Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.

BACKGROUND: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors. PATIENTS AND METHODS: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks. RESULTS: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients. CONCLUSIONS: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

Bioavailability study of oral liquid and tablet forms of alpha-difluoromethylornithine.

The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.

Advances in the systemic treatment of cancers in the elderly.

Cancer is a disease of the elderly. More than 50% of all cancers and deaths occur in people over 65 years. Older cancer patients are less likely to be referred to centers or to be given adequate chemotherapy. The elderly are under-represented in Phase I and II trials. Some of this hesitancy to give chemotherapy is related to the increased presence of co-morbid conditions in the elderly. Toxicity is another concern. This review summarizes data from literature on the effectiveness, outcome, and toxicity of chemotherapy in selected tumors. Information is presented on age related effects. In addition, a summary of new agents and biologics is presented that needs to be looked at for age related effects. Some comments are made on the pharmacokinetic impact of physiologic changes in the elderly on chemotherapy drugs. As the world's population ages, we need to include the elderly in trials to get data on age related effects. Most of the information presented shows that effective chemotherapy can be given safely to the elderly and the outcomes and toxicity are equivalent for many of the common solid tumors.

Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.

PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Palliative medicine in the elderly.

Cancer is primarily a disease of the elderly and the palliation of both disease- and treatment-related symptoms is of importance in the practice of cancer medicine in all patients. Many older patients are treated within community hospitals, in which anticancer therapies are less likely to be given and in which the palliation of symptoms should be of primary importance. Many oncologists struggle with the palliation of symptoms in patients who are near the end of life. This is despite the considerable energies that are spent in palliating symptoms in patients who are receiving anticancer therapies at all disease stages. The management of pain has advanced considerably recently with improvements in pain assessment and pharmacologic interventions. However, elderly patients are less likely than younger patients to receive proper pain management. Elderly patients also are less likely to take opioids for pain because of their attitudes and beliefs. Fatigue, dyspnea, and psychologic issues also are of importance in the management of elderly cancer patients both during anticancer therapy and near the time of death. Some elderly cancer patients die in the care of a hospice, although many are not referred to this service. There are many barriers to the provision of palliative medicine and these may be related to health practitioners, to the patients themselves, or to the health care system of which they are part. The increased educational efforts of health professionals are needed to ensure that all patients, including the elderly, have adequate palliation of their cancer-related symptoms.

Drug development in solid tumors: personal perspective of Dr. Emil J Freireich's contributions.

The development of chemotherapy for patients with the major cancers progressed from the initial success attained in the treatment of acute leukemias and choriocarcinoma. Many of the principles of therapy were based on the concepts developed in the experimental laboratories and early clinical studies done at the NIH Clinical Center and other centers around the country. The purpose of this review is to describe some of the early advances in cancer therapy and show how many are based on the efforts of Dr. Emil J Freireich. Over his career, Dr. Freireich has published more than 500 papers and worked on more than 70 different drugs and combinations. The principles defined by Dr. Freireich, namely, the use of intermittent intensive chemotherapy to induce complete remissions (CRs), intensification of therapy in remission, and the use of unmaintained remissions to assess cure, have been important in developing curative chemotherapy programs in patients with acute leukemias. These same principles were applied to combination therapy of Hodgkin's disease as the nitrogen mustard, vincristine, procarbazine, and prednisone combination was developed. This led to the high CR and cure rate for this disease. The treatment of metastatic breast cancer does not produce a high proportion of CRs, and cures of metastatic disease are unlikely with chemotherapy alone. But adjuvant chemotherapy after surgery has resulted in a significant reduction in cancer mortality. Many challenges remain in increasing the cure rate for the major solid tumors. New avenues of controlling cell growth and metastases need to be explored. One approach that is exploitable is the use of drugs or nutrients to prevent cancer. Laboratory approaches are now becoming a clinical reality.

A progress report of cancer centers and tribal communities. Building a partnership based on trust.

