Carlos Conill

Toxicity of combined treatment of adjuvant irradiation and interferon α2b in high-risk melanoma patients

Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) &agr;2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFN&agr;2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFN&agr;2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFN&agr;2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

Serum Protein S-100 Predicts Clinical Outcome in Patients with Melanoma Treated with Adjuvant Interferon – Comparison with Tyrosinase RT-PCR

Objective: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. Patients and Methods: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2–3 months thereafter. Results: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2–76). In the univariate analysis, under treatment S-100 ≧0.15 µg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels ≧0.15 µg/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67–9.15; p = 0.004) and 2.2 (95% CI, 1.05–4.6; p = 0.016) for S-100 ≧0.15 µg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 µg/l. Conclusions: S-100 ≧0.15 µg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 µg/l.

Diagnostic efficacy of bone scintigraphy, magnetic resonance imaging, and positron emission tomography in bone metastases of myxoid liposarcoma

Myxoid liposarcomas (MLS) have a tendency to metastasize to unusual sites. We report an unusual case of bone metastases not detected by bone scan and neither by fluorodeoxyglucose positron emission tomography (PET‐FDG) and successfully identified with magnetic resonance imaging (MRI) in a patient with metachronic MLS. Histopathological examination of the primary tumor evidenced a tumor with unfavorable prognostic markers, and the biopsy of an iliac bone lesion confirmed the diagnosis of metastatic disease. On histological grounds, the tumor showed features of a more differentiated neoplasm without foci of round cells or necrosis in the latter. MRI allowed the identification of disseminated disease compared to computed tomography (CT) and PET scans. Thus, because of the heterogeneous histological features of MLS and the biolog‐ical behavior of the disease, a combined approach of FDGPET‐CT and MRI, may allow a more accurate staging of soft tissue sarcomas. J. Magn. Reson. Imaging 2008;27:625–628.

Dihydropyrimidine dehydrogenases and cytidine-deaminase gene polymorphisms as outcome predictors in resected gastric cancer patients treated with fluoropyrimidine adjuvant chemotherapy.

Single nucleotide polymorphisms of dihydropyrimidine dehydrogenases gene (DPYD) induces dihydropyrimidine dehydrogenase enzyme (DPD) deficiency resulting in increased activity of 5‐fluorouracil derivatives. Cytidine‐deaminase gene (CDA) polymorphisms have been involved in prognosis in experimental tumours.

Intramedullary spinal cord metastases of melanoma.

Intramedullary spinal cord metastases (ISCMs) are extremely rare. An exact diagnosis may be difficult even when the primary tumour is known. Patients usually present with back pain and signs and symptoms of spinal cord compression, such as hemiparesis or hemisensory impairments. Magnetic resonance imaging (MRI) is considered to be the main diagnostic tool for intramedullary lesions as it is very sensitive, but non-specific, in distinguishing between ISCMs and primary cord tumours. Optimal treatment in patients with ISCMs remains controversial. We report a case of ISCMs of melanoma, with a review of the clinical and radiological characteristics of these medullary lesions and their prognosis, as well as the different therapeutic approaches.

A Phase I, Dose-Finding Study of Sorafenib in Combination with Gemcitabine and Radiation Therapy in Patients with Unresectable Pancreatic Adenocarcinoma: A Grupo Español Multidisciplinario en Cáncer Digestivo (GEMCAD) Study

Purpose Sorafenib, an oral inhibitor of B-raf, VEGFR2, and PDGFR2-beta, acts against pancreatic cancer in preclinical models. Due to the radio-sensitization activity of both sorafenib and gemcitabine, we designed a multicenter, phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy. Methods Patients with biopsy-proven, unresectable pancreatic adenocarcinoma (based on vascular invasion detected by computed tomography) were treated with gemcitabine (300 mg/m2 i.v. weekly ×5 weeks) concurrently with radiation therapy (45 Gy in 25 fractions) and sorafenib (escalated doses in a 3+3 design, from 200 to 800 mg/day). Radiation portals included the primary tumor but not the regional lymph nodes. Patients with planning target volumes (PTV) over 500 cc were excluded. Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression. Results Twelve patients were included. Three patients received 200 mg/day, 6 received 400 mg/day, and 3 received 800 mg/day; PTVs ranged from 105 to 500 cc. No dose-limiting toxicities occurred. The most common grade 2 toxicities were fatigue, neutropenia, nausea, and raised serum transaminases. Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy. There were no treatment-related deaths. Conclusion The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma. A dose of 800 mg/day is recommended for phase II evaluation. Trial Registration EudraCT 2007-003211-31 ClinicalTrials.gov 00789763

Evaluación de la eficacia y eficiencia de una unidad multidisciplinaria para la atención de pacientes con cáncer colorrectal

