bluuebunny/crossref_metadata_2025 huggingface dataset:
High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer.
Authors: Peters W P , Shpall E J , Jones R B , Olsen G A , Bast R C , Gockerman J P , Moore J O
Published: February 2017

To evaluate the effect of high-dose chemotherapy in the treatment of metastatic breast cancer, we performed a phase II trial of a single treatment with high-dose cyclophosphamide (5,625 mg/m2), cisplatin (165 mg/m2), and carmustine (600 mg/m2), or melphalan (40 mg/m2) and bone marrow support as the initial chemotherapy for metastatic breast cancer. Twenty-two premenopausal patients with estrogen receptor negative, measurable metastatic disease were treated. Twelve of 22 patients (54%) obtained a complete response at a median 18 days. The overall response rate is 73% (complete and partial response). Median duration of response in the patients achieving complete response was 9.0 months with a median duration of survival for complete responders that is currently undefined. Relapse occurred predominantly at sites of pretreatment bulk disease or within areas of previous radiation therapy. Toxicity was frequent and five patients died of therapy-related complications. The results indicate that a single treatment with intensive combination alkylating agents with bone marrow support can produce more rapid and frequent complete responses than conventional chemotherapy when used as initial chemotherapy for metastatic breast cancer, although median disease-free and overall survival is not improved. Three patients (14%) remain in unmaintained remission beyond 16 months.
Vincristine and prednisone prolong the survival of patients receiving intravenous or oral melphalan for multiple myeloma: Cancer and Leukemia Group B experience.
Authors: Cornwell G G , Pajak T F , Kochwa S , McIntyre O R , Glowienka L P , Brunner K , Rafla S , Coleman M , Cooper M R , Henderson E
Published: February 2017

A total of 589 patients with previously untreated multiple myeloma were randomized to receive daily oral melphalan, pulse-dose intravenous (IV) melphalan, carmustine (BCNU), or lomustine (CCNU). All patients received an initial tapering course of prednisone (Pred). During week 22 (day 154), patients were randomized to receive or not to receive additional therapy with vincristine (VCR) (1 mg/m2) and prednisone (0.6 mg/kg/d for seven days) at 8-week intervals. The influence of VCR/Pred was determined in 302 patients who remained on study beyond 22 weeks after initial therapy. VCR/Pred converted a significant percentage of nonresponders to responders in patients treated with melphalan (55% v 19%, P = .002), but not in patients treated with a nitrosourea (48% v 23%, P = .06). Survival beyond week 22 was significantly longer following the addition of VCR/Pred in patients receiving melphalan (median, 35.3 months v 27.0 months; P = .003) but not in patients receiving BCNU or CCNU (median, 28.1 months v 26.2 months; P = .91). These differences were seen both for oral and IV melphalan. A trend for beneficial effect of VCR/Pred was definitely seen in the good-risk patients (P = .03) but only suggestive for poor-risk patients (P = .12). Following adjustment for VCR/Pred effects, there were no differences in the survival of patients receiving any of the four initial treatments.
High-dose platinum consisting of combined carboplatin and cisplatin in previously untreated ovarian cancer patients with residual disease.
Authors: Lund B , Hansen M , Hansen O P , Hansen H H
Published: February 2017

A phase II trial of carboplatin, 300 mg/m2 day 1, and cisplatin, 50 mg/m2 days 2 and 3 every 4 weeks for six cycles, was performed in 42 previously untreated patients with residual disease after primary laparotomy. Overall, 79% of patients had primary residual tumor larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 37 evaluable patients was 62%, and in PCRs was 22%. Of the responding patients, 78% had primary residual tumor larger than 2 cm. The toxicity was cumulative but manageable, with thrombocytopenia being the main reason for dose reduction. Dose-limiting nephrotoxicity and neurotoxicity occurred in 22% and 7% of the patients, respectively. Combined high-dose platinum as a "single agent" appears to be as active as combination chemotherapy containing cisplatin, and the treatment is feasible. Further clinical trials of this combination alone or combined with other drugs are warranted.
The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer.
Authors: Rutqvist L E , Cedermark B , Fornander T , Glas U , Johansson H , Nordenskjöld B , Rotstein S , Skoog L , Somell A , Theve T
Published: February 2017

