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To improve the survival of patients with small cell lung cancer, there is a need for new and effective agents to treat this disease. These agents include paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, gemcitabine, and amrubicin. In previously untreated small cell lung cancer patients the response rate for these effective drugs ranges from 27% to 79%. Median survival ranges from 6.6 to 12 months. The major toxicity for these agents is leukopenia. Studies are ongoing to evaluate the efficacy of combination chemotherapy using new agents either together or with other known effective drugs for the treatment of small cell lung cancer. Semin Oncol 28 (suppl 4):27-29.

The search for new combination chemotherapeutic regimens for the treatment of non-small-cell lung cancer is motivated not only by the desire to increase the objective tumor response and survival rates, but also by the desire to reduce toxicity, decrease symptoms, and improve the psychological well-being of treated patients. At present, the overall phase II response rates with existing combination chemotherapeutic regimens are approximately 15% to 30%, and the median survival rates are about 8 to 9 months. The median 1-year survival rates are about 30% to 40%, while the 2-year survival rates are only about 10% to 15%. Thus, while we have made substantial progress in the treatment of this disease, the long-term outcome is still relatively bleak. This article reviews the results of a phase I trial with a new combination chemotherapeutic regimen (gemcitabine [Gemzar] and the novel antifolate, Alimta), and outlines the rationale for, and design of, an ongoing phase II trial.

Six of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach.Thirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation.Twenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months.This 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.

With the advent of several newer agents with single-agent response rates greater than 20% and approximately 30%-40% in combination therapy, non-small cell lung cancer (NSCLC) may now be considered a malignancy that is moderately sensitive to chemotherapy. Examples of these agents include the taxanes, paclitaxel and docetaxel; vinorelbine, a new vinca alkaloid, and the camptothecins, of which CPT-11 is the most actively studied agent. Another new and exciting agent is gemcitabine, a nucleoside analogue structurally related to cytosine arabinoside. Gemcitabine's mechanism of action is activated by deoxycytidine kinase to dFdCMP, dFdCDP and dFdCTP. The latter two compounds, when incorporated into DNA, result in chain termination. Phase I studies using a short infusion schedule given weekly for three weeks followed by one week off established 1,000-1,250 mg/m2/week as the maximum tolerated dose. Single-agent gemcitabine has been extensively studied in patients with chemotherapy-naïve advanced NSCLC with response rates of approximately 20%. Response rates for the combination of gemcitabine plus cisplatin are approximately 28%-54% in phase II trials. Recently, this combination has been studied in randomized phase II and III trials revealing improvements in response rates, time to progression and, in the phase III trial, survival. Current and future studies are evaluating gemcitabine in non-cisplatin combinations (i.e., taxanes).

Therapy for limited-disease (LD) small cell lung cancer (SCLC) includes combined modality therapy using radiation (XRT) and systemic chemotherapy. Because such therapy is effective in treating the disease, LD SCLC is now considered potentially curable. Based on data from the Intergroup study, the current standard chemotherapy regimen is etoposide plus either cisplatin or carboplatin administered concomitantly with XRT given once or twice daily. Paclitaxel has demonstrated efficacy in the treatment of extensive-disease (ED) SCLC and in vitro data suggest that the agent has significant radiosensitizing potential. The Sarah Cannon Cancer Center, Nashville, TN, recently reported the results of two sequential phase II studies evaluating two paclitaxel doses in combination with cisplatin and etoposide for SCLC; patients with LD SCLC also received XRT. Patients with LD SCLC demonstrated a higher overall response rate to the higher-dose regimen; median survival was 17 months with the lower-dose regimen and more than 16 months with the higher-dose regimen. Three additional studies are under way to further evaluate the role of paclitaxel in combination with cisplatin, etoposide, and XRT therapy for the treatment of LD SCLC. Although the number of evaluable patients is limited and all studies are ongoing, preliminary results thus far appear encouraging.

