Maria Caterina Pallotti

Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency.

The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone (Thal-Dex) as induction therapy before autologous peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed multiple myeloma (MM) with renal insufficiency. The study included 31 patients with a baseline creatinine clearance value <or=50 mL/min, 7 of whom required chronic hemodialysis. Patients received 4 months of Thal-Dex, followed by PBSC collection and subsequent transplantation. After induction, a partial response (PR) or greater was obtained in 23 patients (74%), including 8 (26%) who achieved a very good PR. Renal function improved more frequently in patients achieving a PR or greater (82%, vs 37% in patients achieving less than a PR; P = .04). Twenty-six patients underwent PBSC mobilization; in 17 of these patients (65%), >4 x 10(6) CD34(+) cells/kg were collected. Double autologous transplantation was performed in 15 patients, and a single autologous transplantation was performed in 7 patients. After a median of 32 months of follow-up, median event-free survival was 30 months, and median survival was not determined. According to our data, Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency. Given the relationship between recovery of renal function and response to induction treatment, more intensive Thal + bortezomib regimens could be explored to rescue higher numbers of patients.

Three cases of bone metastases in patients with gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib) are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age), and one man (62 years of age). Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

Thalidomide Maintenance in Multiple Myeloma: Certainties and Controversies

TO THE EDITOR: Recent availability of novel agents with documented activity against multiple myeloma (MM) has prompted their use as maintenance treatment to prolong the duration of response achieved after prior therapy at either conventional or (sub)myeloablative doses requiring autologous stem-cell transplantation (ASCT). Controversies exist concerning the role of thalidomide after ASCT. In a randomized study conducted by the Intergroup Francophone du Myèlome comparing thalidomide maintenance versus no maintenance following double ASCT, the whole population of patients treated with thalidomide had a significantly better outcome than the control group in terms of response rate, progression-free survival (PFS) and overall survival (OS). However, in a subgroup analysis this benefit was seen only in patients with less than very good partial response (VGPR) before random assignment. Similar results were found in a study of single ASCT followed by 6-month thalidomide maintenance versus double ASCT without maintenance therapy. Based on these findings, it was suggested that thalidomide was more likely to induce a consolidation, rather than a pure maintenance, effect. Spencer et al recently reported in Journal of Clinical Oncology the results of a phase III study designed to compare thalidomide and prednisolone with prednisolone alone as consolidation/maintenance after a single ASCT. The lack of an increase in the rate of CR after melphalan 200 mg/m (from 5.1% before ASCT to 7% after ASCT in the experimental arm, and from 5.5% to 8%, respectively, in the control arm) is puzzling. By study design, thalidomide after ASCT was given for 12 months, while in both arms prednisolone was continued until disease progression. In comparison with the control group, thalidomide and prednisolone significantly improved the rate of at least VGPR, PFS and OS. The increase in the rate of VGPR or better response found at 4 months after start of thalidomide and prednisolone is comparable with that seen by others at 6 months after thalidomide. Remarkably, in Spencer’s study prolongation of thalidomide beyond 4 months failed to furtherly improve the rate of at least VGPR, suggesting that postautotransplantation reduction in tumor cell mass induced by this agent occurs early, usually within the first 4 to 6 months. Two previously published studies support this conclusion. Alexanian et al observed that thalidomide and dexamethasone given for at least 3 months after ASCT improved the response in 17 out of 21 patients, including 12 (57%) who achieved VGPR or CR. In another study, 29 patients who received thalidomide starting 6 to 8 weeks after transplantion were evaluated at 6 months: 13 of them (or 45%) upgraded to CR or near CR and only 3 additional patients (or 17%) achieved CR after prolongation of thalidomide until disease progression. Based on these observations and given the increase in both neurological toxicity and resistance to salvage therapy related to long-term exposure to thalidomide, we raise a word of caution about the 12-month consolidation therapy recommended by Spencer et al. A more logical approach to improve the response after ASCT may be to plan 4 to 6 months of thalidomide consolidation and to consider further prolongation of this agent, up to no more than a maximum of 10 to 12 months, only in those patients who eventually fail to achieve VGPR or CR and do not suffer from major toxicities. Low thalidomide doses, such as 100 mg or even 50 mg daily, enable most of these patients to stay on the drug for a longer time period, without adversely affecting PFS in comparison with higher, and more toxic, doses. Differently from previously reported studies, Spencer et al emphasized that benefits from thalidomide and prednisolone were also extended to patients with at least VGPR after ASCT. To more carefully address this controversial issue, an important information not provided by Spencer et al is the observed rate of improvement from VGPR to CR, a major determinant of prolonged PFS and OS. Median PFS with thalidomide and prednisolone among patients in VGPR or CR was 2.5 years, as compared with 2.1 years among comparable patients treated with prednisolone alone. The difference between the two groups was of borderline significance (P .054), and the hazard ratio 95% CI was in the range between 0.32 and 1.02. In addition, no difference was seen in terms of OS. Although these data provide an important contribution to the still unresolved issue of thalidomide maintenance in patients in VGPR or CR after ASCT, results of additional studies should be awaited before definite conclusions can be drawn. The value and optimal duration of maintenance therapy in patients in CR is still not well defined. In addition to prolonged PFS, possible improvements in CR status (eg, from conventionally defined CR to so-called stringent, immunophenotypic, or molecular CR) and/or in the duration of OS (albeit potentially influenced by the less or more favorable response to salvage therapy at the time of relapse), as well as evaluation of quality of life are also needed in order to make clear recommendations. Another still controversial issue related to thalidomide therapy after ASCT concerns the role of this agent in patients carrying cytogenetic abnormalities. Several studies questioned the benefit from thalidomide in patients with chromosome (13q) or (17p) deletion, as assessed by fluorescencent in situ hybridization. In the French study comparing thalidomide maintenance versus no maintenance after double ASCT, no improvement in PFS was seen with thalidomide in comparison with the control group, a finding independent from response status before randomization. More recently, Morgan et al reported that thalidomide given as part of induction before, and as maintenance therapy after, ASCT was detrimental for patients with chromosome (17p) deletion. The novel agents bortezomib or lenalidomide which overcome the poor prognosis related to high-risk cytogenetics may be an attractive alternative to thalidomide in these particular subgroups of patients. Both these agents are currently being evaluated after ASCT in the context of randomized clinical trials. A systematic review and meta-analysis of data from pooled studies of thalidomide maintenance after ASCT has recently confirmed the efficacy of this agent in prolonging OS. However, this benefit was lost when a study of double ASCT and thalidomide given from the outset JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 27 NUMBER 32 NOVEMBER 1