The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.
Hypocholesterolemia in patients treated with recombinant interleukin-2: appearance of remnant-like lipoproteins.
Authors: Wilson D E , Birchfield G R , Hejazi J S , Ward J H , Samlowski W E
Published: February 2017

Reversible acute hypocholesterolemia was observed during treatment of metastatic cancer with high-dose intravenous recombinant interleukin-2 (IL-2). Further analysis revealed virtual disappearance of high-density lipoproteins (HDLs) and marked reduction in the concentration of low-density lipoproteins (LDL); the remaining LDL and intermediate-density lipoproteins (IDL) were enriched in triglyceride relative to cholesterol and had broad-beta electrophoretic mobility, properties reminiscent of remnant lipoproteins. These changes differ qualitatively and quantitatively from those previously reported for other cytokines such as tumor necrosis factor (TNF) or the interferons (IFNs).
Immunotoxins: a clinical review of their use in the treatment of malignancies.
Authors: Hertler A A , Frankel A E
Published: February 2017

Immunotoxins are a new class of antitumor agents consisting of tumor-selective ligands (generally monoclonal antibodies [MoAbs]) linked to highly toxic protein molecules that have been modified to remove their normal tissue-binding domains. These immuno-conjugates combine the potency of the parent toxin with the specificity of the attached ligand. Toxins used in the construction of immunotoxins belong to a group of peptides that catalytically inhibit the elongation step of protein synthesis, and include ricin, abrin, pokeweed antiviral protein, gelonin, Pseudomonas exotoxin A, diptheria toxin, and alpha-sarcin. To synthesize immunotoxins, the normal cell-binding function must be removed by chemical cleavage or modification, or in the case of toxins that have been cloned, genetic engineering used to delete amino acids critical to cell binding. Covalent linkage of toxin to ligand generally involves a disulfide or thioether bond, though recently, recombinant toxin molecules with ligands that are genetically engineered into the protein have been made. The most successful clinical application of immunotoxins has been in the depletion of T cells from allogeneic bone marrow grafts to prevent graft-versus-host disease (GVHD). Clinical trials have been conducted using immunotoxins for the systemic treatment of chronic lymphocytic leukemia (CLL), GVHD, and selected solid tumors. With the possible exception of GVHD, responses have been limited. Obstacles have included rapid systemic clearance, poor delivery to extravascular tumor deposits, and humoral immune responses to the immunotoxin. Research to overcome these problems is in progress and should lead to a better definition of the role of immunotoxins in the therapy of malignancies.
Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.
Authors: Goel R , Cleary S M , Horton C , Balis F M , Zimm S , Kirmani S , Howell S B
Published: February 2017

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.
Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer.
Authors: Henderson I C , Allegra J C , Woodcock T , Wolff S , Bryan S , Cartwright K , Dukart G , Henry D
Published: February 2017

Three hundred twenty-five women with metastatic adenocarcinoma of the breast who had failed one prior chemotherapeutic regimen for advanced disease were randomized to receive 14 mg/m2 of mitoxantrone or 75 mg/m2 of doxorubicin intravenously (IV) every 3 weeks. Enrollment was closed on October 31, 1984, after 165 patients were randomized to mitoxantrone and 160 patients to doxorubicin. Patients randomized to the two treatment groups were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. The response rate to mitoxantrone was 20.6%, to doxorubicin 29.3% (P = .07). The median response duration was 151 days for the mitoxantrone group and 126 days for the doxorubicin group (P = .16). The median TTF was 70 days in the mitoxantrone group and 104 days in the doxorubicin group (P = .36). The median survival of patients initially randomized to receive mitoxantrone was 273 days; for doxorubicin 268 days (P = .40). There were three responses among 77 patients crossed over to mitoxantrone after initial treatment with doxorubicin. The major dose-limiting toxicity for both drugs was leukopenia. There was significantly less severe and less frequent toxicity with mitoxantrone administration. Severe nausea and vomiting occurred in 9.5% of mitoxantrone patients and 25.3% of doxorubicin patients (P less than .001). The incidence of severe stomatitis and mucositis was 0.6% in the mitoxantrone group and 8.4% in the doxorubicin group (P = .001). Severe alopecia occurred in 5.1% of mitoxantrone patients and 61.0% of doxorubicin patients (P less than .001). A life-table comparison of the cumulative dose to the development of a cardiac event showed that mitoxantrone had significantly less cardiotoxicity than doxorubicin (P = .0005). This study demonstrates that mitoxantrone is active as a single agent in the treatment of metastatic breast cancer. Compared with doxorubicin it appears to be marginally less active and significantly less toxic. We conclude that mitoxantrone can be used alone or with other standard drugs to palliate the symptoms of metastatic breast cancer, especially in settings where drug toxicity is an important consideration.
Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience.
Authors: Fisher B , Redmond C , Wickerham D L , Bowman D , Schipper H , Wolmark N , Sass R , Fisher E R , Jochimsen P , Legault-Poisson S
Published: February 2017

