Biomedical subjects
Publications and source records attributed to F Holmes.
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Paclitaxel is a novel anticancer drug that is being increasingly used to treat cancer of the breast and other organs. We describe a patient with metastatic breast cancer and liver dysfunction who had severe mucocutaneous toxicity after administration of a standard dose of paclitaxel. Another interesting finding in this patient was that the administration of paclitaxel led to a prompt resolution of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia, which had previously proven to be refractory to multiple conventional antihypercalcemic agents as well as anthracycline-containing chemotherapy combination. The need for definitive guidelines for paclitaxel administration in the setting of hepatic dysfunction and the potentially unique sensitivity of PTHrP--producing cells to paclitaxel are discussed.
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We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m2/d (dose level 0) and 13 at a dose of 2150 mg/m2/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50-0.99 x 10(9)/l) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4-65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.
Molecular biology has provided clinical investigators and basic scientists with the tools to identify those changes present within neoplastic hematopoietic and epithelial cells that lead to the evolution of unregulated patterns of cell growth. This information has made possible the development of therapy that involves genetic modification of either the normal hematopoietic cells (for chemoprotection), or the tumor cells themselves to suppress the growth of these cells. This article will summarize the clinical and laboratory data that is evolving in this area.
We reviewed the management of 55 cases of loco-regional recurrence after limited surgery and irradiation for breast cancer. Forty-three patients had disease localized to the breast, with axillary involvement in seven. Four had axillary relapse without tumor recurrence in the breast. Eight had breast recurrence extending to involve the chest wall. Mastectomy was used successfully for 41 first recurrences, and seven were controlled by wide excision; 21 of 48 patients also received chemotherapy and/or hormonal manipulation. Diffuse soft-tissue tumor required systemic therapy first, followed by wide excision when possible. Eighty-nine percent of first recurrences were controlled but disease recurred again in eight patients. Overall, 80% of cases were free of loco-regional disease at a median follow-up of 27 months. Reconstructive surgery was valuable for wound closure after wide resections, and for cosmetic procedures. Despite the previous irradiation, surgery complications were acceptable.
The records of 42 patients who had axillary metastases compatible with a clinically occult breast primary were reviewed. Forty patients had mammography performed as part of their evaluations. Mastectomy yielded the primary tumor in one of 13 patients; biopsy yielded positive results in one of five. Among the 29 patients who did not undergo mastectomy, 16 received breast irradiation, and 13 were simply observed for signs of the primary tumor. For the patients who did not undergo mastectomy, the 5-year actuarial risk for appearance of a primary was 17% in the irradiated group versus 57% in the nonirradiated group (P = 0.06). Patterns of failure are correlated with stage and local and systemic therapy. The results affirm our belief that patients with axillary metastases histologically consistent with breast tumor should be treated identically to patients with similar nodal stages and proven breast primaries.
A total of 535 evaluable febrile episodes in neutropenic patients were randomly assigned to treatment with ticarcillin-clavulanate plus vancomycin (TV), ceftazidime plus vancomycin (CV), or all three antibiotics (TCV). The TCV regimen was significantly more effective than TV, considering all evaluable episodes, documented infections, gram-negative infections, and infections in patients with persistent severe neutropenia (less than 100 neutrophils/mm3). The results with CV were intermediate between TV and TCV. The toxicities were similar with all three regimens and consisted primarily of skin rashes. The TCV regimen is effective for empiric therapy of fever in neutropenic patients and probably should be utilized in preference to CV or TV, although its superiority over CV in this study was inconclusive.
We studied survival and prognostic factors in all cases of hepatocellular carcinoma seen at a Midwestern teaching hospital from 1947 through 1986. Of the 70 cases, 56 were diagnosed during life and 14 at autopsy. There were 47 males and 23 females with age at diagnosis ranging from 14 to 88. Median survival for the 56 patients diagnosed during life was 106 days. Only 11 patients lived longer than one year. Two patients were long survivors and presumed cured, one living 27 years after diagnosis and surgical treatment and the other 19 years. Cox regression model showed young age at diagnosis and low stage of disease at diagnosis to be significant predictors of long survival. White patients survived nearly twice as long as black patients but the difference was not significant. Gender and year of diagnosis did not appear to be important determinants of survival. Pathologic material was still available for one of the two long survivors and the histology was that of fibrolamellar carcinoma of young adults.
