bluuebunny/crossref_metadata_2025 huggingface dataset:
Small-cell carcinoma of the lung: derivation of a prognostic staging system.
Authors: Sagman U , Maki E , Evans W K , Warr D , Shepherd F A , Sculier J P , Haddad R , Payne D , Pringle J F , Yeoh J L
Published: February 2017

Retrospective data on 22 pretreatment attributes were evaluated in 614 patients with small-cell carcinoma of the lung (SCCL). The series included 284 patients with limited disease (LD) and 328 patients with extensive disease (ED) managed between 1974 and 1986. Prognostic factors were evaluated by univariate analysis and by the Cox multivariate regression model. Recursive partition and amalgamation algorithm (RECPAM), two clustering methods well suited for obtaining strata and adapted for censoring survival data, were developed and used in the formulation of a new prognostic staging system. In univariate analysis, prognosis was significantly influenced by extent of disease (DE), the number of metastatic sites, and the detection of mediastinal spread in LD. Poor performance status (PS), male sex, and advanced age were negatively correlated with survival, as were increased serum levels of alkaline phosphates (AP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), total WBC count (WBCC), and low platelet count and low serum sodium. The Cox model identified plasma LDH and mediastinal spread as the only significant factors in LD; the influence of PS, number of metastatic sites, bone metastasis, brain metastasis, and platelet count were identified as significant in ED. The RECPAM model identified four distinct risk groups defined in a classification tree by the following eight attributes: DE, PS, serum AP, serum LDH, mediastinal spread, sex, WBCC, and liver metastasis. The four groups were distinguished by median survival times of 59, 49, 35, and 24 weeks, respectively (P = .0001). Interactions among prognostic factors are emphasized in the RECPAM classification model as evidenced by reassignment of patients across conventional staging barriers into alternate prognostic groups. The advantages of using RECPAM over the more conventional Cox regression techniques for a new staging system are discussed.
Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil.
Authors: Boussen H , Cvitkovic E , Wendling J L , Azli N , Bachouchi M , Mahjoubi R , Kalifa C , Wibault P , Schwaab G , Armand J P
Published: February 2017

Undifferentiated nasopharyngeal carcinoma (UCNT) is known to be radiosensitive and chemosensitive, but the latter has never been studied prospectively with phase II methodology. After an intensive work-up, 49 patients with recurrent (REC) and/or metastatic (MTS) UCNT were treated with three monthly cycles of cisplatin (CDDP) 100 mg/m2 day 1; bleomycin 15 mg intravenously (IV) day 1, and 16 mg/m2/d continuous infusion (CI) days 1 to 5; and fluorouracil (5FU) 650 mg/m2/d CI days 1 to 5 (PBF). Of the 49 patients, 33 were North African. The sex ratio was three males:one female, and the median World Health Organization (WHO) performance status was 1.6. In the 48 patients assessable for response, we observed nine (19%) complete responses (CRs) and 29 (60%) partial responses (PRs) (60%), for a 79% overall response rate (95% confidence interval, 68% to 90%) in the assessable group and a 78% global rate. There were eight CRs (24%) observed in the group without previous chemotherapy (33 patients) compared with one CR in the chemotherapy pretreated group (16 patients). Four patients are still alive without evidence of disease after 52+, 54+, 58+, and 58+ months, respectively. All of them had less than three bone MTS sites, and received radiation therapy in these sites. The results confirm the chemosensitivity of UCNT, and the observation of unmaintained long-term responders makes curability a possible consideration.
Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study.
Authors: Stoter G , Aamdal S , Rodenhuis S , Cleton F J , Iacobelli S , Franks C R , Oskam R , Shiloni E
Published: February 2017

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.
Cardiac disturbances during the administration of taxol.
Authors: Rowinsky E K , McGuire W P , Guarnieri T , Fisherman J S , Christian M C , Donehower R C
Published: February 2017

