Adjuvant chemotherapy in 2005: standards and beyond.

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.

Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours.

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.

Prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers.

Temozolomide (Temodal) is an oral imidazotetrazine. Increased temozolomide exposure and subsequent depletion of O-alkylguanine alkyltransferase may improve the activity of temozolomide. The rationale for investigating temozolomide plus Caelyx is based on their antitumor activity, their formulation and no significant overlapping toxicities. We conducted a study of a prolonged schedule of temozolomide (orally on days 1-7 and 15-21) plus Caelyx (day 1) every 28 days. Twenty-one patients (melanoma n=10, sarcoma n=7 and other n=4) were assigned to four dose levels (DL; temozolomide+Caelyx, mg/m): DL1: 100+30 (n=3 patients), DL2: 100+40 (n=6 patients), DL3: 125+40 (n=6 patients) and DL4: 150+40 (n=6 patients). Dose-limiting toxicities were noted after 2 or more cycles in one patient at DL3 (stomatitis) and one patient at DL4 (grade 4 ANC >/=7 days). Treatment delays and/or dose reductions (due to hematological toxicity) were necessary in five of six patients receiving DL4 compared with one of six patients at DL3, and one patient at DL1 and 2. Thus, the recommended dose was temozolomide 125 mg/m (daily for 7 days every other week) plus Caelyx 40 mg/m (day 1 every 4 weeks). Other toxicities were mild. Antitumor activity was observed in eight patients, including one complete response (melanoma), three partial responses (one melanoma, two sarcomas) and four patients with stable disease (three melanomas, one Ewing), with a duration lasting from 14 to 135+weeks. Two melanoma patients showed tumor stabilization in non-irradiated cerebral lesions. This schedule of temozolomide allowed higher dose intensity (1750 mg/m in 4 weeks) compared to the standard 5-day regimen (1000 mg/m in the same amount of time).

Clinical phase I and pharmacokinetic study of S 16020, a new olivacine derivative: report on three infusion schedules.

S 16020, a new 9-OH olivacine derivative, is a novel topoisomerase II inhibitor with activity in cell lines presenting the classical multidrug resistance phenotype. This report summarizes, in addition to pharmacokinetic data, the whole phase I clinical experience of S 16020 using three different infusion schedules. Asthenia and skin toxicity were the main side effects. In an attempt to understand the skin toxicity mechanism, experiments in animals were performed, the results of which are reported. S 16020 showed rapid tumor necrotizing activity in some patients, with soft tissue metastases of epidermoïd tumors and pain at the tumor site. To document the side effects of S 16020 and tumor site reactions (pain, edema, inflammatory signs), inflammatory parameters and some cytokines were measured. In our patients there was no hemolysis and no detection of anti-S 16020 antibodies, confirming the absence of immunogenicity of the compound. Based on the overall data of the three infusion schedules of S 16020, the dose of 100 mg/m(2) over 3 h every 3 weeks was selected for phase II studies.

EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organization for Research and Treatment of Cancer.

BACKGROUND: We performed a phase I study of polyethylene glycol (pegylated, Stealth) liposomal doxorubicin (Caelyx, Doxil) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent. PATIENTS AND METHODS: Eligible for the study were metastatic breast cancer patients who had received a maximum of one prior therapy for metastatic disease. The defined dose levels were 60, 70, 80 and 90 mg/m2. RESULTS: Twenty patients were assessed at starting doses of 60 mg/m2 (n = 9) or 70 mg/m2 (n = 11). The dose-limiting toxicity was mucositis. Severe skin toxicity was not observed at the 60 mg/m2 dose level, and occurred in only one patient treated at 70 mg/m2. Significant neutropenia, alopecia, and nausea and vomiting were rare events. No clinical cardiac events occurred, despite a median cumulative doxorubicin dose of 323 mg/m2 (range 5-630 mg/m2). Partial responses were documented in five patients. Pharmacokinetics were assessed in 15 patients, and confirmed the long terminal half-life of the agent (median 77 h) demonstrated in earlier studies. CONCLUSIONS: The recommended dose of Caelyx/Doxil using this schedule is 60 mg/m2 every 6 weeks. This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.

A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors.

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.

Breast cancer therapies in development. A review of their pharmacology and clinical potential.

Although the management of breast cancer has improved over the past few decades, it remains an important challenge for the clinician. Cytotoxic chemotherapy and hormonotherapy, when given in the adjuvant setting, have a definitive though modest impact on the outcome of early-stage breast cancer. In metastatic disease, these therapies help to provide substantial palliation of symptoms but have a limited impact on survival. The discovery of vinorelbine and the taxanes, paclitaxel and docetaxel, certainly represented the most encouraging clinical development of the 1980s in breast cancer therapy. Several other new cytotoxic agents have been recognised for their potential in the treatment of this disorder. Many of them are only in a very early phase of their clinical development and it remains to be proven that they will have a major role in daily practice in the near future.