Despite numerous reports of findings obtained following the use of doxorubicin (Adriamycin [A]; Adria Laboratories, Columbus, OH) for the postoperative treatment of patients with primary breast cancer and positive axillary nodes, no clear consensus exists regarding its worth when used in that setting. In June 1981, the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented two randomized clinical trials aimed at evaluating the worth of doxorubicin when administered in conjunction with melphalan (L-PAM) and fluorouracil (5-FU) (PF). A prior NSABP study identified cohorts of patients who did or did not benefit from tamoxifen (TAM, T) when used with chemotherapy. That information was employed in the design of the present studies. Women considered responsive to TAM (1,106) were randomized between PFT and PAFT, and those nonresponsive to TAM (707) were randomized between PF and PAF. Findings through 6 years of follow-up (mean duration of potential time on study, 64 months and 63 months, respectively) indicate that non-TAM-responsive patients who received PAF had a significantly better disease-free survival (DFS) (P = .003) and survival (P = .05) than did those receiving PF. By contrast, there was no significant difference in DFS (P = .6) or survival (P = .7) between PFT- and PAFT-treated patients. No disparity in the amount of drug received, whether related to the median amount or to dose-intensity, is present to account for the difference in findings between the studies. Aside from alopecia and emesis, the toxicity from the doxorubicin-containing regimens was similar to those in which doxorubicin was omitted. Cardiomyopathy was not a significant finding; there were no deaths from cardiac toxicity. The incidence of arterial and venous complications in patients receiving TAM was less than reported by others.
A phase I study of intraarterial iododeoxyuridine in patients with colorectal liver metastases.
Authors: Chang A E , Collins J M , Speth P A , Smith R , Rowland J B , Walton L , Begley M G , Glatstein E , Kinsella T J
Published: February 2017

Regional delivery of iododeoxyuridine (IdUrd) to patients with colorectal liver metastases was examined in a phase I study. The maximum-tolerated intraarterial (IA) dose (MTD) was 1,333 mg/m2/d administered continuously for 14 days. The dose-limiting toxicity was thrombocytopenia. Thrombocytopenia and leukopenia were correlated with the amount of IdUrd incorporated into DNA of peripheral granulocytes. In contrast to our experience with 5-fluorodeoxyuridine, there was no evidence of hepatobiliary toxicity. In 11 patients who received IA IdUrd alone, seven had a greater than or equal to 50% decrease in carcinoembryonic antigen (CEA) levels, with five having tumor volume reductions of 65%, 48%, 46%, 44%, and 27%. Thus, IA IdUrd alone has antitumor efficacy. Patients subsequently received IdUrd in combination with external beam radiation to a total dose of 2,400 cGy without acute local toxicity. In addition to these favorable clinical findings, we have previously shown that IdUrd is selectively incorporated into tumor DNA compared with normal liver in these patients. Further phase II evaluations of this approach are warranted.
Patterns of failure following local excision and local excision and postoperative radiation therapy for invasive rectal adenocarcinoma.
Authors: Willett C G , Tepper J E , Donnelly S , Wood W C , Shellito P C , Rodkey G V , Stracher M A , Compton C C
Published: February 2017