The clinical development of taxol, a new antimicrotubule agent with a unique mechanism of cytotoxic action, has proceeded slowly due to serious hypersensitivity reactions (HSRs) and shortages in its supply. Nevertheless, large-scale phase II trials have been initiated as taxol has recently demonstrated impressive activity in advanced and cisplatin-refractory ovarian carcinoma. Furthermore, the incidence of HSRs has been reduced substantially with premedications and modifications in the administration schedule. However, various manifestations of potential cardiotoxicity have been observed in several patients who participated in four phase I and II studies of taxol. Asymptomatic bradycardia has occurred in a high proportion of patients, including 29% of ovarian cancer patients who were treated with maximally tolerated doses of taxol in a phase II study. More profound cardiac disturbances, including a range of atrioventricular conduction blocks, left bundle branch block, ventricular tachycardia (VT), and manifestations of cardiac ischemia, have been observed in seven of 140 patients (5%) who received taxol. Descriptions of these events are presented in this report to alert investigators to the potential for these adverse effects. Although these disturbances did not result in serious sequelae in most patients, investigators should continue to maintain a high degree of caution until precise risk factors, frequency, and clinical significance of these adverse cardiac effects are determined.
ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.
Authors: Speyer J L , Green M D , Zeleniuch-Jacquotte A , Wernz J C , Rey M , Sanger J , Kramer E , Ferrans V , Hochster H , Meyers M
Published: February 2017

PURPOSE

To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer.

PATIENTS AND METHODS

Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients).

RESULTS

We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity.

CONCLUSION

By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.
Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.
Authors: Gucalp R , Ritch P , Wiernik P H , Sarma P R , Keller A , Richman S P , Tauer K , Neidhart J , Mallette L E , Siegel R
Published: February 2017

PURPOSE

This multicenter, double-blind, randomized trial was performed to determine the efficacy and safety of pamidronate disodium (APD) in comparison to etidronate disodium (EHDP) in the treatment of cancer-related hypercalcemia.

PATIENTS AND METHODS

Sixty-five male and female adult patients with cancer and corrected calcium levels of greater than or equal to 12.0 mg/dL after 24 hours of hydration were randomized to receive either 60 mg APD given as a single 24-hour infusion or 7.5 mg/kg EHDP given as a 2-hour infusion daily for 3 days.

RESULTS

APD normalized corrected calcium levels in 70% (21 of 30) of patients, whereas EHDP did so in 41% (14 of 34) of patients (P = .026). The mean corrected serum calcium level decreased from 14.6 to 10.5 mg/dL in the APD-treated group and from 13.8 to 11.6 mg/dL in the EHDP-treated group within the first week of treatment. There was no difference in response to APD in patients without versus those with bone metastases (78% v 67%). Both drugs were well tolerated.

CONCLUSION

This study demonstrated that a single 60-mg infusion of APD is safe and more effective than EHDP given at the dose of 7.5 mg/kg for 3 days in the treatment of cancer-related hypercalcemia.
A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer.
Authors: Fukuoka M , Niitani H , Suzuki A , Motomiya M , Hasegawa K , Nishiwaki Y , Kuriyama T , Ariyoshi Y , Negoro S , Masuda N
Published: February 2017

PURPOSE

Camptothecin-11 (CPT-11) is a new semisynthetic derivative of CPT, and has been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity in murine tumors. To evaluate the effectiveness of CPT-11 in patients with non-small-cell lung cancer (NSCLC), a phase II study was conducted between April 1989 and February 1990.

PATIENTS AND METHODS

Seventy-three patients were entered onto the study. All patients had had no previous therapy and had measurable disease. Their median age was 67 years (range, 34 to 75 years). Fifty-four patients had a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, and 19 had a PS of 2. CPT-11 was given at a dose of 100 mg/m2 by intravenous 90-minute infusion once a week. The dose of CPT-11 was modified based on the WBC count obtained on the day of drug administration.

RESULTS

Of 72 assessable patients, 23 (31.9%) showed a partial response (95% confidence interval, 20.2% to 43.6%). Of 40 patients with a stage IV disease, 13 (32.5%) responded. Response rates for patients with PS 0 or 1 and those with PS 2 did not differ (34.0% and 26.3%, respectively). The median duration of response in patients showing a PR was 15 weeks. The median survival time for all patients was 42 weeks. The major toxicities were leukopenia and diarrhea. Grade 3 or 4 leukopenia and diarrhea occurred in 18 patients (25%) and 15 patients (21%), respectively. These toxicities were unpredictable. Other toxicities of greater than or equal to grade 3 included nausea/vomiting (22%), anemia (15%), alopecia (4%) and pneumonitis (3%). One patient died of pulmonary toxicity (interstitial pneumonitis).

