Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

Suppression of heparinization of central venous catheters between cycles of chemotherapy. Results of a phase I study.

A phase I study to evaluate heparinization of tunnelled subclavian catheters (TSC) was conducted in 42 patients who each had a TSC for chemotherapy. They were enrolled in the study from August 1994 to December 1995. The inclusion criteria were: age 18-70, no general anticoagulant treatment, TSC used only for chemotherapy, informed consent. Heparinization was performed at the end of each cycle and then at increasing intervals: 11, 13, 15, 17, 19, and 21 days. A 21-day interval was intended to mimic the suppression of heparinization between cycles. Heparinization was performed with a 250 IU/ml heparin solution. Anti-Xa activity was studied before each heparinization. For each interval, at least 5 patients were followed up for two cycles. If no blockages were present progression to the next step was authorized. If one blockage was observed 5 additional patients were required to have their TSCs heparinized after the same interval. Two blockages (block) after the same interval meant that the previous interval was recorded as the longest tolerable. There were no blocks with the 11-day interval (6 patients), 1 block after 13 days (10 patients), 1 block after 15 days (10 patients), and no blocks after 17 days (5 patients), 19 days (6 patients), or 21 days (5 patients). The median anti-Xa activity (curative rate 0.2-0.6) was, respectively 11 days 6.74; 13 days 5.47; 15 days 4.71; 17 days 3.61; 19 days 3.67; 21 days 5.10 (NS). Heparinization between two cycles of chemotherapy is unnecessary. A high level of heparin activity persisted constantly inside the catheter lumen through the 3-week observation period.

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Metastatic gastric cancer arising from breast carcinoma: endoscopic ultrasonographic aspects.

Linitis plastica of the stomach was diagnosed in four patients. Endoscopic ultrasonography (EUS) was performed in four cases; they were monitored by EUS and had their treatment adapted accordingly. According to the present study, the typical criteria of gastric linitis at EUS are: (a) rigidity of the gastric wall; (b) a wall thickness exceeding 6 mm; (c) a second enlarged layer marginally more echogenic than the fourth hypoechogenic layer (muscularis propria); (d) a third hyperechogenic enlarged layer; and (e) a poor demarcation between layers. Gastric linitis appears more likely to be specific metastasis from lobular breast carcinoma. In most of the follow-up cases, EUS showed correlation with a subsequent decrease of the CA15.3 level. At present, EUS seems to be the most effective and least invasive examination for clinical diagnosis and treatment surveillance of secondary gastric linitis arising from infiltrating lobular carcinoma (ILC) of the breast.

Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU.

BACKGROUND: A phase II prospective trial was carried out to study the concept of 5-fluorouracil (5-FU) dose-intensity in patients with advanced colorectal cancer. Forty patients were treated with 5-FU plus leucovorin (LV), with individually increasing doses of 5-FU. A 5-FU pharmacokinetic follow up was performed and a relationship was sought between its metabolism and its response to treatment, and between 5-FU's toxicity and patient survival. METHODS: 5-FU was administered weekly by 8 hour continuous infusion. The initial dose of 1000 mg/m2 was individually increased every 3 weeks by 250 mg/m2 steps, potentiated by 400 mg/m2 LV. 5-FU plasma concentrations were determined weekly by liquid chromatography. RESULTS: Eighteen overall objective responses and 22 minor responses, stabilizations, or progressions (NR) were observed. 5-FU plasma levels were significantly higher in cases of complete or partial response, whatever the dose. They reached about 2000 micrograms/l as early as the second dose level (1250 mg/m2). Only seven patients who experienced NR reached equivalent levels after the fourth step (1750 mg/m2). High 5-FU plasma levels were predictive of an objective response and better survival (difference not significant). The acute toxicity, whatever the type, was correlated with 5-FU levels > 3000 micrograms/l and not with the dose. CONCLUSIONS: This study shows the wide variability of 5-FU metabolism, whatever the dose, the clear relationship between 5-FU plasma levels, toxicity, and efficacy. This relationship points out the problem of the polymorphism of 5-FU metabolism, the usefulness of the therapeutic range determination and the usefulness of the individual 5-FU dose adaptation.

[Maintenance of the dose-intensity of chemotherapy combining carboplatin, cyclophosphamide, etoposide in women with ovarian cancer aged 70 and over]. / Maintien de l'intensité de dose d'une chimiothérapie associant carboplatine, cyclophosphamide et étoposide chez la femme de plus de 70 ans atteinte d'un cancer de l'ovaire.

