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CPT-11 (Irinotecan) is a water soluble semisynthetic derivative of camptothecin. It acts as an inhibitor of DNA topoisomerase I. Two patients were treated with CPT-11 for colorectal cancer. Both of them had a biliary catheter for extrahepatic biliary obstruction. The 1st patient received CPT-11 on a 100 mg/m2 weekly schedule and the second was administered 350 mg/m2 every 3 weeks. In plasma, the active identified metabolite SN-38 was mainly in the form of a glucuronide conjugate (ratio: 1 to 4 for 100 mg/m2 and I to 12 for 350 mg/m2. CPT-11 was mainly excreted in bile and urine as CPT-II. Cumulative biliary and urinary excretion of CPT-11 and its metabolites over a period of time up to 48 hours was 25% (100 mg/m2 weekly) to 50% (350 mg/m2 every 3 weeks). This means that CPT-11 might be excreted in other not yet identified forms.

A correlation between 06-Alkyl Transferase (O6AT) activity and resistance to nitrosourea treatment has been demonstrated. The activity of 06AT is decreased by procarbazine in “ in vitro ” essay. We study the tolerance and efficacy of a monthly association of oral procarbazine 100 mg/tid (D0–D4) and fotemustine a new nitrosourea derivative at the dose of 100 mg/m 2 in 72 hrs continous infusion. A total of 31 patients (pts) (M22/F11) were enrolled and received 99 cycles. Mean age 49 yrs (21–72). Histological types were: glioblastoma (16), anaplastic astrocytoma (3), oligoastrocytoma (6) and degenerated glioma (8). PS > 90% in 10 pts. Previous radiotherapy in 30 pts. Myelosuppression has been the main toxicity observed with grade 3–4 neutropenia in 3 patients, and grade 3–4 thrombocytopenia in 6 pts. Two treatment related deaths were noticed, 1 aspergillus pneumonia and 1 toxic death (grade 4 myelosupression). Concerning the results we observed 9 PR (27%) and 12 SD (36%). Median time to progression for responders was 10 months. Median survival rate was 8 months. Pretreatment with procarbazine does not seem to increase the response rate when compared with fotermustine alone.

Little is known about the efficiency of chemotherapy in advanced biliary tract carcinoma. Accordingly, we conducted a phase II study of combined 5FU CI and P in this disease. 28 patients (pts) (13 M/15 F) were included. Median age: 57 years. ECOG performance status: grade (g) 0;1: 79%, g 2: 18%, g 3: 3%. More than 10% weight loss: 36% Primary tumor: gallbladder: 11, Vater ampulla: 5, cholangiocarcinoma: 5, bile ducts: 7. 25 patients had metastases, 2 had local recurrences of their tumor and 1 a nodulary intrahepatic non resectable form. Sites of the metastases: liver: 12 pts, abdominal lymph nodes: 6 pts, lung: 6 pts, peritoneum: 6 pts, mediastinal lymph nodes: 1 pt. Treatment schedule: 5FU CI: 1 g/m 2 × 5 days, P: 100 mg/m 2 day 2 repeated every 4 weeks. Results Median number of cycles: 4. 25 pts are evaluable for the tumor response (1 too early, 2 non evaluable), no complete response, partial response (PR): 8, objective response rate = 29% (CI: 12–46%). Minor response: 2, stabilisation: 10, progressive disease: 6. Toxicity was tolerable: g 3 vomiting: 21% of the pts, g 3 mucositis: 4%. Some pts experienced haematological toxicity: g 3 granulocytopenia: 18%, g 4: 4%; no g 3–4 thrombocytopenia. Other toxicities: g 1–2 renal: 3 pts; g 1 neuropathy: 1 pt. No toxic death. Median survival was 10 months and 1-year actuarial survival 33%. We conclude that this regimen is tolerable and active in patients with advanced biliary tract cancer.