CONCLUSIONS

CPT-11 is a very active agent for NSCLC with acceptable toxicities. Further trials in combination with other agents for this disease are warranted.
Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer.
Authors: Shepherd F A , Laskey J , Evans W K , Goss P E , Johansen E , Khamsi F
Published: February 2017

PURPOSE

This study was undertaken to review the clinical and laboratory features and response to treatment of patients with Cushing's syndrome associated with ectopic corticotropin (adrenocorticotropic hormone; ACTH) production and small-cell lung cancer (SCLC).

PATIENTS AND METHODS

We undertook a retrospective chart review of 545 patients with SCLC seen at Toronto General Hospital between 1980 and 1990 and identified 23 patients (4.5%) with Cushing's syndrome and ectopic ACTH production.

RESULTS

There were 17 male and six female patients, with a median age of 60 years. The syndrome was diagnosed at the time of initial presentation of SCLC in 13 patients and at relapse in 10 patients. Seven patients had limited disease and 16 had extensive disease at their initial diagnosis of SCLC, but 20 of 23 had extensive disease at the time of diagnosis of Cushing's syndrome. Ten patients had bone marrow involvement. The most frequent physical findings included edema (83%) and proximal myopathy (61%). All patients had elevated plasma and urinary free cortisol levels; 22 had a hypokalemic alkalosis, and 13 had hyperglycemia. Only one patient had a normal ACTH level. The response rate (complete plus partial) to chemotherapy for patients who had the syndrome diagnosed at initial presentation of SCLC was only 46%, and their median survival was only 3.57 months. Only two patients achieved complete normalization of all hormone parameters, and neither experienced hormone relapse at the time of SCLC relapse. Complications of therapy included gastrointestinal (GI) ulceration (six patients), GI bleeding (four), perforation of a duodenal ulcer (one), pneumonia (10), septic shock (three), and fungal infections (five).

CONCLUSION

Ectopic ACTH production is associated with a low response to chemotherapy, short survival, and a high rate of complication to therapy.
Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience.
Authors: Meyers P A , Heller G , Healey J , Huvos A , Lane J , Marcove R , Applewhite A , Vlamis V , Rosen G
Published: February 2017

PURPOSE

Adjuvant chemotherapy improves disease-free survival (DFS) for patients with osteogenic sarcoma (OS). We reviewed our experience with OS to determine prognostic factors, the role of preoperative chemotherapy and subsequent histologic response, and the role of salvage chemotherapy after poor initial response.

METHODS

From 1975 to 1984, we saw 279 patients with previously untreated OS without metastasis. All patients received intensive chemotherapy and underwent surgical resection of primary tumor. Chemotherapy included high-dose methotrexate; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); and bleomycin, cyclophosphamide, and dactinomycin (BCD). Selected patients also received cisplatin.

RESULTS

DFS was not affected by use of preoperative chemotherapy versus immediate surgery, by use of limb-sparing surgery versus amputation, age, sex, or dose intensity of chemotherapy. DFS did correlate with serum lactate dehydrogenase (LDH), alkaline phosphatase, primary tumor site, race, and histologic response to preoperative chemotherapy. There was no difference in DFS for patients with a poor histologic response who did or did not receive cisplatin, although patients who did receive cisplatin had a longer time to relapse. The 5-year DFS was 76% for patients aged less than or equal to 21 years who had extremity primary tumor and were treated with the T10 protocol.

CONCLUSIONS

Intensive chemotherapy can achieve DFS for a high proportion of patients with OS. Although it is a powerful predictor of DFS, histologic response to preoperative chemotherapy cannot be assessed at diagnosis. We have not shown an ability to salvage patients with an unfavorable response. We need to increase the proportion of patients with a favorable response, identify the patients who will have an unfavorable response, and develop novel treatments to salvage poor responders.
Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years.
Authors: Jones A L , Powles T J , Law M , Tidy A , Easton D , Coombes R C , Smith I E , McKinna J A , Nash A , Ford H T
Published: February 2017

PURPOSE

The study purpose was to evaluate aminoglutethimide (AG) as adjuvant therapy in patients with primary node-positive breast cancer in a randomized double-blind placebo-controlled trial.