Elderly patients are often considered as subjects at risk for bad tolerance to chemotherapy. They are therefore treated in a less aggressive way compared with younger women. In a retrospective study, we evaluated the dose-intensity of a chemotherapy for 15 patients older than 70 years of age, presenting an ovarian carcinoma. Median age was 73 years. All but one were classified in stage III-IV and only four were presented with a complete surgery or with a pathological residue < 2 cm. Six patients were considered as non operable. Performance status (PS) was in 11 cases equal to 0 or 1. The treatment associated from D1 to D4: carboplatine 75 mg/sqm/day, cyclophosphamide 250 mg/sqm/day, etoposide 50 mg/sqm/day for six cycles each over four weeks. We compared for each drug the delivered dose-intensity (DID) all along the six cycles to the forecast dose-intensity (FID). Except for the patients with a PS > or = 2, treated in first intention by a 2/3 dose, the DID/FID ratio was > 90%. It decreased between the 1st and 3rd cycles, then remained unchanged. Treatment was well tolerated by patients with a PS < 2 whose 4/11 have presented a grade III-IV hematologic toxicity. In return, despite the initial dose reduction, 3/4 patients with a PS > or = 2 had severe complications. There were no toxic deaths. Three patients only had a delay for reinduction. Three out of six non operables at first had a surgical second-look with possibility of residual masses cutting of (3 PRh). Four patients were alive in first CR at 18, 22, 23 and 28 months. Women older than 70 years with a good performance status presenting an ovarian carcinoma can be treated as younger women are. A chemotherapy using efficient drugs can be delivered with an acceptable toxicity and a high dose-intensity.

[Implantable sites in cancerology. The percutaneous technique. Results of a homogeneous series of 141 cases]. / Sites implantables en cancérologie. La technique per cutanée. Résultats d'une sérle homogène de 141 cas.

Percutaneous implantation sites were used by the same operator in 141 patients (87 females and 54 males) with usually metastatic cancer. A titanium Districath implantable chamber and a 1.1 mm inner diameter silicone catheter were used. Percutaneous venous access was via the subclavian vein in 139 cases (98.6%). Mandatory safety measures were emphasized. Insertion was complicated by puncture of the subclavian artery in 6 cases (4.2%). There were no case with abscess, disunion, infection or death due to the method. The chamber was removed in 7 cases due to: 3 ruptures of the catheter, 2 septicaemias, 1 rejection reaction and 1 psychological intolerance. In our series, percutaneous implantation via the subclavian vein has been a reliable and rapid technique with little morbidity.

Long-term pharmacokinetic behavior of platinum after cisplatin administration.

PURPOSE: The platinum concentration in plasma was studied in 19 patients treated by 3 or 4 successive courses of chemotherapy including cisplatin for head and neck cancers. METHODS: Cisplatin was given i.v. daily at 25 mg/m2 by 1-h infusions for 4 days every 3 weeks. Total and ultrafiltrable platinum were measured in plasma using an inductively coupled plasma mass spectrometry (ICPMS) technique. RESULTS: A progressive accumulation of total platinum in plasma was observed with consecutive infusions. The mean (+/- SD) total plasma platinum level detected at the end of cisplatin infusion was 1134 +/- 234, 1407 +/- 268, and 1618 +/- 282 micrograms/l at the end of the first, second, and third courses, respectively. The minimal platinum concentration measured before the second and third courses also increased to 221 +/- 59 and 309 +/- 76 micrograms/l, respectively. The steady state was not reached before the third course. However, differences in the evolution of platinum plasma levels were found among the 19 patients. In 14 patients the pharmacokinetics of platinum was characterized by low initial levels, a progressive accumulation, and a long terminal half-life with a very late steady state. In 5 patients, the pharmacokinetic behavior of platinum was different: platinum levels were directly high, without progressive accumulation, the steady state being reached as early as the first course. Significant levels of ultrafiltrable platinum were found throughout the treatment, even during the intervals between courses with this very sensitive analytical method. A close equilibrium between ultrafiltrable and total platinum (ratio, 6%) persisted for as long as 3 weeks after cisplatin administration. DISCUSSION: These results underline the importance of individual differences in platinum metabolism. The relationship between total and ultrafiltrable platinum are discussed.