The clinical course of 40 patients undergoing conservative surgical excision and 26 patients undergoing local excision and postoperative radiation therapy of rectal carcinoma was reviewed. Surgical procedures were transanal excision (55 patients), Kraske procedure (ten patients), and fulguration (one patient). The five-year actuarial survival, disease-free survival, and local control of all 66 patients were 70%, 77%, and 63%, respectively. For patients undergoing local excision alone, the prognostic features of lesion size greater than 3 cm, poorly differentiated histology, invasion into muscularis propria or deeper, moderate to marked stromal fibrosis, vascular or lymph vessel invasion, fragmented resection, and positive resection margins were associated with a local failure rate of 20% or greater. Of the 26 patients receiving postoperative radiation therapy, four patients have developed local failure. For subgroups of patients with small rectal carcinomas confined to the mucosa, local excision may be a reasonable alternative to abdominoperineal resection. For tumors with deeper invasion but limited to the bowel wall, local excision plus pelvic irradiation can be offered to preserve anorectal function.
Cisplatin versus cisplatin plus etoposide in the treatment of advanced non-small-cell lung cancer. Lung Cancer Working Party, Belgium.
Authors: Klastersky J , Sculier J P , Bureau G , Libert P , Ravez P , Vandermoten G , Thiriaux J , Lecomte J , Cordier R , Dabouis G
Published: February 2017

We conducted a randomized study comparing the survival after treatment with cisplatin (120 mg/m2) or cisplatin plus etoposide (100 mg/m2 on days 1, 2, and 3) in 162 evaluable patients with advanced non-small-cell lung cancer (NSCLC). No statistically significant difference in survival was detected; the median survival was 26 and 22 weeks, respectively, for patients receiving cisplatin and for those receiving cisplatin plus etoposide. The objective response rate was 19% for cisplatin and 26% for the combination; the corresponding response rates were 17% and 43% in patients with limited disease. No significant differences were detected between the two study arms as far as toxicity was concerned, except for alopecia and granulocytopenia, which occurred more frequently in patients treated with cisplatin plus etoposide.
Simple nontoxic treatment of advanced metastatic seminoma with carboplatin.
Authors: Horwich A , Dearnaley D P , Duchesne G M , Williams M , Brada M , Peckham M J
Published: February 2017

Between 1982 and 1986, 34 patients with advanced metastatic seminoma were treated with four to six courses of single-agent carboplatin administered at 400 mg/m2 every 4 weeks either on an outpatient basis or during 24-hour admissions. Patients with raised serum alphafetoprotein (AFP) or with multiple (more than three) lung metastases were excluded since these features may indicate a nonseminomatous component. In this series 20 patients were previously untreated except for orchiectomy, and 14 patients had received prior radiotherapy restricted to infradiaphragmatic nodal areas. Treatment was extremely well tolerated. No patient suffered renal damage, neurotoxicity, or ototoxicity, and there were no episodes of neutropenic septicemia, thrombocytopenic hemorrhage, or bruising. The actuarial 2-year survival was 94% (95% confidence intervals, 83% to 100%) with follow-up of 12 to 46 months from completion of carboplatin (mean, 26 months). The actuarial chance of remaining alive and free from progressive disease at 2 years was 80% (95% confidence intervals, 66% to 94%). Of six patients who relapsed, five are currently in remission 9 to 18 months after completion of salvage treatment. This level of antitumor activity is equivalent to that seen with aggressive combination regimens. Single-agent carboplatin should be considered the treatment of choice for advanced stages of malignant seminoma when limitation of toxicity is considered important; however, the rarity, especially of extranodal metastases from seminoma, leads to the need for further investigation using this approach.
Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.
Authors: Rivkin S E , Green S , Metch B , Glucksberg H , Gad-el-Mawla N , Constanzi J J , Hoogstraten B , Athens J , Maloney T , Osborne C K
Published: February 2017

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.
A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer.
Authors: Eisenberger M , Krasnow S , Ellenberg S , Silva H , Abrams J , Sinibaldi V , Van Echo D , Aisner J
Published: February 2017

