms/kg doses. Wide interpatient variation in model independent parameters was observed. There was no suggestion of dose-dependent efficacy at the two dose levels studied. We conclude that granisetron shows promise as a well-tolerated and effective antiemetic. Randomized trials comparing this drug with standard regimens are currently underway.
Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy.
Authors: Doroshow J H , Multhauf P , Leong L , Margolin K , Litchfield T , Akman S , Carr B , Bertrand M , Goldberg D , Blayney D
Published: February 2017

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.
Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian Testicular Cancer Group.
Authors: Klepp O , Olsson A M , Henrikson H , Aass N , Dahl O , Stenwig A E , Persson B E , Cavallin-Ståhl E , Fosså S D , Wahlqvist L
Published: February 2017

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.
Recombinant Human Granulocyte Colony-Stimulating Factor Hastens Granulocyte Recovery After High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in Hodgkin's Disease
Authors: Taylor Kerry McD. , Jagannath Sundar , Spitzer Gary , Spinolo Jorge A. , Tucker Susan L. , Fogel Beverly , Cabanillas Fernando F. , Hagemeister Fredrick B. , Souza Lawrence M.
Published: February 2017

The running head of the report by Taylor et al published in the December 1989 issue (J Clin Oncol 7:1791–1799, 1989) was incorrect. It should have read: "G-CSF AND ABMT IN HODGKIN'S DISEASE."
Why are local recurrences after breast-conserving therapy more frequent in younger patients?
Authors: Kurtz J M , Jacquemier J , Amalric R , Brandone H , Ayme Y , Hans D , Bressac C , Spitalier J M
Published: February 2017

The influence of patient age on risk of recurrence in the breast was retrospectively studied in 496 stage I-II invasive ductal carcinomas treated by macroscopically complete primary tumor excision followed by radiotherapy. With a median follow-up of 71 months, local recurrence occurred in 13 of 62 (21%) patients younger than 40 years, compared with 48 of 434 (11%) older patients (P less than .025). Cox multivariate analysis of 18 parameters identified four that significantly determined risk: major lymphocytic stromal reaction (MCR), unsatisfactory resection margins, increasing histologic grade, and extensive intraductal cancer (DCIS) within the primary tumor. Compared with older patients, those younger than 40 years had tumors that more often exhibited MCR (36% v 20%, P less than .01), histologic grade 3 (42% v 28%, P less than .025), and very extensive DCIS (21% v 6%, P less than .001). The status of resection margins did not differ significantly between younger and older patients. Restriction of Cox analysis to patients younger than 40 indicated that risk was adequately described by MCR and percentage of DCIS, without consideration of grade or margins. For patients younger than 40, local failure occurred in four of five (80%) tumors with both MCR and more than 50% DCIS, in eight of 25 (32%) with either, and one of 32 (3.1%) with neither of these morphologic features. This study suggests that the higher local failure risk observed in patients younger than 40 years reflects the greater prevalence of certain morphologic characteristics in breast cancers in younger patients. Age itself does not appear to be an independent determinate of risk.
Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkin's disease.
Authors: Roach M , Brophy N , Cox R , Varghese A , Hoppe R T
Published: February 2017

Prognostic factors were analyzed retrospectively in 109 patients who relapsed after treatment with radiation only for Hodgkin's disease. Factors analyzed included initial stage, age, time to first relapse, histology, sex, extent of initial irradiation, sites of relapse, relapse stage (RS), average relative dose intensity (ARDI) of chemotherapy, and type of salvage therapy. Ninety-three percent of the patients received either standard or modified mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). With a median follow-up of 8.3 years, the actuarial survival and freedom from second relapse (FF2ndR) was 57% at 10 years. The extent of disease at the time of relapse, or so-called RS was found to be the single most important prognostic factor. Nearly 90% of patients with RS IA or IEA (favorable group) were disease free, and nearly 60% of patients with RS IIA, IIEA, or IIIA (intermediate group) were disease free compared with only 34% of patients with B symptoms or stage IV disease (unfavorable group). In a subset analysis, the use of combined modality therapy (CMT) was associated with an improved FF2ndR and survival in patients from the intermediate and unfavorable relapse groups. Age greater than 50 years was associated with an increased risk of second relapse and a lower survival. The other factors analyzed appeared to be of no independent prognostic value.
Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma.
Authors: Gianni A M , Bregni M , Siena S , Orazi A , Stern A C , Gandola L , Bonadonna G
Published: February 2017