BACKGROUND: Over the past 20 years, considerable progress has been made in the early detection and treatment of cancer. Despite these advances, cancer incidence and mortality rates among Native Americans have not kept pace. Cancer centers are in a unique position to offer technical assistance, resources, and a long term commitment that can help address these concerns within tribal communities. METHODS: The University of Wisconsin Comprehensive Cancer Center developed a proactive plan to build collaborative partnerships with Wisconsin Native Americans. This began with an outreach plan that prioritized intervention strategies. A Native American health professional was hired to serve as liaison and advocate. Resources were committed, and staff was assigned to work with the community to develop intervention strategies that would be culturally competent and able to address the concerns of community members. RESULTS: Various collaborative activities resulted from these efforts. These included participation in Native American cancer work groups, conferences, and seminars. Most importantly, these efforts resulted in a partnership with the Native American community that is based on honor and mutual respect. CONCLUSIONS: Careful planning, prioritization, allocation of resources, and a commitment to Native Americans can result in partnerships with the community and interventions that address their cancer control needs. Building and sustaining these partnerships takes time and thoughtful exploration of issues and concerns to develop mutual trust and respect. Both cancer centers and tribal communities can benefit by recognizing that shared power, as a reciprocal value, can benefit the whole.

Management dilemmas in prostate cancer.

Large numbers of men have an undetected prostate tumor, but in only a small proportion of cases do these lesions ever become clinically significant. That being so, it will take time to demonstrate the PSA screening or any given treatment strategy has benefit. Meanwhile, patients need help deciding whether to undergo screening and, if cancer is found whether to opt for aggressive treatment.

Pharmacologic management of cancer pain.

Pain control should be a priority in cancer care. For most patients, the basic strategies are straightforward and pharmacologic: Up to 85% of cancer pain can be managed with oral agents. Barriers arise from misconceptions about opioids. The greatest single problem may be inadequate pain assessment--a deficiency that can be rectified by relying on patients to rate their pain.

Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators.

PURPOSE: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials. METHODS: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded. RESULTS: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions. CONCLUSION: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.

Hepatocellular carcinoma in the very elderly: to treat or not to treat?

We report a case of a patient with hepatocellular carcinoma (HCC) who has two unusual features. The patient was 95 years old at the time of diagnosis and his excellent response to treatment. The authors briefly review the age distribution of HCC and the treatments used. We concluded that therapy should not be arbitrarily withheld based solely on chronological age. Older cancer patients deserve the right to be treated if they so wish.

Cancer treatment and age: patient perspectives.

BACKGROUND: Despite some evidence that age does not meaningfully influence the efficacy or toxicity of cancer treatment, older patients tend to receive less comprehensive cancer therapies. PURPOSE: We conducted a population-based study to evaluate the selection of cancer treatment among the elderly. METHODS: Between September 1 and November 30, 1990, we interviewed by telephone a sample of 628 female Wisconsin residents recently diagnosed with breast (507) or colorectal (121) cancer. The women, aged 20-74 at the time of diagnosis, were identified through Wisconsin's statewide tumor registry. The approximately 30-minute long telephone interview, part of a larger study of cancer etiology, included questions on treatment history, physician specialty, and reasons for the selection of specific therapies. Analyses compared the proportion of subjects with various treatment characteristics according to age (< 65 and > or = 65 years). In evaluating the effect of age on selected therapies, we adjusted summary proportions for stage of disease using the indirect method. The Mantel-Haenszel chi square statistic was used to evaluate statistical significance of the differences in proportions. RESULTS: After adjusting for stage of disease at diagnosis, substantial variation was observed in cancer treatment according to age for both breast and colorectal cancer. Older women (> or = 65 years) with breast cancer were less likely than younger women (< 65 years) to have received conservative surgery, radiation, and adjuvant therapy. Older women were, in fact, more likely than younger women to accept mastectomy (P = .03). Consultation with a medical or radiation oncologist was less common among older than younger patients (57% versus 73%). Older women were also less likely to have alternative therapies presented to them (19% versus 31%). While older patients were less likely to have been offered adjuvant treatments, like chemotherapy (P < .01), they were also more likely than younger women to reject these treatments when offered (P = .01). These differences were observed in both breast and colorectal cancer patients. Regardless of age, the most common reasons for not selecting treatments were physicians' recommendations and the desire for more comprehensive treatment. Concern about side effects, however, was more frequently reported by older women (P = .07). CONCLUSION AND IMPLICATION: Patients' ages influence the choice of treatment. Physicians offer older women with cancer different treatments from those offered to younger women and are less likely to recommend specialist consultation. Physicians' advice and description of toxicity may influence patients' selection of treatment. However, older patients' concerns about the consequences of cancer treatment may also influence treatment choice.

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

BACKGROUND: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice. PURPOSE: A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]). METHODS: Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels. RESULTS: In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour. CONCLUSIONS: These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day. IMPLICATIONS: Studies investigating prevention of cancers with DFMO are under consideration.