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.
A phase II trial of intraperitoneal cisplatin and etoposide for primary treatment of ovarian epithelial cancer.
Authors: Howell S B , Kirmani S , Lucas W E , Zimm S , Goel R , Kim S , Horton M C , McVey L , Morris J , Weiss R J
Published: February 2017

We conducted a phase II trial of intraperitoneal (IP) cisplatin (DDP) and etoposide (VP-16) in stage III and IV newly diagnosed ovarian carcinoma patients with residual disease of any size. Twenty-three patients were entered, 19 had stage III and four stage IV disease. DDP 200 mg/m2 and VP-16 350 mg/m2 were given in 2 L saline IP via a Port-A-Cath (Pharmacia-Deltec, St Paul, MN). Sodium thiosulfate 4 g/m2 was given intravenously (IV) just before the start of IP instillation, and continued as a constant IV infusion of 2 g/m2/hr IV for a total of 6 hours. Treatment was given once every 4 weeks; six cycles of therapy were planned. Thirteen patients (56%) were in complete clinical remission at the end of treatment (normal physical exam, computed tomographic [CT] scan, CA-125, and peritoneal cytology). Seven of these 13 underwent a second-look laparotomy: three (13%) were in pathologic complete remission and four (17%) had microscopic disease only. Projected survival is 68% at 27 months, with 10 patients being alive and continuously free of disease. There was a very rapid fall in mean CA-125 to within normal limits at the end of the second course of treatment. The major toxicity was myelosuppression with median nadir WBC, granulocyte, and platelet counts of 2,600, 896, and 205,000/microL, respectively. There was no cumulative renal damage, anemia, hypomagnesemia, or chemical peritonitis. Neurotoxicity was similar to that observed with IV dosing. We conclude that therapy with the IP DDP/VP-16/IV thiosulfate regimen, in which all cytotoxic drugs are given only by the IP route, produces less anemia and renal damage than standard IV DDP-containing regimens, and that survival with this regimen appears to be at least as good as that produced by IV programs.
Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group.
Authors: Fryer C J , Hutchinson R J , Krailo M , Collins R D , Constine L S , Hays D M , Heller R M , Davis P C , Nachman J , O'Brien R T
Published: February 2017

Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.
Late neurological complications after prophylactic cranial irradiation in patients with small-cell lung cancer: the Toronto experience.
Authors: Lishner M , Feld R , Payne D G , Sagman U , Sculier J P , Pringle J F , Yeoh J L , Evans W K , Shepherd F A , Maki E
Published: February 2017

We retrospectively analyzed the charts of 58 long-term survivors of small-cell lung cancer (SCLC) (greater than 2 years) for neurological complications and their impact on the well-being of these patients. We also attempted to have patients complete a questionnaire regarding any possible neurological problems. This was done in 14 patients. Metastasis to the CNS occurred significantly less often in patients who received prophylactic cranial irradiation (PCI) in a dose of 20 Gy in five equal fractions (two of 48), compared with patients who did not receive it (four of 10) (P less than .006). Delayed neurological complications occurred in nine of 48 (19%) patients who received PCI. However, in only two patients did PCI appear to be responsible for progressive dementia. In the other seven patients (one with weakness in the arms and legs, one with transient left hemiparesis, two with hearing loss, and three with various visual disturbances), chemotherapeutic agents (mainly cisplatin and vincristine) and underlying diseases probably contributed significantly to the occurrence of these complications. In addition, these neurological disturbances were transient or ran a stable course and did not adversely affect the daily life of these patients. In comparison, amongst the 10 patients who did not receive PCI one had progressive dementia and another had hemiparesis secondary to probable brain embolism. We conclude that the use of PCI in these doses was effective in reducing the frequency of CNS metastases and had an adverse effect on the daily life and well-being only in a minority of the patients. Until results of controlled randomized studies show otherwise, PCI should continue to be used as a part of the combined modality treatment of completely responding patients with limited SCLC.
Chemotherapy of intermediate- and high-grade non-Hodgkin's lymphomas with a high-dose doxorubicin-containing regimen.
Authors: Zuckerman K S , LoBuglio A F , Reeves J A
Published: February 2017

