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Since 1970, the Gynecologic Oncology Group (GOG) has been a leader in clinical research in female pelvic cancers. Currently comprising 59 institutions and their affiliates in the United States, Canada, and elsewhere, the GOG has defined, principally through phase III randomized clinical trials, the standard of care for several stages and types of gynecologic cancer. This review will briefly summarize, in the context of research done concurrently by other groups and institutions, important GOG trials that have moved the field forward, especially in ovarian, endometrial, and cervical cancers. The role of cisplatin, carboplatin, and paclitaxel, as well as other drugs and combinations, in gynecologic cancer has been extensively studied by the GOG, as has chemoradiation in cervical cancer. Surgical staging of cervical and endometrial cancers has provided new insights and guidance for management. The benefits and limitations of radiation therapy in these diseases have been examined carefully. Thus, the stage has been set for further progress in this field.

To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III–IV or bulky Stage II disease, and an ECOG performance status of 0–1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3–4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m² on Day 1 and etoposide 100 mg/m² on Days 1–3 with doxorubicin 50 mg/m² on Day 1, vincristine 1.4 mg/m² (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1–5. With the addition of G-CSF at 200 μg/m² on Days 5–19, the MTD was cyclophosphamide 1500 mg/m² and etoposide 160 mg/m² on Days 1–3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 μg/m² to 400 μg/m² did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23–39) and 48% (95%CI, 40–57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17–52) and 51% (95%CI, 33–70), respectively. Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP. Cancer 2001;92:207–17. © 2001 American Cancer Society.

Background:The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor. Objective:We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL). Methods:Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (≥50%) clearing of patches and plaques. Results:Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P= .677). Conclusion:Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL. (J Am Acad Dermatol 2001;44:940-7.)

The pharmacokinetic parameters of peldesine (BCX‐34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2′‐deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2in four and in six divided doses orally Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high‐pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2′‐deoxyguanosine, using high‐pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2′‐deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX‐34. For the single‐dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half‐life was 3.5 ± 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple‐dose pharmacokinetics indicated that steady‐state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose‐related elevation of plasma 2′‐deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half‐life of inosine and 2′‐deoxyguanosine was 15.3 ± 1.8 h and 1.3 ± 0.1 h, respectively.

Objective.Although doxorubicin is not currently popular as a primary agent in ovarian cancer, overviews of previous studies suggest that the inclusion of doxorubicin may have improved outcome. The purpose of this phase I study was to determine the maximal dose of doxorubicin that could be added to standard doses of paclitaxel and cisplatin with G-CSF support.

From November 1973 through July 1982, 225 women with Stage I or II uterine srcoma were entered on a protocol which evaluated the use of doxorubicin in the adjuvant setting. Of these, 157 patients had a minimum follow-up of 2 years. Following complete surgical removal of all known clinical disease, consenting patients were randomized to reciece either 30 mg/m 2of doxorubicin every 3 weeks for eight courses or no further theraphy. The use of radiation therapy in this protocol was optional, and a review of protocol cases was undertaken to determine progression-free interval, survival rates, and site of first recurrence in the radiation therapy and no radiation therapy groups. In patients with Stage I or II leiomypsarcoma of the uterus, there was no difference in the progression-free interval, absolute two-year survival rate, or site of first recurrence in the two groups. There was no difference in the progression-free interval groups. However, those who received radiation therapy to the pelvis experienced a statistically significant reduction of recurrence within the radiation treatment field.

The Southeastern Cancer Study Group conducted a randomized clinical trial in acute myeloblastic leukemia and the blastic phase of chronic myelocytic leukemia to compare: Two induction programs (Schedule A) cytosine arabinoside and 6-thioguanine or (Schedule B) cytosine arabinoside, 6-thioguanine and daunorubicin; two consolidation programs (Schedule C) continuation of induction programs at a reduced dose or (Schedule D) a combination of cyclophosphamide, methotrexate and vincristine; and two maintenance programs — (Schedule E) 1 month of BCG, followed by methotrexate or (Schedule F) methotrexate. Over a 3 year period 372 patients were entered and 295 were judged evaluable. None of 11 patients with blastic phase of chronic myelocytic leukemia responded. There were no significant differences between the schedules in the number of patients with acute myeloblastic leukemia achieving complete remissions (37%, Schedule A vs. 41% Schedule B). The relapse rates on consolidation were similar (43%, Schedule C and 39%, Schedule D). BCG significantly prolonged the duration of first remission following consolidation (P<0.05) from 13.0–23.9 weeks. Survival was not significantly prolonged (92.7 weeks vs. 71.7 weeks). There were no serious complications from BCG therapy.