Late nauseas (N) and vomiting (V) are still an unsolved problem during chemotherapy (CT). It seems interesting to quantify and evaluate them in order to know how they affect the patients (Pts) QOL. Materials and methods A list of questions was proposed to Pts receiving CT with Cisplatinum (80–100 mg/m 2 ) every 3 weeks. Questions were about conditions of life (in couple, alone, helped or not), and habits (activities, hobbies, health, family life). During CT, all Pts received the same an-tivomiting protocol: 5 HT3, corticotherapy, metoclopamid IV. At home, alizaprid wasn’t systematically advised. This period is the subject of this study. 20 Pts were evaluated: 42–75 years, 16 men, 4 women. Results We could identify 2 groups (G) of Pts. GI: 9 Pts graded OMS 0 for digestive toxicity, GII: 11 Pts graded OMS I to 3 (G1: 2, G2: 4, G3: 5). Out of these 20 Pts, only 3 had systematic antivomiting treatment at home. They belonged to GII. In GI, all of the 9 Pts had a stable weight. They defined a helping circle of family and friends and were able to fulfil themselves with hobbies or social activities. In GII: 10 out of 11 Pts lost weight from 1 to 6 kg and described a perturbation in their QOL (7 out of 10 fell alone, in distress or with a family life perturbated), 8 Pts underlined having no social activity, not being able to fulfil themselves. None of Gil Pts used non medical methods to lace N. V (relaxation, fizzy drinks…). Conclusion This study suggests that psychological factors, and not only drugs, could influence late N.V after Cisplatinum. This study is still going on, in order to confirm or not these observations.

Combination of E and P has shown high response rate in NEC. A pilot study was performed to study the tolerance and efficacy of a new combination ore 120 mg/m 2 day 1 to 3 and P 100 mg/m 2 day 2 every 3 or 4 weeks in the treatment of these patients (pts). 16 pts (male/women: 12/4) have been enrolled Median age was 46 years. Performance status was Results Toxicity: mainly haematological: grade 3 and 4 granulocytopenia in 17 and 18 cycles (2 neutropenic fever), grade 3–4 thrombocytopenia (5 c), grade 4 emesis (7 c), grade 1–2 neurologic (7 c) and grade 1–2 renal (2 c). Response Rate: 8/16 PR (50%) with 6/11 in poorly differentiated. NEC, 5 SD and 3 PD. Median duration of response was 7.3 month. Median survival was 10 months. A complete resection was performed in 1. Conclusion Administration of E and P with these doses and schedule result in high response rate with an easily manageable toxicity.

The Camptotethecins, synthetic and semi-synthetic plant alkaloid derivatives, are specific inhibitors of Topoisomerase I. They open a promising chapter in cancer chemotherapy. These nuclear enzymes are rooted in the bihelical geometry of DNA. They catalyze relaxation of torsionally strained supercoiled DNA in producing a transient single strain break. At the target level, camptothecin analogues specifically inhibit the break-rejoining reactions of DNA topoisomerase I. Approximately ten drugs of this class are presently investigated, but, only four are in the clinical development phases. The choice of the optimal dose schedule recommended for phase II is a common problem of these camptothecins. Phase II studies have been initiated for 9-AC. Topotecan and irinotecan are the most widely tested in Europe. The most interesting activity of Topotecan seems to be reported in ovarian cancer and SCLC. Irinotecan is the only one already commercialized (in Japan: SCLC, NSCLC, cervical ovarian cancer). A major European trial (n = 213) of Irinotecan in colorectal cancer showed a RR of 20.5% in the evaluable patients. Similar results were obtained in chemotherapy naive and pretreated patients. Other Japanese, American and European studies have confirmed this original activity in colorectal cancer and have shown promising results particularly in lung, cervical and pancreatic cancers. In conclusion, Irinotecan is the only camptothecin derivative having shown significant clinical efficacy in a large spectrum of tumours particularly in patients with colorectal cancer.