Forty-seven previously untreated patients with intermediate- or high-grade non-Hodgkin's lymphoma were treated with four courses of a regimen that consisted of high-dose (120 mg/m2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine (2 mg), cytarabine (3 gm/m2), and dexamethasone (50 mg intravenously [IV] on day 1 and 20 mg/day orally on days 2 to 5) (AVAD), which was administered every 3 to 4 weeks. The median age of the patients was 58 years; 72% were Ann Arbor stage IV, 49% had "B" symptoms, 62% had masses larger than 7 cm, 40% had masses at least 10 cm in diameter, and 49% had serum lactate dehydrogenase (LDH) greater than 250 U/L. Overall, 72% of the patients (89% of diffuse large-cell lymphoma [DLCL] patients) attained complete (CR) or probable complete responses (PCR), and relapses occurred in 32%. There were no episodes of clinical congestive heart failure, but one patient developed recurrent ventricular arrhythmias. Fever during neutropenia occurred with 65% of treatment courses. Three deaths were attributed primarily to complications of therapy. The lymphoma-free survival of all entered patients is 51% (24 of 47), with a follow-up of 30 to 67 months (median, 58 months). These results confirm that high CR/PCR and long-term survival rates can be achieved in patients with aggressive histologies of non-Hodgkin's lymphomas, even in groups with poor prognostic factors, using high-dose anthracycline-containing chemotherapy regimens delivered over a short period of time. However, the apparently higher relapse rate in comparison to our previous study leads us to speculate that consolidation with noncross-resistant agents may be helpful in increasing even further the cure rate in this group of patients.
Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study.
Authors: Löwenberg B , Verdonck L J , Dekker A W , Willemze R , Zwaan F E , de Planque M , Abels J , Sonneveld P , van der Lelie J , Goudsmit R
Published: February 2017

Recent investigations have suggested a role for marrow ablative chemotherapy and radiotherapy given with autologous bone marrow transplantation (auto-BMT) in the treatment of acute myeloid leukemia (AML), but prospective studies have not been reported. We assessed the comparative values of auto-BMT and allogeneic marrow transplantation (allo-BMT) in 117 15- to 60-year-old consecutive patients (median, 43 years) with AML following remission-induction therapy. In 32 cases of the 90 (77%) complete responders, auto-BMT (nonpurged) was undertaken at a median of 3.8 months and in 23 eligible cases human leukocyte antigen (HLA)-matched allo-BMT occurred at 3.0 months after attainment of remission. Thus, nearly 60% of complete responders had access to transplantation, the others being withdrawn because of relapse, refusal, or other causes. Median time of regeneration to neutrophils 0.5 x 10(9)/L and platelets 20 x 10(9)/L were 39 and 63 days following auto-BMT versus 21 and 19 days after allo-BMT, respectively. AML relapse was the predominant cause of failure after auto-BMT (17 of 32) and procedure-related death was seen in three of 32 patients. The actuarial rates of relapse at 3 years are 60% (auto-BMT) and 34% (allo-BMT) (log-rank, P = .03). Patients treated with auto-BMT and allo-BMT have an overall survival of 37% and 66% at 3 years posttransplant, respectively (P = .05). Relapse-free 3-year survival rates are 35% and 51%, respectively (P = .12). Survival of the nongrafted complete responders is less than 10%. This study shows that allo-BMT in adult patients with AML in first complete remission (CR) results in more rapid hematopoietic reconstitution, is followed by fewer recurrences, and provides better survival than auto-BMT.
Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer.
Authors: Kemeny N , Israel K , Niedzwiecki D , Chapman D , Botet J , Minsky B , Vinciguerra V , Rosenbluth R , Bosselli B , Cochran C
Published: February 2017

