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Gliomas are the mostfrequent subtype of primary brain tumors. They are lethal tumors, characterized by diffuse infiltration of the brain and a high resistance to conventional cancer therapies. Following maximal neurosurgical resection, bound to the limits of acceptable neurological sequelae, immediate post-operative radiotherapy is indicated in the majority of patients. Chemotherapy with the alkylating agent temozolomide, administered daily concomitantly to radiotherapy, and followed by six adjuvant monthly cycles, significantly improves the survival of newly diagnosed glioblastoma patients and has become the standard of care. Temozolomide is also the most often used chemotherapeutic treatment for recurrent low-grade and anaplastic gliomas after initial surgery and irradiation. The potential role of postoperative temozolomide in the first line treatment for low-grade and anaplastic glioma is currently under investigation in phase III trials. After failure of temozolomide, there is only limited activity of any other cytotoxic agent and the benefit of such second line therapy seems to be limited to a small subgroup of patients with the most chemosensitive gliomas. Abnormal hypermethylation of the promoter of the MGMT gene has been correlated with the response of glioma to alkylating chemotherapy. The loss of chromosomal arms 1p and 19q are genetic markers characteristic for gliomas with oligodendroglial differentiation which are also most sensitive to treatment. The predictive and prognostic value of these molecular markers is currently being determined prospectively in phase III studies. Anti-angiogenic agents and targeted receptor tyrosine kinase inhibitors are new pharmacological classes with activity against malignant gliomas. Phase III clinical studies evaluating combinations of these new agents with classical cytotoxic agents in first and in second line have recently been initiated.

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. Considerable progress has been made in enhancing the efficacy of therapeutic anticancer vaccines. First, dendritic cells (DCs) have been identified as the key players in orchestrating primary immune responses. A better understanding of their biology and the development of procedures to generate vast amounts of DCs in vitro have accelerated the development of potent immunotherapeutic strategies for cancer. Second, tumor-associated antigens have been identified which are either selectively or preferentially expressed by tumor cells and can be recognized by the immune system. Finally, several studies have been performed on the genetic modification of DCs with tumor antigens. In this regard, loading the DCs with mRNA, which enables them to produce/process and present the tumor antigens themselves, has emerged as a promising strategy. Here, we will first overview the different aspects that must be taken into account when generating an mRNA-based DC vaccine and the published clinical studies exploiting mRNA-loaded DCs. Second, we will give a detailed description of a novel procedure to generate a vaccine consisting of tumor antigen-expressing dendritic cells with an in vitro superior capacity to induce anti-tumor immune responses. Here, immature DCs are electroporated with mRNAs encoding a tumor antigen, CD40 ligand (CD40L), CD70, and constitutively active (caTLR4) to generate mature antigen-presenting DCs.

Background: Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression., Case Description: In our experience, pseudoprogression after concomitant RT plus TMZ is typically not observed at first imaging immediately after completion of the therapy; but delayed focal enhancement mimicking tumor progression frequently occurs during the 6 months of maintenance therapy with TMZ. Pseudoprogression may reflect the radiosensitizing effect of TMZ during concomitant therapy, and retaining patients on treatment allows them to have enhanced survival and preserved quality of life. We observed 3 cases of pseudoprogression among 54 consecutive patients who were treated with this regimen. These patients developed pseudoprogression within 2 to 6 months after completion of concomitant RT plus TMZ, but all 3 patients completed maintenance chemotherapy and remained progression free for at least 15 months after diagnosis., Conclusion: Functional imaging may improve the noninvasive diagnosis of pseudoprogression, but randomized prospective studies are needed to evaluate the real impact of pseudoprogression and validate neuroradiological techniques able to make a reliable distinction between tumor recurrence and pseudoprogression.