PATIENTS AND METHODS

In a multicenter trial, 354 postmenopausal women with early breast cancer and histologically confirmed positive axillary lymph nodes were randomized after surgery to received aminoplac. Patients were prescribed either AG 250 mg four times per day and hydrocortisone 20 mg twice per day or placebos of identical appearance for 2 years.

RESULTS

After a median follow-up of 8.1 years, there has been no overall benefit for AG in terms of either event-free survival or overall survival (OS). However, the results are consistent with interim analyses with a significantly improved event-free survival for patients who received AG for up to 4 years, although this benefit subsequently disappears. Similarly, there is an improved OS for patients who received AG for up to 4 years, but this also subsequently disappears. There was a marginal advantage for estrogen receptor (ER)-positive patients who received AG (n = 74; P = .054). There was no difference in the sites of relapse. There was a significant increase in toxicity for patients who received AG.

CONCLUSION

The lack of survival benefit with long-term follow-up for AG may indicate that aromatase inhibitors have less of an impact on early breast cancer than tamoxifen and may imply different biologic mechanisms of action.
A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.
Authors: Bramwell V H , Burgers M , Sneath R , Souhami R , van Oosterom A T , Voûte P A , Rouesse J , Spooner D , Craft A W , Somers R
Published: February 2017

PURPOSE

A randomized pilot study was undertaken to assess the acute and chronic toxicities of two short intensive chemotherapy regimens, and to evaluate the feasibility of conservative surgery in this setting. Additional aims were to determine the clinical and radiologic response and the degree of histologic necrosis after chemotherapy. With extension of the study, eventual accrual was sufficient to compare disease-free survival (DFS) and overall survival (OS).

PATIENTS AND METHODS

Between July 1983 and December 1986, the European Osteosarcoma Intergroup (EOI) entered 198 eligible patients with classic high-grade extremity osteosarcoma onto a randomized trial that compared doxorubicin (DOX) 25 mg/m2/d times three, intravenous (IV) bolus plus cisplatin (CDDP) 100 mg/m2, 24 hour infusion, every 3 weeks times six; the same combination was preceded 10 days earlier by high-dose methotrexate (HDMTX) 8 g/m2, 6-hour infusion, every 4.5 weeks times four. In the majority of patients (179), chemotherapy was commenced after biopsy; definitive surgery was scheduled at 9 weeks in both groups.

RESULTS

Toxicities for both regimens did not differ substantially from those that occurred in other trials of adjuvant chemotherapy in osteosarcoma. Local recurrence (9%) and surgical complications (18%) after conservative surgery were acceptable. With a median follow-up of 53 months, DFS at 5 years is superior (P = .02) for DOX/CDDP, 57% versus 41%, although OS, 64% versus 50%, is not different significantly (P = .10). In a subset of 66 patients for whom pathologic data on the resected specimen were available, DFS (P = .003) and OS (P = .008) were better for those who demonstrated > or = 90% necrosis.

CONCLUSION

A brief intensive chemotherapy regimen of DOX/CDDP has produced excellent long-term results, which are similar to those that have been achieved in cooperative group studies of longer, more complex multiagent chemotherapy, and provide the basis for a direct comparison in the next EOI study.
Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance.
Authors: Yahanda A M , Alder K M , Fisher G A , Brophy N A , Halsey J , Hardy R I , Gosland M P , Lum B L , Sikic B I
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer.

PATIENTS AND METHODS

Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI.

RESULTS

Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression.

CONCLUSIONS

Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).
Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.
Authors: Lum B L , Kaubisch S , Yahanda A M , Adler K M , Jew L , Ehsan M N , Brophy N A , Halsey J , Gosland M P , Sikic B I
Published: February 2017

PURPOSE

To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer.

PATIENTS AND METHODS

Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss).

RESULTS

CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles.

CONCLUSIONS

High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.
Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.
Authors: Smith M A , Adamson P C , Balis F M , Feusner J , Aronson L , Murphy R F , Horowitz M E , Reaman G , Hammond G D , Fenton R M
Published: February 2017

PURPOSE

Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy.

PATIENTS AND METHODS

A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed.

RESULTS

The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing.

