Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B study 9473.

The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of fish oil fatty acid capsules containing omega-3 fatty acid ethyl esters. Twenty-two patients with neoplastic disease not amenable to curative therapy who had lost 2% of body weight over a previous 1 month time period were given an escalating dose of fish oil fatty acids. The maximum tolerated dose was found to be 0.3 g/kg per day of this preparation. This means that a 70-kg patient can generally tolerate up to 21 1-g capsules/day containing 13.1 g of eicosapentaenoic acid + docosahexaenoic acid, the two major omega-3 fatty acids. Dose-limiting toxicity was gastrointestinal, mainly diarrhea, and a poorly described toxicity designated as "unable to tolerate in esophagus or stomach." A patient with chronic lymphocytic leukemia taking the fish oil provided an unusual opportunity to perform a detailed biochemical study of the effect of fish oil capsules on the lipids of malignant cells at several sequential time points in treatment. Studies of the malignant lymphocytes, serum, and whole blood of this one patient revealed an increase in eicosapentaenoic acid, the major component of the fish oil capsules, during fish oil capsule treatment. This study provides a scientific basis for the selection of omega-3 fatty acid doses for future studies in cancer. The maximum tolerated dose found is considerably higher than anticipated from published studies of many human diseases. The observation of a modification of the lipids of leukemic cells, serum, and blood in a patient with chronic leukemia provides a biochemical basis for a possible effect of fish oil supplements on cancer cachexia and tumor growth.

A Southwest Oncology Group and Cancer and Leukemia Group B phase II study of doxorubicin, dacarbazine, ifosfamide, and mesna in adults with advanced osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma.

BACKGROUND: Ewing's sarcomas, osteosarcomas, and rhabdomyosarcomas are significantly more responsive to chemotherapy than other sarcomas. Adjuvant chemotherapy is used routinely based on data from randomized trials. Although a percentage of children with locally advanced or metastatic tumors remain curable, few data exist regarding the tumor's natural history or response and survival in adults. METHODS: This Phase II study evaluated doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) in adults with inoperable or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma. RESULTS: Between 1987-1991, 81 patients were entered; 69 patients were eligible. One patient died of neutropenic infection. Ten patients (14%) responded completely and 34 patients (49%) had a complete or partial response. Response rates were significantly higher for patients with Ewing's sarcoma and rhabdomyosarcoma than for those with osteosarcoma (77%, 64%, and 26%, respectively; P < 0.005). Although there were no significant differences in progression free survival by histology, survival for patients with Ewing's sarcoma was significantly longer than for patients with osteosarcoma (P = 0.004.) At the time of last follow-up, 7 patients (10%) were alive without progression: 3 with Ewing's sarcoma, 1 with osteosarcoma, and 3 with rhabdomyosarcoma. CONCLUSIONS: MAID chemotherapy is an active regimen in adults with advanced or metastatic Ewing's sarcoma and rhabdomyosarcoma. Although there was no direct comparison with a doxorubicin and cisplatin-based regimen, the response rate and survival in patients with osteosarcoma suggest that doxorubicin and cisplatin-based chemotherapy would remain the accepted initial chemotherapy regimen. For patients with rhabdomyosarcoma and Ewing's sarcoma, 10-20% of patients remained disease free at 5 years.

A phase II study evaluating the efficacy of carboplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in patients with stage IIIB and IV non-small cell lung cancer and extensive small cell lung cancer.

We initiated a phase II pilot study to determine whether adding paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to combination carboplatin/etoposide is tolerable and active in patients with advanced non-small cell lung cancer and extensive small cell lung cancer. Patients were given carboplatin (area under the concentration-time curve of 6) followed by etoposide 80 to 100 mg/m2 intravenously on days 1 through 3 followed by paclitaxel 200 mg/m2 intravenously over 3 hours on day 3. On days 4 through 18, granulocyte colony-stimulating factor 5 microg/kg was administered subcutaneously. Each cycle was repeated every 21 days. Fourteen patients have been accrued to the study and 12 were evaluated for toxicity, the first 10 of whom were treated with 80 mg/m2 etoposide. Among the first 10 evaluable patients, significant grade 4 neutropenia occurred in one patient, grade 4 thrombocytopenia in three patients, grade 2 neuropathy in two patients, and grade 3 neurotoxicity in two patients. None of the four patients with non-small cell lung cancer responded to treatment, while six of seven small cell lung cancer patients have obtained major responses to therapy. We have increased the etoposide dose to 100 mg/m2 in subsequent patients. The combination chemotherapy regimen of carboplatin, etoposide, and paclitaxel is tolerable and active in patients with small cell lung cancer.

Phase I trial of etoposide, carboplatin, and GM-CSF in extensive small-cell lung cancer: a Cancer and Leukemia Group B study (CALGB 8832).

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.