Successful radiotherapy for local control of progressively increasing metastasis of gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are known to be poorly responsive to conventional chemotherapy and historically considered resistant to radiotherapy. In the past the mainstay of GIST treatment was surgery, but the introduction of tyrosine kinase inhibitors (TKIs) imatinib and sunitinib marked the beginning of a new era in the treatment of GIST patients. To date, radiotherapy for GIST has not been administered in clinical practice except for limited palliative settings and there are no clear data on the administration of radiotherapy, alone or in combination with TKIs, with a purely cytoreductive intent. We describe the clinical case of a 48-year-old woman with metastatic GIST treated with external radiotherapy in a critical supraclavicular tumor localization progressively increasing in size with several symptoms and not responsive to systemic TKI therapies. We obtained an initial shrinkage of the mass and subsequent stabilization with an immediate and clear clinical benefit. Although the historical medical literature considered GISTs resistant to radiation therapy, our clinical case suggests this treatment may be appropriate in selected patients.

Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.

Development of a Nephrotic Syndrome in a Patient with Gastrointestinal Stromal Tumor during a Long-Time Treatment with Sunitinib.

A patient with advanced gastrointestinal stromal tumor (GIST) receiving second-line treatment with sunitinib developed edema, increase of the serum creatinine, weight gain, nephrotic syndrome with proteinuria of 12 g/24 h, dyslipidemia, hypoalbuminemia and also presented with hypertension. A kidney biopsy showed an immunocomplex glomerulonephritis. Steroid treatment was started, but the clinical conditions and laboratory values did not improve. So in the hypothesis that the nephrotic syndrome was induced by sunitinib, sunitinib was temporarily discontinued with a subsequent reduction of proteinuria and improvement in blood pressure control. In the last years, the introduction of sunitinib has modified the natural history of advanced GIST. However, due to chronic and prolonged intake of this drug, there is increasingly frequent detection of late and unknown toxicities in clinical practice. In particular, the late renal toxicity from sunitinib may be the primary clinical problem with this drug in the case of prolonged treatment. Monitoring of kidney function and blood pressure should be performed for early detection of side effects such as hypertension and kidney dysfunction in advanced GIST patients receiving long-term treatment with sunitinib. A clinical collaboration between oncologists and nephrologists could be useful with the objective to optimize the management of sunitinib.