Dose optimization of anthracyclines.

Despite the fact that anthracyclines are one of the most commonly used and active classes of anticancer agents and that their pharmacokinetic behavior has been extensively studied, optimal anthracycline dosage regimens have not yet been defined. Only a few pharmacokinetic-pharmacodynamic (toxicity and response) relationships have been determined so far for anthracyclines and are here reviewed. The use of prolonged continuous infusion and fractionated schedules reduces doxorubicin cardiotoxicity but no sufficient data are available to date to demonstrate if those schedules result in equivalent antitumor efficacy to that achieved by IV bolus. Not enough data are available to conclude which is the best pharmacokinetic parameter to use in order to predict anthracycline-induced myelosuppression, other toxicities and/or clinical tumor response. Dosing adjustments of anthracyclines in the presence of liver dysfunction are still based on empirical guidelines instead of a more rational basis. Much work still remains to be done if we are to improve our knowledge of anthracyclines' pharmacodynamics. Limited sampling strategies will be of great help in the establishment of pharmacokinetic-pharmacodynamic relationships, which is essential to optimize the dosage regimen of anthracyclines in order to maximize their efficacy and/or minimize their toxicity in individual patients.

Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis.

PURPOSE: This phase I study of Taxotere (RP 56976, NSC 628503; docetaxel, Rhône-Poulenc Rorer, Antony, France) was undertaken to determine the maximum-tolerated dose (MTD), toxic effects, and basic pharmacokinetics of a day-1 and -8 schedule of this novel semisynthetic product related to Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT). PATIENTS AND METHODS: Thirty-two eligible patients with refractory solid malignancies have been treated with a 1-hour infusion of Taxotere on a day-1 and -8 schedule every 3 weeks as long as patients maintained a polymorphonucleotide count > or = 1,500/microL and a platelet count > or = 100,000/microL. Dose levels tested have ranged between 20 and 110 mg/m2 per course. RESULTS: Considering 128 assessable courses, the main toxicities have been neutropenia (which was dose-limiting), asthenia, alopecia, hypersensitivity reactions, skin toxicity, and edema. No significant cardiac or platelet toxicity has been observed. Seven patients have had aggravation of preexisting paresthesias or new onset of sensory symptoms during Taxotere treatment. The MTD at this schedule appears to be 110 mg/m2 per course, with six of 10 patients at this level experiencing severe toxicity. Five partial remissions have been observed in four heavily pretreated patients with breast cancer and in one patient with adenocarcinoma of unknown origin. Two patients with ovarian cancer have had meaningful decreases in CA125 levels. CONCLUSION: Like Taxol, this novel chemotherapeutic agent appears to possess promising activity in patients with refractory breast and ovarian neoplasms, with tolerable toxicities. Using this schedule, 100 mg/m2 per course is the recommended dose for future phase II trials.

Potential role of oral anthracyclines in older patients with cancer.

Two anthracycline analogues, idarubicin and menogaril, have acceptable bioavailability via the oral route of administration. Encouraging antitumour activity of oral idarubicin has been reported in breast cancer, non-lymphocytic leukaemia, non-Hodgkin's lymphoma and myeloma. The outlook for menogaril is less clear, given the modest antitumour activity reported so far. Although the oral formulations of idarubicin and menogaril remain investigational, they represent a step forward in the direction of developing new active anticancer drugs with oral bio-availability. Further prospective studies of the orally-active anthracyclines in elderly patients with cancer are justified. These studies should address specific issues such as optimal dosage regimens as a function of 'physiological age', and quality of life.

Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex.

Forty-six patients with refractory solid malignancies received the new platinum complex [2,2-bis(aminomethyl)-1,3-propanediol-N-N'] [1,1-cyclobutanedicarboxylato] [(2-)0,0')] platinum (zeniplatin). Zeniplatin was given, without hydration or mannitol, as a 60- to 90-min i.v. infusion every 3 weeks at doses ranging from 8 to 145 mg/m2. The maximum tolerated dose of zeniplatin was 145 mg/m2. The dose-limiting toxicity of zeniplatin was dose-related leukopenia and neutropenia, with the nadir usually observed between 1 and 2 weeks after therapy and recovery usually occurring by 3 weeks after therapy. Thrombocytopenia was rare. The most prominent non-hematological side-effect of zeniplatin was nausea and vomiting. Other non-hematological side-effects were mild or absent. Zeniplatin did not induce significant neurological or auditory toxicity. Zeniplatin was not nephrotoxic at doses less than or equal to 120 mg/m2. At 145 mg/m2, the clearance decreased by a mean of 40% after 2 cycles of therapy. Two patients, one with malignant melanoma and one with renal cell cancer, achieved a partial response. Pharmacokinetics of free (plasma ultrafiltrates) and total platinum in plasma were determined in 5 patients. An in vitro study of the rate and extent of zeniplatin binding to protein in human plasma was also performed. Free and total platinum were measured by flameless atomic absorption spectrometry; free zeniplatin was measured in ultrafiltrate by HPLC. Total and free plasma platinum concentrations were co-modelled using the information from the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs.