Recruiting cancer patients to participate in motivating their relatives to quit smoking. A cancer control study of the Cancer and Leukemia Group B (CALGB 9072).

BACKGROUND: A diagnosis of cancer provides a teachable moment in which a physician can counsel or teach the patient. The Cancer and Leukemia Group B hypothesized that this teachable moment could also be used to encourage counseling of the patients' relatives who smoke. The authors' first study sought to determine the feasibility of such an intervention, the cooperation of the patients, and the compliance of relatives who were smokers. The long-range goal is to recruit by mail a large population of adult smokers into an intervention program and to assist them in quitting cigarette smoking. METHODS: Oncologists and their clinical research associates asked recently diagnosed cancer patients to identify their relatives who were smokers and assist in persuading them to quit. Consenting patients spoke to relatives and mailed them a personalized motivational leaflet along with a list of the benefits of quitting smoking. Intervention was continued only with relatives who were contacted in this manner. The participating physicians then wrote to the smokers, advising them to quit; enclosed with each physician's letter were the National Cancer Institute booklet "Clearing the Air," which is about quitting smoking, and a questionnaire determining "stage of change" (the stage of the smoker's inaction or action regarding quitting smoking). After 6 months, a postintervention questionnaire was mailed to the relatives. RESULTS: Written consent was obtained from 89% of 144 eligible patients solicited. Eighty percent of patients involved in the study contacted relatives. Sixty-three percent of contacted relatives returned the first questionnaire and 40% answered the second. Nine percent of all contacted relatives reported having quit smoking after the intervention. CONCLUSIONS: The intervention proved to be feasible and will lead to the next study, which will randomize relatives who smoke within a more intensive intervention over 12 months and compare the results with nonintervention controls.

Neurotoxicity in a phase I trial of continuous infusion cisplatin with hyperfractionated radiotherapy for locally advanced head and neck cancer.

BACKGROUND: Both twice daily fractionated radiotherapy and concurrent cisplatin with once-daily radiotherapy have been shown to improve local disease control in patients with head and neck cancer. The objective of this phase I trial was to determine the maximum tolerated dose of cisplatin which could be given as a continuous infusion concurrent with twice-daily radiotherapy to patients with locally advanced head and neck cancer. METHODS: Patients were treated with radiotherapy at doses of 110 cGy twice daily for 5 days per week to a total dose of 7040-7590 cGy. Concurrent with radiotherapy, patients received continuous-infusion cisplatin for 5 days per week. Groups of 3-6 patients were treated with doses of 1-3 mg/m2/day. RESULTS: Central nervous system toxicity became dose-limiting. At 1 mg/m2, 2 mg/m2, and 3 mg/m2 confusion was observed and one patient had a seizure. At 3 mg/m2, another patient suffered severe sensory and motor neuropathy. Despite bulky tumors, 12 of the 14 patients had an objective response and 3 achieved a complete response. CONCLUSION: the combination of twice-daily fractionated radiotherapy and concurrent cisplatin by continuous infusion is severely toxic and achieves results similar to less toxic programs. It is not recommended for further investigation or therapy.

Phase II trial of edatrexate in patients with metastatic colorectal cancer.

Edatrexate is an analog of methotrexate which in vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m2/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.

Nonoperative management of non-small cell lung cancer: the current cancer and leukemia group B experience.

The Cancer and Leukemia Group B (CALGB) is studying nonoperative management in two subgroups of patients with advanced non-small cell lung cancer. In patients with regional disease, primarily those with bulky N2 or T4 disease or those with contralateral mediastinal involvement (N3), a phase III trial is under way to explore concurrent carboplatin as intensification of local therapy and additional systemic treatment. This builds on prior CALGB work demonstrating the benefits of induction chemotherapy prior to radiation for selected patients with stage III disease. For patients with still more advanced disease, a trial evaluating efficacy and cost of two supportive care modalities during intensive chemotherapy is about to begin accrual. Following its completion, the CALGB plans to evaluate new chemotherapy combinations based on one or more of the exciting new agents now being tested for the nonoperative management of non-small cell lung cancer.

A phase II study of recombinant beta-interferon at maximum tolerated dose in patients with advanced non-small cell lung cancer: a cancer and leukemia group B study.

Forty-one patients with advanced non-small cell lung cancer (NSCLC) were entered into a phase II study of high dose recombinant interferon (rIFN)-beta. Patients received intravenous (i.v.) rIFN-beta on a Monday, Wednesday, Friday schedule with a weekly dose escalation until > or = grade 3 toxicity or 720 x 10(6) IU/dose was achieved. Thirty-eight patients were eligible. Seventeen patients received the highest planned dose of rIFN-beta and 11 experienced dose-limiting toxicity at lower doses. Ten patients developed progressive disease before grade 3 toxicity was reached. There were no objective responses observed. Significant and dose-limiting toxicities included nausea and vomiting, fever, rigors, severe dyspnea, hypotension, and hypertension. IFN-beta has no measurable antitumor activity against NSCLC even at maximum tolerated doses (MTDs).