One hundred twenty-two chemotherapy-naive patients with histologically confirmed colorectal adenocarcinoma were entered into a randomized trial comparing infusional fluorouracil (FU) versus cisplatin (CDDP) and FU. In both groups, patients received continuous infusion FU 1,000 mg/m2/d for 5 consecutive days every 4 weeks. Patients randomized to CDDP/FU also received CDDP 20 mg/m2 intravenous (IV) bolus on days 1 to 5 of each cycle. Patients were comparable in terms of age, performance status, baseline laboratory values, dominant sites of measurable disease, and percent of liver involvement. The partial response rate was significantly greater in patients who received CDDP/FU versus FU alone (25% v 3%, P = .001). Patients who received CDDP/FU experienced significantly greater toxicity compared with FU alone: grades 3 and 4 hematologic toxicity occurred in 22% and 0% of patients, respectively (P = .0001); grades 2 to 4 nausea and vomiting occurred in 80% and 15% of patients, respectively (P = .0001). There were no significant differences in either the duration of response (median, 6 and 4.7 months for CDDP/FU and FU groups, respectively) or survival (median 10, and 12 months, respectively). Compared with infusional FU alone, CDDP/FU provided a significantly greater partial response rate with increased toxicity, but it did not improve overall survival in patients with advanced colorectal carcinoma. Therefore, the use of CDDP/FU as routine therapy for the treatment of colorectal carcinoma cannot be recommended.
Phase II study of amonafide: results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer.
Authors: Evans W K , Eisenhauer E A , Cormier Y , Ayoub J , Wierzbicki R , Laberge F , Shepherd F A
Published: February 2017

Thirteen previously untreated patients with extensive small-cell lung cancer (SCLC) were treated with the investigational agent amonafide in a dose of 300 mg/m2 intravenously (IV) over 1 hour daily for 5 consecutive days. No responses were seen in 12 eligible patients. Myelosuppression was only occasionally seen. Other toxicities included diaphoresis, chest pain, local irritation at the injection site, arthralgias, nausea and vomiting, and neuromuscular problems. There were two early deaths, both attributable to tumor progression with resultant obstruction of a vital structure. Ten patients crossed over to alternate active therapy (etoposide [VP-16]-cisplatin) and five responded. The median survival time (MST) of the whole group of treated patients was 31 weeks. In future trials of investigational new drugs in previously untreated SCLC, we recommend that patients with the following characteristics be excluded: Eastern Cooperative Oncology Group (ECOG) performance status 2, 3, and 4; superior vena cava (SVC) obstruction; any major paraneoplastic syndrome; serious comorbid illness; and extensive hepatic involvement by tumor. The trial design should include prompt crossover to active alternative therapy, such as VP-16 and cisplatin, for disease progression or for failure to respond after two treatment cycles. Also, the trial design should use an early stopping rule based on interest in identifying only very active agents with a minimum response rate of 30%.
Toxicity, immunogenicity, and tumor radioimmunodetecting ability of two human monoclonal antibodies in patients with metastatic colorectal carcinoma.
Authors: Steis R G , Carrasquillo J A , McCabe R , Bookman M A , Reynolds J C , Larson S M , Smith J W , Clark J W , Dailey V , Del Vecchio S
Published: February 2017

Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.
High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease.
Authors: Jones R J , Piantadosi S , Mann R B , Ambinder R F , Seifter E J , Vriesendorp H M , Abeloff M D , Burns W H , May W S , Rowley S D
Published: February 2017

Patients with Hodgkin's disease who have failed two or more chemotherapy regimens or who have relapsed after an initial chemotherapy-induced remission of less than 12 months are seldom cured with conventional salvage therapies. We studied the effect of high-dose cytoreductive therapy followed by bone marrow transplantation in 50 such patients with relapsed Hodgkin's disease. Twenty-one patients with histocompatibility locus antigen (HLA)-matched donors had allogeneic marrow transplants, one patient received marrow from an identical twin, and 28 patients without a matched donor received autologous grafts purged with 4-hydroperoxycyclophosphamide. Busulfan plus cyclophosphamide was the preparative regimen for the 25 patients who had received extensive prior irradiation, and the other 25 patients received cyclophosphamide plus total body irradiation. The overall actuarial probability of event-free survival at 3 years was 30%, with a median follow-up of 26 months. The event-free survival following transplantation was influenced by the number of chemotherapy failures and the patient's response to conventional salvage therapy prior to transplant. The 16 patients who were transplanted at first relapse, while still responsive to standard therapy, had a 64% actuarial probability of event-free survival at 3 years. Age, presence of extranodal disease, preparative regimen, and type of graft (autologous v allogeneic) were not significant prognostic factors. The majority of transplant-related deaths were from interstitial pneumonitis; inadequate pulmonary function, multiple prior chemotherapy regimens, and prior chest irradiation all appeared to increase the transplant-related mortality. These results suggest a role for marrow transplantation in a subset of patients with relapsed Hodgkin's disease who are unlikely to be otherwise cured but are still responsive to conventional-dose cytoreductive therapy.
Phase II study of cytarabine and etoposide in children with refractory or relapsed non-Hodgkin's lymphoma: a study of the French Society of Pediatric Oncology.
Authors: Gentet J C , Patte C , Quintana E , Bergeron C , Rubie H , Pein F , Demaille M C , Philip T , Raybaud C
Published: February 2017

