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Gastrointestinal cancer is a commonly encountered problem in the elderly. Screening for colorectal cancer is cost effective and is increasingly important in this population because incidence rises rapidly in the seventh and eighth decades of life. Surgery remains by far the most important curative option and may be appropriate even at an advanced age. For patients who are not curable, quality of life is the yardstick by which palliative options should be evaluated.

Summary Background Advanced pancreatic cancer is a rapidly fatal disease whose course has been little influenced by chemotherapy. Earlier studies have shown some modest promise for the combination of protracted infusional 5-fluorouracil (PIF) and cisplatin. We sought to evaluate a regimen of possibly lesser toxicity, PIF plus weekly carboplatin. Patients and Methods Fifty-four patients with advanced adenocarcinoma of the pancreas were treated with a regimen of protracted infusional fluorouracil 300 mg/m2/day for 70 days and carboplatin 100 mg/m2/weekly on weeks 1 through 10 of a 12-week cycle. After a two-week rest, cycles were repeated until progression. Results Median duration on treatment was 82 days (range 4–490 days). Toxicity was mild. Grade 3–4 toxicities were anemia 11%, leukopenia 6%, thrombocytopenia 2%, nausea/vomiting 7%, diarrhea 9%, mucositis 9%, and renal 2%. Response was evaluable in 47 patients. There were two complete and seven partial responses (17% overall objective response rate among all patients). Stable disease for greater than 12 weeks was seen in 19 patients (40%) and progression in 19 (40%). The median overall survival was 22 weeks (1–99), with 61 weeks median survival in responders (22–99). One-year survival was 13%. Conclusions Response and survival results with this regimen are at least equal to the best combination regimens reported, and were obtained with a low overall rate of serious toxicity.

Pancreatic cancer is an aggressive disease and its patients typically have a short survival, usually marked by pain and rapid debilitation. The disease has been considered relatively chemoresistant, although many chemotherapy regimens have been described.Clinical results with chemotherapy, since the first publication of response in 1960, were reviewed for efficacy and toxicity. Emphasis was given to prospective trials with adequate power and clear evaluation criteria and endpoints.Published response rates vary enormously in this disease, with rates in earlier single-institution trials tending to be much higher than those in studies with stringent response criteria, particularly recent cooperative group trials. Using stringent criteria, the upper limit of the objective response rate is approximately 20%. No convincing improvements in median survival can yet be attributed to chemotherapy. Few trials have measured quality of life, but symptomatic palliation rates may exceed objective response rates. Some low-toxicity regimens (such as those based on infusional 5-FU) yield response rates as high as some more toxic combinations.Many early trials significantly overstate the efficacy of chemotherapy for patients with pancreatic cancer, apparently due to flexibility of response criteria. However, useful symptomatic palliation may occur even without an objective partial response. It is possible that slow resolution of the desmoplastic component of these tumors may underestimate tumor killing. Thus, quality of life is an important parallel endpoint (with survival and response) in chemotherapy trials in this disease.

Pancreatic cancer is one of the most lethal neoplasms. Incidence in the United States has remained fairly stable over the past 25 years, with about 25,000 cases annually. Almost 100% of cases are fatal. Incidence in the developed world parallels that in the United States. Incidence in undeveloped nations is lower but may be underreported. Worldwide incidence is about 185,000 cases per year. There are no striking environmental risk factors, and geographic variation is less than with other gastrointestinal cancers. The most significant risk appears to be cigarette smoking, with a risk ratio of about 2. Alcohol and coffee consumption have been reported as possible risks in some (but not in most) studies. Diet is probably a significant factor, but is difficult to evaluate quantitatively. Other putative associations, including diabetes, probably are unimportant.

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

An intensive weekly chemotherapeutic treatment for extensive disease small-cell lung cancer was piloted in 14 patients. The regimen consisted of 6 drugs. Two drugs were given each week for a total of 12 weeks of treatment. Modifications were required in the protocol to attempt to overcome excessive toxicity. Unexpected toxicity included anemia requiring transfusions in 8 of 10 patients completing treatment, sepsis in 8 of 14 with 3 related deaths, and prolonged grade III motor neurotoxicity in 2 patients. All 3 patients who died of sepsis had shown evidence of response, and 8 of the remaining 11 had 90% or greater tumor shrinkage. Two others had a partial response. Median survival time for all patients was 9.3 months.

