Randomized adjuvant study comparing two schemes of 5-fluorouracil and leucovorin in stage B2 and C colon adenocarcinoma: study design and preliminary safety results. Groupe d'Etude et de Recherche Clinique en Oncologie Radiotherapies.

The aim of this randomized open-label study was to compare a bimonthly with a monthly regimen of 5-fluorouracil (5-FU) and leucovorin for the adjuvant treatment of colon and high-rectum adenocarcinoma. The bimonthly regimen was administered for 2 consecutive days every 14 days as d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 as a 2-hour infusion followed by 5-FU bolus of 400 mg/m2 and a 600 mg/m2 5-FU 22-hour continuous infusion (LVSFU2). In the monthly regimen, d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 15-minute infusion followed by a 400 mg/m2 15 minute 5-FU bolus was administered for 5 consecutive days every 28 days (FUFOL). Nine hundred five patients with recently resected stage B2 or C colon or high-rectum adenocarcinoma (inferior pole of the tumor subperitoneal) were recruited into the study. Patients were randomized in a 2 x 2 factorial design to receive either LV5FU2 or FUFOL for 24 or 36 weeks. Characteristics of the patients in the two different treatment groups were similar at baseline. Compliance was good. Mean 5-FU dose intensities were 930 mg/ m2/wk and 463 mg/m2/wk for LVSFU2 and FUFOL, respectively. The incidence of maximal grade III-IV toxicities for LVSFU2 and FUFOL was neutropenia 6% and 16% (P < .001), diarrhea 4% and 10% (P < .001), and mucositis 2% and 7% (P < .001), respectively. Maximum grade III-IV toxicities in the LV5FU2 treatment group were significantly lower than in the FUFOL group (10% v 26%; P < .001). Although patients in the LV5FU2 group received twice the dose of 5-FU compared with those in the FUFOL group, LV5FU2 was shown to be less toxic. Efficacy data will be available in 2001.

Favorable outcome of gemcitabine-induced respiratory distress syndrome.

Gemcitabine, a deoxycytidine analog, is used to treat solid tumors, like non-small-cell lung carcinoma. The most commonly reported adverse effects are reversible and generally not fatal. However, among the five cases of acute respiratory distress syndrome (ARDS) secondary to gemcitabine treatment reported since 1997, four were fatal despite corticosteroid therapy. We describe here a patient who received gemcitabine for bronchial epidermoid carcinoma and developed ARDS which spontaneously regressed after gemcitabine withdrawal.

Vinorelbine and ifosfamide for unresectable non-small cell lung cancer.

PURPOSE: The study assessed the efficacy of combination therapy with vinorelbine and ifosfamide in patients with unresectable non-small cell lung cancer. PATIENTS AND METHODS: Forty patients with non-small cell lung cancer whose tumour was unresectable by virtue of the extent of disease or severity of impairment of lung function and who were considered unsuitable for treatment with a cisplatin based treatment were entered onto the study. Thirty-four patients received two cycles of treatment and were considered to be evaluable for response. The treatment schedule consisted of vinorelbine (Navelbine, Pierre Fabre Medicament) 25 mg/m2 on days 1 and 8, and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily given on days 1 to 3; cycles were repeated every 21 days and treatment continued in responding patients until progression occurred. RESULTS: Objective responses were observed in 12 patients (30%; CI95, 16-44) with one completed response (CR) and 11 partial response (PR). CONCLUSION: This schedule achieves good levels of response without the use of cisplatin so it is suitable for patients whose performance status or concomitant medical condition precludes the use of platinum based chemotherapy.

[Subcutaneous administration of interleukin-2 in ambulatory treatment of patients with metastatic renal cancer. Three-year results of the SCAPP I program]. / Traitement ambulatoire par interleukine 2 administrée par voie sous-cutanée chez des patients porteurs d'un cancer du rein métastatique. Résultats à 3 ans du programme SCAPP i.

