Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

Observational study of vaccination in cancer patients: How can vaccine coverage be improved?

BACKGROUND: Chemotherapy increases the risk of infections, often severe, and some of them are vaccine-preventable infections. We aimed to assess vaccination coverage and associated factors in oncology and hematology patients. METHODS: Consecutive adult patients followed in a French university hospital for hematological malignancy or solid cancer voluntarily completed an anonymous questionnaire in September and October 2016. It included questions on underlying disease, chemotherapy, flu, and pneumococcal vaccination uptakes, and attitudes toward vaccination. Factors associated with vaccination uptake were assessed by multivariate logistic regression. RESULTS: The response rate was 41.9% (N=671) among 1,600 questionnaires distributed; 232 patients had underlying hematological malignancy and 439 had solid cancer. Half of the patients were aged over 65 years. Chemotherapy was ongoing or discontinued for less than one year in 74.7% of patients. In patients aged <65 years undergoing chemotherapy, flu vaccination rate was 19.9% whereas patients aged >65 years had coverage of 47%. Pneumococcal vaccine uptake was 7.3%. However, 64.7% of patients were favorable to vaccination. Vaccine uptake was associated with age >65 years (OR 4.5 [2.9-7.0]), information about vaccination delivered by the family physician (OR 12.9 [5.5-30.1]), follow-up in hematology unit (OR 2.0 [1.3-3.1]), and positive opinion about vaccination (OR 2.0 [1.3-3.1]). CONCLUSION: Despite specific recommendations regarding immunocompromised patients, anti-pneumococcal and flu vaccinations were rarely conducted, even in elderly patients. Targeted information campaigns to family physicians, oncologists, and patients should be implemented to improve vaccine coverage in patients with underlying malignancies.

Is current initial empirical antibiotherapy appropriate to treat bloodstream infections in short-duration chemo-induced febrile neutropenia?

INTRODUCTION: Fever of unknown origin is by far the most common diagnosis in low-risk febrile neutropenic patients undergoing chemotherapy. The current empirical regimen combines amoxicillin-clavulanic acid and fluoroquinolones in low-risk neutropenic patients. The aim of this study was to assess the appropriateness of antibiotherapy and the outcome of bloodstream infections (BSI) in patients with expected neutropenia of short duration. METHODS: This 2-year monocentric retrospective study included all consecutive neutropenic febrile adult patients with expected duration of neutropenia ≤ 7 days. They were classified into low- and high-risk groups for complications using the MASCC index. Appropriateness of initial empirical antibiotic regimen was assessed for each BSI. Multivariate analysis was performed to identify factors associated with mortality. RESULTS: Over the study period, 189 febrile episodes with positive blood cultures in neutropenic patients were reported, of which 44 occurred during expected duration of neutropenia ≤ 7 days. Patients were classified as high-risk (n = 27) and low-risk (n = 17). Gram-negative bacteria BSI represented 57% of cases, including only two multidrug-resistant bacteria in high-risk patients. Initial empirical antibiotherapy was appropriate in 86% of cases, and inappropriate in the event of coagulase-negative Staphylococcus BSI (14%), although the outcome was always favorable. In low-risk patients, no deaths and only 12% of severe complications were reported, contrasting with mortality and complication rates of 48% (p < 0.001) and 63% in high-risk patients (p < 0.001), respectively. CONCLUSIONS: Outcome of BSI is favorable in low-risk febrile neutropenic patients, even with inappropriate empirical initial antibiotic regimen for coagulase-negative Staphylococcus BSI. Initial in-hospital assessment and close monitoring of these patients are however mandatory.

Phase I dose-escalation study of oral vinflunine in combination with erlotinib in pre-treated and unselected EGFR patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated. PATIENTS AND METHODS: Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg. RESULTS: Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease. CONCLUSION: The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Phase I dose-escalation study of oral vinflunine administered once daily for 6 weeks every 8 weeks in patients with advanced/metastatic solid tumours.

