[A trans-hospital pilot programme for onco-geriatry. The experience of the CHC-Liege]. / Programme pilote trans-hospitalier d'onco-gériatrie.

The authors offered to 296 consecutive cancer patients aged > or = 70 to undergo a joint comprehensive geriatric and oncological assessment. After pluridisciplinary discussion, several reflections have emerged: the need in 15 - 32% of cases to reinforce the role of the paramedical staff; the correlation between age, low clinical indices, alteration of renal function as well as geriatric characteristics; 67% of evaluated cases presented a significant geriatric profile; recommendations for patients' management in relation to their pattern of frailty and health aging (standard, adapted or palliative treatment).

Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study.

Thirty-six metastatic colorectal cancer patients received every 2 weeks, as first- (17) or second-line (19) treatment a combined chronotherapy with CPT-11 (infused at day 1 from 2 to 8 a.m.; peak at 5 a.m.), given with 5FU (700 mg/m(2) per day; days 2-5) and folinic acid (300 mg/m(2) per day; days 2-5) both infused from 10 p.m. to 10 a.m. with a peak at 4 a.m., and carboplatin (40 mg/m(2) per day; days 2-5; infused from 10 a.m. to 10 p.m.; peak at 4 p.m.). The doses of CPT11 could be easily pushed from 120 to 180 mg/m(2) in successive cohorts in the phase I part of the study (11 cases). Twenty-five patients were then treated in the phase II of the trial. The overall toxicity was mild leading to dose-reductions in only 11-13% courses. The tumoral activity was interesting with 81% responses and 94% tumour control. Also prolonged survivals were recorded with 8.8 months of progression free and 15.6 months overall survivals. More prolonged survivals were observed in chemotherapy naive patients. Seven patients (19%) could be reoperated from their residual disease.

[Chronotherapy with 5-fluorouracil folinic acid and oxaliplatin delivered over 48 hours every second week in colorectal cancer. The CHC-Liège experience (Belgium)]. / Chronochimiothérapie à base de 5-fluorouracil, acide folinique et oxaliplatine administrée en deux jours toutes les deux semaines pour le cancer colorectal. L'expérience du CHC-Liège (Belgique).

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients.

[Chemotherapy for human gastric cancer: a review]. / Qu'attendre de la chimiothérapie dans le cancer de l'estomac en 2008?

The authors review the actual position of medical treatment for human gastric cancer. Chemotherapy has been evaluated first in palliative situation, then as adjuvant post-surgical approach either through systemic or intraperitoneal route. Now chemotherapy may also be proposed as neoadjuvant (before surgery) treatment as part of an integrated global pluridisciplinary approach. New hopes to improve the prognosis come then from both neoadjuvant and adjuvant chemotherapy (+/- radiotherapy) and further from less toxic infusional therapies (chronomodulation), new schedules with proved active molecules (docetaxel, oxaliplatin, irinotecan, pemetrexed) as well as from new targeted treatments (against ie, EGF-receptor and angiogenesis).

[Interest of chronotherapy in multidisciplinary management of oesophageal and gastric cancers]. / Intérêt de la chronothérapie dans le traitement pluridisciplinaire des cancers de l'oesophage et de l'estomac.

The authors evaluated the impact of a chronotherapy with 5-FU, folinic acid and carboplatine (chronomodulated infusions by ambulatory pumps; 5/21 days) for the management of oesophagus (52 cases) and gastric (56 cases) cancer patients. The overall tolerance of treatment was gauged excellent (grade 3-4; % patients: mucitis: 11-23%; leucopenia 6-19%; thrombopenia 18-50%; almost no digestive disturbances nor alopecia). Also tumor outcome was considered interesting with major responses rate in 61% (gastric) to 79% (oesophagus) of patients. The median survival of oesophageal cancer was limited to 9.2 months; the one of disseminated gastric cancer was 12.7 months but 72% of curatively resected patients were alive at 5+ years.

[Chronotherapy combining 5-fluorouracil, folinic acid and carboplatin as first line treatment in metastatic colorectal cancer. A phase 2 study]. / Chronothérapie associant le 5-fluorouracile, l'acide folinique, et le carboplatine en première ligne thérapeutique dans le cancer colorectal métastatique. Une étude de phase 2.

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

[Feasibility survey (Phase I-II) of a four drugs combination (5-fluorouracil, folinic acid, carboplatin and irinotecan) delivered using a chronomodulated infusion in the treatment of advanced colorectal cancer]. / Etude de faisabilité (Phase I-II) d'une quadruple combinaison associant le 5-fluorouracile, l'acide folinique et le carboplatine à de l'irinotecan administrés en infusion chronomodulée pour le traitement du cancer colorectal avancé.

