Mitogen-induced blastogenesis and receptor mobility inhibition by breast cancer serum with elevated orosomucoid (alpha 1-acid glycoprotein) levels.

Sera from cancer patients have been shown to suppress normal lymphoid cell responsiveness in vitro. In the present study, sera from breast cancer patients were demonstrated to be inhibitory to the concanavalin A (Con A)-, Proteus vulgaris-derived phytohemagglutinin-, and pokeweed mitogen-induced blastogenic responses of normal lymphoid cells. Orosomucoid (OR) (alpha 1-acid glycoprotein), an acute-phase reactant, was elevated in these sera, and a positive correlation existed between the OR level in the sera and its immunosuppressive capacity. When normal lymphoid cells were reached in fluorescein isothiocyanate-labeled Con A, cells that had been preincubated in breast cancer sera known to contain an elevated level of OR showed a significant decrease in Con A receptor mobility as compared to the receptor mobility of the same lymphoid cells preincubated in normal sera. Thus a component(s) from the sera of the breast cancer patients had the capacity to inhibit lymphocyte activation. This inhibition might have resulted from an interaction of OR with the membrane.

Maximizing differences in the concanavalin A-induced blastogenic responses of lymphocytes from breast cancer patients and controls by the use of alpha-methyl-D-mannoside.

In an attempt to magnify differences in the immune responses of potentially immunosuppressed cancer patients and normal controls, an assessment was made on the effects of the competitive inhibitor alpha-methyl-D-mannoside on the concanavalin A (Con A)-induced blastogenic responses of lymphocytes from each of these populations. Lymphocytes from breast cancer patients with metastatic disease were significantly deficient in their capability to undergo blast transformation regardless of whether the monosaccharide inhibitor was added to the assay cultures. In contrast, lymphocytes from breast cancer patients who did not display metastatic disease were capable of normal blastogenic responses to Con A. The addition of alpha-methyl-D-mannoside to lymphocyte cultures caused a significantly greater inhibition of the blastogenic responses of these patients' cells as compared to cells of normal controls. Thus the monosaccharide seems to serve as a useful reagent for optimizing differences between lymphocyte blastogenic responses of normal donors and those of immunodepressed donors. The results suggest that lymphocytes from breast cancer patients without clinically evident metastases possess some modification of their cell membrane. One possibility discussed was that the number or distribution of receptors for Con A on the membrane of lymphocytes of these patients is deficient.

Hepatitis B virus infection and primary hepatocellular carcinoma.

Ninety-three patients with biopsy-proven primary hepatocellular carcinoma (PHC) from Uganda, Zambia, and the United States were examined for serologic evidence of hepatitis B virus (HBV) infection. Patients were tested for hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs), antibody to the hepatitis B core antigen (anti-HBc), hepatitis B e antigen (HBeAg), and its antibody (anti-HBe). Active HBV infection, as indicated by positive tests for HBsAg (with or without anti-HBs) and anti-HBc (without anti-HBs), was present in 62% of PHC patients (58 of 93), in contrast with 10% of African controls (9 of 90), and less than 1% of most United States adult populations reported in the literature. The presence of HBeAg or anti-HBe was rare among PHC patients and controls.

Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

PURPOSE: To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen. PATIENTS AND METHODS: One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease. RESULTS: The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen. CONCLUSION: We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer.

PURPOSE: Scintigraphic flare in association with response to therapy has been well described in the medical literature. During the course of a recent breast cancer trial, it became apparent that several patients with worsening bone scan but no other clinical evidence of disease progression might have potentially benefited from continued therapy, but had therapy discontinued. A retrospective analysis of this issue was performed to assess the magnitude and scope of this problem. MATERIALS AND METHODS: A total of 648 patients with hormone receptor-positive or unknown advanced breast cancer were treated as part of a large-scale trial of first-line hormonal therapy. Patients were assessed for response to therapy, including response duration, progression-free interval (PFI), overall survival, and quality of life. The retrospective analysis presented here was performed to assess whether patients with a possible scintigraphic flare within the first 16 weeks of therapy might have had therapy discontinued prematurely due to a worsening bone scan attributable to tumor flare, rather than due to disease progression. RESULTS: Analysis of the hormonal trial showed that of 376 assessable patients 108 (29%) with bone disease had a possible scintigraphic flare by week 8 or 16 of the trial, based on data on the case report forms and radiology reports (bone scans and x-rays). Of these, 69 patients (64%) were continued on study therapy, which resulted in clinical benefit in 50 (72%) of those patients. In contrast, 39 patients (36%) with possible scintigraphic flare were removed from the trial. CONCLUSION: We conclude that changes in bone scintigraphy that mimic progressive disease early in the course of hormonal treatment of patients with breast cancer metastatic to bone may represent scintigraphic flare associated with response. Thus, clinicians must be cognizant of the phenomenon of scintigraphic flare to avoid premature discontinuation of a potentially beneficial treatment.

Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer.

PURPOSE: We evaluated the safety and efficacy of weekly paclitaxel therapy in women with metastatic breast cancer in a phase II multicenter trial. Entry criteria were relatively liberal to reflect the heterogeneity of metastatic breast cancer in clinical practice. PATIENTS AND METHODS: Patients had histologically confirmed and measurable metastatic breast cancer. Up to two prior chemotherapy regimens for metastatic disease, including prior therapy with anthracyclines and taxanes and prior high-dose therapy, were allowed. Paclitaxel 80 mg/m(2) was administered weekly for 4 weeks per 4-week cycle. RESULTS: We enrolled 212 patients; 211 were assessable for toxicity and 177 were assessable for response. Ninety percent of patients had received prior chemotherapy (adjuvant, metastatic, or both), 46% of patients had three or more involved metastatic sites, and 60% of patients had visceral-dominant disease. Responses were documented on two occasions and were independently reviewed. The overall response rate (complete plus partial response) was 21.5% (95% confidence interval, 15.4% to 27.5%), with 41.8% of patients having disease stabilization. Median time to progression was 4.7 months, and overall survival in all 212 patients enrolled was 12.8 months. Therapy was well tolerated, with a 15% incidence of grade 3/4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity; other serious toxicities were rare. The response rate and toxicity profile in the 34% of patients > or = 65 years of age were similar to that of younger patients. CONCLUSION: Weekly paclitaxel therapy was well tolerated and demonstrated reasonable activity in this relatively heavily pretreated population with advanced disease. Further study of weekly paclitaxel in combination therapy is warranted.

Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group.

PURPOSE: To compare the efficacy and tolerability of anastrozole (1 and 10 mg once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol acetate (40 mg four times daily), in postmenopausal women who progressed following tamoxifen treatment. PATIENTS AND METHODS: Two randomized, double-blind for anastrozole, open-label for megestrol acetate, parallel-group, multicenter trials were conducted in 764 patients. Because both trials were identical in design, an analysis of the combined results was performed to strengthen interpretation of results from each trial. RESULTS: The median follow-up duration was approximately 6 months. The estimated progression hazards ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole 1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole 10 mg versus megestrol acetate. The overall median time to progression was approximately 21 weeks. Approximately one third of patients in each group benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%), and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks. For all end points, individual trial results were similar to the results of the combined analysis. Anastrozole and megestrol acetate were well tolerated. Gastrointestinal disturbance was more common among patients in the anastrozole groups than the megestrol acetate group; the difference between the anastrozole 10 mg and megestrol acetate groups was significant (P = .005). Significantly fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups had weight gain than in the megestrol acetate group. More than 30% of megestrol acetate-treated patients had weight gain > or = 5%, and 10% of patients had weight gain > or = 10%. Patients who received megestrol acetate continued to gain weight over time. CONCLUSION: Anastrozole, 1 and 10 mg once daily, is well tolerated and as effective as megestrol acetate in the treatment of postmenopausal women with advanced breast cancer who progressed following tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain associated with megestrol acetate treatment.

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Randomized trial of cyclophosphamide, doxorubicin, and 5-fluorouracil alone or alternating with a "cycle active" non-cross-resistant combination in women with visceral metastatic breast cancer: a Southeastern Cancer Study Group project.

Patients with visceral patterns of metastatic breast cancer were stratified according to dominant metastatic site and performance status and then randomized to therapy with cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) or CAF alternating with a "cell-cycle active" regimen including cytosine arabinoside, methotrexate with leucovorin rescue, and oncovin ( CAMELEON ). One hundred eighty-seven patients were randomized; response rate for CAF was 44% and for CAF + CAMELEON , 40%. Durations of disease control and survival were not significantly different. Toxicity of CAF was as anticipated with predominant granulocytopenia, vomiting, and alopecia. Toxicity of CAMELEON was less severe than that of CAF, and CAF toxicity was not worsened by preceding courses of CAMELEON ; however, the CAF- CAMELEON regimen was cumbersome and complex leading to both physician and patient noncompliance. Contrary to the preliminary results of a pilot study, and preliminary reports of the present trial suggesting benefit for the CAF- CAMELEON regimen the present randomized trial does not confirm any significant benefit of CAF- CAMELEON over CAF alone in patients with visceral metastatic breast cancer although this conclusion must be viewed in light of the high inevaluability rate due to patient and physician noncompliance.

Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors.

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Postsurgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: a South-Eastern Cancer Study Group (SEG) Trial.

