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Background: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma., Methods: A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate., Results: Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%)., Conclusions: Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity., (Copyright © 2012 American Cancer Society.)

Background: It has been shown that concomitant chemotherapy (C) with reirradiation (ReRT) is feasible and effective for select patients with recurrent or second primary head and neck cancer (HNC). To examine potential prognostic factors associated with survival, the authors of this report retrospectively reviewed the outcomes of patients who received CReRT., Methods: The study cohort comprised previously irradiated patients with nonmetastatic disease from 9 consecutive phase 1 and 2 protocols for poor-prognosis HNC. For all patients, reirradiation (ReRT) was delivered with concurrent chemotherapy. Chemotherapy generally was 5-fluorouracil, hydroxyurea, and a third agent., Results: One hundred sixty-six patients were identified, including 81 patients who underwent surgical resection or debulking before enrollment. The median ReRT dose was 66 gray. After a median follow-up of 53 months among surviving patients, the median overall survival (OS) was 10.3 months. The 2-year rates for OS, disease-free survival, locoregional control, and freedom from distant metastasis were 24.8%, 19.9%, 50.7%, and 61.4%, respectively. Thirty-three patients (19.9%) died of treatment-related toxicity. In subgroup analysis, survival was significantly reduced in patients who received previous concurrent chemoradiotherapy (CRT) compared with patients who were naive to CRT (2-year OS rate, 10.8% vs 28.4%; P = .0043). In multivariable analysis, prior CRT was associated independently with OS along with surgery before protocol treatment, full-dose ReRT, and radiotherapy interval., Conclusions: CReRT achieved a long-term cure for a small group of patients with recurrent or second primary HNC. Previous treatment with CRT was among the important prognostic factors for survival. Because of the associated risk of severe toxicity, CReRT should be limited only to carefully selected patients., (Copyright © 2011 American Cancer Society.)

Background: The objective of this phase 2 study was to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated-boost (SIB), intensity-modulated radiation therapy (IMRT) into a well described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen., Method: Patients with stage IVA and IVB or high-risk stage III squamous cell carcinomas of the head and neck were enrolled on a phase 2 trial. Prior organ-conserving surgery or induction chemotherapy was allowed off protocol. SIB-IMRT was prescribed to low-risk volumes (43.2 gray [Gy] to 48 Gy) and intermediate-risk volumes (54-63 Gy). A separate IMRT cone-down plan was targeted to macroscopic disease (72 Gy). The median radiation dose was 72 Gy (range, 60-72 Gy) administered in 1.5 Gy fractions twice daily during Weeks 1, 3, 5, 7 and 9. Concurrent systemic therapy consisted of 5-FU (600 mg/m²), HU (500 mg twice daily), and cetuximab (250 mg/m²)., Results: From January 2007 through April 2008, 33 patients were enrolled. At a median follow-up of 24 months, the 2-year rates of locoregional control, distant control, disease-free survival, and overall survival were 83%, 79%, 69%, and 86%, respectively. Grade 3 toxicity consisted of mucositis in 33% of patients, radiation dermatitis in 15%of patients, anemia in 18% of patients, leukopenia in 18% of patients, neutropenia in 12% of patients, and thrombocytopenia in 3% of patients. Most patients (64%) were able to tolerate treatment without a feeding tube, and there were no acute or late grade ≥4 adverse events., Conclusions: The current results indicated that concurrent 5-FU, HU, and cetuximab plus SIB-IMRT is a promising and reasonably well tolerated approach to incorporating molecularly targeted therapy into curative therapy for patients with locally advanced head and neck cancer., (Copyright © 2010 American Cancer Society.)

Background: This study determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients., Methods: All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed., Results: A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures., Conclusions: Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet-derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity.

Background: The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach., Methods: Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA)., Results: Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms., Conclusions: Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.