Based on accumulated efficacy and tolerance experiences (JCO 91, ASCO 91–92), in 01/92 we started a new Ph I–II study in LA and REC/MTS UCNT, combining four known active agents in UCNT. Protocol: FU 700 mg/m 2 /d CIV dl-4, B 10 mg IV dl + 12 mg/m 2 /d CIV dl-4, E 70 mg/m 2 /d d1, P 100 mg/m 2 /d d5 (dl = d21). As 3/95, 33 patients (pts) were enrolled, 23 M/10 F, mean age 50 years (15 – 71). PS (WHO): 0 – 1: 31,2 – 3: 2, 16 pts with LA disease (T3–T4: 56%, N2N3: 100%) (VICC-AJCC 87),8 with isolated locoregional REC, 5MTS alone and 4 bath. Tumor sites 12 nasopharynx (NP), 6 bone, 3 liver, 2 extraregional nodes (ERN), 3 lung. All REC/MTS pts were pretreated, 6 RT alone, 11 pts CT + RT, lO ofthem Platinum based. Toxicity (WHO) III cycles (c) and 33 pts evaluable, Gr3 – 4: mucositis 20c, in 7/8 pts preirradiated locoregionally, PNN 45c (22 pts), mean duration of neutropenia brief 3 days (1 – 7), Hemoglobin 9c (7 pts), platelets 15c (8 pts), febrile neutropenia 10c (7 pts), Gr3 nausea-vom: 5c (3 pts), Gr2 skin 4 pts, lung 3 pts, oto 2 pts, 1 death pulmonary fibrosis, 5-FU revesible cardiomyopathy 1 pt. Response (Res) (WHO) in LA disease (Group 1: G1) 16 pts evaluable after CT (1 CR, 14 PR, 1 NC) (ORR 94%) and 14 pts after RT (13 CR, 1 PD) (2 pts too early). In REC/MTS disease (G2) 16 evaluable (1 refusal), 4 CR and 8 PR, 3S D, I PD (ORR 75%). Res by site CR liver 2/3, bane 1/6, ERN 2/2, lung 2/3, NP 4/12. In G2 median Res duration 10 m (CR = 6 + – 26 +, PR = 5 + – 19). With median followup (FUp) of 16 m (4 – 39): G1: 11 NED (7 + – 25 +),2 AWD (13 +, 22 +), I DOD at 5 m and 2 still on treatment. G2: 4 still responding free of progression (12 + – 34 +),4 AWD (20 + – 34 +). This regimen shows high CR in visceral sites, with good Res duration in the palliative setting and good activity as induction chemotherapy. A larger accrual is needed with increased FUp before comparing it with our current standard of B, E, P. (E. Cvitkovic et al., ASCO 94.)

In our wide experience of treating advanced breast carcinoma with chemotherapy, the combination of doxorubicin (DOX), vincristine (VCR), cyclophosphamide (CPM) and fluorouracil (FU) gave a complete plus partial response rate of over 60%, with 100% alopecia and frequent cardiac toxicity depending on total dose. After the EORTC Clinical Screening Group phase II trial we have conducted an "expected difference method" comparative phase II trial using the combination DOX, VCR, CPM, FU and the combination of MTX (10mg/m2), VCR, CPM and FU on a population of 50 breast carcinoma patients similar to those taking part in the first study. The reasons for similarity of action will be presented and discussed.

Brequinar sodium (NSC 368390; DUP 785) is a new inhibitor of pyrimidine de novo biosynthesis which has completed Phase I clinical trials within the framework of the Early Clinical Trials Group of the European Organization for Research and Treatment of Cancer (EORTC). The main side effects of this compound are myelosuppression, nausea and vomiting, stomatitis and/or mucositis, and skin rash. In this report, the authors describe the pattern of mucocutaneous side effects of Brequinar sodium in patients who received the drug by four different schedules: (1) short-term intravenous (IV) infusion every 3 weeks; (2) weekly; (3) twice weekly; and (4) five times daily every 4 weeks. Mucocutaneous toxicities of Brequinar sodium included mainly cytotoxic reactions (stomatitis and/or mucositis and skin rash). However, rare episodes of local reactions (phlebitis at the site of injection), photosensitivity reactions (to sun light), angioneurotic edema, and localized secondary hyperpigmentation of the inflamed skin also occurred. Stomatitis and/or mucositis appeared to be dose-dependent and schedule-dependent. The skin rash consisted of a drug-induced toxic dermatitis which occurred mostly at the highest dose levels. Initial recommendations for the management of mucocutaneous toxicities of Brequinar sodium during Phase II trials are discussed.