In the human clonogenic assay, mitoxantrone possesses among the steepest dose–response curves of any cytotoxic agent against ovarian cancer. To test the potential clinical relevance of this observation, we conducted a phase 2 trial of moderately high dose single agent mitoxantrone (28 mg/m2delivered every 3–4 weeks) along with granulocyte–macrophage colony stimulating factor (250 μg/m2/day beginning 24 h after mitoxantrone and continuing until neutrophil recovery) in 34 patients with clinically defined platinum and paclitaxel-refractory ovarian cancer. The major toxicity of treatment was severe neutropenia which was almost universal. However, there were no treatment-related infectious deaths. Significant cardiac toxicity was not observed. Five of 33 evaluable patients demonstrated objective evidence of a response to treatment (1 patient achieving a partial response of measurable tumor masses, 4 patients achieving a ≥50% reduction in CA-125 antigen level), with a median duration of response of 3 months (range 2–5 months). We conclude that moderately high dose mitoxantrone has definite, although very limited, single agent activity in platinum and paclitaxel-refractory ovarian cancer. Unfortunately, as this regimen produces severe hematologic toxicity and response durations are short, it cannot be recommended for routine clinical use. The role of an even higher dose mitoxantrone schedule employed as a component of a high dose chemotherapy program with bone marrow or peripheral progenitor cell protection in the treatment of ovarian cancer remains to be defined.

Studies of acute leukemia with the 4;11 translocation have yielded conflicting results regarding the lineage of the cell of origin in this disease. To investigate this issue further, we have examined the state of immunoglobulin genes in tumor cells from two affected patients, immunopheno-typed their leukemic cells using a number of monoclonal antibody reagents with specificities for lymphoid or myelo-monocytic antigens, and examined the malignant cells by electron microscopy. DNA was extracted from leukemic bone marrow cells and hybridized with radiolabeled DNA fragment probes specific for the constant region of immunoglobulin heavy chain and κ and X light chain genes. Autoradiographs revealed rearrangement of both allelic heavy chain genes, but a germline configuration of light chain genes in both cases. Surface marker analysis showed that blasts from both patients expressed HLA-DR and the myeloid antigens Leu-M1, 1C2, 2D1, and 4B3, but lacked common acute lymphocytic leukemia antigen or T antigens. Furthermore, they did not have sheep erythrocyte receptors nor did they express surface or cytoplasmic immunoglobulin or B cell precursor determinants. Electron microscopy analysis showed that blast cells from patient 1 exhibited numerous monoribosomes, polyribosomes, and isolated strands of rough endoplasmic reticulum in their cytoplasm. These ultrastructural features are characteristic for both common acute lymphocytic leukemia and pre-B-ALL cells, but not for T-ALL or acute myelogenous leukemia cells. Peroxidase was undetectable in cells from both patients. Our study suggests that this disorder represents a unique subtype of leukemia. The cell of origin may be an early B cell progenitor that shares certain surface antigens with myeloid cells or a stem cell with the potential for both lymphoid and myelomonocytic differentiation. © 1985 by Grune & Stratton, Inc.