In a prospective study of 622 women with breast cancer, those with one to three histologically positive axillary lymph nodes were randomised after mastectomy to receive cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously on days 1 and 8, and fluorouracil 600 mg/m2 intravenously on days 1 and 8 every 28 days for six cycles (CMF x six), or for twelve cycles of the same chemotherapy (CMF x 12). Those with > or = four positive nodes were randomised to one of these two groups or to 5000 cGy of postmastectomy regional radiotherapy (RT) followed by six cycles of the same chemotherapy (RT + CMF x six). With about 10 years median follow-up, there was no significant difference in survival or disease-free survival among the three groups. There was evidence of decreased locoregional recurrence in patients with > or = four nodes who received RT + CMF x six (relative risk 0.53, P = 0.067). Multivariate analysis indicated that the presence of > or = four positive nodes (negatively) and the percentage of ideal (full) dose of CMF received (positively) were the strongest factors predictive of survival. This study shows no advantage for 12 over six cycles of CMF chemotherapy in women with breast cancer and positive axillary nodes. There was a suggestion of decreased locoregional recurrence but no improvement in survival with radiotherapy for women with > or = four positive nodes.

Combination chemotherapy with vinorelbine (Navelbine) and mitoxantrone for metastatic breast cancer: a review.

Trials establishing the safety and efficacy of single-agent vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) as first- and second-line chemotherapy for metastatic breast cancer led to testing of the combination of vinorelbine and mitoxantrone. Three phase II clinical trials in Europe and South America, and one phase I trial in the United States have studied the effects of this combination on advanced breast cancer. In the two phase II trials that used vinorelbine and mitoxantrone only, response rates were 56% for patients who received the combination as first-line therapy and 36% for those who were anthracycline resistant. A third phase II trial looked at the effects of a combination of mitoxantrone and vinorelbine plus ifosfamide with mesna in patients who had failed at least two prior chemotherapy regimens; a 41% response rate was noted. In the phase I trial, the combination of vinorelbine and mitoxantrone with prophylactic granulocyte colony-stimulating factors was explored. Further trials are needed to study the combination of vinorelbine and mitoxantrone.

Hormonal approaches to breast cancer treatment and prevention: an overview.

Hormonal agents play a critical role in the palliation of advanced breast cancer, as well as adjuvant therapy to surgery and radiation in patients with primary breast cancer. Tamoxifen appears to be the therapy of choice for the initial treatment of metastatic breast cancer in both premenopausal and postmenopausal women, although some clinicians prefer oophorectomy or the use of luteinizing hormone releasing hormone analogues in premenopausal patients. Historically, second-line hormonal therapy for metastatic disease has been with a progestin; however, due to the troubling side effects of weight gain and dyspnea, progestins may soon be replaced by aromatase inhibitors. The development of new antiestrogens lacking estrogen-agonist activity for metastatic disease is in its earliest clinical developmental phases. For adjuvant therapy in postmenopausal women, there is conflicting evidence as to whether the combination of a hormonal agent (ie, tamoxifen) plus chemotherapy provides an advantage over hormonal therapy alone. In premenopausal women areas of active investigation include combination hormonal therapy (eg, tamoxifen plus luteinizing hormone releasing hormone analogues or oophorectomy) and combination chemohormonal therapy (concomitant v sequential). Tamoxifen had been associated with rare cases of thromboembolic events and secondary endometrial cancers. The etiology of these secondary cancers is unclear and controversial; however, the benefits of tamoxifen far outweigh the risks for both palliative and surgical adjuvant therapy. The success of tamoxifen in preventing cancer recurrence in the contralateral breast has led to clinical investigation of the drug for the chemoprevention of breast cancer in women at high risk for development of the disease. The role of tamoxifen for this indication remains to be determined following completion of the National Surgical Adjuvant Breast and Bowel Project trial in North America and additional trials in the United Kingdom and Italy.

A review of vinorelbine in the treatment of breast cancer.

As combinations and sequences of anthracyclines and taxanes increasingly become standard adjuvant treatment for early breast cancer, a major need for new treatment options for metastatic breast cancer will arise. Vinorelbine is highly active in the treatment of metastatic breast cancer, both as a single agent and in combination regimens. Furthermore, it is well tolerated, with a low incidence of subjective toxicities. It is anticipated, therefore, that vinorelbine will become increasingly utilized for treating metastatic breast cancer due to its favorable safety profile, good tolerability, and promising results in combination with other chemotherapy agents. Combinations with trastuzumab and newer molecular targeting agents are being explored. Doublets or triplets of vinorelbine with drugs other than anthracyclines and taxanes could be considered in the next generation of adjuvant and neoadjuvant trials, where it is anticipated that anthracycline/taxane combinations are likely to replace anthracycline/cyclophosphamide combinations as the mainstay of adjuvant treatment.