CONCLUSIONS

The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.
Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.
Authors: Clift R A , Buckner C D , Appelbaum F R , Schoch G , Petersen F B , Bensinger W I , Sanders J , Sullivan K M , Storb R , Singer J
Published: February 2017

PURPOSE

The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse.

PATIENTS AND METHODS

Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen.

RESULTS

The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05).

CONCLUSIONS

For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.
Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma.
Authors: Einzig A I , Wiernik P H , Sasloff J , Runowicz C D , Goldberg G L
Published: February 2017

PURPOSE

Based on the results of our phase I study that demonstrated the antitumor activity of taxol in a previously treated patient with ovarian cancer, a phase II study was conducted to evaluate the efficacy of taxol in patients with metastatic ovarian cancer and to evaluate further the toxicity of taxol in this group of patients.

PATIENTS AND METHODS

Thirty-four patients with metastatic ovarian cancer received taxol (180 to 250 mg/m2) as a 24-hour continuous infusion. A premedication regimen was used to reduce the likelihood of an acute hypersensitivity reaction.

RESULTS

Six of 30 assessable patients demonstrated complete responses (one patient) or partial responses (five patients; 20%; 95% confidence interval [CI], 6% to 34%; range, 2 to 30 months). Additionally, one patient had a less than partial objective response (2 months), and two patients had stable disease for 6 and 15 months. Those responders had a median survival of 27 months, and the nonresponders had a median survival of 6 months (P = .0001). Myelosuppression was the most significant toxicity. Other adverse effects included alopecia and peripheral neuropathy.

CONCLUSION

Taxol has significant activity in ovarian cancer and should be studied in combination with other active agents earlier in this disease.
CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer.
Authors: Masuda N , Fukuoka M , Takada M , Kusunoki Y , Negoro S , Matsui K , Kudoh S , Takifuji N , Nakagawa K , Kishimoto S
Published: February 2017

PURPOSE

The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed.

RESULTS

Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients.

CONCLUSIONS

A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.
Phase I evaluation of thrice-daily intravenous bolus interleukin-4 in patients with refractory malignancy.
Authors: Atkins M B , Vachino G , Tilg H J , Karp D D , Robert N J , Kappler K , Mier J W
Published: February 2017

PURPOSE

A phase I dose-escalation trial of recombinant human interleukin-4 (IL-4) was performed to determine its toxicity, biologic activity, and potential antineoplastic effects.

PATIENTS AND METHODS

Ten patients with refractory malignancies received IL-4 by bolus intravenous injection every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) of a 31-day study period. Three patients received 10 micrograms/kg per dose and seven received 15 micrograms/kg per dose of IL-4.

RESULTS

Toxic symptoms noted at the second dose level included nasal congestion, diarrhea, nausea and vomiting, fatigue, anorexia, headache, dyspnea, and capillary leak syndrome (median weight gain, 6.1%; range, 3.4% to 11.7%). Fever or sustained hypotension sufficient to require pressors did not occur. Decreases in lymphocyte count and serum bicarbonate, sodium, albumin, fibrinogen and immunoglobulin (Ig) levels, and increases in hematocrit, prothrombin time/partial thromboplastin time (PT/PTT), soluble CD23, and, occasionally, serum creatinine and transaminases occurred. All side effects resolved by day 31. Phenotypic analysis of peripheral-blood mononuclear cells (PBMC) showed a decrease in the percentage of circulating CD16 and CD14(+) cells. Plasma tumor necrosis factor (TNF) and IL-1 beta levels were unaffected, whereas serum C-reactive protein (CRP) concentrations increased slightly and plasma IL-1 receptor antagonist (IL-1RA) levels increased markedly. No tumor responses were observed.

CONCLUSIONS

We conclude that 10 micrograms/kg per dose of IL-4 is the maximum-tolerated dose for this schedule, although 15 micrograms/kg per dose can be tolerated if more intensive, but still non-intensive care unit level care is provided. The results of this study should aid in the design of future phase II trials that involve IL-4 alone or phase I studies that combine IL-4 with other cytokines such as IL-2.
Improvement in outcome for children receiving allogeneic bone marrow transplantation in first remission of acute myeloid leukemia: a report from the Groupe d'Etude des Greffes de Moelle Osseuse.
Authors: Michel G , Gluckman E , Blaise D , Esperou-Bourdeau H , Vernant J P , Kuentz M , Bordigoni P , Milpied N , Rubie H , Thuret I
Published: February 2017

PURPOSE

We retrospectively analyzed the outcome of children with acute myeloid leukemia (AML) in first complete remission (CR) who received HLA-identical bone marrow transplantation (BMT) in 13 French transplant centers.