One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.

Two of 200 patients treated with chlorozotocin have evidenced interstitial pulmonary disease. The cumulative doses of chlorozotocin were 480 and 670 mg/m2 when symptoms developed. Pulmonary function tests in both patients showed impaired diffusion, and an alveolar-arterial gradient which worsened with exercise. Open-lung biopsy in one patient showed typical interstitial inflammation and early fibrosis, and excluded lymphangitic spread of tumor. Discontinuation of chlorozotocin resulted in either improvement or stabilization of the pulmonary disease.

Twenty-one patients with metastatic colorectal cancer were treated with high-dose intravenous interferon alpha-2 (30-50 X 10(6) units/m2) administered daily for 5 consecutive days. Courses of therapy were repeated every 2 to 3 weeks. No tumor responses were seen among 15 evaluable patients. In two subjects, disease remained stable for 3 and 7 months, respectively. Toxicity was substantial and a de-escalation of dose was frequently required. Fevers, gastrointestinal symptoms, fatigue, leukopenia, and elevated serum transaminases were common. High-dose interferon was found to be ineffective in the treatment of metastatic colorectal cancer. A daily dose of 50 X 10(6) units/m2 was greater than the maximum tolerated dose in this group of patients.

We have conducted a phase I study of the cyclic peptide echinomycin (Quinomycin A) on a schedule of administration of once every 4 weeks. Ten dose levels between 20 and 1800 micrograms/m2 were studied. Acute gastrointestinal toxicity, thrombocytopenia, and transient elevations of serum transaminases occurred at doses of greater than or equal to 1000 micrograms/m2. Gastrointestinal toxicity was severe and dose-limiting in several patients at doses of 1800 micrograms/m2. Thrombocytopenia was erratic, but generally increased with drug doses. Platelet count nadirs occurred 5-10 days after administration. Hepatic toxicity was reflected in transient elevations of serum transaminases without hyperbilirubinemia. Three patients experienced apparent anaphylactic reactions to doses of 1500 micrograms/m2. The maximum tolerated single dose of echinomycin was 1800 micrograms/m2. A starting phase II dose of 1500 micrograms/m2 is recommended.

Gastric cancer is the most chemotherapy-responsive adenocarcinoma of the major gastrointestinal sites. For patients with advanced disease, the response rates and survival achieved with recently designed Adriamycin-based regimens represent an improvement over the past use of 5-fluourouracil alone or combined with a chloroethylnitrosourea. Effective palliative treatment can be administered in an out-patient setting without the necessity of producing severe or life-threatening toxicity. Nevertheless, response durations are finite, as is patient survival. It is essential that Phase II trials of new drugs be continued in an attempt to identify agents with greater therapeutic activity for this disease. For the locally unresectable stage, combined modality therapy incorporating palliative resection of the primary tumor, regional radiation therapy and chemotherapy, has provided long-term disease-free survival for 15--25% of all patients. The most promising aspect of current clinical investigation is the application of the Adriamycin-based drug combinations in controlled trials of surgical adjuvant therapy.

Thirty-three patients with metastatic malignant melanoma, some of whom had received previous chemotherapy, immunotherapy, or radiotherapy, were entered in a trial of three different doses and schedules of administration of lymphoblastoid alpha interferon. The overall response rate was 9%; some patients had long-lasting response and two achieved complete response. There was no clear advantage to any one regimen. Dose-related flu-like syndrome, granulocytopenia, hepatocellular enzyme elevation, and anemia were observed as the most common toxic effects. Interferon deserves further study in the treatment of malignant melanoma.

The acute aspects of organophosphate poisoning are well understood. Persistent weakness and muscular wasting in some cases have been attributed to neuropathic effects resulting in muscular atrophy from denervation. Recently, necrosis of skeletal muscle has been induced by chronic inhibition of cholinesterase with organic phosphates in a reproducible experimental model. The literature on organophosphate poisoning in man alludes to cases in which it appears plausible to postulate this mechanism as a cause of a residual myopathy. A new case in which chronic organophosphate intoxication may be implicated in the etiology of a proximal myopathy is presented. Reports of additional cases, followed up from the onset of symptoms, are needed to determine whether primary myopathic effects are a clinically significant complication of chronic organophosphate poisoning.