The dysregulation of both myc gene expression and retinoid signaling pathways commonly occurs in small cell lung carcinoma (SCLC). Because preclinical data showed that all-trans-retinoic acid (RA) inhibited SCLC growth, altered myc expression, and blocked transition to a treatment-resistant phenotype, a Phase II trial was designed to determine the effects of the combination of RA, cisplatin, and etoposide in patients with SCLC.Patients with untreated, extensive stage SCLC were treated with up to 8 cycles of cisplatin, 60 mg/m2, intravenously (i.v.) on Day 1 and etoposide, 120 mg/m2, i.v. on Days 1-3 in addition to up to 1 year of oral RA, 150 mg/m2/day.Of 22 assessable patients 1 had a complete response and 9 had a partial response, for an overall response rate of 45% (95% confidence interval, 24-68%). The median survival was 10.9 months and the 1-year survival was 41%. The median duration of chemotherapy was 6 cycles and the median duration of RA treatment was 2.8 months. Thirteen patients discontinued RA prematurely due to toxicity and only 4 responders were receiving RA at the time of recurrence. Toxicity-limiting RA treatment mainly was comprised of mucocutaneous changes and headaches.RA at a dose of 150 mg/m2/day was tolerated poorly in combination with cisplatin plus etoposide, leading to early discontinuation of RA in the majority of patients. The hematologic toxicity, response rate, and survival were similar to those associated with cisplatin and etoposide in prior trials. Further studies with more active and less toxic agents will be required to determine the role of retinoids in the treatment of SCLC.

Management of disseminated non-small-cell lung cancer has changed over the past 10 years. Newer agents, such as vinorelbine (Navelbine) and paclitaxel (Taxol), have been shown to modestly improve survival in patients with advanced disease when administered in conjunction with cisplatin (Platinol). Compared with older regimens consisting of cisplatin and a Vinca alkaloid or a podophyllotoxin, the newer regimens yield a 10- to 15-week improvement in median survival and an additional 10% to 15% in 1-year survival. Based on these results derived from randomized trials, it appears that metastatic non-small-cell lung cancer patients with good performance status should be treated with regimens containing either vinorelbine or paclitaxel in conjunction with cisplatin.

Lung cancer is the leading cause of death due to cancer in the United States, and approximately 178,100 new cases were estimated to occur last year. Small-cell lung cancer (SCLC) accounts for approximately 17% to 25% of all lung cancers. Due to its aggressive nature and rapid proliferation rate, small-cell lung cancer is usually widespread at diagnosis. Therefore, chemotherapy is the cornerstone of therapy for this disease. Cisplatin (Platinol) is an active chemotherapeutic agent used to treat small-cell lung cancer, but its toxicity, including nausea and vomiting, nephrotoxicity, neurotoxicity, and ototoxicity, has led to the investigation of combination regimens with different toxicity profiles. Carboplatin (Paraplatin), a derivative of cisplatin, has far less nonhematologic toxicity, although myelosuppression may be slightly greater than that observed with cisplatin. The reduced toxicity and equivalent efficacy of carboplatin have resulted in the increased use of carboplatin-based regimens to treat small-cell lung cancer. Phase I and II trials of carboplatin as single-agent treatment for small-cell lung cancer resulted in overall response rates of approximately 60% for previously untreated patients and 17% for those who had received prior therapy. New combination chemotherapy regimens that include carboplatin may improve survival in patients with small-cell lung cancer and potentially cure those patients with limited disease. Further investigation of carboplatin and other new agents is warranted.

An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma.Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method.Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking.Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

Ifosfamide as a single agent has produced overall response rates greater than 5O% in the treatment of small cell lung cancer (SCLC). Etoposide/ifosfamide/cisplatin (VIP) has produced overall response rates of 74% to 100% with complete response rates of 27% to 64% in SCLC patients. In a Hoosier Oncology Group randomized study involving extensive-disease SCLC patients, VIP was superior to etoposide/cisplatin with regard to median time to progression (6.6 v 5.8 months), median survival times (9.1 v 7.3 months), and 2- and 3-year survival rates (13% v 5% and 5% v 0%, respectively). In limited-disease SCLC, ifosfamide/carboplatin/etoposide (ICE) achieved overall response rates of 76% to 94%, median durations of survival ranging from 14 to 19 months, and 2-year survival rates of 24% to 37%; in extensive disease, overall response rates ranged from 72% to 100%, median durations of survival ranged from 9 to 14 months, and 2-year survival rates ranged from 14% to 22%. The use of high-dose ICE plus epirubicin and peripheral blood stem cell support appears promising in the treatment of limited-disease SCLC.