PURPOSE: Vinflunine ditartrate is a microtubule inhibitor belonging to the vinca alkaloid family. This phase I study was carried out to evaluate the maximal tolerated dose, the safety profile, the pharmacokinetics and the activity of oral vinflunine (VFL) given daily in patients with advanced/metastatic solid tumours and who have failed standard therapy. METHODS: Patients were treated with oral VFL administered once daily for 6 weeks followed by a two-week rest. Sequential dose-escalating cohorts of patients were enrolled into 5 dose levels: 20, 40, 60, 75 and 95 mg/day. RESULTS: In total, 27 patients received 53 cycles. Dose-limiting toxicities (DLT) were observed from 60 mg/day. The dose levels 75 and 95 mg/day were both assessed as maximal tolerated dose. The most frequent dose-limiting toxicities were of haematological origin. The recommended dose was defined as 60 mg/day, dose at which 4 patients experienced long stabilizations (≥4 months) and also received longer treatment duration in comparison with the other dose levels. Blood exposure of VFL and its active metabolite 4-O-deacetyl vinflunine (DVFL) increased proportionally to the dose levels. The concentrations of VFL and DVFL reached a steady state at, respectively, 5 and 20 days and remained stable for the rest of the cycle. Increased incidence of DLT/SAE was consistent with the increase of VFL dose and drug exposure. CONCLUSIONS: These results showed the feasibility of daily oral vinflunine administration on a 6-week treatment duration. This new schedule of administrations enabled sustained and stable blood concentrations of both VFL and DVFL. The recommended dose was defined at 60 mg/day, dose at which 4 patients experienced clinical benefit.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

Supportive care organisation in France: an in depth study by the French speaking association for supportive care in cancer (AFSOS).

BACKGROUND: Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy. PATIENTS AND METHODS: The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients. RESULTS: Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres - CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p=0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p=0.01). Adverse event information was performed more by an oncologist than other specialists (p=0.01). CONCLUSION: Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients.

An evaluation of a preparation of Mycobacterium vaccae (SRL172) as an immunotherapeutic agent in renal cancer.

Two studies were carried out to evaluate heat-killed Mycobacterium vaccae SRL172 as an immunotherapeutic agent for patients with metastatic, post-nephrectomy, renal cell carcinoma. In the first study, 60 patients in France and the UK received injections of SRL172, and their survival was compared with that of historical controls who had been treated either with biological response modifiers (IL-2, IFN-alpha) or chemotherapy. In the second study, 36 patients were randomised to receive treatment with IL-2 alone or IL-2 plus SRL172. Survival and adverse events related to the treatments were assessed and compared between treatment groups. The first study showed that those treated with SRL172 alone survived equally as long as those receiving IL-2 or IFN-alpha and both treatment groups survived longer than those on chemotherapy (p<0.001), a result supported by Cox's proportional hazards regression analysis. The second study, stopped early due to drug supply issues, showed that the addition of SRL172 to IL-2 made no difference to survival compared to IL-2 alone, in the limited numbers treated. Adverse events occurring in those receiving SRL172 in the first study were mild and in the second study those receiving IL-2 alone had significantly more adverse events than those receiving SRL172 plus IL-2 (p<0.001). It is concluded that SRL172 may have activity in metastatic renal cancer and has very low toxicity, making it worthy of further study.

The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression.

CDKN2A locus on chromosome 9p21 encodes two tumour suppressor proteins pl6INK4A, which is a regulator of the retinoblastoma (RB) protein, and p14ARF, which is involved in the ARF-Mdm2-p53 pathway. The aim of this study was to determine if CDKN2A gene products are implicated in differentiated thyroid carcinogenesis and progression. We used real-time quantitative RT-PCR and immunohistochemistry to assess both transcripts and proteins levels in 60 tumours specimens. Overexpression of p14ARF and pl6INK4A was observed in follicular adenomas, follicular carcinomas and papillary carcinomas, while downregulation was found in oncocytic adenomas compared to nontumoral paired thyroid tissues. These deregulations were statistically significant for pl6INK4a (P=0.006) in follicular adenomas and close to statistical significance for p14ARF in follicular adenomas (P=0.06) and in papillary carcinomas (P=0.05). In all histological types, except papillary carcinomas, we observed a statistically significant relationship between p14ARF and E2F1 (r=0.64 to 1, P<0.05). Our data are consistent with involvement of CDKN2A transcript upregulation in thyroid follicular tumorigenesis as an early event. However, these deregulations do not appear to be correlated to the clinical outcome and they could not be used as potential prognostic markers.

