Alain Spatz

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

BACKGROUND Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Cutaneous side-effects of kinase inhibitors and blocking antibodies.

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial

BackgroundDC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome.Patients and methodsExosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 × 1014 molecules) or peptides (10 versus 100 μg/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression.ResultsThe GMP process allowed to harvest about 5 × 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood.ConclusionThe first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

The development of optimal pathological assessment of sentinel lymph nodes for melanoma

1158 sentinel lymph nodes (SLNs), excised from patients with primary cutaneous melanoma, were assessed pathologically using histology with immunohistochemistry (IHC) on all nodes, and RT‐PCR for Mart‐1 and tyrosinase on 55 nodes. RT‐PCR was compared with the histology and IHC assessed on the same nodes. The evaluation of progressively more detailed protocols for histology and IHC modulated by the RT‐PCR results led to a procedure that consistently detects metastases in 34% of patients submitted to SLN biopsy for cutaneous melanomas with a vertical growth phase and a mean thickness of 2.02 mm (range 0.25, with regression, to 19 mm). As this technique is virtually free of false positives and produces only a marginally lower detection rate than RT‐PCR, which was subject to false positives of 7% in our study, it is suggested that this extended protocol should be the basis on which further evaluation of the place of RT‐PCR in SLN assessment takes place. The evolved protocol described here has been adopted by the EORTC as the standard procedure for pathological handling of sentinel lymph nodes for melanoma when SLN status is a criterion in their clinical trials or studies. Copyright

Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor.

OBJECTIVES To provide an accurate description and to evaluate the incidence and severity of cutaneous reactions induced by sorafenib tosylate, a new oral multikinase inhibitor. DESIGN Double-blind, prospective dermatologic substudy performed on all consecutive patients included in our center in a large phase 3 trial. SETTING Institutional practice at the Gustave Roussy Institute. PATIENTS Eighty-five patients with renal cell cancer treated between November 1, 2003, and February 28, 2005. Interventions Patients were randomized to receive either sorafenib (n = 43) or placebo (n = 42). Dermatologic examination was performed before treatment, every 3 weeks during the first 4 cycles, and every 4 weeks thereafter. MAIN OUTCOME MEASURES Incidence and severity of cutaneous reactions to sorafenib. RESULTS Thirty-nine patients (91%) experienced at least 1 cutaneous reaction in the sorafenib group vs 3 (7%) in the placebo group. A hand-foot skin reaction that appeared to be clinically distinct from the well-known chemotherapy-induced hand-foot syndrome was observed in 26 patients receiving sorafenib (60%). Reversible grade 3 hand-foot skin reaction was documented in 2 patients receiving sorafenib and led to a dose reduction. Other cutaneous reactions were facial erythema, scalp dysesthesia, alopecia, and subungual splinter hemorrhages. CONCLUSIONS Sorafenib induces frequent cutaneous adverse events, some of which may lead to a dose reduction. Close collaboration between oncologists and dermatologists is needed to improve both the characterization and the management of these side effects. Appropriate patient education before the initiation of therapy and the introduction of early symptomatic measures may improve management.

Prognosis in Patients With Sentinel Node–Positive Melanoma Is Accurately Defined by the Combined Rotterdam Tumor Load and Dewar Topography Criteria

PURPOSE Prognosis in patients with sentinel node (SN)-positive melanoma correlates with several characteristics of the metastases in the SN such as size and site. These factors reflect biologic behavior and may separate out patients who may or may not need additional locoregional and/or systemic therapy. PATIENTS AND METHODS Between 1993 and 2008, 1,080 patients (509 women and 571 men) were diagnosed with tumor burden in the SN in nine European Organisation for Research and Treatment of Cancer (EORTC) melanoma group centers. In total, 1,009 patients (93%) underwent completion lymph node dissection (CLND). Median Breslow thickness was 3.00 mm. The median follow-up time was 37 months. Tumor load and tumor site were reclassified in all nodes by the Rotterdam criteria for size and in 88% by the Dewar criteria for topography. RESULTS Patients with submicrometastases (< 0.1 mm in diameter) were shown to have an estimated 5-year overall survival rate of 91% and a low nonsentinel node (NSN) positivity rate of 9%. This is comparable to the rate in SN-negative patients. The strongest predictive parameter for NSN positivity and prognostic parameter for survival was the Rotterdam-Dewar Combined (RDC) criteria. Patients with submicrometastases that were present in the subcapsular area only, had an NSN positivity rate of 2% and an estimated 5- and 10-year melanoma-specific survival (MSS) of 95%. CONCLUSION Patients with metastases < 0.1 mm, especially when present in the subcapsular area only, may be overtreated by a routine CLND and have an MSS that is indistinguishable from that of SN-negative patients. Thus the RDC criteria provide a rational basis for decision making in the absence of conclusions provided by randomized controlled trials.

Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032)

PURPOSE To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. PATIENTS AND METHODS A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m(2)/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m(2)/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. RESULTS Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P=0.99). Median progression-free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P=0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. CONCLUSION Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine.

Dermatologic symptoms associated with the multikinase inhibitor sorafenib

BACKGROUND The multikinase inhibitor sorafenib (Nexavar) is associated with a relatively high incidence of dermatologic symptoms. OBJECTIVE We sought to evaluate and provide guidance on the diagnosis and clinical management of dermatologic symptoms associated with sorafenib in patients with advanced solid tumors. METHODS English-language studies representative of a patient population with a variety of tumor types, who received single-agent sorafenib, were selected. Particular emphasis was placed on the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs). RESULTS Frequently observed dermatologic side effects (any grade in TARGETs) of sorafenib include rash/desquamation (40%), hand-foot skin reaction (30%), alopecia (27%), and pruritus (19%). Generally, dermatologic symptoms resolve with appropriate management, including topical treatments, dose interruptions, dose reductions, or a combination of these. LIMITATIONS The results presented here are based on a limited number of studies. CONCLUSION Although sorafenib is associated with dermatologic symptoms, these are usually resolved with appropriate intervention, patient-led practical treatment, and preventative measures.

EANM-EORTC general recommendations for sentinel node diagnostics in melanoma

The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to “general consensus” and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.