Background: The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma (HNC) with a high risk of recurrence after salvage surgery., Methods: Between 1991 and 1996, 25 patients having a recurrence or a second primary tumor in a previously irradiated area (> 45 grays [Gy]) were entered in this prospective study. All of them received salvage surgery and had a positive surgical margin and/or lymph node involvement with capsular rupture (N+R+). Adjuvant radiochemotherapy was given, delivering 60 Gy per 30 fractions with concomitant hydroxyurea and 5-fluorouracil. The median total cumulative dose of the 2 irradiations was 118 Gy. The median follow-up after the second irradiation was 66 months., Results: During the reirradiation course, Grade 3 and 4 mucositis were observed in 40% and 12%, respectively. Analysis of late effects (> 6 months after reirradiation) showed that 16% of the patients had osteoradionecrosis and 40% had Grade 2-3 cervical fibrosis (Radiation Therapy Oncology Group scoring system). The patterns of failure were as follows: local only (n = 9), lymph node only (n = 2), local and lymph node only (n = 1), and metastatic (n = 4). The 4-year survival rate after reirradiation was 43% (95% confidence interval, 25-62)., Conclusions: Full dose reirradiation combined with chemotherapy after salvage surgery in high risk patients with HNC was feasible with an "acceptable" toxicity and led to a relatively good 5-year survival rate. These results prompted the authors to initiate a multicentric randomized trial that is ongoing (GETTEC-GORTEC 99-01) to evaluate the benefit of adjuvant radiochemotherapy in these types of patients., (Copyright 2001 American Cancer Society.)

Background: To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea., Methods: A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest., Results: Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed., Conclusions: 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.

Background: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses., Methods: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV., Results: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively., Conclusions: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.

The treatment of advanced colorectal cancer has improved in recent years. Prospective randomized trials comparing innovative therapies with the "standard" bolus dose of 5-fluorouracil (5-FU) found increased response rates after biochemical modification of the drug, infusion administration of 5-FU, and direct intrahepatic arterial infusion. Although the impact on survival of these techniques has been minimal, it is possible that these innovative approaches provide an incremental survival advantage for certain subgroups of patients that may be the foundation for additional therapeutic improvements in the future.

Oral hydroxyurea (HU) was added to a regimen of 5-fluorouracil (5-FU) plus leucovorin (LCV) administered as a continuous 24-hour infusion for 14 days. A previous report of the 5-FU plus LCV infusion established optimal dosages of 200 mg/m2/d and 5 mg/m2/d, respectively, for each agent. Oral HU was added to the regimen in total dosages of 0.5 g/d, 1.0 g/d, 1.5 g/d, or 2.0 g/d. Twenty-two patients received a total of 45 courses of treatment. Stomatitis was the dose-limiting side effect; it occurred in 3 of 14 courses with HU at 0.5 g/d (21%) and 9 of 17 courses with HU at 1.0 g/d (53%). Dosage escalation to 1.5 g/d or 2.0 g/d was possible in only 3 of 22 patients (17%). The median time to stomatitis was 10 days (range, 7 to 12 days). One response was observed in this heavily pretreated population. Phase II trials of HU plus LCV dual modulation of infusional 5-FU should use initial HU dosages of 0.5 g/d for the 14-day regimen described, with dose escalation as tolerated. Variable oral absorption presumably accounts for the small group of patients who can tolerate the higher doses of HU.

Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.

Sixty-six patients with locally advanced (Stages III and IV) carcinoma of the head and neck were treated with three cycles of induction chemotherapy, consisting of cisplatin, fluorouracil (FU) infusion, bleomycin, mitomycin, and hydroxyurea, followed by radiotherapy and/or surgery. There were 48 men and 18 women with a median age of 55 years (range, 18 to 75 years) and Karnofsky performance status of 80 (range, 40 to 90). Primary site was nasopharynx (28 patients), followed by larynx (12) and others (26). Forty-one (62%) patients were presented with Stage IV disease. The response rate to induction chemotherapy was 27% complete response, 50% partial response, 20% stable disease, and 3% progressive disease. There was no significant difference in response rate between patients with cancer of nasopharynx or other sites (P greater than 0.1). Survival was 61% at 24 months. Patients with cancer of nasopharynx had a better survival than those with other primaries (P = 0.033). Toxicities from chemotherapy included alopecia (73%), nausea/vomiting (66%), leukopenia (54%), stomatitis (36%), anemia (32%), thrombocytopenia (16%), and diarrhea (9%). Grade IV toxicity was not observed. Induction chemotherapy with this new regimen resulted in a high response rate but may not be superior to cisplatin and FU alone. It can be safely combined with radiotherapy as a potentially curative therapy in squamous cell carcinoma of the head and neck. Chemotherapy followed by radiation therapy may yield survival similar to radical surgery in laryngeal and other head and neck cancers.