Vinflunine -- an active chemotherapy for treatment of advanced non-small-cell lung cancer previously treated with a platinum-based regimen: results of a phase II study.

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.

Expression of TAp73 and DeltaNp73 isoform transcripts in thyroid tumours.

AIM: This study was aimed to determine p73 status in thyroid tumours. METHODS: Differential expression of the TAp73, DeltaTAp73 transcripts was measured in a panel of 60 thyroid malignancies by quantitative RT-PCR. RESULTS: By comparison to normal thyroid tissue surrounding the tumours, we observed significant downregulation of TP73 transcripts in adenomas and in differentiated carcinomas. Correlations were found in normal tissue specimens between the expression of TAp73 and DeltaNp73 transcripts and that of p53, p14ARF p16INK4a, but these correlations were lost in carcinomas (PTC or FTC). CONCLUSIONS: We have found significant variations of TAp73, DeltaNp73, p53, p14ARF p16INK4a, expressions and correlations between the expressions of those different genes in thyroid cancer.

Safety and efficacy of subcutaneous and continuous intravenous infusion rIL-2 in patients with metastatic renal cell carcinoma.

A retrospective analysis was conducted on data from four open-label, nonrandomised, phase II trials of recombinant interleukin-2 (rIL-2) in patients with metastatic renal cell carcinoma to compare the safety and efficacy of administration by subcutaneous (s.c.) and continuous intravenous (c.i.v.) infusion (n=103 s.c. and n=225 c.i.v.). No statistically significant differences were found between the cohorts in terms of overall response rate (s.c.: 13.6% vs c.i.v.: 12.4%, P=0.77), response duration (s.c.: 9.8 months vs c.i.v.: 10.1 months, P=0.99), and overall survival (P=0.08). Compared with c.i.v. administration, more patients in the s.c. cohort experienced stable disease (50.5 vs 29.8%) and fewer underwent disease progression (35.0 vs 43.6%). Subcutaneous administration was associated with a significantly lower incidence of grade 3 or 4 adverse events (46 vs 76%; P<0.001), and fewer s.c. patients required dose reductions because of toxicity (20 vs 82%). At the doses and within the schedules tested, this comparative analysis did not detect any difference in efficacy between s.c. and c.i.v. administration of rIL-2 in terms of overall survival, duration of response and response rate in patients with metastatic renal cell carcinoma. However, s.c. delivery of rIL-2 was associated with improved tolerability.

[Operable lung cancer and synchronous adrenal masses: role of laparoscopic adrenalectomy combined with pulmonary resection]. / Cancer bronchique opérable et lésion surrénalienne synchrone: intérêt du traitement cumulé associant surrénalectomie sous coelioscopie et exérèse pulmonaire.

STUDY AIM: Assessment of laparoscopic adrenalectomy in the management of operable non-small cell lung cancer (NSCLC) associated with solitary and synchronous adrenal mass. PATIENTS AND METHODS: In a retrospective study, we reviewed 3 patients with operable NSCLC proved by pulmonary biopsy and an isolated synchronous adrenal mass shown by abdominal CT scan. We first performed a laparoscopic adrenalectomy followed by pulmonary resection. RESULTS: All patients had a laparoscopic adrenalectomy without any conversion or treatment-related death. Hospitalization stay ranged from 5 to 6 days. A left pneumonectomy has been performed immediately after this first hospitalization in 2 cases and after a first cycle of chemotherapy in the third case. Pathologic examination showed a NSCLC adrenal metastasis in 2 cases and an adrenocortical adenoma in the last case. During the follow-up 2 patients died of other distant metastasis and a mediastinal lymph node recurrence has been diagnosed in the third patient, actually treated by a second line chemotherapy. CONCLUSION: Despite those bad results that concern patients T3 M+ in 2 cases, laparoscopic adrenalectomy seems to be very interesting in selected cases. Considering that pulmonary resection can be done after, it represents a mean of diagnosis at least better than fine needle aspiration biopsy. Laparoscopic adrenalectomy might also be considered in the resection of a synchronous and isolated metastasis as a way to improve survival.

Value of autologous stem cell transplantation with purged bone marrow as first-line therapy for follicular lymphoma with high tumor burden: a GOELAMS phase II study.

