Lung cancer--a philosophical, ethical, and personal perspective.

Lung cancer is a formidable worldwide health problem causing more deaths than breast, prostate, and colorectal cancer combined. Eighty percent are non-small cell type (NSCLC) and less than one in five patients can have a curative resection. Decisionmaking in treating cancer, and lung cancer specifically, requires an understanding of the basic ethical principles as well as a prioritization of values beyond medical knowledge alone. Choosing a treatment plan can be difficult because of the multiple confronting dilemmas occurring simultaneously. Economic analysis also is required of every major treatment strategy proposed. Active patient involvement is helpful in making these important and difficult choices at the same time clinicians must be mindful of their roles as healers, educators, and innovators of knowledge in a disease that has a five year mortality rate of nearly 90%. Finally, because end of life care issues are so common with this illness, clinicians must be aware of their importance in making dying easier for so many individuals.

Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer.

Gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) are active cytotoxic drugs against pancreatic cancer. Preclinical data evaluating the combination of gemcitabine and irinotecan suggest dose-dependent synergistic interactions in SCOG small-cell lung cancer and MCF-7 breast cancer cell lines. Two phase I trials of this combination have been reported to date: the day 1 and 8 every-3-week schedule (IrinoGem trial), and the day 1, 8, and 15 every-4-week schedule (MSKCC trial). Both trials aimed to determine the maximum tolerated dose of irinotecan when administered as a 90-minute i.v. infusion either immediately after (IrinoGem) or before or immediately after (MSKCC) gemcitabine at 1,000 mg/m2 by 30-minute i.v. infusion in patients with solid tumors. The achieved maximum tolerated dose of IrinoGem has a higher dose intensity of irinotecan (100 mg/m2 on days 1 and 8, every-3-week cycle) compared with the MSKCC schedule (60 mg/m2 on days 1, 8, and 15, every-4-week trial). In IrinoGem, two of three previously untreated metastatic pancreas cancer patients had durable radiologic partial responses. The third had stable disease with clinical benefit for eight cycles. In addition, a patient with metastatic adenocarcinoma of unknown primary--potentially pancreatic--has had a durable response and is alive more than 30 months after the diagnosis. Preliminary results of a 45-patient multicenter phase II trial with IrinoGem in advanced and metastatic pancreas cancer were recently reported. Toxicity was modest, with no toxic deaths or neutropenic fever. Radiologic response rate was 20% of patients (9 out of 45), and a CA 19-9 decrease of more than 50% from baseline values occurred in 32.5% of patients (13 out of 40). Median survival was 6 months (range: 0.9 to 12.2+ months) and median time to treatment failure was 2.9 months (range: 0.1 to 11.3+ months). A pivotal international multicenter phase III trial comparing IrinoGem to single-agent gemcitabine in advanced and metastatic pancreas cancer is ongoing.

Semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor for patients with metastatic gastrointestinal adenocarcinomas: a pilot phase I study.

The authors report the results of a phase I clinical study using semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat patients with metastatic adenocarcinomas of the gastrointestinal tract. A specially engineered cell line, FO1-12, was used to generate semiallogeneic hybrids by fusion with patient-derived tumor cells; the hybrids express HLA class I and II haplotypes derived from both parental cells. For treatment, the vaccine was mixed with GM-CSF, irradiated, and injected intradermally into patients at weekly or biweekly intervals. Vaccinations were associated with minimal or no toxicity and showed that semiallogeneic hybrids formulated with GM-CSF can induce a specific antitumor immune response in some patients, as measured by a delayed-type hypersensitivity response to autologous tumor cells. Because of the simplicity, feasibility, and flexibility of this immunotherapeutic approach, semiallogeneic hybrid vaccines have the potential to be used in the treatment of virtually any type of cancer.

Docetaxel followed by gemcitabine and irinotecan in solid tumors.

Docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (Camptosar, CPT-11) are active single agents in a variety of solid tumors. In combination, synergism may be schedule dependent. Preclinical studies suggested synergistic interactions when docetaxel was administered 24 hours before gemcitabine or irinotecan. The objective of this phase I trial in patients with refractory solid tumors was to determine the maximum tolerated dose of docetaxel followed 24 hours later by gemcitabine and irinotecan. Two different schedules were tested: docetaxel escalated by 5 mg/m2/cohort from an initial dose of 20 mg/m2 on days 1 and 8 (schedule A) or escalated by 15 mg/m2/cohort from 45 mg/m2 on day 8 only (schedule B). In both schedules, docetaxel was given over 1 hour. Gemcitabine and irinotecan were given on days 2 and 9 (arm A) or 1 and 9 (arm B) at fixed doses of 1,000 mg/m2 over 30 minutes and 100 mg/m2 over 90 minutes, respectively. Escalation of docetaxel was planned in groups of three patients, with three additional patients added at the first indication of dose-limiting toxicity. Four dose levels in arm A and one dose level in arm B have been tested. Seventeen patients were evaluable in arm A; one died of an unrelated cause on cycle 1, and another withdrew consent before beginning treatment. Five of six patients were evaluable in arm B; one patient inadvertently received G-CSF on cycle 1. Forty-two cycles have been delivered in arm A (mean; 2.2 cycles/patient), and 25 cycles in arm B (mean, 4.2 cycles/patient); the maximum tolerated dose of docetaxel on arm A was 20 mg/m2. The dose-limiting toxicities were grade 3 diarrhea in one patient, grade 3 infection in two patients, and grade 4 neutropenia for > 4 days in one patient at the 25 mg/m2 level. The dose-limiting toxicities on arm B occurred at the first dose level and included grade 3 diarrhea in one patient, grade 4 diarrhea in one patient, and grade 4 neutropenia for 4 days in another patient. Accrual to schedule B was closed after testing the cohort 1 dose level because testing of a single deescalated docetaxel dose given on day 8 was not considered clinically relevant.