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.
Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse.
Authors: Freedman A S , Takvorian T , Anderson K C , Mauch P , Rabinowe S N , Blake K , Yeap B , Soiffer R , Coral F , Heflin L
Published: February 2017

One hundred patients with B-cell non-Hodgkin's lymphoma (NHL) in sensitive relapse or incomplete first remission underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MAb)-treated autologous bone marrow transplantation (ABMT). These patients demonstrated good performance status with a Karnofsky score of 80% or greater. The majority of these patients had one or more adverse prognostic features including a failure to achieve a complete remission (CR) with conventional combination chemotherapy (37 patients), bone marrow infiltration (69 patients), a history of extranodal disease other than bone marrow infiltration (42 patients), and histologic conversion (18 patients). At the time of ABMT, only 52 patients were in CR; however, all patients achieved a minimal disease state following conventional intensive therapy. Moreover, at the time of marrow harvest, 37 of these patients had histologic evidence of lymphoma cells infiltrating the marrow. Following high-dose ablative therapy, two acute in-hospital treatment-related deaths were observed. Two late deaths were observed, not due to recurrent lymphoma. Of the remaining 96 patients, 61 are in unmaintained CR with a median follow-up of 13 months. Kaplan-Meier actuarial analysis predicts 50% probability of disease-free survival (DFS) at 37.8 months. This very low treatment-related mortality provides the rationale to apply high-dose therapy and ABMT as consolidative therapy for patients in first remission who are at high risk for relapse following conventional therapy.
Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: a subset analysis of the Head and Neck Contracts Program.
Authors: Jacobs C , Makuch R
Published: February 2017

To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.
Active-specific immunotherapy for melanoma.
Authors: Mitchell M S , Harel W , Kempf R A , Hu E , Kan-Mitchell J , Boswell W D , Dean G , Stevenson L
Published: February 2017

Twenty-five patients with metastatic melanoma were treated with a therapeutic vaccine ("theraccine") consisting of allogeneic melanoma lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, three partial remissions, and a long-term (17-month) stability. Two other patients had mixed responses, with partial remissions of numerous subcutaneous nodules. Sites of responsive disease included primarily the skin, but ileal, breast, and a liver metastasis also responded. Removal of residual lesions in patients with partial remissions, whose other lesions had disappeared during treatment, led to long disease-free survivals. The median duration of remission was 17 months, with four of the five responders alive for at least 24 months after treatment. An increase in precursors of cytolytic T cells (CTLs) correlated with clinical outcome, when complete, partial, and mixed responses and long-term stability were considered. The CTLs recognized melanoma-associated antigens on many cell lines, but not other types of tumor or normal lymphocytes. Skin-test reactivity to melanoma antigens and serum antibodies against the melanoma cells was unrelated to clinical response. Toxicity was minimal, restricted largely to minor soreness at the site of injection. Only five patients, four of whom were treated with repeated courses, developed severe granulomas. These results confirm that active-specific immunization with allogeneic lysates of melanoma administered with the adjuvant DETOX can induce immunity to melanoma, and can induce regressions of disease in a proportion of patients with metastatic disease with little toxicity.
Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin.
Authors: Kreis W , Ahmann F R , Lesser M , Scott M , Caplan R , Gau T , Vinciguerra V
Published: February 2017

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.
Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study.
Authors: McCracken J D , Janaki L M , Crowley J J , Taylor S A , Giri P G , Weiss G B , Gordon W , Baker L H , Mansouri A , Kuebler J P
Published: February 2017