This prospective phase II study was undertaken to evaluate the efficacy and toxicity of early intensive therapy followed by purged autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma with high tumor burden. All patients received the VCAP regimen (vindesine, cyclophosphamide, doxorubicin and prednisone) as conventional chemotherapy and DHAP as second-line therapy. Twenty-nine consecutive patients were included in the study. Twenty-seven patients were grafted, seven in first complete remission (CR) and 20 in first partial remission (PR). Preparative therapy consisted of cyclophosphamide and total body irradiation (TBI) in all the patients. With a median follow-up of 6 years, the actuarial overall survival is 64% and the actuarial event-free survival is 55%. Two treatment-related early deaths were observed. Eleven patients were informative for serial PCR analysis of minimal residual disease after ABMT: two relapsed, four remained disease-free with PCR positivity and five were disease-free with PCR negativity. These encouraging results lay the basis of future prospective randomized trials comparing autologous stem cell transplantation as front-line treatment with conventional chemotherapy for patients with bad prognostic factors.

Feasibility and preliminary results of intensive chemotherapy and extensive irradiation in selected patients with limited small-cell lung carcinoma--results of three consecutive phase II programs.

We report the results of three consecutive programs combining initial intensive chemotherapy and radiotherapy in the treatment of patients with limited small-cell lung cancer (SCLC). The objective was to test the feasibility and the effect of high-dose chemotherapy and three thoracic irradiation programs on survival and patterns of relapse. Forty-two patients with limited SCLC were enrolled. All patients received high-dose chemotherapy (vindesine, etoposide, doxorubicin, cisplatin and cyclophosphamide or ifosfamide). In the SC 84 program, chest and brain radiotherapy was delivered during each course of chemotherapy, with a complementary irradiation after chemotherapy. In the SC 86 and SC 92 programs, patients received chemotherapy followed by thoracic irradiation and prophylactic brain and spinal axis radiotherapy. At the end of treatment, 40 patients (95%) were in complete response. During chemotherapy, high levels of toxicity were noted. All patients had grade IV hematological toxicities. The extra-hematological toxicities were digestive (grade III: 21%; grade IV: 7%) and hepatic (grades III and IV: 14%). During irradiation, patients presented digestive, pulmonary and hematological toxicities. Five patients developed late toxicities and a second malignancy was observed in 4 patients. The 2- and 5-year survival rates for all patients were 51% and 27%, respectively. Despite the marked toxicity of the initial intensive chemotherapy, the treatments are tolerable and effective in the control of extra-thoracic micrometastases, whereas they are less effective for thoracic primary tumor.

Oxaliplatin, 5-fluorouracil, and folinic acid (Folfox) in patients with metastatic renal cell carcinoma: results of a pilot study.

We report the results of a chemotherapy regimen combining oxaliplatin, 5-fluorouracil, and folinic acid in patients with metastatic renal cell carcinoma. The objective of this pilot study was to define the potential efficacy of this second-line combination in patients previously treated with interleukin-2 alone or in combination with interferon alpha. Fourteen patients with metastatic renal cell carcinoma in failure after immunotherapy were included in this trial. During treatment, patients received six chemotherapy courses (Folfox regimen) administered every 2 weeks. Each cycle combined oxaliplatin day (D) D1 and folinic acid plus 5-fluorouracil D1 and D2. At completion of treatment, no objective response was observed and two patients presented stable disease. This chemotherapy schedule in patients with metastatic renal cell carcinoma previously treated with immunotherapy does not seem to be effective.

Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies.

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associated with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies, also called the "anti-Hu syndrome," is believed to result from an immune response triggered by tumor antigens and misdirected to the neurons. To further assess the issue of cell-mediated immunity in this disease, the peripheral blood lymphocyte surface phenotype was studied in 15 patients suffering from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein was used to stimulate in vitro peripheral blood mononuclear cells of 10 seropositive patients and of 10 patients from each control group. Phenotypic analysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO+CD4+) T cells in the seropositive group in comparison with the two control groups. Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [3H]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells revealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant increase of the interferon-gamma/interleukin-4 ratio was found in culture supernatants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protein is an antigenic target for autoreactive CD4+ T cells, presumably of the Th1 subtype, which could therefore be directly involved in cell-mediated injury of the nervous system as well as in antitumoral immunity.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.