Preliminary results of a phase I study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given by 3-hour infusion, followed by carboplatin in chemotherapy-naive patients with stage IV non-small cell lung cancer indicate that both agents can be combined at clinically relevant single-agent doses. The paclitaxel (mg/m2)/carboplatin area under the concentration-time curve (mg.min/mL) dose level of 225/7 is projected to be the maximally tolerated and recommended phase II dose level for future evaluations. Dose-limiting neutropenia, thrombocytopenia, and nausea and vomiting preclude treatment with carboplatin doses estimated to target an area under the concentration-time curve of 9 mg.min/mL when given with paclitaxel 225 mg/m2. The heterogeneous nature of the principal toxicities, as well as the ability to administer clinically relevant single-agent doses of both agents in combination, also indicate that further dose escalation of paclitaxel and carboplatin using hematopoietic growth factors would not be feasible. The preliminary antitumor activity noted to data, as well as the safety associated with the clinically relevant single-agent doses that can be given in combination, indicate that phase II/III evaluations of this regimen are warranted in patients with both advanced and early stage non-small cell lung cancer.

Clinical trials of hyperfractionated radiation therapy and induction chemotherapy followed by standard radiation therapy have shown improved survival in patients with unresectable nonsmall cell lung cancer (NSCLC). Radiosensitization may improve local tumor control when chemotherapy is given concurrently with hyperfractionated radiation therapy, but also may increase toxicity. A Phase I/II trial, Radiation Therapy Oncology Group 90-15, was designed to evaluate whether this strategy could improve survival with acceptable toxicity and be part of a Phase III trial of chemoradiation sequencing.Vinblastine (5 mg/M2 weekly x 5 weeks) and cisplatin (75 mg/M2 days 1, 29, and 50) were given during twice-daily irradiation (1.2 Gy, 6 hours apart) to 69.6 Gy in 58 fractions in 6 weeks. Eligible patients had American Joint Committee on Cancer (AJCC) Stage II (unresected) or IIIA-B NSCLC and Karnofsky performance status 70 or greater; there were no weight loss restrictions.Of 42 eligible patients, 76% had greater than 5% weight loss, 45% had T4 primary tumors, and 62% were Stage IIIB. All protocol treatment was completed in 53%. Acute toxicity was predominantly hematologic with 19 of 42 (45%) having Grade 4 toxicity or higher, three (7%) with septic death. Ten of 42 (24%) had Grade 3 or higher esophagitis. There were two (4.7%) patients with Grade 3 or higher (1 lung and 1 esophagus) and two (4.7%) with Grade 4 or higher (1 lung and 1 hematologic) late toxicities. Median survival time was 12.2 months, with an overall 1-year survival of 54%, an estimated 2 year survival of 28% and a 1-year progression free survival of 38%.For patients with unresectable nonsmall cell lung cancer, who were not selected on the basis of weight loss, concurrent hyperfractionated irradiation and chemotherapy had more intense acute toxicity than hyperfractionation alone, but late toxicity was acceptable. One and 2-year survival rates were 54 and 28%, respectively.

In a randomized Eastern Cooperative Oncology Group study, single-agent ifosfamide used to treat extensive-disease small cell lung cancer patients produced a 49% response rate compared with 56% for patients receiving standard combination chemotherapy (cyclophosphamide/doxorubicin/vincristine). When the drug was combined with carboplatin and etoposide to treat extensive-disease small cell lung cancer patients, overall response rate was 83%, median survival time was 9 months, and 2-year survival rate was 14%. The major toxicity was myelosuppression. These results confirm those of other investigators who have shown the effectiveness of the ifosfamide/carboplatin/etoposide regimen in treating patients with small cell lung cancer.

This study was designed to examine the efficacy and toxicity of high-dose cyclophosphamide (CY), and to evaluate the potential added effect of vincristine (VCR) given at a theoretic time of malignant cell stimulation in a group of patients with multiple myeloma, refractory to or relapsing after, treatment with standard doses of chemotherapy.Patients were randomly assigned to receive CY 2400 mg per M2 as a single-day dose and VCR 1.4 mg per M2 given on Day 1 or Day 9 after the CY.There were 108 cases suitable for analysis. No difference in objective response (17.6%, 23.5%), subjective response, remission duration, or survival was observed in the two treatment arms.The authors conclude that a single, high dose of cyclophosphamide is more toxic and provides equal or less response than the equivalent dose given over 4 consecutive days and that no improved effect was detected using timed-sequential therapy with VCR.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-min infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate posttreatment period at the 240-mg/m2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +/- 4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and SN-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50% of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)