We report a french experience of subcutaneous administration of interleukin-2 in treatment of patients with metastatic renal cell carcinoma. Thirty-nine patients with metastatic renal cell carcinoma were included in the study. During the 10-week induction period, interleukin-2 was administrated subcutaneously 5 days a week for 8 weeks. The weekly dosage were 90 MIU during weeks 1 and 6; 63 MIU during weeks 2 to 4 and 7 to 9. After evaluation, responders and patients with stable disease received maintenance treatment which was discontinued upon the appearance of disease progression or unacceptable toxicity. During the maintenance period, interleukin-2 was administered 5 days a week for 4 weeks followed by a 2-week rest period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. After completion of induction treatment, 7 of 39 evaluable patients (18%) had objective responses with 1 complete response. A diminution of dose or interruption of treatment occurred with 7 patients because severe toxicity. Other systemic side effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. The median follow-up of all the patients included was 21 months. The 1, 2 and 3 years survivals were 64%, 33% and 22% respectively. This multicentric trial confirms the efficacity of subcutaneously-administered interleukin-2 in patients with metastatic renal cell carcinoma in terms of both response rate and survival. Unfortunately, increasing total doses of administrated interleukin-2 does not seem to increase efficacity according to response rate, but is more toxic.

[Induction chemotherapy followed by concomitant combined radiotherapy and chemotherapy in stage III non-small cell bronchial carcinoma]. / Chimiothérapie d'induction suivie d'une association concomitante de radiothérapie et de chimiothérapie pour les carcinomes bronchiques non à petites cellules de stade III.

PURPOSE: To determine the efficacy and safety of induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of stage III non-small cell lung cancer and whether the response to induction chemotherapy can predict the response to subsequent chemoradiotherapy and survival. MATERIALS AND METHODS: Between December 1987 and June 1993, 46 patients with previously untreated stage III non-small cell lung cancer received every 21 days induction chemotherapy (ICT) including three cycles of 5-fluorouracil (600 mg/m2/d in short infusion from d1 to d5), cisplatin (15 mg/m2/d from d1 to d5), etoposide (50 mg/m2/d from d1 to d5) and hydroxyurea (1,500 mg/d from d1 to d5). The first 21 patients also received bleomycin (3 mg/m2/d from d1 to d5). All patients received concomitant chemotherapy and had chest radiotherapy (CCRT). Patients received irradiation (65 Gy/33-6 fractions/7 weeks) on d25 after the third cycle of chemotherapy. Concomitant chemotherapy was composed of cisplatin (20 mg/m2) and 5-fluorouracil (500 mg/m2) that were administered each Monday and Thursday during radiotherapy. Maintenance chemotherapy consisted of thiotepa (10 mg/m2) and methotrexate (10 mg/m2) that were administered every 2 weeks for 6 months. RESULTS: Pulmonary toxicity was observed in four out of 21 patients who had received bleomycin and subsequently developed pulmonary fibrosis, leading to death for two of them. ICT alone produced five complete responses (11%) and 13 partial responses (28%). The combination of chemotherapy and radiotherapy led to 19 complete responses (41%) and 14 partial responses (30%). Eighteen of the 18 responders (100%) to ICT responded to subsequent CCRT, of whom 13 (72%) became complete responders. Fifteen of the 28 non-responders to ICT (53%) responded to CCRT, six of them being complete responders (21%) (P < 0.001). The median overall survival rate was 17 months when considering all patients, 25 months in patients responding to ICT and 13 months in non-responders. The 2-year survival rates were 28, 55 and 11%, respectively (P < 0.05). ICT did not influence the rate of subsequent metastatic events. However, locoregional reprogression was lower in responders to ICT. The number of metastatic events was not significantly related to response to ICT. By contrast, the rate of local failure was higher when there was resistance to ICT (75% versus 39%). Out of the 19 complete responders to CCRT (13 responders to ICT and six non-responders to ICT), four developed secondary locoregional reprogression (21%) and six developed metastatic disease (31%). In complete responders to CCRT, the rate of locoregional failure was 15% in responders to ICT (2/13) and 33% (2/6) in non-responders to ICT. Four out of the 13 responders to CCRT after response to ICT (31%) and two out of the six complete responders to CCRT developed metastatic disease after non-response to ICT. CONCLUSION: There is a statistically significant relationship not only between the response to ICT and the response to CCRT, but also between the response to ICT and the local outcome and survival.