Introduction: We report the long term and overall results of a triplet induction chemotherapy regimen followed by standard radiotherapy in patients with locally advanced inoperable stage III non-small cell lung cancer., Methods: Three cycles of paclitaxel, carboplatin, and gemcitabine were administered every 3 weeks before standard fractionated consolidation radiotherapy starting at least 4 weeks after the last chemotherapy administration. Toxicity and antitumor response was assessed in detail as well as the progression free and overall survival., Results: Sixty-four patients (25 stage IIIA and 39 stage IIIB) received a total of 179 cycles of chemotherapy. Fifty-six received the planned three cycles. Full-dose radiotherapy was administered in 47 patients (73%), a reduced dose in 11 (17%) and none in six (10%). A 55% objective response rate (OR) (one complete and 34 partial responses) was observed after induction chemotherapy. After completing the whole treatment including radiotherapy, the OR was 40 of 47 evaluable patients (85%). Median time to progression was 10.9 month and median overall survival was 17.2 month, with a significant difference between stage IIIA and stage IIIB patients (23.4 versus 10.5 month; p = 0.011). The strongest predictor for a favorable long-term outcome was a metabolic complete response after chemotherapy., Conclusion: Induction chemotherapy with the paclitaxel, carboplatin, and gemcitabine regimen preceding radiotherapy in patients with locally advanced inoperable stage III non-small cell lung cancer was feasible and active. Radiotherapy could be administered at a full dose in the majority of patients with acceptable toxicity. Long-term survival results of this sequential chemoradiotherapy regimen appear similar to those of concurrent treatment. Patients not achieving a metabolic complete response after induction chemotherapy should be the focus of studies aiming at improved local control.

Background: Both hepatic arterial infusion (HAI) of chemotherapy and cetuximab (CET) have interesting activity for the treatment of colorectal cancer liver metastases (CRC-LM)., Patients and Methods: Intravenous CET with HAI oxaliplatin (OXA) or i.v. Irinotecan (IRI) followed by HAI of infusion of folic acid modulated 5-fluorouracil 5-FU/l-FA was administered to patients (pts) with CRC-LM who had failed at least one line of prior chemotherapy., Results: Eight pts received i.v. CET with HAI-OXA (5 pts) and i.v.-IRI (3 pts) and HAI-5-FU/l-FA. Adverse events: repeated grade 3 skin toxicity (1 pt), abdominal pain with elevated liver enzymes and asthenia (2 pts), duodenal ulcer (2 pts) with catheter migration and intestinal bleeding (1 pt), reversible interstitial pneumonitis (1 pt), and cystic bile duct dilatation (2 pts) with arteriobiliary fistulisation (1 pt). A partial response was documented in 5 pts (62%). The median time to progression was 8.7 months (95% confidence interval 8-14 months)., Conclusion: Intravenous administration of CET with HAI of chemotherapy is feasible and has promising activity but is associated with specific toxicity.

Background: Despite the progress made in the treatment of metastatic colorectal cancer (CRC), the results of second-line chemotherapy remain poor., Patients and Methods: The feasibility of hepatic arterial infusion (HAI) of oxaliplatin (100 mg/m2 over 6 h) followed by l-folinic acid (L-FA) (400 mg over 2 h i.v.)-modulated continuous HAI of 5-Fluorouracil (5-FU) (60 mg/kg over 42 h; q2w) as second-line chemotherapy for metastatic CRC limited to the liver was investigated., Results: A median of 9 treatment cycles were administered (range 4-14). Treatment-limiting toxicity consisted of: abdominal pain (3 patients), elevated liver enzymes accompanied by fatigue (3), elevated bilirubin (2), neutropenia (2), thrombocytopenia (3) and hypersensitivity to oxaliplatin (1). Normalization for >4 weeks of the carcinoembryonic antigen (CEA) level was documented in 3 patients and a decline of >50% for >4 weeks in 5 patients. A confirmed partial response (PR) was documented in 5, stable disease (SD) in 1 and progressive disease (PD) in 3 patients. In the latter 3 patients, lung metastases developed while a PR was observed in the liver metastases. A pathological complete response (CR) was documented in 2 patients. The median time to progression was 7.2 months (95% CI 1.3-13) and the median overall survival 18.3 months (95% CI 16.3-20.3)., Conclusion: HAI of oxaliplatin plus CI5-FU/LV is feasible and merits further evaluation.