PATIENTS AND METHODS

Seventy-four children were treated from June 1979 through December 1990. The conditioning regimen included total-body irradiation (TBI) in 54 cases and busulfan in 20. Prophylaxis of graft-versus-host disease (GVHD) consisted of cyclosporine (CycloA) plus methotrexate (MTX) for 38 patients, MTX for 17, CycloA for 18, and T depletion without other prophylaxis for one. The mean value of the interval from diagnosis to transplantation was 167 days.

RESULTS

Sixteen patients died of transplant-related complications, 12 relapsed, and 46 are alive in continuous remission with a median follow-up of 46 months. We examined results obtained over three successive periods: 1979 to 1982 (n = 14 children), 1983 to 1986 (n = 29), and 1987 to 1990 (n = 31). Probabilities of event-free survival (EFS) were 43%, 48%, and 82% for the three successive periods, respectively (P < .02). This improvement in EFS was linked to a decreased risk of transplant-related mortality: 36%, 36%, and 3%, respectively (P < .01). Other factors associated with a better EFS in the univariate analysis were a short time interval from diagnosis to transplant (< 120 days), the absence of significant (grade > or = 2) acute GVHD, and the absence of chronic GVHD. In the multivariate analysis, two factors had a favorable impact on long-term survival: the year of transplantation (years 1987 to 1990 v others) and the absence of acute GVHD.

CONCLUSION

The outcome for children receiving allogeneic BMT in first CR of AML has improved in France during recent years.
Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy.
Authors: LeVeque F G , Parzuchowski J B , Farinacci G C , Redding S W , Rodu B , Johnson J T , Ferretti G A , Eisenberg P D , Zimmer M B
Published: February 2017

PURPOSE

This open-label, multicenter trial evaluated the efficacy of a mucoadherent, anesthetic medication (MGI 209) for relief from painful oral ulcers associated with cytotoxic chemotherapy.

PATIENTS AND METHODS

Twenty-eight eligible cancer patients who had up to five discrete oral ulcers (total area < or = 5 cm2) completed this study. Mean age was 53.5 years (range, 21 to 81). Subjective assessments of oral discomfort before and after an orange juice pain challenge (OJPC), which was measured using a visual analog scale (VAS), and visual estimates of the amount of MGI 209 that remained on treated ulcers were collected at (1) baseline (before MGI 209 treatment); and (2) 30, 60, 120, and 180 minutes posttreatment.

RESULTS

Most subjects had low VAS scores (4 or less), which was indicative of oral discomfort, at baseline before and after the OJPC. At 30, 60, 120, and 180 minutes after MGI 209 treatment, most subjects had high VAS scores before and after an OJPC compared with baseline scores, which was indicative of a substantial increase in oral comfort; these differences were statistically significant (P < .0001). Mean percent of MGI 209 estimated to remain on ulcers at the previously mentioned times was 93.7%, 90.3%, 79.6%, and 71.3% of the total amount applied, respectively.

CONCLUSION

Benzocaine hydrochloride in combination with the protective, mucoadherent film-coating relieved discomfort for at least 3 hours even with exposure to an irritating beverage. MGI 209 treatment should allow patients with chemotherapy-induced oral ulcers to drink and eat with significantly diminished pain or no pain.
A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck.
Authors: Jacobs C , Lyman G , Velez-García E , Sridhar K S , Knight W , Hochster H , Goodnough L T , Mortimer J E , Einhorn L H , Schacter L
Published: February 2017

PURPOSE

To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial.

PATIENTS AND METHODS

Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks.

RESULTS

The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm.