Logistic regression model of fotemustine toxicity combining independent phase II studies.

BACKGROUND: To optimize fotemustine chemotherapy, the authors considered how to combine independent Phase II trials to predict the risk of first occurrence of severe toxicity as a function of initial patient characteristics. METHODS: Clinical data from six Phase II trials were collected. Of the 478 patients enrolled 442 (male/female, 259/183; age range, 15-81 years) were evaluable for toxicity (1384 cycles of chemotherapy), including 221 with malignant malignant melanomas, 138 with primary brain tumors, 29 with lung carcinomas, 8 with head and neck carcinomas, and 46 with miscellaneous cancers. The influence of age, sex, performance status, type of tumor, number and location of metastases, and previous treatment by chemotherapy and/or radiotherapy was studied. The logistic regression method was applied to predict occurrence of leukopenia, thrombocytopenia, anemia, digestive tract, and/or hepatic toxicity. RESULTS: Univariate analysis showed that predictive factors for hematologic toxicity were age (> 50 years), type of tumor (brain < melanoma < others), number of metastatic sites (> 3), location of metastases (nonvisceral), and previous chemotherapy. Performance status and previous radiotherapy did not affect the toxicity of fotemustine Nausea and vomiting were predictable based on the type of tumor (head and neck < lung < brain < melanoma < others), the number of metastatic sites (> three) and visceral metastases. Hepatic disorders occurred preferentially in patients with hepatic metastases and more than three metastatic sites. Individual risk of hematologic and hepatic toxicity for patients with melanoma and primary brain tumors was predicted using logistic regression models. CONCLUSIONS: By combining clinical data from independent Phase II trials, the logistic model developed could predict the probability of fotemustine hematologic and hepatic toxicity.

Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma. Results of a multicenter SCAPP1 trial.

BACKGROUND: This multicenter phase II trial was conducted in order to evaluate the efficacy and toxicity of the subcutaneous route of administration of rIL-2 in the treatment of patients with metastatic renal cell carcinoma and to check whether an increased cumulative dose of rIL-2 increases efficacy. PATIENTS AND METHODS: Thirty-nine patients with metastatic renal cell carcinoma were included in this study. During the induction period, rIL-2 was administered subcutaneously 5 days a week for 8 weeks. The weekly dosages were 90 MIU during weeks 1 and 6;63 MIU during weeks 2 to 4 and 7 to 9. After evaluation, responders and patients with stable disease received maintenance treatment which was discontinued upon the appearance of disease progression or unacceptable toxicity. During the maintenance period, rIL-2 was administered 5 days a week for 4 weeks followed by a 2-week rest period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. RESULTS: After completion of induction treatment, 7 of 39 evaluable patients (18%) had objective responses (95% CI: 9% to 37%) with one complete response. Treatment was interrupted or reduced due to toxicity for seven patients: Neuropsychiatric symptoms (3 patients), joint pain (1 patient), major asthenia and anorexia (1 patient), stroke (1 patient), and septicemia (1 patient). Other systemic side effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. In none of the patients did the response status improve during this maintenance period. The median follow-up of all of the patients included was 19 months. The one- and two-year survivals were 65% and 33%, respectively, ad the median duration of response was 11 months (5 to 16+). CONCLUSIONS: This multicentric study confirms the efficacy of subcutaneously-administered rIL-2 in patients with metastatic renal cell carcinoma in terms of both response rate and survival. The role of a maintenance therapy needs further evaluation.

Somatostatin receptor imaging in small cell lung cancer.