Two phase II studies of paclitaxel involving patients with advanced non-small cell lung cancer (NSCLC) have been completed. The first study, conducted by the Eastern Cooperative Oncology Group (ECOG), involved 25 previously untreated patients who received intravenous (i.v.) paclitaxel 250 mg/m2 over 24 hours every 3 weeks. Among 24 evaluable patients with stage IV disease, 5 partial responses (21%) were observed, median survival was 24.1 weeks, and 1-year survival was approximately 45%. Common toxicities included leukopenia (66% grade 4), neurotoxicity (28% grade 3), and cardiotoxicity (12.5% grade 3). The second trial, conducted at the M.D. Anderson Cancer Center, yielded similar results. Twenty-seven previously untreated patients with stage IV disease received paclitaxel 200 to 250 mg/m2 i.v. over 24 hours every 3 weeks, yielding 1 complete response and 5 partial responses (24%) in 25 evaluable patients. The major toxicity was leukopenia. No cardiac toxicity was seen. For the past several years ECOG has tested several agents against previously untreated NSCLC, and none has demonstrated a response rate greater than 10%, other than paclitaxel. Given these results, the ECOG plans to conduct a three-arm phase III study involving patients with advanced NSCLC comparing 'standard' cisplatin/etoposide chemotherapy to two paclitaxel-containing arms: (1) paclitaxel 135 mg/m2 i.v. over 24 hours plus cisplatin 75 mg/m2 i.v.; (2) paclitaxel 250 mg/m2 i.v. over 24 hours plus cisplatin 75 mg/m2 i.v. plus recombinant human granulocyte colony-stimulating factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Paclitaxel (TAXOL), a novel diterpene plant product isolated from the western yew Taxus brevifolia, is an active agent in the treatment of lung cancer. In two studies, the drug produced 21% and 24% objective response rates among patients with non-small cell lung cancer. A response rate of 34% was reported in a single trial involving patients with extensive-stage small cell lung cancer. Additional trials are needed to evaluate single-agent paclitaxel in the treatment of small cell lung cancer. Studies also are planned to measure the effect of paclitaxel as a radiosensitizer and in combination regimens with other active agents for the treatment of lung cancer.

4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemical-biological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that metabolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development. Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominantly alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two-compartment first order elimination model, The relationship between IPO dose and area under the disposition curve was curvilinear, suggesting saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (lambda 1 and lambda 2) were 6.7 and 114.5 min, respectively. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antitumor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The Chemotherapy and Treatment Scheduling System provides integrated appointment and facility scheduling for very complex procedures. It is fully integrated with other scheduling systems at The Johns Hopkins Oncology Center and is supported by the Oncology Clinical Information System (OCIS). It provides a combined visual and textual environment for the scheduling of events that have multiple dimensions and dependencies on other scheduled events. It is also fully integrated with other clinical decision support and ancillary systems within OCIS. The system has resulted in better patient flow through the ambulatory care areas of the Center. Implementing the system required changes in behavior among physicians, staff, and patients. This system provides a working example of building a sophisticated rule-based scheduling system using a relatively simple paradigm. It also is an example of what can be achieved when there is total integration between the operational and clinical components of patient care automation.

Ifosfamide, an analogue of the alkylating agent cyclophosphamide, is one of the most active agents in the treatment of small cell lung cancer (SCLC). As a single agent, the drug produces a greater than 50% objective response rate. Recent studies using ifosfamide in combination with other active agents, ie, cisplatin, carboplatin, and etoposide, In the treatment of limited-stage and extensive-stage SCLC have achieved high overall response rates and complete responses (CRs). However, the CR rate is higher in limited-disease patients. Additional studies are needed with the various ifosfamide-containing regimens to precisely define their role in the treatment of SCLC in both limited-disease and extensive-disease patients.

In today's medical care environment of cost containment and restricted reimbursement, it is important to maximize the use of expensive facility and personnel resources. Concurrently, it is important to provide superior and timely patient services in order to remain competitive in an extremely flexible market. There are many areas in today's larger hospital environments where such ideals can be easily achieved. One of the more obvious areas is the automation of appointment and resource scheduling for ambulatory care services. This article focuses on maximizing the use of available physical and personnel resources in the ambulatory care setting of large and specialty hospitals. The Johns Hopkins Oncology Center's integrated outpatient scheduling and resource management systems are used as examples of what can be achieved. It is hoped that the experiences of the Oncology Center in developing these integrated systems will help others in similar efforts.