Combination chemotherapy appears superior to single‐agent therapy in treating a wide variety of tumors. Encouraged by this data, we conducted a pilot study using cyclophosphamide, adriamycin, intermediate dose methotrexate and folinic acid rescue (CAMF) in patients with advanced lung cancer. Forty‐eight patients with unresectable tumors were entered on this trial, and treated with 500 mg/m2intravenously administered cyclophosphamide, 50 mg/m2intravenously administered adriamycin, 40 – 200 mg/m2orally administered methotrexate (4 doses/24 hrs), and 5 mg orally administered folinic acid (6 doses/36 hrs); this regimen was repeated every three weeks if tolerable. There were 43 patients evaluable for toxicity and 34 (non‐small cell types) for response. The major toxicities were myelosup‐pression and nausea and vomiting. The overall response rate (complete and partial responses) was 29.4% (10/34) and in 13 patients (38%), the disease was stabilized. Those responding had a median survival time of 10.5 months versus 4 months for nonresponders. Patients in whom the disease was stabilized had a median survival time of 8 months. CAMF is a well‐tolerated drug combination with promising results in patients with advanced lung cancer.

The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) µM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2,P=0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P=0.005) and pretreatment blast count (P=0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P=0.315,P=0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.

Abstract:  Purpose: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. Methods: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin (≥80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. Results: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P=0.034) longer median time to the first emetic episode (10.1 h vs >24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. Conclusions: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration.

Background. The Gynecologic Oncology Group (GOG) has completed six major randomized trials in advanced ovarian carcinoma over the 15‐year period between 1976 and 1990. This large database of 2123 patients provides a well‐studied patient population with which to examine the importance of age as a prognostic factor.

One hundred and ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration from beginning of maintenance was 18.7 versus 25.9 months (P = 0.36) for standard maintenance therapy and late intensification, respectively, and the median survival from randomization was 25.8 versus 28.5 months (P = 0.94) respectively. There was a suggestion that the late intensification strategy was helpful with respect to remission duration, and this trend was sustained in long-term follow-up. However, relapse proved to be common during the earlier phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in the course of treatment should be evaluated, including transplantation in selected patients.

Although major progress has been made in the treatment of childhood leukemia, the optimal chemotherapy of acute lymphoblastic leukemia (ALL) in adults has been unclear. In addition, the value of central nervous system prophylaxis (CNS-P) in adults has been assumed, but not established in a systematic fashion. The Southeastern Cancer Study Group has completed a prospective study in which the use of vincristine plus low-dose methotrexate and high-dose prednisone in adult acute lymphoblastic leukemia has produced an 80% (79/99) complete remission rate in patients age 15 yr and over. Younger patients had a significantly higher remission rate but no increase in remission duration. This induction regimen was associated with minimal toxicity. Random assignment to CNS-P or to no prophylaxis, after a multidrug consolidation regimen, has demonstrated a significant prolongation of CNS relapse-free interval (p= 0.008) in favor of CNS-P. CNS-P did not improve hematologic remission duration or survival. All complete remitters were maintained on mercaptopurine, methotrexate, and cyclophosphamide with pulses of prednisone and vincristine; the median time from remission to either hematologic or CNS relapse was 19.3 mo after CNS-P, and survival for these patients was 26.1 mo. We conclude that our current induction regimen is highly effective in adult ALL and that CNS prophylaxis is indicated in such patients.

An in vitroassay measuring AMP: and IMP: pyrophosphate phosphoribosyltransferase (EC 2.4.2.7 and EC 2.4.2.8) levels in intact leukocytes has been described. Intact erythrocytes incorporate insignificant amounts of precursor compared with leukocytes. The mean level of IMP pyrophosphate phosphoribosyltransferase in leukocytes from nine patients with acute myelogenous leukemia in relapse was significantly higher (0.010.001)) than in normal leukocytes. The levels of leukocyte AMP: pyrophosphate phosphoribosyltransferase were higher in leukemics but not significantly so compared with normal values. No significant reduction of IMP: pyrophosphate phosphoribosyltransferase activity was observed in leukocytes from leukemics clinically resistant to purine analogs. No correlation could be found between leukocyte enzyme activity and relapse, remission or therapy of leukemia. Enzyme levels in leukocytes isolated from patients with other malignancies were in the normal range. However, in a number of leukemics with apparently normal differential blood smears, the enzyme activities of the nonleukemic cells were greater than normal.