Liver cell dysplasia: a premalignant condition.

Liver cell dysplasia is defined as cellular enlargement, nuclear pleomorphism, and multinucleation of liver cells occurring in groups or occupying whole cirrhotic nodules. The prevalence, natural history, and relationship to the Australia or hepatitis-associated antigen (HAA) have been studied in 552 Ugandan African patients with normal, cirrhotic, and cancerous livers. Liver cell dysplasia was found in only two of 200 (1%) patients with normal livers, in three of 43 (6.9%) of patients with normal livers bearing primary liver cell carcinoma, 35 of 175 (20.3%) patients with cirrhosis, and 80 of 124 (64.5%) of patients with cirrhosis and primary liver cell carcinoma. Cirrhotic patients without dysplasia were, on average, ten years younger than those with dysplasia and the latter were on average six years younger than those with cirrhosis and carcinoma. Liver cell dysplasia occurred more frequently in males than in females. It was found in all but one instance in macronodular or mixed forms of cirrhosis only. There was a strong relationship between dysplasia and the presence of HAA in 104 patients that suggests a possible carcinogenic mechanism for the longincubation (serum or B) hepatitis virus in liver cell carcinoma. It is concluded that the presence of liver cell dysplasia identifies a group of patients with a high risk of liver cell carcinoma and that they should be followed up by serial alpha-fetoprotein estimations.

Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting.

Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.

Phase II and III clinical trials of toremifene for metastatic breast cancer.

Toremifene (Fareston) received FDA approval in 1997 for the first-line treatment of postmenopausal women with estrogen receptor (ER)-positive or -unknown metastatic breast cancer. Phase II and III trials have demonstrated that first-line therapy with toremifene, 60 mg/d, is as effective and as well tolerated as tamoxifen (Nolvadex), 20 or 40 mg/d, in such patients. To date, phase III trials have failed to show a statistically significant advantage of higher toremifene doses over standard doses of tamoxifen in these women. Studies appeared to indicate minimal efficacy of high toremifene doses in women with ER-negative tumors, but the number of patients studied was small. Although results of some trials of high-dose (240 mg/d) toremifene in tamoxifen-"refractory" patients were negative, other trials that included prolonged (> or = 6 months) stable disease as an indication of clinical benefit yielded positive results.

A phase I clinical trial of a combination of mitoxantrone, 5-fluorouracil, and high-dose leucovorin given on a day 1 and day 8 schedule to patients with metastatic breast cancer.

In a Phase I-II clinical trial, 19 ambulatory women with metastatic breast cancer were treated with a combination of mitoxantrone, 5-fluorouracil, and leucovorin (MFL). The planned schedule of mitoxantrone intravenously (i.v.) on day 1 with 5FU and leucovorin (days 1, 8, and 15) was better tolerated on a day 1 and day 8 schedule. Dose-limiting toxicity was found to be granulocytopenia with very little subjective toxicity encountered. Platelet toxicity and more profound granulocyte toxicity appeared to occur in patients with liver metastases. Since most patients did not have easily measurable disease, a response rate could not be determined, although at least four patients had probable antitumor responses. We conclude that doses of M (7.5 mg/m2 i.v. day 1) and 375 mg/m2 days 1 and 8 of F and L should be the starting doses for Phase II trials on this treatment schedule and should be well tolerated subjectively. Dose escalation and deescalation schemata should be included in a Phase II study design, recognizing that some patients may not encounter toxicity at these doses, while patients with liver metastases may develop inordinate toxicity.

Intratumoral cisplatin/epinephrine-injectable gel as a palliative treatment for accessible solid tumors: a multicenter pilot study.

Intratumoral injections of cisplatin/epinephrine-injectable gel were administered weekly for 4 weeks in 45 patients with malignant tumors of various histologic types. Tumors were located on the skin and subcutaneous tissue primarily of the head, neck, and trunk, and on the tongue, oral pharynx, and esophagus. Patients were not candidates for surgery, radiation, or systemic chemotherapy. Each of the treated tumors (n = 82) was evaluated 2, 4, 8, and 12 weeks after the final injection. The initial dose of cisplatin was 1 mg/cm3 tumor volume, with escalation to 6 mg/cm3 allowed, depending on observed toxicities. The mean cumulative dose per patient for the four treatments ranged from 0.56 to 380 mg cisplatin. No dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. The overall objective tumor response rate was 50% (41 of 82), with 40% (33 of 82) complete responses and a median response duration of 160 days. Complete responses for adenocarcinoma and squamous cell carcinoma were 58% (21 of 36) and 38% (12 of 32), respectively. These results justified further clinical trials to evaluate the role of local chemotherapy with intratumoral cisplatin/epinephrine-injectable gel in the palliative treatment of patients with selected accessible solid tumors.