Previous experience using 131I anti-CEA antibody, which irradiates at a variable low dose rate in combination with a multimodality treatment program, has demonstrated acceptable toxicity and response in primary intrahepatic cholangiocarcinoma. In attempting to improve therapy, Cis-platin was added to the prior regimen. Induction therapy was unchanged. One month later, chemotherapy was given (doxorubicin, 15 mg, 5-fluorouracil, 500 mg, plus Cis-platin, 20 mg/M2) followed the next day by outpatient administration of 20 mCi 131I anti-CEA by i.v. bolus. Five days later, 10 mCi was administered. The latter regimen (chemotherapy plus 20 + 10 mCi 131I anti-CEA) was repeated every 2 months using polyclonal antibodies derived from different species (rabbit, pig, baboon, and horse). Twenty-four patients (29% with prior chemotherapy and/or metastases) were prospectively treated according to this regimen. Toxicity was limited to hematologic toxicity and was manifested by thrombocytopenia and leukopenia (17% and 4% grade 4, respectively, according to RTOG toxicity criteria). Tumor remission was evaluated by CT volumetric analysis and demonstrated a 14% response rate for the induction portion of therapy, 24% for the radioimmunoglobulin portion of treatment, and 50% remission rate when all subsequent tumor volumes were compared to the pre-treatment volume (entire program). The median survival for the entire group of patients was 10.1 months. This result is superior to previously reported trials and, in comparison to our previous study (10.1 vs 6.5 months median survival), further advancement in protocol design appears to have been made. In view of the rarity of this disorder, a randomized trial is not possible and strict statistical analyses cannot be made. The mechanism of 131I-anti-CEA variable low dose irradiation and chemotherapy interaction is discussed as well as further potential modifications for treatment improvement.

Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of hepsulfam's myelosuppression. Because hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.

Eighteen women with metastatic breast cancer previously untreated with chemotherapy were entered on a phase II trial of intravenous menogaril, a new anthracycline derivative. Treatment was given at 140 mg/m2 on days 1 and 8 of each 28 day cycle. The most common toxicities were leukopenia in all patients and burning and phlebitis at infusion sites in 72%. Serial assessment of cardiac function by resting and stress gated blood pool scans showed temporary decrements in ejection fraction in only 2 patients (11%). The response rate to the therapy was 19% [95% CI 0-38%] including 1 complete and 2 partial responses. The median time to relapse among responders was 6.5 months. Mean survival in all patients entered was 15.8 months from date of entry. Menogaril at this dose and schedule has modest activity as first line therapy for metastatic breast cancer but also has significant marrow and local toxicity.

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.

Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.

CA 549, a new marker for breast cancer, was measured in serum of 719 patients by an immunoradiometric assay involving two monoclonal antibodies: BC4E 549, developed against a breast-tumor cell line, and BC4N 154, developed against milk fat-globule membrane. The reference interval for healthy women was 0-11 kilo-units/L. The percentages of patients with CA 549 greater than 11 kilo-units/L for benign conditions are: 0% pregnancy, 1% breast, 26% liver; and for nonbreast metastatic cancers: 12% endometrial, 33% lung, 40% prostatic, and 50% ovarian. In women with breast cancer who were receiving or had completed adjuvant therapy with no evidence of disease there was an 11% increase in CA 549. For patients with metastatic breast cancer, 19% of those in complete remission, 63% of those in partial remission, and 88% of those with systemic progression had increased CA 549. CA 549 is a more specific marker than carcinoembryonic antigen (CEA) in nonmalignant disease, nonbreast malignancies, and adjuvant breast-cancer patients, and it is more sensitive in breast-cancer patients with progressive disease than is CEA. We could show CA 549 to be superior to CEA for detecting active breast cancer in patients with malignant or nonmalignant breast diseases. In monitoring 19 adjuvant-treated patients, CA 549 correlated more closely with the clinical course than did CEA values and, when increased, predicted a clinical recurrence. In 18 breast-cancer patients with metastasis, monitored for two to three years, the change of CA 549 values paralleled disease courses more often than did CEA values.