Twenty-three patients with regionally advanced non-small cell lung cancer (NSCLC) (Stage III) were treated with continuous infusion 5-fluorouracil (5-FU) augmented by high-dose oral leucovorin and hydroxyurea and concomitant radiotherapy. This chemoradiotherapy regimen was administered during 5 days of every other week for six cycles (total radiation dose, 6000 cGy). Three patients (13%) had stable disease, 13 patients (57%) had a partial response (PR), and 1 patient (4%) had a complete response (CR). The overall response rate was 61% (95% confidence interval, 41% to 81%). At a median follow-up time of 19 months, the median survival time for all 23 patients was 12 months. The median time to disease progression was 6 months. Twelve patients have had disease progression outside of the chest, and only 3 patients have had intrathoracic disease progression as the site of first failure. The toxicities of this regimen consisted of mild to moderate myelosuppression and moderate degree dermatitis and mucositis. It was concluded that concomitant chemoradiotherapy with this regimen results in high local activity at acceptable toxicity. However, the systemic activity of this regimen was low, resulting in a high distant recurrence rate and a median survival time that was not different from that achieved with standard therapy. Therefore, its use, as defined in this study, cannot be recommended.

Hydroxyurea was administered by means of two schedules designed to provide continuous 72-hour exposure of tumor cells to therapeutic drug levels. Toxicity and pharmacokinetics were determined for both an oral pulse dose schedule (every 4 hours x 18 doses) and continuous intravenous (IV) infusion for 72 hours. The maximal tolerated dose (MTD) was 800 mg/m2 every 4 hours for the oral route and 3.0 mg/m2/min x 72 hours for IV infusion. Granulocytopenia was dose-limiting for both schedules and correlated well with plasma-HU levels. Serial sampling of normal bone marrow (10 patients) and tumor tissue (3 patients) showed a modest degree of synchronization induced by continuous IV infusion of hydroxyurea. Interindividual pharmacokinetic variations severely limit the usefulness of the oral pulse schedule as a potential means of synchronizing cells. Hydroxyurea administered by continuous IV infusion may be useful as a synchronizing agent in humans.

The results of three Phase III studies of DTIC in 580 patients with metastatic melanoma were reviewed to evaluate the subsequent course of 26 patients who achieved a complete response (CR) to chemotherapy. The majority (17 of 26) of these patients had soft tissue metastases. Six of the 26 patients remained in CR at last report (30-259 weeks), two died of other causes while remaining free of melanoma, and 18 relapsed and died. Ninety-five percent of the 26 patients were alive at 1 year, and survival was 31.1% at 72 months. Seven of the eight patients with sustained remission received chemotherapy for at least 6 months after CR developed, whereas 10 of 18 relapsing patients were treated for less than 6 months after CR was achieved. Long-term sustained CR to chemotherapy occurs in 1% to 2% of patients treated with DTIC, and late relapse is rare in patients who remain in CR for 2 years.

Seven new organoplatinum (Pt) compounds, cyclophosphamide (CY), and hydroxyurea (HU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 X DBA/2 mice. In each experiment the Pt + CY combination was supra-additive, as has been shown with other Pt compounds when used with CY. HU at the dose used (1000 mg/kg) was only minimally effective when used alone. However, six of the seven Pt + CY + HU combination regiments enhanced markedly the increased life span of treated mice when compared with the corresponding dual Pt + CY combination. The triple drug regimen yielded cure rates (760-day survival) up to 70% in individual experiments. Collectively, the cure rate was 11% with the various Pt + CY combinations, and was increased to 53% upon inclusion of HU in the regimen. It is suggested that HU may inhibit a process whereby potentially lethal DNA damage produced by Pt + CY would otherwise be repaired. A reduced efficacy of HU when used at a single, high-dose level was also noted, and a possible mechanism and potential significance of this observation are discussed.

Two hundred-eighty patients were randomized to receive either BCNU, hydroxyurea and imidazole carboxamide (BHD), BHD plus levamisole, or high-dose DTIC plus actinomycin D. There was no difference in response rate in the three groups (24%, 25% and 22%). Females responded better than males and, as expected, those with a better performance status responded more favorably than those with poor performance status. Patients whose primary site of melanoma was on the extremities did significantly better than those melanomas originating on the trunk or head and neck. Patients with lymphocyte counts greater than 2000/mm3 fared better than those with lymphopenia. Those responders who received high-dose DTIC plus actinomycin D had a significantly longer length of response than those receiving the immunotherapy limb. This was also true in those patients who had a prior disease-free interval of greater than 6 months before being placed in this study. Although there was no difference in survival from the start of treatment in all patients, those patients receiving high-dose DTIC plus actinomycin D and who had a prior disease-free interval of greater than 6 months, had significantly superior survival when compared to the immunotherapy limb. It is concluded that the addition of Levamisole to BHD does not improve response rate and may in certain subsets be detrimental to disease-free response and survival. High-dose DTIC plus actinomycin D is equally effective to BHD.