To determine its usefulness, we evaluated 111In-DTPA-Octreotide (octreotide scintigraphy) in the initial staging of 19 patients with histologically proven small cell lung cancer (SCLC) and compared the results to those of conventional imaging. Images performed during initial staging demonstrated 21 known pulmonary lesions and two known supraclavicular nodes. We detected a previously unknown mediastinal lesion. The number of metastases was underestimated, with no liver (5), brain (1) or skin metastases detected. Bone lesions were identified in 4 out of 5 patients. There were fewer lesions detected with octreotide scintigraphy than with bone scintigraphy (except for one case). We therefore conclude that octreotide scintigraphy is a highly effective method for detecting SCLC primary tumour and supraclavicular nodes; the procedure is of limited value for distant metastasis. Further studies are needed to establish its ability for detecting residual intrathoracic disease, and confirm the value of octreotide scintigraphy in differentiating residual disease from other benign lesions.

Sequential functional imaging with technetium-99m hexakis-2-methoxyisobutylisonitrile and indium-111 octreotide: can we predict the response to chemotherapy in small cell lung cancer?

A case of small cell lung carcinoma (SCLC) demonstrating uptake on functional indium-111 octreotide scintigraphy is presented. Technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI) scintigraphy clearly delineated an absence of radionuclide uptake at the tumour site. This suggested the presence of multidrug resistance-mediated P glycoprotein (Pgp) on tumour cells, which recognizes certain chemotherapeutic agents as well as MIBI as a substrate and avoids radionuclide concentration. Following three courses of chemotherapy, the patient failed to improve and eventually died. This case demonstrates the importance of functional images, which have the potential to predict the outcome in response to chemotherapy.

Cisplatin-5-fluorouracil in small cell lung cancer. A phase II study in 109 patients.

One hundred nine previously untreated patients with small cell lung cancer were treated for five consecutive days with 20 mg/m2/day of cisplatin and 600 mg/m2/day of 5-fluorouracil. One cycle of chemotherapy was administered every three weeks. The patients received a median number of three cycles. Then they were transferred to CAE chemotherapy. A 77% overall response rate (95% confidence interval of 0.70-0.85) was observed after initial cisplatin-5FU treatment. Twenty-three complete responses (21%) and 62 partial responses (56%) were obtained. In cerebral metastases the response rate was high at 91% (21 out of 23), with 43% complete responses. In the limited forms, statistical survival at 1 year was 25%. A Grade 3-4 thrombocytopaenia was observed in 10 patients (9%) and a Grade 2-3 leukopaenia in four patients. Three patients suffered from a Grade 2 cardiac toxicity. The cisplatin-5-fluorouracil combination demonstrates promising initial response rate in small cell lung cancers. Its main interest is in its important action on cerebral metastases and its moderate haematological toxicity.

[Malignant melanoma of the uvea]. / Mélanomes malins de l'uvée.

Intraocular melanoma is the most common primary ocular malignancy in Whites. Epidemiologic studies demonstrated the role of sun exposure as a risk for uveal melanoma. Conservative treatment techniques are indicated for localised tumors when feasible. External radiation therapy and radioactive eye plaque brachytherapy seem as effective as surgery in term of survival. High tumor doses can be safely administered with either helium or proton beams. A partial preservation of the vision is possible in most of patients. However, even for locally controlled patients, distant metastases can occur. Liver is the most frequent metastatic site, and also the first involved. Liver metastases are associated with a low response rate, to dacarbazine and nitrosourea. Recent studies using a new nitrosourea, fotemustine, administered locally through an intra-arterial catheter, show that it produces encouraging results with a good hepatic and hematologic tolerance.

[Cancer of the kidney: changes in blood lymphocyte subsets induced by treatment with interferon alpha-2b and interleukin-2r]. / Cancer du rein: variations des populations lymphocytaires sanguines sous traitement par interféron alpha-2b et interleukine-2r.