Low-grade gliomas (LGG) are a group of uncommon neuroglial tumors of the central nervous system. They are characterized by a grade I or II according to the WHO classification. Grade I tumors are non-invasive and amenable to surgical resection with curative intent. Diffuse infiltrating LGG (WHO grade II) are tumors with a highly variable prognosis. Curative resection can only rarely be achieved and progression is characterized by transformation into a high-grade glioma (WHO grade III-IV). There are only limited evidence-based treatment recommendations for the management of progressive LGG because of a lack of data from prospective randomized trials. Most often radiotherapy is offered to patients with symptomatic and/or progressive disease. Three randomized trials have failed to demonstrate a survival improvement with either early versus delayed radiation or with a higher dose of radiation. The potential role of chemotherapy for the treatment of LGG has only been addressed in phase II trials. The PCV-chemotherapy regimen is associated with considerable toxicity that limits its applicability. The results with temozolomide (TMZ) chemotherapy have been more promising. Patients with chemosensitive LGG as predicted by heterozygotic loss of chromosomal arms Ip and 19q or methylation of the promoter of the MGMT-gene in the genome of the glioma cells respond to TMZ. Radiotherapy will be compared to chemotherapy asfirst line treatment for LGG in two phase III studies that are planned for by the brain tumor group of the European Organization for Research and Treatment of Cancer (BTG-EORTC) and Radiation Therapy Oncology Group (RTOG).

Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent high-grade gliomas in prospective phase II studies. Limited information is available on TMZ when prescribed outside a clinical trial. We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from five hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaive patients and 150 mg/m2 x5d q28d for pre-treated patients. Toxicity was generally mild. Thrombocytopenia was the most frequent treatment related adverse event (grade 3/4 in 17% of patients). Its occurrence was correlated with a starting dose of 200 mg/m2/d and stresses the need to monitor toxicity. The overall objective response rate (complete and partial response) was 29 and 34% of patients achieved an objective disease stabilization. The median progression-free survival was 104 days (95% CI: 85-123) and the median overall survival was 215 days (95% CI: 161 269). In multivariate analysis a 'deep localization' of the glioma (as opposed to a cortico-subcortical localization) and 'the preceding history of a low-grade glioma' were respectively identified as a negative and positive independent prognostic variable for survival. No significant difference in terms of response or median survival was observed between patients with anaplastic astrocytoma or oligo-astrocytoma and chemonaive glioblastoma multiforme. This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial.

Background: Treatment of metastatic colorectal cancer (CRC) with raltitrexed results in an objective response rate (OR) and overall survival (OS) comparable to bolus 5-fluorouracil (5-FU). A phase III trial found raltitrexed to be inferior to continuous infusion of 5-FU (ci5-FU)., Patients and Methods: This phase II trial studied the activity and toxicity of methotrexate-modulated ci5-FU (ci5-FU/MTX) after failure of raltitrexed in patients with metastatic CRC., Results: Of 32 patients who received raltitrexed, 27 were evaluable for response. An OR was observed in 19%. Grade 3/4 toxicity occurred in 47% of patients. Eighteen patients received second-line ci5-FU/MTX. One complete response (CR) and five stable diseases (SD) were observed. CR and SD were observed in patients with raltitrexed-resistant disease. Toxicity to ci5-FU/MTX was mild and predictable, even in patients with severe toxicity under raltitrexed., Conclusion: ci5-FU/MTX is ineffective after failure of raltitrexed in patients with metastatic CRC. However, response to ci5-FU/MTX in patients with raltitrexed-resistant disease indicates incomplete cross-resistance.