Raffaele Longo

Inhibitors of cyclo-oxygenase 2 : a new class of anticancer agents?

Experimental studies have shown that cyclo-oxygenase 2 (COX2) is involved in tumour development and progression. Selective inhibitors of COX2 (coxibs) block tumour growth through many mechanisms, especially by antiangiogenic and proapoptotic effects. In experimental models, coxibs potentiate the activity of cytotoxic agents, hormones, and radiotherapy. Large clinical studies have shown chemopreventive activity of coxibs in colorectal cancer. The findings of preclinical studies coupled with the overexpression of COX2 observed in advanced human tumours are the basis for new therapeutic anticancer strategies based on combinations of coxibs with other anticancer treatment modalities. Early clinical studies have documented the feasibility, good tolerability, and promising activity of coxibs combined with chemotherapy in patients with advanced colorectal and non-small-cell lung cancers. Here, we describe the recent findings on the antitumour effects of coxibs with particular focus on the opportunities that have emerged for treatment of cancer.

Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth facto...

Angiogenic inhibitors: A new therapeutic strategy in oncology

Angiogenesis is a multistep, complex and tightly regulated process that is necessary for tumor growth and metastasis. Based on data of preclinical models, several antiangiogenic compounds has been shown to modify activated tumor endothelium, which suggests that these compounds can improve cytotoxic drug delivery. Such agents have entered clinical trials as single agents or in combination with cytotoxic drugs, and have shown promising antitumor activity. The pharmacodynamic and pharmacokinetic characteristics of antiangiogenic drugs are reviewed here. Most of the early clinical testing of these agents was conducted in patients with advanced disease resistant to standard therapies. Phase III trials compared the efficacy of standard chemotherapy alone with standard chemotherapy in combination with an experimental angiogenesis inhibitor. Although some of these studies were negative or controversial, recent studies validated in large clinical trials with an anti-vascular endothelial growth factor antibody demonstrated significant clinical benefit and renewed enthusiasm for this therapeutic strategy. This review describes the clinical studies of antiangiogenic agents and highlights the challenges related to choosing appropriate strategies for the selection of patients, study design and choice of appropriate endpoints for the studies development.

Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53–85% of patients, and in prospective studies this complication has been reported in 36–71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. We propose a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism. Prospective trials are needed to define the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and potentially other TKIs. The safety and efficacy, and optimal dosing and timing of starting replacement therapy in patients affected by TKI-related hypothyroidism need accurate appraisal and should be evaluated prospectively in appropriately designed trials.

Thalidomide is inactive in heavily pretreated patients with metastatic breast cancer

Experimental studies have demonstrated that thalidomide has anti-tumor activity mediated by blockage of angiogene-sis, with clinical efficacy in multiple myeloma, glioblastoma multiforme, and renal cell cancer. We investigated the therapeutic activity and toxicity of thalidomide in patients with progressive metastatic breast cancer pretreated with chemotherapy. Inclusion criteria were metastatic breast cancer in progression of disease after at least two lines of chemotherapy, age ≤ 18 years, performance status ≥ 2, and adequate hematologic, renal, and hepatic functions. Twelve patients entered the study, eight of whom were pretreated with three or more lines of chemotherapy (66.7%). Thalidomide was well tolerated: the most common side effects were constipation and somnolence (58.3% of patients). No objective response or durable stable disease was observed. Median time to progression and median overall survival were 8 weeks (range, 4–10 weeks) and 16 weeks (range, 8–54 weeks), respectively. In conclusion, thalidomide is an ineffective treatment in patients with progressive metastatic breast cancer heavily pretreated with chemotherapy.

An unusual case of three synchronous tumors in a young woman.

The occurrence in the same young patient of three synchronous tumors deriving from different embryogenic tissues and without a clear correlation with a common etiopathogenic factor is very unusual. We report a case of a Caucasian woman submitted to wide resection of a large retroperitoneal liposarcoma and right radical nephrectomy for suspected tumor infiltration. Histological examination of the right ureter and renal pelvis showed the presence of a multifocal urothelial carcinoma that was clinically asymptomatic. Two months later, during follow-up, chest X-ray and computed tomography documented a coin lesion of the upper left lung, confirmed by positron emission tomography. This nodule was surgically removed and examined histologically, resulting in a diagnosis of sclerosing hemangioma. The patient is alive without evidence of recurrent disease.

Sequential adjuvant hormone therapy in postmenopausal breast cancer : rationale and clinical results

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer. We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.