Patients who had measurable evidence of recurrent or metastatic colorectal carcinoma following surgery and radiotherapy but no prior chemotherapy were randomized to one of five combination chemotherapy programs. Four of the treatments utilized five consecutive days of fluorouracil (FU) (days 1--5 and days 36--40) plus one oral dose of semustine (ME) (day 1) every ten weeks: (A) FU + ME; (B) FU + ME + vincristine (VC) (day 1 and day 36); (C) FU + ME + dacarbazine (DC) (days 1, 2, 36, 37); (D) FU + ME + VC + DC. The fifth treatment option(E) used a weekly treatment program of FU I.V. on day 1 plus hydroxyurea (HU) P.O. on day 4. The overall response rate was 13% (60/472) and the median survival time from start of therapy for all patients was 31 weeks. The response rate and the median survival time for each combination was (A) 9/103 = 9%, 26 weeks; (B) 10/92 = 11%, 28 weeks; (C) 15/101 = 15%, 37 weeks; (D) 11/91 = 12%, 27 weeks; (E) 15/85 = 18%, 38 weeks. There is no statistical difference in response rate or survival duration among any of the treatment options. The therapies containing DC produced the only complete responses (3 patients on treatment C and 2 on D). Treatment D was also associated with the longest median response duration (Treatment D = 55 weeks). Treatment A (FU + ME) was associated with the highest incidence of life-threatening toxicity.

One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.

Seventy-nine adult patients with acute nonlymphoblastic leukemia (ANLL) were treated on the L-6 protocol at Memorial Sloan-Kettering Cancer Center between May 1970 and January 1974. Forty-two patients achieved a complete remission (CR) and nine of these are still disease free, with a minimum of seven years of follow-up. An extensive statistical analysis has been carried out on a large number of pretreatment and treatment characteristics to identify factors related to CR and remission duration. Multivariate regression techniques yielded as favorable characteristics associated with CR, in order of importance: young age at diagnosis, the presence of Auer rods at diagnosis, and treatment with Pseudomonas vaccine. A regression model for remission duration identified as favorable prognostic factors for long-term remission: at most two courses of induction therapy, an intermediate age range, and a low platelet count at diagnosis.

An unexpectedly high rate of long-term survivors in acute myeloid leukemia (AML) has been observed in a group of patients who achieved a first complete remission (CR) after induction of a therapeutic regimen including daunorubidomycine, vincristine, prednisone and stanozolol, and anabolizing steroid. The rate of CR was 52%. Maintenance therapy was very simple and the only association with stanozolol during this period suggested to us that an androgen, at low dosages, might be responsible for the unusual long-term survival time (45 months with a 95% confidence limit from 30 to 86 months). On the basis of our first observation, high dosages of the androgen were used during the induction phase of treatment but failed to demonstrate any advantage when associated with a drug regimen, including cytosine arabinoside (ARA-C). The reevaluation of each parameter for our group of patients did not allow selection of patients in terms of their age or the hematologic data obtained at presentation. Effects of androgen on the socalled normal hemopoietic cells and on the leukemic cells are discussed, particularly the possible antagonistic effect with ARA-C. A prospective statement is made concerning the possible condition of the prolongation of the complete remission in AML according to some experimental data which enforce the stimulative activity of androgen on the myeloid proliferation.

Thirty-six patients with advanced squamous cancer of the head and neck received chemotherapy with hydroxyurea, 2 g/m2 orally two of three weeks, plus methotrexate, bleomycin, and cisplatin (MBD) on a previously established schedule. Nineteen patients had objective responses, including six complete remissions. Eight of 13 patients with regional disease without prior radiation responded, as did 1 of 3 with distant metastases without prior radiation, and 10 of 20 with recurrent disease after radiotherapy. The median duration of response in those with recurrent or metastatic tumor was 6 months, and median survival was 6.5 months. These results are no better than those previously achieved without the addition of hydroxyurea. Toxicity, however, was milder than had previously been observed with MBD, suggesting that higher doses or more intensive schedules of hydroxyurea could be safely administered together with the other three drugs.