The urinary excretion of doxifluridine (5'dFUrd) and its metabolites was determined during five days of chemotherapy using fluorine-19 nuclear magnetic resonance spectrometry. The daily urinary excretion of 5'dFUrd and its metabolites was high (congruent to 100% of the 5'dFUrd administered) and nearly constant throughout the treatment. By far the major excreted compounds were unchanged 5'dFUrd and alpha-fluoro-beta-alanine which made up respectively congruent to to 40% and congruent to to 50% of the total. Neither accumulation of 5'dFUrd nor significant modifications in its metabolism were observed during the treatment.

A phase II trial of idarubicin (IDR-4 demethoxydaunorubicin) was carried out in patients with advanced breast cancer. A dose of 45 mg/m 2 was given orally once every 3 weeks. A total of 66 eligible patients were entered into the trial, 56 of whom were evaluable for response ( 65 were evaluable for toxicity at least). Therapeutic activity was demonstrated with an overall objective response rate of 21% ( 95% CI: 11–32% ). When used as a first-line treatment, the response rate was 33% ( 95% CI: 9–57% ) but this dropped to 17% when the treatment was administered after chemotherapy. Nausea-vomiting was the most frequent and severe non-hematological toxicity observed (WHO grade 3–4: 29% ). Loss of hair was noticed in 48% of the patients but only 4% suffered from complete alopecia. Moderate myelotoxicity was reported but no cardiac dysfunction was noticed. IDR could be very advantageous as compared to other anthracyclines, due to its simplicity of administration associated with the lack of risk of extravasation or chemical phlebitis and also the possibility of it being able to reduce cardiotoxicity. Even if the equiefficacy of IDR and DXR has not, as yet, been clearly demonstrated, IDR should be chosen with preference to DXR when administration is not suitable.

Twenty-two patients with advanced colorectal cancer (CRC) (12 without prior chemotherapy) and fourteen with pretreated breast cancer (BC) were given mitozolomide (MTZ), IV infusion, every six weeks. The starting dose was 90 mg/m2. When it was well-tolerated, dose escalation was done up to 100-115 mg/m2. Toxicity was mild, limited to thrombocytopenia with a median nadir of 1.27 x 10(5) (0.20-4.86). No response was observed in these patients. MTZ, according to these schedule and dosage, does not show activity in human CRC and pretreated BC.

Nineteen patients with advanced head and neck cancer were given mitozolomide (MTZ), i.v. infusion, every 6 weeks. The starting dose was 100 mg m-2. When it was well tolerated, dose escalation was performed up to 110-115 mg m-2. The limiting toxicity was thrombocytopenia, often mild, but occasionally severe, with hemorrhage and the need for platelet transfusions in two patients. The platelet nadir was 85 x 10(9) l-1 (11-225). No response was observed in 14 evaluable patients. MTZ, according to this schedule and dosage does not show significant activity in human squamous cell head and neck cancer.

The electrophilic properties of the antitumour drug N(2)-methyl-9-hydroxyellipticinium acetate (Celiptium) are revealed by the detection of thiol-conjugate metabolites in man and rat urine. Besides the unchanged drug and its glucuronide, the cysteinyl- (in man) and the N-acetylcysteinyl- (in man and rat) conjugates have been unambiguously characterized using NMR, UV and mass spectral data. The urinary excretion profile exhibits total excreted products of 21% (in man) and 9% (in rat) with respect to the administered dose. The unchanged drug is found to be the major excreted compound from urine in both species (17% in man, 6.3% in rat); whereas the glucuronide (2.6% in man, 1.5% in rat), cysteinyl- (1.3% in man) and N-acetylcysteinyl- (0.2% in man, 1.2% in rat) conjugates represent the minor excreted compounds. The presence of the latter thio-conjugates provides an indirect proof of the in vivo generation of an oxidized intermediate form of the administered drug.