CONCLUSION

Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.
Prolonged administration of oral etoposide in non-small-cell lung cancer: a phase II trial.
Authors: Waits T M , Johnson D H , Hainsworth J D , Hande K R , Thomas M , Greco F A
Published: February 2017

PURPOSE

The trial was undertaken to investigate the activity and toxicity of a prolonged schedule of oral etoposide in the treatment of advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Between March 1989 and August 1990, 25 patients with advanced NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days, repeated every 28 to 35 days. The median patient age was 60 years (range, 38 to 84 years); male:female ratio was 12:13. Eight patients had stage IIIB disease; 17 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy with standard agents; nine patients had received previous or concurrent radiation therapy. Plasma etoposide concentrations were measured to estimate etoposide bioavailability and kinetics.

RESULTS

Five of 22 patients (23%; 95% confidence interval [CI], 10% to 43%) had partial responses. Median response duration was 5 months (range, 2 to 6 months). Four of five responders were female. Besides alopecia, which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/microL; only four of 69 courses produced a leukocyte nadir less than 1,000/microL. Severe thrombocythemia (less than 75,000/microL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 micrograms/mL. A mean serum etoposide concentration greater than 1 microgram/L was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously.

CONCLUSIONS

Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses.
Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials.
Authors: Gregory W M , Richards M A , Malpas J S
Published: February 2017

PURPOSE

A meta-analysis was performed to compare survival after treatment with melphalan and prednisolone (M + P) with that after combination chemotherapy (CCT) in patients with multiple myeloma.

METHODS

Meta-analysis was performed on 18 published trials comprising 3,814 patients comparing M + P with CCT. Two-year survival percentages with observed and expected deaths at 2 years were calculated for each trial, and the overview methodology was applied to these figures.

RESULTS

Overall results from the 18 trials suggest that there is no difference in efficacy between the two treatments. This finding, however, masks a highly significant correlation between 2-year survival rates for M + P-treated patients in individual studies and the difference between the M + P and CCT 2-year survival rates for that study (r = .69; P = .0008). In separate overviews, those studies with a high M + P 2-year survival rate showed a survival difference in favor of M + P (P = .02), whereas those with a low rate suggested a difference in favor of CCT (P V .07). Comparison of the 2-year survival rates in the M + P treatment arms of each of the studies with available data showed an inverse correlation between survival and the proportion of patients with either poor performance status (P less than .001) or immunoglobulin A (IgA) M band (P = .02).

CONCLUSIONS

These results imply that M + P is superior for patients with an intrinsically good prognosis and inferior for those patients with a poor prognosis. If reliable prognostic factors can be established for this disease, they could be used to select therapy for individual patients.
Molecular and immunophenotypic characterization of AIDS-associated, Epstein-Barr virus-negative, polyclonal lymphoma.
Authors: Shiramizu B , Herndier B , Meeker T , Kaplan L , McGrath M
Published: February 2017

PURPOSE

A molecular analysis of non-Hodgkin's lymphomas (NHLs) from patients with AIDS was undertaken to determine the prevalence and immunophenotype of polyclonal B-cell lymphoma.

MATERIALS AND METHODS

DNA was extracted from 40 diagnostic biopsy specimens obtained from patients seen at University of California, San Francisco (UCSF) between 1986 and 1990. Clonality, infection with Epstein-Barr virus (EBV), and presence of a rearranged c-myc gene were determined by Southern blot analysis. Lymphoma immunophenotypes were determined by frozen-section immunohistochemical analysis.

RESULTS

The most prevalent genotype of lymphoma in this study was that of polyclonal, EBV-negative tumors with no evidence of c-myc rearrangement (14 of 40; 35%). Monoclonal, EBV-positive tumors with no evidence of c-myc rearrangement comprised the second most prevalent class (10 of 40; 25%), and polyclonal, EBV-positive tumors similar to those seen in transplant patients were observed in only a small subset (three of 40; 8%) of specimens analyzed. The immunophenotype of B cells in the polyclonal EBV-negative subset was equally divided into B-cell-predominant and mixed-phenotype lymphomas, with the latter category containing numerous infiltrating T cells. The B cells in each category were immunoglobulin M-positive (IgM+), CD20+, CD21-. All but one of the polyclonal NHLs had large-cell histology.

CONCLUSIONS

EBV-negative, AIDS-associated, polyclonal B-cell lymphoma appears to be a new class of human immunodeficiency virus (HIV)-associated disease more prevalent in the current study than any other molecular subclass. The absence of CD21, the EBV receptor, may explain in part the absence of EBV within this polyclonal B-cell population.