Twenty patients (6 females and 14 males), age range 36-70 years-old, with metastatic renal cell carcinoma (MRCC), received interferon alpha-2b (IFN-A) 10 x 10(6) units/day IM for 5 days followed by continuous i.v. infusion of interleukin-2 (IL-2) 18 x 10(6) units/day for 5 days. The median follow-up was 10 months. We observed four partial responses (20%), 13 stable (65%) and three progressive diseases (15%). The mean CD4/CD8 ratio, obtained before therapy in patients with MRCC, was compared with CD4/CD8 ratio in 51 patients with different advanced malignancy and in patients with no cancer. The CD4/CD8 ratio was higher in patients with MRCC (2.55) than in other cancers (1.474) and than in populations with no cancer (1.66 x chi 2 = 17,378). The surface phenotypes of peripheral lymphocytes were analysed by cytofluorometry in patients with MRCC during and after treatment with IFN-A and IL-2. Immune modulatory effects of therapy immediately induced a decrease of different sub-populations of lymphocytes except CD25+. Far from the first course, a rise in lymphocyte count was observed. The proliferation effect was as follows: CD4+, CD8+, CD4+ CD45RA- and CD16+ CD8- cells. Far from the second and 3rd course, the sub-populations of lymphocytes decreased, except the CD4+ and CD4- CD45RA+ cells. The CD4/CD8 ratio increased progressively during treatment. Before each course, the CD4/CD8 ratio of patients with response to treatment was higher than the CD4/CD8 ratio of patients with no response. Results were non-significant due to the small number of subjects with responses in this study.

[Infectious complications during treatments with interleukin-2]. / Complications infectieuses au cours des traitements par l'interleukine 2.

Between January 1989 and May 1991, 97 patients were treated with interleukin 2 in the Oncology Department of the Avicenne Hospital (Bobigny, France). IL 2 was given over 5 days by continuous infusion through an implantable port. Ten patients (4 males, 6 females), mean age 46 years (36-67) with various cancers (breast 3, kidney 1, melanoma 1, colorectal 5), developed infection: 4 local infections around the port, 1 phlebitis, 4 septicemias, 1 bacteremia were observed. In 9 cases blood cultures were positive: Staphylococcus aureus 5, Staphylococcus epidermidis 3, Streptococcus G 1. In 5 cases the same pathogen was isolated from the port and from the blood. The mean leucocyte count was 10,627/mm3 at the time of infection. The delay between the beginning of interleukin 2 treatment and the infection was 3 months. The mean dose of IL 2 administered before infection was 456 million IU. In all cases infection was controlled without lethal complication by antibiotics and catheter removal. This high incidence (8 percent) of staphylococcal infection is partly due to the skin toxicity of IL 2 and to depressed neutrophil chemotactic response. Prophylactic antibiotics are warranted during IL 2 intravenous therapy.

[Contribution of a new nitrosourea compound: fotemustine]. / Apport d'une nouvelle nitroso-urée: la fotémustine.

Fotemustine is a new nitrosourea which is active against disseminated malignant melanoma. A global response rate (RR) of 24.2% was obtained in a multicenter trial including 153 patients. The RR was 25% on cerebral metastases. A multivariate analysis of the long term survival considering the main prognostic factors, has been achieved. It confirms the efficacy of fotemustine. As a matter of fact, the best survival of good responders compared to non responders is not correlated to the metastatic site. The combination of fotemustine and dacarbazine led to a global RR of 27.2%, up to 40% in non visceral metastases. As an other way of research the administration of fotemustine by the intraarterial hepatic route in the treatment of hepatic metastases of malignant ocular melanoma seems to give higher response rates than those obtained with chemotherapies administered by intravenous route (near 40% of response rate). Fotemustind alone or associated with cisplatinum allowed also interesting results in the treatment of metastatic non small cell lung cancer (NSCLS).

[The blood-brain barrier: implications for chemotherapy in brain tumors]. / La barrière hémato-encéphalique: implications dans la chimiothérapie des tumeurs cérébrales.