Irinotecan in the management of patients with pancreatic cancer.

Synergy with no overlapping toxicities has been demonstrated for the combination of irinotecan (Camptosar, CPT-11) and gemcitabine (Gemzar) in vitro. Results of a single-institution phase I study in which patients with previously untreated pancreatic cancer were given irinotecan and gemcitabine were promising, with two of three patients achieving a partial response. Because of the favorable outcome of the phase I study, a multicenter phase II trial was undertaken in previously untreated patients with pancreatic carcinoma. Data from other sites entering patients in this phase II study have been analyzed, and a multicenter phase III trial of single-agent gemcitabine vs the irinotecan combination in first-line treatment of patients with locally advanced or metastatic pancreatic cancer is underway.

Assessment of pain in advanced cancer patients.

This study tested the feasibility of standardized pain assessment instruments in a population of patients with far advanced cancer at the time of admission to a specialty hospital. As pain is a symptom, pain control must be based on patients' self-report. Cognitive impairment and severe physical illness, however, limited the ability to use these tools. Almost one-half (44.8%) of the patients were unable to use the McGill-Melzack Pain Questionnaire, the Memorial Pain Assessment Card, or the Faces Pain Rating Scale. Patients with far advanced cancer fall into three groups: those who report pain, those who report no pain, and those who are unable to state whether or not they have pain. This study demonstrates the need to undertake pain assessment while the patient is able to respond and to monitor behaviors that could be indicative of changes in pain.

Pain management issues as part of the comprehensive care of the cancer patient.

Pain is a common, feared, but treatable component of malignancy. The ability, however, to successfully relieve the difficult symptoms of progressive disease, including pain, require an understanding of tumor behavior, complications, and cancer therapy. Despite the treatability of cancer pain and multiple clinical options, the clinician faces many challenges to adequate pain management.

Pain, opioid use, and survival in hospitalized patients with advanced cancer.

PURPOSE: Pain is a common and feared symptom for patients with incurable cancer. Comprehensive assessment provides the foundation for effective pain management, and data that clarify the relationship between pain and other relevant factors also facilitate this process. The main objective of the study was to develop a clinical data base for advanced cancer patients and to survey data to determine (1) pain severity at admission, (2) opioid use at admission, (3) change in opioid use during the hospital stay, and (4) survival in the hospital. PATIENTS AND METHODS: Information was collected prospectively on 1,103 patients admitted and on 1,017 patients who died within 6 months of the study's end. Demographic and clinical data were recorded 72 hours after admission and soon after death or discharge. RESULTS: Seventy-three percent of patients had pain at admission. Cancer of the cervix was frequently (68%) associated with severe pain, as were prostate (52%) and rectal/sigmoid tumors (49%). Severe pain was more probable in those with bone metastasis, those admitted from home, and in those younger than 55 years of age. The majority (71.7%) of patients had a stable dosing pattern, and only 4.2% of the patients required dose increases of at least 10% per day. CONCLUSION: This study demonstrated the wide variability in opioid doses required. No reliable predictor of opioid requirement was identified, and this lack of predictability of cancer pain severity underscores the need for ongoing assessment.

Hospitalized advanced cancer patients: a profile.

More than half of all individuals diagnosed with cancer will not be cured and will require supportive care for some period. Nonetheless, few large scale studies have documented the prevalence and complexity of the problems of advanced disease. This study examined the demographic treatment and outcome variables for 1,103 admissions to a specialty acute care hospital devoted to the care of patients with advanced cancer. The population is profiled, and significant relationships among these variables are identified. The prevalence of major symptoms is documented. This data base study provides a foundation for further research.

Clinitron therapy and pain management in advanced cancer patients.

Many patients with advanced malignancy develop bone metastases, pathologic fractures, and skin breakdown, all of which compromise comfort and interfere with the delivery of patient care. In 1986, 38 Clinitron beds were utilized at Calvary Hospital, a specialty hospital for advanced cancer, for patients who were immobile and/or had significant pain. Twenty-five patients were entered into an open study to assess and document this experience. Twenty-two patients experienced improved comfort while Clinitron therapy was in use. Global questionnaires relating to pain, comfort, appetite, and sleep were completed by the patients, their primary nurses, and attending physicians. No adverse effects were noted. The results suggest that Clinitron therapy is effective in promoting comfort in select advanced cancer patients. The difficulties encountered in research in this patient population are presented.

Reason, courage, and grace: notes of a death watcher.

Dying is strikingly private and personal, and it breaks the interconnectedness of all human life. It is at such a time that the physician's humanity must touch the unique personhood of the afflicted if the death is to be "good". A physician's duty does not rest on the medical profession's code of conduct; it consists of the physician's moral obligation to a specific person in a specific situation. That person's entire identity--not just the physical being--is assaulted by terminal illness; the emotional, familial, and social dimensions of selfhood are ravaged by the disease as surely as is the body. Each individual is involved in his or her suffering in a way that is unique and that cannot be understood or appreciated by anyone else. But the physician must try to bridge the distance that is placed around the sufferer by the dying process. And it is only with his or her own humanity that the care giver can accomplish this. That humanity should inform all decision making, and thus bring with it genuine control and comfort. In this way the patient can truly "own" his or her own death. The patient can thereby attain reason and courage, which together are the quality of grace.