Between December 1979 and June 1983 the Eastern Cooperative Oncology Group (ECOG) treated 893 good-performance status patients with metastatic non-small-cell lung cancer (NSCLC) on one of seven phase III combination chemotherapies. The overall median survival was 23.5 weeks with no significant differences between treatments. One hundred sixty-eight patients (19%) survived greater than 1 year and 36 (4%) for greater than 2 years. The etoposide-platinum combination had the highest proportion of 1-year survivors (25%). Mitomycin-vinblastine-platinum (MVP), which had demonstrated the highest response rate, had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Analysis of pretreatment characteristics that distinguished patients who survived greater than 1 year from those who did not demonstrated that an initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large-cell histology, less than 5% prior weight loss, no symptoms of shoulder or arm pain, and no liver metastases were predictors of longer survival. Of particular interest was the finding that response duration was significantly longer (P = .002) for those patients who experienced a longer time to best response. In addition, patients who survived greater than 1 year experienced greater degrees of nonlethal toxicity, in particular, gastrointestinal and hematologic, than patients who did not survive 1 year, (P = .006). A detailed chart review of 32 2-year survivors and 32 matched controls demonstrated that maintenance or improvement of performance status and maintenance of serum albumin levels at 3 months from the initiation of treatment were both important predictors of longer survival.

The levels for serum protein bound neutral carbohydrates (fucose, mannose, and galactose) were determined at specific intervals for 40 patients with small cell carcinoma of the lung and compared to the corresponding carcinoembryonic antigen (CEA) levels. In pretreatment samples, the frequency of elevation was 92.5% for fucose and 77.5% each for mannose and for galactose. CEA determined in these same samples was elevated (greater than 5 ng/ml) in 45.0%. One or more of the three carbohydrate levels were elevated in pretreatment serum of 95.0% of the patients. The individual frequency of elevation for each carbohydrate was significantly related to initial stage of disease (P less than 0.01). Median survival was significantly longer for patients based on a discriminant of less than 3 carbohydrates elevated in pretreatment samples (25 months) to all 3 elevated (11 months) with P = 0.0302. A single value, termed the biomarker index, was calculated to represent the summation of the individual carbohydrate levels per individual serum sample. The biomarker index was found to be directly correlated with extent of primary disease, number of metastic sites, tumor burden, and clinical response categories assessed at serial time points. For patients with both low Biomarker Index values and normal CEA levels in pretreatment samples, an initial rise in both determinations occurred frequently corresponding to partial or complete tumor response. The occurrence of such discordant results must be considered as a likely possibility for those patients with low or normal pretreatment biological marker levels and subsequent response to primary chemotherapy.

A case of gastric carcinoma, occurring 16 years after irradiation for gastric lymphoma, is presented. Factors which may have contributed to gastric carcinogenesis in this patient are discussed.

This case report describes a patient who presented with Stage IV B Hodgkin's disease and autoimmune thrombocytopenia. Prior to the institution of therapy the presence of platelet-associated IgG was documented. When the patient was treated with steroids and chemotherapy, the thrombocytopenia resolved and platelet-associated IgG disappeared. Splenectomy alone did not correct the thrombocytopenia. The literature on Hodgkin's disease and autoimmune thrombocytopenia is reviewed.

Carcinoembryonic antigen (CEA) was measured at specific intervals in the plasma of 56 patients with small cell carcinoma of the lung. Of these patients, 47 had serial analyses for varying periods during their illness, 42 had pretreatment CEA levels, and 17 of the latter patients had determinations throughout the entire course of their disease. Pretreatment CEA levels were elevated above 2.5 ng/ml for 74% of the 42 patients and above 5.0 ng/ml for 48%. Although exceptions were noted, in general, a direct relationship was found between pretreatment CEA levels and extent of disease or tumor burden. Initial stage of disease, however, was more predictive of survival than was the pretreatment CEA level. With response to therapy, a corresponding decrease in CEA levels occurred for patients with an elevated pretreatment level. For those patients with a pretreatment CEA level below 5.0 ng/ml, an immediate slight increase in level was often seen associated with response and followed by a subsequent fall after one month. A rising CEA level was usually found with recurrence or progression of disease after initial response and occurred frequently prior to clinical evidence of progression. In combination with careful clinical evaluation, serial CEA measurements can aid in assessing tumor changes associated with treatment in patients with small cell carcinoma of the lung particularly at the times of recurrence or disease progression following a partial or complete response.