The blood-brain barrier (BBB) is located between the blood and the extracellular space of the brain. This barrier is formed by the brain capillaries whose endothelial cells have tight intercellular junctions. Transcellular passage of drugs from the bloodstream to the brain occurs selectively, in a manner dependent on the ability of the molecules to penetrale through cell membranes. The blood-brain barrier is one of the main factors of chemotherapy failure in central nervous system tumors. Penetration of a molecule from the bloodstream to the brain is dependent on the compound's liposolubility, expressed by the octanol-water separation coefficient. Following intravenous administration, most drugs fail to achieve adequate levels in the central nervous system for a sufficiently long period of time. A variety of techniques have been used in an attempt to increase CNS penetration of drugs normally shut out by the blood-brain barrier: high-dose chemotherapy, intrathecal injections, intraarterial injections, induction of hyperosmolarity to make the blood-brain barrier permeable. The best results are obtained using liposoluble drugs with optimal octanol-water separation coefficients, such as fotemustine. This compound given as single drug therapy in brain metastases from malignant melanomas has yielded response rates of up to 28.2%.

[Brain metastases of malignant melanomas]. / Métastases cérébrales des mélanomes malins.

Cerebral metastases of malignant melanoma are correlated with a very poor prognosis. Surgery of an isolated metastase can lead to a long survival but the brain lesions are frequently numerous and associated with an extracerebral diffusion. Dacarbazine (DTIC) gives a mean response rate of 21% on visceral localisations but doesn't cross the blood brain barrier (BBB). Neither do the biological response modifiers like Interleukin 2 (Il2) that leads to 25% response rate in disseminated melanoma. Nitrosoureas like carmustine (BCNU) and semustine (CCNU) have been investigated in different non randomised studies and the clinical results didn't illustrate their theorical ability to cross the BBB. Radiotherapy is also used as a palliative therapy with 7 to 16 weeks survival. Fotemustine (muphoran), a new amino acid linked nitrosourea, can give a response rate up to 28.2% in patients with cerebral metastases and the increased survival of responding patients is significant. The availability of this new drug may suggest associations with surgery and radiotherapy in the future to improve the survival of such patients.

[Metastasis of renal cancer]. / Métastases du cancer du rein.

The prognosis of renal cell carcinoma (RCC) is related to the initial staging, assessed by nephrectomy. Metastases are present at the time of diagnosis in 30% of cases. Solitary metastases are rare. The most common metastatic sites include lungs, lymph nodes and bones. Anatomical pathways as well as local events in the secondary sites are responsible for the site specificity of the tumor spread. Patients with disseminated disease have a 5 years survival rate of less than 10%. RCC is intrinsically chemo-resistant. Vinblastine leads to a global response rate (RR) of 15%. In view of the lack of effective chemotherapeutic agents, interest has been directed towards the potential value of biological response modifiers (BRM). Response rates are about 15% with IFN alpha. Significant synergy between IFN alpha and vinblastine has not been proved. Interleukin-2 (IL-2) with or without Lymphokine Activated Killer (LAK) cells leads to a RR of 20%. Some durable complete remissions have been reported. Ideal doses and schedules remain to be determined.

[Interferon and interleukin 2 in metastatic cancer of the kidney. Apropos of 18 cases]. / Interféron et interleukine 2 dans le cancer du rein métastasé. A propos de dix-huit cas.

Eighteen patients with advanced renal cancer received a combination of IFN alpha 10 x 10(6) U/m2/Day (D) x 5D followed by Interleukin 2 (IL2) 18 x 10(6) UI/m2/D x 5 D. The median follow-up is 10 months. Four partial responses were observed lasting 7 to 13 months (22.2%). The clinical safety was satisfactory. The survival for responding patients is 12 months (median). The safety of treatment is an argument in favour of future trials in an attempt to demonstrate the benefit of combinations of biomodulators.