Summary Serum methotrexate (MTX) levels were measured in 20 patients who received an oral, intermediatedose MTX regimen preceded by an IV loading dose, with or without probenecid. Plateau serum MTX levels were relatively modest (≤2x10-6M) during the 24 h of treatment. Pretreatment with probenecid (PBC) led to a doubling of the serum MTX level and a significant increase in the area under the concentration-time curve. Nevertheless, oral therapy is not a suitable means of producing sustained, high (10-5 molar) MTX levels, even with the addition of PBC.

To the Editor.—In regard to the report by Oye and Shapiro,1 it is apparent that survival comparisons between responders and nonresponders in cancer clinical trials are misleading. Anderson et al2 have made similar observations. However, I think further discussion is needed of that subset of patients who achieve a "complete" response, that is, currently available techniques fail to demonstrate persistent cancer. In virtually every tumor type in which complete response can be achieved in some fraction of treated patients, there is a dramatic improvement in survival for that fraction compared with partial responders or those with "stable" disease; moreover, cured patients are found within the subset of complete responders, but not elsewhere. Clinical trials should focus initially on maximizing the complete response rate rather than searching for a survival advantage for partial responses. The latter simply provide clues that may lead to regimens with better complete response

TO THE EDITOR. —In regard to the interesting report by Knospe and Gregory on "Smoldering Acute Leukemia" (Arch Intern Med127:910-918,1971). I would like to suggest the alternative interpretation that at least in some instances, seemingly indolent leukemia may represent "wheel spinning" rather than "smoldering." It should be apparent that the population kinetics of this disorder must be rather unusual. Either the cells proliferate very slowly or they proliferate at usual or even supranormal rates, but have a high spontaneous death rate, resulting in little net growth of the disease.Clarkson et al1 have studied the cell kinetics of a similar patient, and found that the leukemic cells were in fact rapidly proliferating. This patient, in his 70s, subsequently had a one year remission after treatment.Thus, the smoldering leukemics should be carefully studied, not only as Knospe and Gregory have done, but also in regard to their

To the Editor.—Immersion oil for use with microscopes is messy when it gets on the outside of the container, which it seems to do sooner or later. Various improvised devices and containers have been used in the past to cope with this problem, such as imbedding the bottle of immersion oil in a small platform of wax. A neat and simple holder for a common type of immersion oil bottle (1 fl oz capacity) can be made from the plastic top of an aerosol spray container if the outer diameter of the inner cap measures about 32 mm (Figure).The inner diameter of the inner cap and the diameter of the bottle to be held in it vary from sample to sample, so some element of custom fitting is necessary. This arrangement is unlikely to tip over, and after a five-year trial, has not become messy.

TO THE EDITOR.— In regard to the report by Leavell and Yarbro of "Hydroxyurea: A New Treatment for Psoriasis" (Arch Derm 102:144-150, 1970), I was disappointed that they did not make specific reference to some of the studies of other cytotoxic agents in the treatment of psoriasis. Purine analogues,1-3 alkylating agents2,3 and other antimetabolites4 have been reported to be effective in psoriasis. Thus, the question is whether hydroxyurea has a better therapeutic index and less side effects in the treatment of psoriasis compared with these other cytotoxic drugs. A comparison study would be of interest. I share the feeling of the authors that there may be better, safer drugs than methotrexate in severe psoriasis.

To the Editor.—Two related points were not, in my opinion, adequately dealt with in the report by Greenberg et al (221:261,1972) and the EDITORIAL by DeVita (221:298, 1972) on the treatment of Hodgkin's disease. Is it appropriate to identify as "private practitioners" a group of specialists in hematology and oncology who are prepared to conduct, tabulate, and report the results of their clinical trials, but who happen to run their own offices? Their situation would seem to have little relevance to that of the general physician or internist who has neither the training and experience to optimally manage this disease, nor sufficient perspective about the problem to recognize the pressing questions, nor enough time to keep careful records and report his results. Clearly, the questions posed by Dr. DeVita need to be answered as soon as possible. But what should be the role of the trained specialist outside the

To the Editor:—Although the assay for hypoxanthine-guanine phosphoribosyl transferase deficiency described by Frost et al (212:316, 1970) is very interesting, it does not appear to have any advantage as a diagnostic test of Lesch-Nyhan syndrome compared with the assay of blood samples, such as described by Seegmiller et al1 and by Berman et al.2