Rapid relief of anxiety in cancer patients with both alprazolam and placebo.

This study evaluated 36 cancer patients who were enrolled in a randomized, double-blind, placebo-controlled trial conducted over a 4-week period to evaluate the efficacy of alprazolam in the treatment of anxiety associated with cancer. Hamilton Anxiety Scale scores declined significantly between baseline and the end of the first week of the study in both treatment groups. There was no significant difference in response between the patients receiving alprazolam and placebo. Similar results were obtained from other instruments. These results suggest that nondrug factors or spontaneous improvement may play a more important role than pharmacotherapy in the treatment of anxiety associated with cancer.

Screening for depression and anxiety in cancer patients using the Hospital Anxiety and Depression Scale.

Nine hundred and thirty inpatients and outpatients with cancer were approached to complete the Hospital Anxiety and Depression Scale (HADS). Eight hundred and nine (86.9%) of those approached participated in this screening. Using the suggested cutoff score of 8 for the anxiety and depression subscales, we found that 47.6% of this population would warrant further psychiatric evaluation. Twenty-three percent (23.1%) had scores 11 or greater and would be the most likely to have had anxiety (17.7%) or depressive (9.9%) disorders based on DSM-III-R criteria. Patients with active malignant disease and inpatient status were more likely to have higher depression scores. The HADS was an easily administered tool that identified a large proportion of cancer patients as having high levels of anxiety or depression. However, clinical psychiatric interviews were not performed, so it is not possible to determine what proportion of patients would benefit from treatment.

Leptomeningeal carcinomatosis following craniofacial resection of an ethmoid tumor.

Leptomeningeal carcinomatosis (LMC) is a rare complication following treatment for head and neck cancer. In this paper, we report a case of LMC following surgery and localized radiation therapy for an ethmoid carcinoma, in which laceration of the dura during craniofacial resection may have provided an access for cancer cells into the cerebrospinal fluid (CSF). As a result, the patient developed LMC manifested as multiple spinal nerve root involvement. The patient died 3 months after the diagnosis of LMC. To avoid this type of complication, special care must be taken to prevent tears in the dura during craniofacial resection. Also, we recommend CSF examination be performed prior to radical surgery if there is any suspicion of meningeal invasion.

Carboplatin in non-small cell lung cancer: an update on the Cancer and Leukemia Group B experience.

Since 1984, the Respiratory Committee of the Cancer and Leukemia Group B (CALGB) has evaluated carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). All patients had an Eastern Cooperative Oncology Group performance status of 0 to 2 and had not received previous treatment with chemotherapy. In 70 patients with stage IIIB or IV disease, carboplatin 400 mg/m2 administered intravenously once every 4 weeks produced a 16% overall response rate and an acceptable toxicity profile. Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups. Response rates of 11%, 12%, and 20%, respectively, were obtained. Myelosuppressive toxicity was substantially greater with carboplatin/etoposide and carboplatin/vinblastine than with carboplatin alone. Carboplatin/vinblastine demonstrated efficacy similar to that of the cisplatin/vinblastine combination previously evaluated by CALGB for treatment of similar patients with advanced NSCLC; ease of administration and lack of significant nephrotoxicity also compared favorably with cisplatin-based therapy. In regional NSCLC patients, carboplatin 100 mg/m2/wk can be administered intravenously concurrently with 60 Gy thoracic radiotherapy given over 6 weeks. The impact of concurrent carboplatin added to a sequential chemotherapy-radiotherapy program for patients with regional NSCLC is currently under study by the CALGB Respiratory Committee.

Trimetrexate in untreated and previously treated patients with metastatic breast cancer: a Cancer and Leukemia Group B study.

Twenty-two patients with previously untreated metastatic breast cancer and nineteen patients with refractory metastatic breast cancer were treated with trimetrexate (TMTX). Patients received TMTX 8 mg/m2/day if previously treated or 12 mg/m2/day if previously untreated, both given by intravenous bolus days 1-5, every 21 days. None of the patients previously treated for metastatic disease responded to TMTX. There was one partial responder among the 22 patients with previously untreated metastatic disease. The primary toxicity was hematologic and occurred more frequently in patients with a pleural effusion, low serum protein or albumin, or poor performance status. There were three toxic deaths. The study for previously untreated patients required cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) after 4 cycles of TMTX. This study design for previously untreated patients allows the Cancer and Leukemia Group B (CALGB) to prospectively evaluate the activity of new agents in "chemotherapy-sensitive" metastatic breast cancer.

Silver-stained nucleolar organizer regions in the differentiation of prostatic hyperplasia, intraepithelial neoplasia, and adenocarcinoma.