The Southwest Oncology Group (SWOG) has conducted a phase II study to explore the efficacy and toxicity of initial, concurrent use of radiation therapy with cisplatin, etoposide (VP-16), and vincristine in limited-stage small-cell carcinoma of the lung. Two courses of cisplatin, VP-16, and vincristine chemotherapy were given with concurrent radiotherapy (XRT) to the primary tumor to a total dose of 4,500 cGy. Elective brain XRT was given to all patients concurrent with a third course of cisplatin/VP-16 therapy. Consolidation chemotherapy consisting of vincristine, methotrexate, and VP-16 alternating with Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide, was given for 12 weeks following the initial induction chemotherapy/XRT program. Patients with a complete response had all therapy discontinued. Among 154 eligible patients treated, the complete response rate was 56%, with a partial response rate of 27%. The median survival is 17.5 months with an estimated 30% survival rate at 4 years from initiation of treatment. Combined modality toxicities were acceptable with the predominant toxicity being moderate to severe leukopenia and mild radiation esophagitis. The results of this treatment program appear superior to any previously reported by our group and compare favorably to those in the literature at large.
Failure of 1H nuclear magnetic resonance spectroscopy of blood plasma to detect malignancy.
Authors: Okunieff P , Greenberg M D , Zietman A , Kahn J , Westgate S , Neuringer L J
Published: February 2017

Water-suppressed proton nuclear magnetic resonance (NMR) of plasma was proposed as a technique for detecting malignant tumors. In that analysis, bloods drawn from cancer patients at the Beth Israel Hospital (BIH; Boston, MA), were easily distinguished from normal subjects by measuring and averaging the proton NMR methyl and methylene line widths of plasma lipoproteins. We collected blood at the Massachusetts General Hospital (MGH), including from normal controls, patients with untreated and treated malignant tumors, and patients with nontumor diseases. The plasma NMR analyses were carried out blind. The code was not broken until all patient charts and pathology records were reviewed, plasma analyses were completed, and patients had been divided into appropriate clinical groups. Analysis of these data showed no differences between the means of the study groups (false-positive and false-negative frequencies 46% and 57%, respectively). An inverse correlation of methyl/methylene line widths with age (P less than .01), and a correlation with nitrate-requiring cardiovascular disease (P less than .05) was, however, evident. This test cannot be validly used to detect malignancy.
Wilm's tumor with pulmonary metastases at diagnosis: the significance of primary chemotherapy. International Society of Pediatric Oncology Nephroblastoma Trial and Study Committee.
Authors: de Kraker J , Lemerle J , Voûte P A , Zucker J M , Tournade M F , Carli M
Published: February 2017

Data from patients with pulmonary metastases (PM) from Wilms' tumor at diagnosis (stage IV) were collected from six European centers. All patients were pretreated with a chemotherapy (CT) regimen consisting of vincristine (VCR), dactinomycin (AD), and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). After nephrectomy, local therapy for residual pulmonary disease was considered to avoid whole-lung irradiation. Only four of 36 patients still had multiple inoperable metastases after preoperative CT. Thirty patients survived. Four of them were irradiated. Of the six patients who died, four died of PM, one died of abdominal recurrence, and one of therapy-related disease. Disease-free survival and actuarial survival rates are 83% with a mean follow-up of 4 years postnephrectomy.
Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment.
Authors: Champlin R , Gajewski J , Nimer S , Vollset S , Landaw E , Winston D , Schiller G , Ho W
Published: February 2017

Results of postremission chemotherapy for adults with acute myelogenous leukemia (AML) were assessed in two sequential prospective studies involving similar induction therapy and two courses of intensive consolidation treatment. Fifty-six patients achieving remission on the acute leukemia protocol (ALP3) study received high-dose cytarabine and daunorubicin as course one and standard-dose cytarabine and daunorubicin as course two. Results are compared with forty-six patients achieving remission on the ALP2 study who received azacitidine and doxorubicin as consolidation course one and standard-dose cytarabine, daunorubicin, and thioguanine as course two. The ALP3 regimen resulted in a significantly improved 5-year disease-free survival of 32% +/- 19% versus 20% +/- 11% for the ALP2 study (P = .03). Survival from remission was also improved, 40% +/- 14% versus 24% +/- 12% (P less than .01). Favorable prognostic factors for disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults less than or equal to 45 years of age was 58% +/- 19% with the ALP3 postremission chemotherapy regimen, comparable to most studies of BMT for AML in first remission. Actuarial 5-year survival for ALP3 patients greater than 60 years of age was 18% +/- 20% with no improvement compared with ALP2.