This report describes the preliminary results from a randomized study comparing megestrol acetate with tamoxifen in the treatment of postmenopausal women with advanced breast cancer, correlating estrogen receptors (ER) and progesterone receptor (PgR) status with response. Patients received megestrol acetate (40 mg) orally four times daily or tamoxifen (10 mg) orally twice daily. If the initial therapy failed, patients were crossed over to the alternate treatment. Of 197 patients entered in the study, 190 were considered evaluable. The overall response rates were 35% with megestrol acetate and 42% with tamoxifen. Twenty-three percent (7/30) of patients responded to megestrol acetate after being crossed over from tamoxifen, while 22% (6/27) responded to tamoxifen after being crossed over from megestrol acetate. Response did not correlate significantly with combined receptor (ie, ER plus PgR) levels. A significant trend was seen between ER level and response only in the tamoxifen group. There was no association between PgR levels and response for either tamoxifen or megestrol acetate.

A precise and accurate gas-liquid chromatographic (GLC) method has been developed for the quantitative analysis of the neutral sugars L-fucose (6-deoxygalactose), mannose, galactose, and glucose in ethanol precipitates of human serum proteins. The chromatographic conditions and sample preparation resulted in short analysis time (20 min per run) and made routine analyses practicable (twelve samples per day). The alditol acetate derivatization yielded single derivatives for each sugar. Complete separation was achieved on a 2.0 m X 2 mm I.D. column with 2.0% Silar-7CP on Chromosorb W AW 80--100 mesh. The results of hydrolysis showed that the release of fucose and galactose preceded the release of mannose. Hydrolysis with AG 50 W-X8 (H+) ion-exchange resin in 0.5 N HCl at 100 degrees for 7 h optimized glycosidic bond cleavage with only minimal destruction of fucose, mannose and galactose. A combination of strong cation- and anion-exchange resin columns was used to remove chromatographic background of peptides, amino acids, amino sugars, and inorganic ions. An average R.S.D. of less than 4% with recovery of greater than 86% for the three sugars was achieved. The homogeneity of the chromatographic peaks for the neutral sugars of normal human serum glycoproteins was confirmed by GLC--mass spectrometry. Significantly elevated ratios of fucose, galactose, and mannose to serum protein were observed for patients with small cell lung and ovarian carcinomas.

The monitoring utility of serial patterns of a single marker (carcinoembryonic antigen) level and multiple marker (three carbohydrates-fucose, mannose and galactose) levels in patients with small cell carcinoma of the lung was investigated using a quantitative approach. A serial multiple regression (SMR) model was formulated to assess the disease response following the first to the tenth course of therapy and resulted in the multiple correlations ranging from 0.183 (NS)-0.706 (P less than 0.005) for CEA, and 0.502 (P less than 0.250)-0.760 (P less than 0.025) for three carbohydrates, respectively. The appraisal of these markers utilizing the SMR model points out that: (1) the serial levels of CEA greater than 5.0 ng/ml are significantly correlated with the disease course whereas the serial levels less than 5.0 ng/ml reflect the trend of variation in the disease course, but with less accuracy; and (2) the levels of three carbohydrates, any one elevated before and during therapy, are significantly correlated with the disease course.

Five minor base ribonucleosides, primarily degradation products of transfer ribonucleic acid (tRNA), were evaluated as potential biological markers for patients with small cell carcinoma of the lung. The urinary concentration for pseudouridine, 1-methyladenosine, 1-methylinosine, N2-methylguanosine, and N2,N2-dimethylguanosine was determined by means of reversed-phase high performance liquid chromatography and quantitatively expressed as a function of creatinine excretion. Comparisons were made with carcinoembryonic antigen (CEA) plasma levels. The total frequency of elevated values for the five nucleosides in pretreatment urine samples was directly related to stage of disease with 24/60 (40%) determinations increased in 12 patients with limited disease and 69/85 (81%) in 17 patients with extensive disease. For these same patients, CEA levels were elevated respectively in 2/11 (18%) of the former and 9/17 (53%) of the latter group. The frequency and degree of elevation of the nucleoside/creatinine ratios in pretreatment samples from patients with extensive disease was correlated directly with increasing number of metastatic sites. Of the five nucleosides, the mean number elevated was two for limited disease, 3-4 for extensive disease with one metastatic site, 4 for two or three, and 5 for four or more sites of metastases. Based on a summation of pretreatment nucleoside/creatinine ratios, a discriminant for survival was derived giving curves separating patients (P = 0.086) similar to the discriminant based on stage of disease. Although discordant results were noted, an overall correlation of 75% agreement with clinical assessment was estimated in response categories when monitoring changes associated with therapy.

