Ensayos de nuevos tratamientos de TNE pancreáticos

Se han publicado dos nuevos ensayos de nuevos tratamientos médicos de tumores neuroendocrinos pancreáticos en el NEJM de 10 de Febrero de 2011. El primero con sunitimib y el segundo con everolimus.
En el mismo número hay un editorial que copio en parte
Pancreatic neuroendocrine tumors are classified as functional (10 to 30% of the tumors) or nonfunctional (50 to 80%).1 Functional pancreatic neuroendocrine tumors have long fascinated physicians because they produce florid syndromes, owing to ectopic secretion of various biologically active hormones (e.g., insulin and gastrin).1 In the past, the hormone excess syndrome was the leading cause of death; however, with advances in surgical and medical treatments, the natural history of pancreatic neuroendocrine tumors is becoming the major determinant of death in patients with functional tumors, similar to patients with nonfunctional tumors. This is occurring because more than 50% of all pancreatic neuroendocrine tumors, except insulinomas, are malignant, and many pursue an aggressive course.1,2

For a number of reasons, functional pancreatic neuroendocrine tumors pose a particularly challenging management problem. First, the 5-year survival rate of patients with metastatic disease (which involves more than 50% of the cases reported in most studies) is 30 to 40%1,2 and has not changed for 20 years.3 The reason the outlook has not changed is that no specific new treatments for malignant pancreatic neuroendocrine tumors have been developed during this time. Furthermore, studies of chemotherapy for these tumors report an objective response rate of 10 to 45%, responses are rarely complete, and such treatment is associated with considerable adverse events. Second, the development of new treatments is complicated by the fact that the pathogenesis of pancreatic neuroendocrine tumors is poorly understood and appears to differ from that of common adenocarcinomas.1,4 Furthermore, it is difficult to culture pancreatic neuroendocrine tumor cells for prolonged times in vitro, and in vivo models for studying new agents are not widely available.4 Third, although pancreatic neuroendocrine tumors are uncommon (1.3% of all pancreatic tumors), these tumors, in contrast to pancreatic adenocarcinomas, are increasing in frequency, and because patients can live for several years with metastatic disease, the tumors cause considerable illness.3,5 Finally, the somatostatin analogue octreotide LAR can increase progression-free survival in patients who have gastrointestinal carcinoids with limited metastatic disease.6 However, it is not established whether similar therapy is effective in patients with advanced pancreatic neuroendocrine tumors, which have not only a different pathogenesis, but also a worse prognosis, than do gastrointestinal carcinoids.1,2,7 Several in vitro, in vivo, phase 1, and phase 2 studies provide evidence that inhibition of growth factor receptors (vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit) that are frequently expressed by pancreatic neuroendocrine tumors, as well as inhibition of the mammalian target of rapamycin (mTOR) pathway, can inhibit their growth, and may have clinical benefit.7–9

In this issue of the Journal, two groups of investigators report results that hold promise for patients with malignant pancreatic neuroendocrine tumors; one group studied the tyrosine kinase inhibitor sunitinib10 and the other, the mTOR inhibitor everolimus.8 Both studies involved patients with progressive malignant disease and were phase 3, multicenter, double-blind, randomized, placebo-controlled trials, with sufficient numbers of patients (171 in the sunitinib study and 410 in the everolimus study) to yield clear statistical results. Sunitinib (at a dose of 37.5 mg per day), as compared with placebo, caused more than a doubling in progression-free survival (11.4 months vs. 5.5 months, P<0.001), an increase in the rate of objective tumor response, and an increase in overall survival.10 Everolimus (at a dose of 10 mg per day) caused a 65% reduction in the estimated risk of progression (progression-free survival of 11.0 months with everolimus vs. 4.6 months with placebo, P<0.001) and an increase by a factor of 3.7 in estimates of the proportion of patients with progression-free survival at 18 months (34% with everolimus vs. 9% with placebo).8 With both drugs, benefit was maintained across various subgroups, including subgroups defined according to whether patients had or had not received previous antitumor treatments.

Similar to findings in other studies, both sunitinib and everolimus treatment caused drug-related adverse events in significant numbers of patients, which resulted in an increase by a factor of 2 in the case of everolimus and 3 in the case of sunitinib, as compared with placebo, in the number of patients requiring dose reductions or temporary treatment interruptions. Most adverse events were grade 1 or 2, although grade 3 or 4 adverse events did occur; the most common grade 3 or 4 events with sunitinib were neutropenia (12.0%) and hypertension (9.6%),10 whereas with everolimus, hematologic events, diarrhea, stomatitis, and hyperglycemia were the most prevalent (ranging from 3% to 7%).8 Despite these side effects, no difference was noted in the quality-of-life index with sunitinib treatment, and with both drugs, side effects were generally manageable with dose reduction, temporary interruption of therapy, or both.

These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before; however, the studies also raise some important unanswered questions that make the optimism guarded. Will the improvement in disease-free survival with everolimus result in improved overall survival, as was seen with sunitinib? This end point is obscured by the fact that patients randomly assigned to placebo were able to cross over to the active agent if the disease progressed — an ethically sound design that compromises the assessment of overall survival. Will patients have to continue taking these drugs for years since both drugs primarily stabilize, rather than cure, the disease? If patients no longer have a response to one drug, can they then be effectively treated with the other drug or with a combination of the two drugs? Can these drugs be used as neoadjuvant or adjuvant therapy (with surgery) or in combination with peptide-receptor radionuclide therapy or somatostatin analogue therapy? Finally, it is unclear how the side-effect profiles will affect long-term adherence to treatment. The drug-related side effects that develop in a patient with a malignant pancreatic endocrine tumor are particularly important to consider, given that treatment will be long term and that many patients have an excellent quality of life with no treatment until late in the disease course, even with advanced disease that is progressive. Thus, patients may be less willing to accept long-term side effects. The answers to these latter questions will be particularly important in helping to determine the widespread usefulness of these new drugs in the treatment of malignant pancreatic neuroendocrine tumors.