Introduccion . El aumento de la complejidad del abordaje diagnostico-terapeutico de los pacientes con cancer colorrectal (CCR) hace aconsejable su atencion en unidades multidisciplinarias especializadas. El objetivo de este estudio fue evaluar la eficacia y la eficiencia de una unidad de cancer colorrectal (UCCR) en el abordaje diagnostico-terapeutico de estos pacientes. Pacientes Y Metodos . Se han seleccionado dos grupos de 50 pacientes con cancer de colon atendidos en nuestro centro antes y despues de la implementacion de la UCCR. Se ha analizado el cumplimiento del protocolo asistencial en relacion con la estadificacion del tumor, el tratamiento quirurgico y complementario, el seguimiento, el intervalo hasta la terapia, la estancia hospitalaria, la morbilidad y mortalidad inmediata, y la duracion global del proceso diagnostico-terapeutico. Ademas, se ha evaluado la carga asistencial y se ha realizado un analisis de minimizacion de costes. Resultados . La UCCR ha permitido reducir el intervalo hasta la cirugia (20,3 ± 12,0 frente a 28,9 ± 20,4 dias; p = 0,05), la estancia hospitalaria (9,8 ± 7,7 frente a 14,5 ± 9,3 dias; p = 0,01), el tiempo transcurrido hasta el inicio del tra-tamiento adyuvante (29,4 ± 10,2 frente a 39,7 ± 19,8 dias; p = 0,03), y la duracion global del proceso (60,4 ± 23,8 frente a 82,1 ± 46,1 dias; p = 0,05), lo que supone un ahorro de 978,85 euros por paciente. Esta mejora ha tenido lugar a pesar del incremento de la carga asistencial (24% en 5 anos en relacion con el numero de ingresos) y no ha afectado la morbilidad (26 frente a 24%; NS) ni la mortalidad inmediata (6 frente a 4%; NS). Conclusion . Las unidades multidisciplinarias especializadas favorecen un abordaje mas eficaz y eficiente de los pacientes con cancer de colon.

Temozolomida en pacientes con metástasis cerebrales de melanoma tratados con irradiación holocraneal

Fundamento y objetivo: La irradiacion holocraneal (RTH) sigue siendo el tratamiento de eleccion para los pacientes con metastasis cerebrales de melanoma. La temozolomida ha demostrado ser eficaz en el tratamiento del melanoma metastasico. El objetivo fue evaluar el beneficio potencial de este farmaco asociado a RTH. Pacientes y metodo: Se ha efectuado un estudio retrospectivo en 26 pacientes, 10 de ellos tratados con RTH (20 Gy/5 fracciones de 400 cGy) y 16 con RTH mas temozolamida como agente unico (200 mg/m2) o en combinacion con quimioinmunoterapia (150 mg/m2). Resultados: La supervivencia mediana del grupo fue de 3 meses (intervalo de confianza [IC] del 95%, 2-4 meses). La supervivencia mediana del grupo RTH mas temozolomida fue de 6 meses (IC del 95%, 0-12 meses), y de un mes para el grupo RTH (IC del 95%, 1-2 meses) con diferencias estadisticamente significativas (p < 0,0001). El analisis de supervivencia en diferentes intervalos (90, 180 y 270 dias) mostro un beneficio en el grupo tratado con RTH mas temozolomida (p = 0,016). Conclusiones: Estos resultados indican el beneficio de la temozolomida asociada a RTH en la supervivencia de los pacientes con metastasis cerebrales de melanoma.

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases

IntroductionWhole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma in terms of symptom palliation, especially when extracranial systemic disease is present. Temozolomide (TMZ) has shown efficacy in the treatment of metastatic melanoma. The objective was to evaluate the potential benefit in survival of two different schedules of total dose and fractionation (20 Gy/5 fractions vs 30 Gy/10 fractions) and further TMZ based chemotherapy.Materials and methodWe have conducted a retrospective study in a group of twenty-one patients (RTOG Recursive Partitioning Analysis class II) of the use of WBRT with 20 Gy/5 fractions (n=11) and 30 Gy/10 fractions (n=10). All patients received further TMZ based chemotherapy administered as a single chemotherapeutic agent or in combination with chemo-immunotherapy.ResultsPrognostic variables such as: age, Karnofsky performance status, extracranial metastases and number of brain metastases, were analyzed in both groups of treatment without statistically significant differences. The median survival time (MST) for WBRT 20 Gy group was 4 months (CI 95%: range 2–6 months) and for WBRT 30 Gy group was 4 months (CI 95%: range 0–7 months) without statistically significant differences (Log rank p=0.74). There was one complete response and two partial responses.ConclusionsThe results suggest that MST was not significantly affected by the total dose/fractionation schedule.

Secondary orbital metastases from cutaneous melanoma.

Secondary orbital melanomas comprise a heterogeneous group of malignant pigmented tumours. They may present as extrascleral extensions of uveal melanomas, as orbital extensions of conjunctival and eyelid melanomas, as local recurrences after surgical or conservative treatment of ocular melanomas, or as orbital metastases from distant cutaneous melanomas. The differential diagnosis of an orbital sign such as an intraconal mass or enlargement of one or more extraocular muscles includes myositis, Graves’ disease, pseudotumour, trichinosis, Cryptococcus, arteriovenous malformation, carotid cavernous fistula, acromegaly, amyloidosis, lymphomas and other primary neoplasms [2,3].