Nucleolar organizer regions (NORs) are loops of chromosomal DNA that ultimately direct the development of the nucleolus. These NORs are associated with argyrophilic acidic nonhistone proteins which have allowed the demonstration of NORs by a simple silver stain. This staining technique has been used to examine the number of silver-stained NORs (AgNORs) in malignant and benign conditions, and, in general, AgNOR numbers are increased in malignant tissues when compared with normal or benign conditions. More recently, this technique has been applied to premalignant lesions with varying results. We applied this silver stain to prostate lesions where nucleolar features are of diagnostic importance. The stain was applied to ten cases of prostatic hyperplasia, ten cases each of prostatic intraepithelial neoplasia (PIN) grades 1 through 3, and ten cases each of low grade, intermediate grade, and high grade adenocarcinoma. The counting was performed by image analysis. A significant mean difference did exist between low grade and the two higher grades of adenocarcinoma. There was no significant difference in AgNOR counts per nucleus in hyperplasia, PIN, or adenocarcinoma or between the three grades of PIN. The AgNOR silver stain is not useful in the differentiation of hyperplasia, the three grades of PIN, and adenocarcinoma. Also because of overlap among the three grades of adenocarcinoma, it is not useful in the differentiation of these lesions.

Distress associated with cancer as measured by the illness distress scale.

Over 400 cancer patients were given the Illness Distress Scale (IDS), a brief measure of the physical and emotional distress related to serious illness. Physical manifestations of the disease proved to be the source of greatest discomfort among these patients. Greater distress was reported by younger patients and by those who were unmarried. Also, patients with more advanced disease scored higher on the scale. The IDS appeared to measure four dimensions of distress related to the experience of illness, including loss of meaning, physical disease, medical treatment and social isolation. Scores on the instrument correlated highly with a measure of depression, the Beck Depression Inventory. The IDS appears to be a reliable and valid measure of distress associated with serious illness.

Non-Hodgkin's lymphoma of the head and neck: the University of Iowa experience.

The evaluation of a patient with a mass in the head and neck may require the consideration of lymphoma in the process of differential diagnosis. Non-Hodgkin's lymphoma is a well-described heterogeneous group of lymphoid malignancies characterized by a natural history ranging from indolent to aggressive growth. Little has been written, however, concerning the specific features of this disease in the head and neck. Between 1974 and 1984, 287 patients were treated for non-Hodgkin's lymphoma presenting in the head and neck. A multivariant analysis of these cases forms the basis of this report. All case material was reviewed and classified according to the working formulation of the National Cancer Institute and the Ann Arbor Classification System for lymphomas. Sites of initial presentation, methods of diagnosis, choice of therapy and subsequent response to treatment were related to the manifestations of non-Hodgkin's lymphoma in the head and neck. Of particular interest to the head and neck surgeon is the constellation of presenting signs and symptoms which point one to the possibility of non-Hodgkin's lymphoma.

Short course prophylactic cranial irradiation for small cell lung cancer.

Ninety-one patients with small cell carcinoma of the lung were given a shortened, intensive course of prophylactic cranial irradiation consisting of 2,000 rad in five fractions. The CNS relapse rate was 21%, but in only one of 91 patients was the brain the first and only site of relapse. Acute toxicities consisting of headache (16%) and nausea and vomiting (15%) were observed. Results are compared with previous results from other studies of cranial irradiation.

Effects of intravenous hyperalimentation during treatment in patients with small-cell lung cancer.

One hundred nineteen patients were entered onto a randomized trial of the role of intravenous hyperalimentation (IVH) in patients with small-cell lung cancer. IVH was given during the first 30 days of induction chemotherapy to 54 patients. IVH did not effect any improvement in response or survival from therapy. In view of the lack of benefits from IVH, an analysis was made of the toxicities suffered by the 54 patients receiving IVH as well as any effects IVH might have made on chemotherapy-induced toxicity. Toxicities observed included mechanical difficulties with the catheter leading to temporary or permanent discontinuation of the IVH (11 patients), subclavian vein thrombosis (one patient), sepsis in nine patients v none of the 62 control patients, fluid overload (27 patients), hyponatremia (25 patients), and hyperglycemia requiring insulin (13 patients). Patients receiving IVH had higher granulocyte counts on days 14 and 21 of the first cycle of chemotherapy. Analysis shows that this difference is likely caused by fever and infection associated with IVH rather than any nutritional effect on granulopoiesis. In this population of patients, IVH had significant complications but did not ameliorate chemotherapy-induced toxicity and it did not effect any clinical benefit. Future studies of adjunctive nutritional therapy must consider the significant risk in this older population and must limit IVH volume or exclude patients with even mild compromise in cardiovascular functions. Further, any new trial must have a significant rationale for adjunctive use to justify the potential risks.