• A review of 2262 squamous cell carcinomas of the tonsillar region seen at the Institut Gustave-Roussy, Villejuif, France, from 1970 to 1986 showed 1837 well- and poorly differentiated squamous cell carcinomas and 425 undifferentiated squamous cell carcinomas. Eighteen patients with undifferentiated squamous cell carcinomas presented histologic characteristics of undifferentiated carcinomas of nasopharyngeal type. Radiosensibility and radiocurability (complete sterilization with 70 Gy administered) was found in this group with an excellent long-term control of local disease (77% at 10 years actuarial). Epstein-Barr virus–related serologic tests were performed for seven patients. Four of them presented the serologic anti–Epstein-Barr virus titer patterns, generally associated with undifferentiated carcinomas of nasopharyngeal type (1280 to 5120 for viral capsid antigen/IgG and 40 to 320 for viral capsid antigen/ IgA). These observations confirm that undifferentiated carcinomas of the nasopharyngeal type may arise outside the nasopharynx. (Arch Otolaryngol Head Neck Surg.1989;115:731-734)

We have conducted a multicenter randomized clinical trial comparing in advanced post-menopausal breast cancer patients 500 mg vs 1 g AG/day. The hydrocortisone dose was 40 mg/day in both groups. One hundred and seventy patients have been randomized; 161 were evaluable for tolerability, 149 for effectiveness. Response rates were similar in both groups, 19 and 24% respectively for the 500 mg and 1 g groups. No difference was observed according to tumor site. Duration of response was the same in both groups (14 months), as was mean time to response (about 3 months). Survival (studies in 125 patients) was similar in both groups (responders and non-responders). No response could be obtained with 1 g after relapse or failure with 500 mg (n = 17). Tolerability was good in 91% of the 500 mg group patients and 78% of the 1 g group patients (P less than 0.03). It was poor in 4 and 15% respectively (P less than 0.03). Side-effects were the same in both groups but less frequent and less severe in the 500 mg group; however, these patients more frequently had 'moon face'.

PURPOSE In contrast with other carcinoma cells, cells from nude mice transplanted undifferentiated carcinoma of nasopharyngeal type (UCNT) release the soluble fragment of the CD23 antigen (sCD23). We sought to study the level of sCD23 in sera of untreated UCNT patients. PATIENTS AND METHODS Pretherapeutic sera from 65 consecutive, locally advanced, initially nonmetastatic UCNT patients were assayed for sCD23. Patients were treated with a neoadjuvant chemotherapy/full-dose radiotherapy sequence. The mean follow-up duration is 50.5 months (range, 28 to 77). The Cox proportional hazards model was used to study the association between sCD23 levels and clinical signs and disease evolution. RESULTS sCD23 levels showed an association with disease-free survival (DFS; P = .08) and overall survival (OVS; P = .08). Patients with sCD23 levels greater than a cutoff value of 0.6 ng/mL (greater cutoffs were found to be equally significant, but less sensitive), have a relative risk (RR) of relapse of 3.3 (95% confidence interval, 1.6 to 6.9; P = .002), and an RR of death of 2.9 (95% confidence interval, 1.2 to 7.3; P = .02), when taking other prognostic factors into account. CD23 does not correlate with either the response to treatment or the development of metastases, but appears to be related to local control (cutoff, 0.6 ng/mL; RR = 5.1 [95% confidence interval, 1.2 to 21.7]; P = .02). CONCLUSION The serum level of sCD23 appears to be an independent prognostic factor for initially nonmetastatic, locally advanced UCNT patients, treated with chemotherapy and radiotherapy. Our data indicate an association between this marker and local relapses. Thus, a simple enzyme-linked immunoadsorbent assay (ELISA) could help to identify a high-risk group among nonmetastatic UCNT patients. CD23 could be a marker for two groups of UCNT tumors, with distinct biologic characteristics and clinical behaviors.