Twenty-five children or adolescents with relapsed or refractory non-Hodgkin's lymphoma (NHL) were included in this phase II study of the combination of cytarabine (ARA-C) 50 mg/m2/d by 12 hours continuous infusion day 1 to day 5, ARA-C 3 g/m2/d in 3 hours day 1 to day 4, and etoposide (VP 16) 200 mg/m2 daily from day 1 to day 4. Twelve patients had B-cell, 12 T-cell, and one non-T, non-B-cell lymphoma; according to Murphy's staging system, 15 had stage III and nine stage IV disease with bone marrow involvement at diagnosis. All had previously received ARA-C by push or continuous infusion. Two patients had received epipodophyllotoxins. At the time of the study, three children had initial refractory disease, 18 were in first relapse (14 on therapy), two in first refractory relapse, and two in second relapse (on therapy). The overall response rate (RR) was 60%: eight complete responses (CRs), seven partial responses (PRs) (two became CRs after a second course). The RR was 66% (four CRs plus four PRs) in B-cell and 54% (four CRs, three PRs) in non-B-cell NHL. It was 20% (one PR per five patients) in initial or relapsed refractory disease. In four patients with measurable CNS disease, there were three CRs. Duration of response was nonassessable since all the responding patients received high-dose polychemotherapy followed by autologous bone marrow transplantation (ABMT) (five are alive with long follow-up [FU]). Toxicity was marked mostly by pancytopenia for 2 weeks, and half the patients encountered a grade-3 infection. One severe diarrhea was observed. In conclusion, high-dose ARA-C (HD-ARA-C) and VP 16 are an effective regimen in relapsed NHL, especially with CNS disease, and its toxicity is acceptable with regards to the prognosis of the disease.
Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin.
Authors: Gershenson D M , Morris M , Cangir A , Kavanagh J J , Stringer C A , Edwards C L , Silva E G , Wharton J T
Published: February 2017

Since 1984, we have treated 26 patients with malignant ovarian germ cell tumors with a combination of bleomycin, etoposide (VP-16), and cisplatin (BEP) at The University of Texas MD Anderson Cancer Center (UTMDACC). The median age of the patients was 19 years (range, 8 to 32). All patients underwent initial surgery (unilateral salpingo-oophorectomy in 14, unilateral salpingo-oophorectomy plus abdominal hysterectomy in one, and bilateral salpingo-oophorectomy with or without hysterectomy in 11 patients). Twenty patients had no residual disease, three had less than or equal to 2 cm (one each, dysgerminoma, mixed, and immature teratoma), and three had more than 2 cm lesions (two dysgerminomas, one endodermal sinus tumor). Fourteen patients had pure dysgerminoma (five, stage I; one, stage II; six, stage III; and two, recurrent), and 12 had nondysgerminomatous tumors (five, stage I; two, stage II; three, stage III; and two, recurrent). All four patients with clinically measurable disease had a complete response. All four patients who underwent second-look laparotomy had negative findings. Twenty-five patients (96%) remain in sustained remission 10.4 to 54.4 months from the start of chemotherapy. One patient died of progressive disease 14 months after beginning chemotherapy. We conclude that the BEP regimen has excellent activity and acceptable toxicity in patients with malignant ovarian germ cell tumors.