A chemotherapeutic regimen consisting of BCNU, cyclophosphamide, vincristine, and procarbazine was evaluated in 43 patients with small cell carcinoma of the lung. The majority of patients received radiation therapy of the primary tumor, but chemotherapy alone was utilized in a group of patients with widely disseminated disease. In addition to thorough staging with radioisotope scans and bone marrow biopsies, a study of calcitonin and histaminase as biochemical markers was performed. The BCVP chemotherapy resulted in a complete and partial response rate of 53% when given alone or in conjunction with radiotherapy. The survival data are preliminary, but the complete responders do have a statistically significant better survival (mean of + -95 days) than the partial responders and nonresponders. Hypercalcitonemia was not detected in our patients, but elevated histaminase activity was found in eight of 24 patients with small cell carcinoma and in only one of 19 patients with squamous and large cell carcinoma.

Dosimetric studies are reported for 22 patients with hepatoma who received treatment with 131I-labeled antiferritin IgG. Studies included liver and tumor volume computations based on computerized axial tomographic scan analysis, in-vivo quantitation of the activity deposited in hepatic tumors and normal liver tissue, and effective half-life measurements of the activity in the tumor, liver, and total body. Administered activities of polyclonal and affinity-column purified 131I-labeled antiferritin IgG ranged from 32 to 157 mCi. Tumor volumes at the time of radioimmunoglobulin infusion ranged from 220 to 3020 cm3 and total liver volumes ranged from 900 to 4620 cm3. For tumor volumes ranging from 220 to 1700 cm3, the maximum tumor activity was linearly proportional to tumor volume, but independent of antiferritin preparations and administered activities. In this range of tumor volumes, the mean value of tumor-to-liver ratios of specific activities was 4.8:1. Hepatomas ranging from 2290 to 3020 cm3 had reduced tumor uptake of radiolabeled antiferritin IgG and had a tumor-to-liver ratio of specific activities of 1.6:1. For all patients studied there was a linear relationship between the volume of normal liver tissue and the maximum activity deposited. These data, in conjunction with toxicity studies and tumor effective half-life measurements, led to the present treatment regimen of administering 30 mCi of polyclonal antiferritin IgG on Day 0 and 20 mCi on Day 5 following the first injection. This has resulted in the same range of absorbed dose to the tumor as was achieved with larger administered activities, but with a significant reduction of total-body irradiation to the patient.

Breast disease is a common problem found in approximately one of four women from puberty to old age. Of greatest importance to the health care provider is identifying the type of breast disorder and its relative seriousness. Precancerous mastopathy is of major concern, as are other significant forms of benign breast disease, both symptomatic and asymptomatic. Awareness of the many facets of benign breast disease on the part of the health care provider and the patient can heighten sensitivity to subtle changes in breast tissue. Identification of precancerous mastopathy has its greatest impact for early diagnosis of breast cancer. The patient with benign breast disease can be offered reassurance, support and symptomatic treatment for the benign breast disorder by the primary health care provider.

Taxol is a unique plant-derived antineoplastic agent that appears to exert its cytotoxic effect by interfering with microtubule structure and function. In this phase I trial, in which the drug was given as a brief iv infusion every 3 weeks, the dose-limiting toxicity was leukopenia, with thrombocytopenia being seen much less frequently. Sensory neuropathy was frequently seen at the highest dosage, with numbness and paresthesias appearing in a glove-and-stocking distribution. In some cases, this appeared to be a cumulative effect. Total alopecia was common. Other toxic effects observed included nausea and vomiting, mucositis, myalgias, and phlebitis. The frequent occurrence early in the study of acute cardiovascular and pulmonary toxicity suggestive of hypersensitivity reactions was decreased in frequency and severity by prolonging the infusions and premedication with corticosteroids and antihistamines. Two heavily treated patients appeared to respond to this agent, one with non-small cell lung cancer and one with ovarian cancer. Based on these data, we recommend a starting dose in phase II trials of 212 mg/m2 in patients with minimal prior therapy and 170 mg/m2 in heavily treated patients. At least initially, these trials should be carried out in institutions familiar with the use of this drug.