We have developed a pharmacokinetic/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a "target" cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells, of plasma from 11 acute myeloblastic leukemic patients treated with daunorubicin (DNR). Plasma, obtained before and serially for 24 h after DNR treatment, was assayed by HPLC for DNR and daunorubicinol (DNRol), its active metabolite. The corresponding observed PCA values (PCAobs) against HL-60 cells were also measured with a flow-cytometric cell-survival assay that we had developed previously. The pharmacodynamics, i.e. PCA, were co-modeled (dual Hill equation with an interaction term to allow synergism or antagonism) with the pharmacokinetics. The integration of the PCA profile provided the area under the observed PCA versus time curve (AUCobs). For each patient, we also generated an "interaction panel", by adding known amounts of DNR and DNRol to his or her pretreatment plasma. The corresponding cytotoxicities were measured, and then applied to the pharmacodynamic model. This provided a standard surface from which the PCA of each sample obtained after therapy was predicted (PCAprd), on the basis of assayed concentrations of DNR and DNRol in that sample. For plasma samples obtained after treatment, the model simultaneously fit all three outputs, i.e. PCA and DNR/DNRol concentration, very well. We observed substantial interpatient variability in HL-60 growth rate in medium containing patient pretreatment plasma, in DNR activity in pretreatment plasma, and in the in vitro activity (PCA) of plasma obtained after DNR treatment. We also compared the AUCprd to the AUCobs for each patient, and we identified a subset of 4/11 acute myeloblastic leukemic patients who had developed much more PCA after DNR administration that could be explained by the measured concentrations of DNR and DNRol. This may be due to unidentified active metabolites or to factors produced in the plasma in response to the treatment. This pharmacokinetic/pharmacodynamic model is promising to describe pharmacodynamics and interactions of anticancer drugs in cancer patients.

Phase I clinical trial with carbetimer.

Carbetimer, a low molecular weight polymer derived from ethylene and maleic anhydride, belongs to a class of chemical compounds different from previously available anticancer agents. It has shown moderate antitumor activity against the Madison 109, Lewis lung, colon 26 and M5076 ovarian carcinomas. In the human tumor stem cell assay, antitumor activity was seen against carcinomas of the breast, ovary, lung, colon and kidney. A total of 26 patients with solid tumors were entered into this trial; carbetimer was given on 5 consecutive days as a 1-2-h intravenous infusion. The dose was escalated from 1.08 to 11 g/m2/day. The drug did not induce the usual side-effects of chemotherapy: leukopenia, thrombocytopenia, alopecia and mucositis were minimal or totally absent. Gastrointestinal toxicity was limited to mild to moderate nausea and vomiting; these were observed at all dose levels and required antimetics in only two patients. The major side-effects of carbetimer consisted of hypercalcemia and neurotoxicity. Hypercalcemia was dose- and treatment duration-dependent. The precise mechanism of hypercalcemia is presently under investigation, but remains unclear. Neurotoxicity was observed only after prolonged therapy; two patients, who received cumulative doses higher than 250 g/m2, developed a peripheral neuropathy with paresthesia, decrease in sensory perception and motor weakness. One patient recovered completely; the other patient improved slightly before developing fatal brain metastases. Two patients with malignant melanoma exhibited major antitumor response; both were previously treated; after excellent partial responses to carbetimer, both were operated on and one is presently disease-free 2 1/2 years after completion of therapy with carbetimer. In conclusion, carbetimer is a new compound with an unusual pattern of side-effects and interesting antitumor activity against malignant melanoma. Its antitumor activity is presently being investigated in phase II trials.

[Diagnosis and treatment of unknown primary tumors]. / Mise au point diagnostique et thérapeutique des tumeurs de site primitif inconnu.