[Acute cardiac toxicity of 5-fluorouracil: pharmacokinetic correlation]. / Toxicité cardiaque aiguë du 5-fluorouracile: corrélation pharmacocinétique.

High-dose 5-fluorouracil (5-FU) continuous infusion over a 4-day period seems to dramatically increase the frequency of cardiac complications, which were however extremely rare in the past when it was injected in bolus form (1.6%). In order to evaluate their real incidence we looked for a relation between cardiac toxicity and clinical or 5 FU pharmacokinetic parameters. One hundred and thirty-three patients were followed up from January 1989 to March 1990, treated for head and neck, breast and colorectal cancers by high-dose 5-FU infusion (1,000 mg/sqm/d x 4 d) and cis-platinum (20 mg/sqm/d x 4 d). During each treatment course, daily electrocardiogram and 5 FU plasma assays were performed by high performance liquid chromatography, at 8 am and 8 pm. Twenty-eight patients presented 36 ischemic cardiac manifestations which were sometimes severe. Of these, 29 were asymptomatic. Cardiac toxicity frequency was not increased in the group treated for head and neck cancers. Pharmacokinetic analysis showed wide variations in 5-FU plasma levels in the 133 patients under study (from 20 to 1,200 ng/ml). Cardiac manifestations always appeared during the hours following very high 5-FU plasma levels (greater than 450 ng/ml). Cardiotoxicity seems to be linked to 5-FU plasma levels. Cis-platinum probably increases toxicity in this regimen. These findings indicate the advisability of a close follow-up by daily ECG when 5-FU is administered at high doses in continuous infusion and associated with cis-platinum. We are continuing to study 5 FU cardiac toxicity, especially in other regimens containing 5 FU and aim to evaluate the contribution of cardiac isotopic exams.

An assay system for factors involved in mammalian DNA replication.

An assay for cellular factors stimulating DNA synthesis by partially lysed CHO cells is presented. The assay is based on the observation that in highly lysed cells, DNA synthesis, as determined by [3H]dTTP incorporation, was only 2-5% of that in gently lysed cells, and that this low level of DNA synthesis could be increased by a factor of approx. 50 by the addition of CHO cell extract (i.e. supernatant of a cell homogenate subjected to high-speed centrifugation). Highly lysed cells were obtained by treatment with 0.1% Brij-58 and 240 mM KCl, while for the preparation of gently lysed cells, 0.01% Brij-58 and 80 mM KCl were used. Incorporation of [3H]dTTP reflected DNA synthesis qualitatively similar to that in intact cells. It was semiconservative, and no repair synthesis was detected unless cells were irradiated with ultraviolet light prior to parital lysis. DNA molecules of 4 S were synthesized and converted to DNA of more than 25 S via 6-12-S intermediates. DNA synthesis was restricted to nuclei from cells in S phase, and cell extract did not induce DNA synthesis in nuclei from cells in G1 phase. Stimulation of DNA synthesis by cell extract was concentration-dependent. Cell extract activity was recovered to more than 50% after (NH4)2SO4 precipitation. Heat-inactivation experiments suggested that cell extract contained at least tow factors timulating DNA replication. This system may, therefore, be used for the purification and characterization of factors participating in DNA replication of mammalian cells.

[beta2-Microglobulin in cancer patients (author's transl)]. / La beta2-Microglobulineen pathologie cancéreuse.

Cancerembryonic antigen (CEA) and beta2-microglobulin (beta2m) have been measured in cancer patients and patients with benign diseases. Of 168 patients with intestinal cancer, almost 90% had increasing concentrations of either CEA or beta2m or both. In 29 patients at different stages of pancreatic cancer there was a high incidence of increased values in the more severe cases. In 60 patients with histologically classified colorectal cancer the TNomegaMomega group of 19 patients had 47% and 42% of elevated beta2m and CEA respectively. A significant correlation of beta2m or CEA to extension of disease was noted. In benign intestinal disease like cirrhosis and pancreatitis both beta2m and CEA is commonly elevated. Of 26 breast cancer patients, seven had elevated CEA and five had elevated beta2m values before treatment. In the patients with extraganglionary metastasis almost 90% had high beta2m or CEA or both. Of 40 patients with uterine cancer, 26 were found to have increased values of beta2m or CEA or both. Finally, 140 colorectal cancer patients, 62 patients with breast cancer and 10 patients with uterine cancer have been followed longitudinally.