Alternative schedules or integration strategies to maximise treatment duration with sunitinib in patients with gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumour of the gastrointestinal tract. The advent of targeted kinase-inhibitors has revolutionised treatment strategies and clinical outcomes for patients with advanced GIST. In the majority of countries, sunitinib is the only approved second-line treatment option for advanced GIST patients, who are resistant or intolerant to imatinib. However, sunitinib is associated with various adverse events, which often result in a reduction of the dosage, and interruption or suspension of therapy. Effective therapy management is essential to obtain the maximum clinical benefit, and includes adequate side effect management as well as optimization of dosing and treatment duration. In the current study, examples of maximization of treatment with sunitinib are presented, describing three clinical cases in which therapy with sunitinib was continued via the adoption of alternative reduced schedules or an additional loco-regional treatment, in order to manage toxicities or overcome progressive disease.

Surgical second-look in high risk gastrointestinal stromal tumor of small intestine: A case report

INTRODUCTION The peritoneum is one of the most common sites of distant gastrointestinal stromal tumor (GIST) metastases. In particular, GIST arising from the small intestine with resected minimal synchronous macroscopic peritoneal carcinomatosis or with primary tumor rupture has a higher risk of developing peritoneal recurrence. Current clinical practice does not envisage second-look surgery in GIST patients at high risk of developing peritoneal recurrence, and no literature data are available. PRESENTATION OF CASE We describe a 45-year-old woman who underwent emergency surgical resection of jejunal GIST presenting with spontaneous tumor rupture, synchronous ovarian and minimal macroscopic peritoneal involvement, and subsequent second-look surgery after 13 months of imatinib treatment. DISCUSSION Second-look surgery confirmed a 2.6cm lesion close to the mesenteric border of the fourth jejunal loop, and 11 peritoneal lesions with a macroscopic necrotic aspect related to treatment response. After conversion to an open procedure, a segmental jejunal resection was performed with removal of all peritoneal lesions and macroscopic radical cytoreduction. CONCLUSION Second-look surgery in selected GIST patients may be performed after at least 12 months of medical treatment with tyrosine-kinase inhibitors to identify those patients with limited peritoneal disease not disclosed by instrumental imaging who could undergo radical cytoreduction of peritoneal lesions.

Evaluation of bone disease in multiple myeloma patients carrying the t(4;14) chromosomal translocation

T(4;14) chromosomal abnormality is one of the most adverse prognostic factors predicting for poor outcome in multiple myeloma (MM) patients. It has been recently suggested that bone disease, as evaluated by spinal magnetic resonance imaging (MRI), is relatively infrequent in these patients. In the present study, we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared with negative patients. For this purpose, 53 consecutive newly diagnosed MM patients (35M, 18F, median age = 55 yr) underwent evaluation of total skeletal X‐ray, whole spine MRI, and at the same time, quantification of markers of bone resorption (urinary N‐terminal telopeptide, pyridinoline, deoxypyridinoline, serum crosslaps), and bone formation (bone alkaline phosphatase and osteocalcin) was performed. The presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), was detected in 11 patients (20.7%), whose clinical characteristics were similar to those observed in t(4;14) negative patients. The type of marrow involvement at spinal MRI (diffuse vs. focal vs. negative) was the same in both groups of patients, even though overt vertebral fractures were more frequently found in t(4;14) positive cases (82% vs. 43%, P = 0.05); in line with this finding, skeletal lesions were more common in t(4;14) positive patients (mean skeletal score = 8.54 ± 1.36 SE, as compared with 3.42 ± 0.57 SE in t(4;14) negative cases, P = 0.000). These data were confirmed by the evaluation of serum crosslaps, that were significantly increased in patients with t(4;14) abnormality as compared with negative individuals (10 400 pmol/L ± 2160 SE vs. 5640 pmol/L ± 859 SE P = 0.02) Our results indicate that, at variance to what has been previously reported, bone resorption is more prominent in t(4;14) positive patients.

Palliative medicine in Mediterranean countries: different approaches, same philosophy

Despite the fact that Italy and Spain are culturally similar, there are important differences in palliative care services development. For example, Italy has a greater proportion of hospice teams compared with Spain, while Spain has a greater proportion of hospital support teams.1 Noting these differences, we decided to compare a major palliative care service model from each country: the Seragnoli Hospice Foundation (FHS), Italy, and the Palliative Care Support Team (PCST) at the Clinica Universidad de Navarra (CUN), Spain, where an oncologist from FHS recently completed a 4-week rotation. We compare the institutions according to symptom assessment and management, psychological and spiritual care, caregiver support and impact on the rest of the hospital. Initially, the differences between the two teams, such as culture and practice, were more noticeable, but by the end of the rotation the shared values were what stood out. FHS is a private non-profit foundation in Italy composed of three hospices that care for advanced and terminal patients, each with a …