Seventeen colorectal cancer patients received as first (12 cases) or second line (5 cases) treatment a combined chronotherapy with CPT 11 (infused at day 1 from 2 to 8 am; peak at 5 am), given with 5 FU (700 mg/m2 per day ; days 2-5) and folinic acid (300 mg/m2 per day, days 2-5) both infused from 10 pm to 10 am with a peak at 4 am, and carboplatin (40 mg/m3/day - days 2-5 ; infused from 10 am to 10 pm - peak at 4 pm). The doses of CPT 11 could be easily increased from 120 up to 180 mg/m2 in successive cohorts of four patients through acceptable toxicity. Thus, five patients have already been treated in the phase II part of the trial. An interesting tumoral outcome has been observed: 88% major responses with no progression; median time to progression: nine months and median survival: 19.7 months.

[Adjuvant chemotherapy for Dukes B2 and C colon cancer combining 5-fluorouracil and folinic acid with or without carboplatin. Feasibility and comparison between standard and chronomodulated deliveries]. / Chimiothérapie adjuvante pour le cancer du colon de stades Dukes B2 et C comportant du 5-fluorouracile et de l'acide folinique, avec ou sans carboplatine. Faisabilité et comparaison d'une administration standard à une administration chronomodulée.

Thirty-seven patients operated from a Dukes B2-C colon cancer were randomised to receive as adjuvant infusional chemotherapy, nine 5 FU and folinic acid courses with or without carboplatin, as standard (de Gramont; 2 days every 2 weeks) or chronomodulated administration (4 days every 2 weeks). The overall tolerance was judged excellent with less than 7% courses with dose-adaptations. The two carboplatin arms presented an enhanced haematological toxicity, while some more cutaneous toxicity was observed in the chronomodulated arm with the three drugs.

[Chronobiological considerations for the management of human head and neck cancer]. / Considérations chronobiologiques pour la prise en charge des tumeurs de la tête et du cou chez l'homme.

The authors reviewed experimental and clinical data (ie, cell kinetics and its circadian control by cyclins, circadian expression of clock genes, chronotolerance to anticancer agents.) justifying to consider the temporal dimension in the medical treatment of human head and neck cancer. A complex infusional chronotherapyschedule (with 5-fluorouracil, folinic acid and carboplatin) was administered to 48 patients. Excellent tolerance and interesting tumour outcome allowed to conclude to an optimised therapeutic index.

[Randomised study to evaluate the chronotolerance of a combination infusional chemotherapy with 5-fluorouracil, folinic acid and carboplatin in non small cell lung cancer (NSCLC) patients]. / Etude randomisée évaluant la chronotolérance d'une association de 5-fluorouracile, acide folinique et carboplatine chez des patients porteurs d'un cancer pulmonaire non à petites cellules (CPNPC).

An infusional ambulatory chronotherapy with 5-FU, folinic acid (FOL) and carboplatin was administered to 45 advanced NSCLC patients. The patients were randomised into 3 groups varying according to the time of administration peak of drugs (reference hours: 4 a.m. for 5 FU (and FOL); 4 p.m. for carboplatin; +/-8 h). The reference schedule appeared best tolerated (regarding hematology and mucositis). This study has prospectively validated the chronotolerance concepts of this complex combination chemotherapy.

[Chronopharmacologic approach to the administration of anticancer agents in pancreatic adenocarcinoma. Pilot experience]. / Approche chronopharmacologique de l'administration des agents anticancéreux dans l'adénocarcinome pancréatique. Expérience pilote.

The authors first analyzed the potential interest of the delivery of anticancer agents according to chronobiological concepts for human pancreatic cancer. They report their experience on 41 patients treated in adjuvant (12 cases) or palliative (29 cases) situations. The excellent therapeutic index observed warrants further evaluations of this concept in randomized trials.

Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial.

The aim of this study was to develop a phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. 60 patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10. 00 am peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea/vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases, 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients; 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 2 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation in the first-line treatment of metastatic colorectal cancer.

Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion.

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.

Summary report of the TD-3 workshop: characterization of 83 antibodies against prostate-specific antigen.

Twelve research groups participated in the ISOBM TD-3 Workshop in which the reactivity and specificity of 83 antibodies against prostate-specific antigen (PSA) were investigated. Using a variety of techniques including cross-inhibition assays, Western blotting, BIAcore, immunoradiometric assays and immunohistochemistry, the antibodies were categorized into six major groups which formed the basis for mapping onto two- and three-dimensional (2-D and 3-D) models of PSA. The overall findings of the TD-3 Workshop are summarized in this report. In agreement with all participating groups, three main antigenic domains were identified: free PSA-specific epitopes located in or close to amino acids 86-91; discontinuous epitopes specific for PSA without human kallikrein (hK2) cross-reactivity located at or close to amino acids 158-163; and continuous or linear epitopes shared between PSA and hK2 located close to amino acids 3-11. In addition, several minor and partly overlapping domains were also identified. Clearly, the characterization of antibodies from this workshop and the location of their epitopes on the 3-D model of PSA illustrate the importance of selecting appropriate antibody pairs for use in immunoassays. It is hoped that these findings and the epitope nomenclature described in this TD-3 Workshop are used as a standard for future evaluation of anti-PSA antibodies.