Cancers of unknown origin represent approximately 5% of all cancers and are therefore as frequent as some solid tumors such as gastric or pancreatic cancers. The diagnosis of cancer of unknown origin should be based on a detailed pathological examination including immunohistochemical techniques and electron microscopy; hormonal receptors should also be measured. Besides detailed medical history and physical examination, only a few additional tests should be carried out: routine chemistry including the assay of HCG, alphafoetoprotein and specific antigen of the prostate, chest X-ray, thyroid scan, mammography and abdominal CT scan. Other tests are generally not of sufficient specificity and sensitivity. Unknown primary tumors arising in the cervical area are frequently squamous cell carcinomas corresponding to occult primary tumors of the upper aerodigestive mucosae and are efficiently treated by cervicofacial radiotherapy or lymph node dissection. Women presenting with axillary lymph nodes with no obvious primary tumor should be treated according to the guidelines used for breast cancer. The patients with inguinal lymph nodes of unknown origin are usually treated with radiation therapy. The syndrome of germinal tumors of extragonadic origin corresponds to cases of undifferentiated or poorly differentiated carcinomas in patients under 50 years of age and with one of the following characteristics: involvement of the median organs, lung involvement, lymph node involvement or increase of alphafoetoprotein or HCG. The therapeutic approach recommended for these patients consists of the chemotherapeutic combination used for testicular cancer. For all other patients, the prognosis remains poor. Patients with local symptoms may be treated by radiation therapy; others may receive a combination of fluorouracil, doxorubicin and mitomycin.

Six-year results of a multimodality treatment strategy for locally advanced breast cancer.

Between 1976 and 1982, 59 patients with locally advanced breast cancer were treated with preoperative supervoltage radiotherapy, adjuvant preoperative and postoperative hormonochemotherapy, and modified radical mastectomy. Systemic treatment, which was started simultaneously with radiotherapy, consisted of a combination of daily oral tamoxifen and a monthly alternation of Doxorubicin + vincristine and cyclophosphamide + methotrexate + 5-fluorouracil (CMF). One of each cycle was given preoperatively at half dosage and five of each were repeated postoperatively at full dosage. All patients became operable. Results of pathologic examination of the operative specimen, available in 51 patients, showed complete disappearance of tumor tissue in breast areas in eight patients, of which three still had positive axillary nodes. After a median follow-up time of 6 years locoregional failure was observed in 12 patients (20%) but in only three (5%) did it occur before distant failure. The actuarial median survival of the entire patient population is close to 4 years. Seven patients are alive without recurrence at greater than 9 years. This aggressive multidisciplinary treatment approach is associated with a projected 30% long-term survival (10 years), excellent local control, but substantial toxicity.

Phase I clinical and pharmacokinetic trial of oral menogaril administered on three consecutive days.

Eighteen adult patients with solid tumors were treated with oral menogaril, a new anthracycline antibiotic active against human breast cancer after intravenous administration. The drug was given orally on 3 consecutive days every 4 weeks at doses ranging from 50 to 175 mg/m2/day. Reversible and dose-related leukopenia was the dose-limiting toxicity. Thrombocytopenia was less frequent. Hematologic toxicity was maximal usually 2 weeks after treatment and recovery usually occurred within 4 weeks. At doses from 50 to 150 mg/m2/day, non-hematologic side-effects of oral menogaril were infrequent and mild and consisted of nausea and vomiting (one patient), alopecia (two patients), mucositis (two patients) and liver function test abnormalities (three patients). The single patient treated at a daily dose of 175 mg/m2/day developed grade IV leucothrombocytopenia, with fever and gastrointestinal bleeding. This was followed by heart failure and the patient died from multisystem organ failure. Peak plasma concentrations of menogaril ranged from 0.043 to 0.409 microM and were linearly correlated with the dose. Similarly, the area under the plasma concentration versus time curve varied from 0.33 to 9.59 microM X h and was linearly correlated with the dose. The mean harmonic half-life was 11.3 +/- 6.4 h. A comparison of the data from the present trial and our previous study with intravenous menogaril indicates a bioavailability of 32 +/- 12%. There was an excellent relationship between the white blood cell decrease (as a percentage of the pretreatment value) and several pharmacokinetic parameters; the best correlation was obtained with the plasma concentration of menogaril at 4 h after treatment. A dose of 150 mg/m2/day for 3 consecutive days is recommended for phase II trials with oral menogaril but the bioavailability of the drug should be monitored carefully and, more specifically, the concept of a pharmacokinetic adjustment of the dose of menogaril should be evaluated prospectively.

Phase I clinical trial of oral menogaril administered on three consecutive days.

Eighteen adult patients with solid tumors were treated with oral menogaril, a new anthracycline antibiotic active against human breast cancer after intravenous administration. The drug was given orally on 3 consecutive days every 4 weeks at doses ranging from 50 to 175 mg/m2/day. Reversible and dose-related leukopenia was the dose-limiting toxicity. At doses from 50 to 150 mg/m2/day, non-hematologic side effects of oral menogaril were unfrequent and mild and consisted of nausea and vomiting (1 patient), alopecia (2 patients), mucositis (2 patients) and liver function test abnormalities (3 patients). The only patient treated at a daily dose of 175 mg/m2 developed grade IV leukothrombocytopenia, with fever and gastrointestinal bleeding. This was followed by heart insufficiency and the patient died from multisystem organ failure. A dose of 150 mg/m2/day for 3 consecutive days is recommended for phase II trials with oral menogaril.