We studied 4,968 cases of prostatic carcinoma to determine if there is a relationship between tumor grade and patient age at diagnosis. Cases were stratified into arbitrary age groups and classified as either better differentiated (Grades I and II) or worse differentiated (Grades III and IV). The 4,596 graded cases were distributed by stage as follows: Local 3,451 (75%), Regional 509 (11%), and Distant 636 (14%). When patients in all stages were considered together, the percentage of men with better differentiated tumors dropped from 77.8% of patients under 60 to 67.5% of patients 80 or older (P less than 0.00001). This trend for older patients to have more poorly differentiated tumors was also seen in patients with localized disease (P less than 0.0005). The fact that occult, biologically inactive prostate cancer is common in older men has led some to extrapolate that clinically apparent disease follows a more benign course in the elderly. Our findings suggest that, on the contrary, elderly men with clinically apparent disease have worse differentiated tumors than their younger counterparts.
Acute leukemia is more common in older people than in the young or middle-aged. However, the possibilities of achieving remission or prolonging survival are both inversely correlated with increasing age. We studied survival in 118 acute leukemia patients over the age of 64 seen at a university hospital from 1970 to 1987. Seventy percent had myeloid morphology. Median survival times were 106 days in those diagnosed in the 1970s and 71 days for those diagnosed in the 1980s. This was little changed from an earlier series from the same hospital extending back to the 1940s in which median survival was 69 days. Considering the two decades separately, age at diagnosis, sex, race, type of leukemia, and whether or not disease-specific treatment was applied had no significant effect on survival duration. Acute leukemia in the older patient demands difficult medical and ethical choices. Supportive therapy provides immediate comfort and relatively limited morbidity with certainty of death within a few months. Disease-specific therapy causes immediate morbidity for all, shortened life for the majority, and extended life for the minority.
To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.
We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.
Forty six episodes of infection in 43 cancer patients were treated with oral ciprofloxacin at a dose of 750 mg every 8 h. The overall clinical response was 85%. Patients with microbiologically proven infections had a higher response rate (90%) than patients with infections from whom no causative organism(s) could be isolated (69%). Two of three neutropenic patients responded favourably. Favourable responses were seen in a variety of infections including bacteraemia, urinary tract infection, respiratory tract infection and skin and soft-tissue infection. Resistance to ciprofloxacin developed in one isolate of Pseudomonas aeruginosa. Side effects were mild and were predominantly gastrointestinal in nature. Orally administered ciprofloxacin is safe and effective for the therapy of many serious infections in cancer patients. However, more data are required in patients who are neutropenic.
We studied predisposing factors in 56 women with anal cancer, comparing them with 56 matched controls drawn from the population. A detailed pretested questionnaire was administered to each study subject in a structured interview and blood was drawn for detection of herpes simplex virus antibodies by radioimmunoassay. Pathologic material from cases was obtained and evidence of human papilloma virus infection was sought. By univariate analyses we found associations between anal cancer and positive herpes simplex virus 2 titer (p = 0.0017), cigarette smoking (p = 0.0028), previous positive or questionable cervical Papanicolaou smear (p = 0.0124), and increasing number of sexual partners (p = 0.0224). By the multivariate technique of logistic regression there were independent and significant associations with cigarette smoking (p = 0.0126), previous use of hemorrhoid preparations (p = 0.0149), and history of disturbed bowel habits for greater than 1 mo (p = 0.0273). Anal cancer in women is a rare disease associated with cigarette smoking and sexual experience. Its association with previous anorectal disease is unclear and deserving of further study.
Fourteen patients with disseminated breast cancer with primary or secondary resistance to tamoxifen were treated with LY156758. There were no complete or partial responses and 1 patient showed a minor response. These data illustrate that LY156758 did not have significant antitumor activity in patients previously treated with tamoxifen therapy.
Sixty-six patients who underwent endomyocardial biopsy for detection of mitoxantrone (Novantrone; dihydroxyanthracenedione) cardiac toxicity were evaluated. All but one had breast cancer, 29 had received prior doxorubicin and 29 of the 37 patients who had not had prior doxorubicin received it or another anthracycline subsequently. Endomyocardial biopsy was carried out initially after four courses of chemotherapy with increasing intervals thereafter. Although cardiac ejection fraction was determined before each course of chemotherapy, our data are limited to cardiac ejection fractions from our own institution which were repeated approximately every four courses. Endomyocardial biopsy changes consisting of dilatation of the sarcoplasmic reticulum with vacuole formation, and myofibrillar dropout are similar to the early changes of anthracycline cardiomyopathy. While there was a slight suggestion of increasing biopsy grade with increasing mitoxantrone dose, no significant changes in cardiac ejection fraction could be associated, regardless of prior doxorubicin therapy. We concluded that mitoxantrone does show morphologic evidence of cardiac toxicity; however, the structural changes are minor and are haemodynamically insignificant. Determination of how much mitoxantrone treatment may contribute to the deterioration of pre-existing doxorubicin damage must await the outcome of longer follow-up.
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