Relative affinity and specificity of monoclonal antibodies against prostate-specific antigen.

The relative affinities of a panel of antibodies submitted to the ISOBM TD-3 PSA Workshop were determined by direct-binding ELISA. The Workshop antibodies were also tested for reactivity with the prostate-specific antigen alpha1-antichymotrypsin complex (PSA-ACT) and cross-reactivity with porcine pancreatic kallikrein. There was a wide range of affinities observed for the panel of antibodies. Twelve antibodies failed to react with the PSA-ACT complex, and 1 antibody was found to recognize an epitope on ACT but not on PSA. Only 2 antibodies were found to react with porcine pancreatic kallikrein, a protein with 64% sequence homology with human glandular kallikrein-2 (hK2).

Efficient bispecific monoclonal antibody purification using gradient thiophilic affinity chromatography.

Bispecific monoclonal antibodies (bsMAbs), due their unique design, have a wide range of potential applications in immunodiagnostics and immunotherapy. One of the major limitations for the use of bsMAbs produced by hybrid-hybridomas is the concomitant production of parental monospecific antibodies. The relative amount of bsMAb secreted may vary between different hybrid-hybridomas. Hence, the purification of the desired bispecific molecule from other forms is crucial. Current purification methods include anion-exchange, HPLC on different matrices, and dual affinity methods. Most of those methods include multiple steps and have limitations on the purity or yield of the desired species. We report here a simple single-step purification method, using inexpensive thiophilic chromatography. This new method can potentially be scaled up, for industrial proposes. Finally, based on the amino acid sequences and assembly of the two heavy chains we attempt to explain the possible mechanism by which thiophilic chromatography was able to resolve the bsMAbs from the monospecific species.

A new method to generate quadromas by electrofusion and FACS sorting.

Bispecific monoclonal antibodies (bsMAbs) are unique molecules incorporating two different paratopes in a single antibody molecule. BsMAbs can be useful in different areas of research as well in clinical applications. Traditionally, bsMAbs are produced by hybrid-hybridomas that are generated by the fusion of two pre-established hybridomas. The development of such hybrid-hybridomas can be difficult and time-consuming. Here, we introduce a new technique to generate such hybrids, electro-FACS-fusion. In this procedure, before the electrofusion, one of the hybridomas is labeled with fluorescein isothiocyanate (FITC) and the other with tetramethylrhodamine isothiocyanate (TRITC). The mixture of cells is then electrofused, and cells exhibiting dual fluorescence are selected by fluorescence activated cell sorting (FACS). The fused cells are directly plated in microplates for clonal growth. Using this technique, we produced three new hybrid-hybridomas secreting bsMAb that could be used for the next generation of immunoassays.

Summary report on the ISOBM TD-6 workshop: analysis of 20 monoclonal antibodies against Sialyl Lewisa and related antigens. Montreux, Switzerland, September 19-24, 1997.

The ISOBM TD-6 Workshop is the first international workshop on monoclonal antibodies against the Sialyl Lewisa (SLea) antigen. Eight research groups participated in a blind study to characterize the epitope binding, relative affinity and performance in immunoradiometric assays, of a panel of 20 monoclonal antibodies. The antibodies were tested against a diverse panel of neoglycoconjugates, purified antigens and human serum pools from gastrointestinal malignancies. Epitope specificities were determined for the majority of antibodies in the panel. Cross-reactivity with related saccharide structures was noted in several antibodies. Overall, the results of the TD-6 Workshop show further development of SLea immunoassays may yield yet more specific assays for the detection and management of gastrointestinal and other malignancies.

Mimetic ligand-based affinity purification of immune complexes and immunoconjugates.

We developed a simple purification method to purify alkaline phosphatase/anti-alkaline phosphatase IgG as immune complexes using mimetic affinity chromatography wherein the antibody was either a monospecific antibody, a bispecific antibody or a commercial polyclonal IgG conjugated with alkaline phosphatase (AP-IgG) covalently. The immune complexes or conjugates were efficiently bound on the mimetic Blue A6XL column and eluted under mild conditions (5-20 mM phosphate buffer). A similar strategy of purifying peroxidase/anti-peroxidase antibody complexes was also successfully demonstrated using the mimetic Red 3 column. Mimetic affinity chromatography thus appears to be a simple method to purify the desired monospecific or bispecific antibodies from the respective hybridomas and quadromas.