Multidisciplinary approach to the treatment of bone metastases: Osteo-Oncology Center, a new organizational model.

AIMS AND BACKGROUND: Bone metastases are responsible for high morbidity in cancer patients. The frequency of pain and other serious complications associated with such metastases depends on the site and type of lesions and preventive therapy. The present paper aims to inform the scientific community about a new organizational health care model specifically designed for patients with bone metastases, in the hope of stimulating the creation of similar initiatives whose goals are to decrease the high morbidity of this pathology, reduce the frequency of complications, limit psychophysical distress of patients, and improve quality of life. METHODS: In January 2005, an Osteo-Oncology Center was opened in our institute to provide multidisciplinary care (19 specialists involved) for patients with bone metastases, to train physicians, and to conduct research in the field. RESULTS: In its first three years of activity, 601 multidisciplinary team consultations were made and a total of 425 patients were seen. The most frequent primary tumor site was the lung in males and the breast in females. Upon presentation at the Center, 79% of patients reported experiencing a level of pain (median pain intensity, 3.69) that interfered with normal daily activities. An anonymous questionnaire was also completed on the quality of the service provided: 75% of patients were very satisfied, 23% were satisfied, 1% responded "I don't know", and only 1% expressed dissatisfaction. CONCLUSIONS: Our preliminary results confirm the usefulness of a multidisciplinary center for the management of patients with bone metastases, especially in terms of decreasing psychophysical suffering.

Free DNA and carcinoembryonic antigen serum levels: an important combination for diagnosis of colorectal cancer.

PURPOSE: The identification of new molecular markers for the early detection of colorectal cancer has become an important objective. We compared the sensitivity and specificity of free circulating DNA with that of the more conventional carcinoembryonic antigen (CEA) and evaluated the two markers in combination. EXPERIMENTAL DESIGN: The study was carried out on 75 healthy donors and 75 colorectal cancer patients. Free DNA was determined in serum with quantitative PCR analysis. The diagnostic accuracy of each assay was calculated using receiver operating characteristic (ROC) curves. The diagnostic relevance of the two-marker combination was analyzed by the logistic regression model. RESULTS: Median free DNA concentration was approximately 5-fold higher in patients than in healthy donors (P < 0.001). The area under the ROC curve was 0.86, and when 12.5 ng/mL was used as cutoff, 81.3% sensitivity and 73.3% specificity were observed for the overall series. As CEA and free DNA provided independent diagnostic information, they were also considered in combination. ROC curve analysis of the combined CEA and free DNA algorithms showed a higher diagnostic capacity (area under the ROC curve, 0.92) than that of markers considered singly, with 84% sensitivity and 88% specificity. CONCLUSIONS: Free circulating DNA, especially when used in combination with CEA, represents a potentially useful tool for the diagnosis of early-stage colorectal cancer.

Time-dependent pharmacokinetics of 5-fluorouracil and association with treatment tolerability in the adjuvant setting of colorectal cancer.

The authors evaluated the influence of 5-fluorouracil (5-FU) on treatment tolerability in 81 colorectal cancer patients given adjuvant 5-FU intravenously plus folinic acid for 6 cycles. The pharmacokinetics of 5-FU and its inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) were measured on days 1 and 5 of the first chemotherapy cycle, 5 and 45 minutes after bolus administration. 5-FU clearance was significantly lower on day 5 (62.64 ± 20.16 L/h/m(2)) than on day 1 (74.83 ± 31.61 L/h/m(2)). The lower 5-FU clearance values also predicted the side effects during the entire course of chemotherapy. In particular, patients with low clearance values on day 1 had a further reduction in this parameter on day 5, associated with severe toxicities. In conclusion, 5-FU alters its clearance, which could be partly due to a reduction in 5-FDHU biotransformation. These findings have safety implications for poor metabolizers whose drug clearance may fall below the threshold during repeated treatment cycles.

Bone metastases detection by circulating biomarkers: OPG and RANK-L.

Osteoprotegerin (OPG) is a decoy receptor of the receptor activator of nuclear factor-κB ligand (RANK-L) and plays an important role in the formation of metastatic bone lesions. We evaluated the usefulness of circulating OPG and RANK-L for the detection of bone metastases. We enrolled 143 individuals in the study: 30 healthy donors (HD) and 113 breast cancer patients. Among patients, 49 had no evidence of disease (NEDP), 54 had bone metastases (BMP) at first diagnosis, and 10 had visceral metastases (VMP). Both transcripts were determined in peripheral blood samples using quantitative PCR. Receiver operating characteristic (ROC) curve analysis was used to calculate the diagnostic accuracy of OPG, RANK-L, CEA and CA15-3. OPG and RANK-L median values were significantly lower in BMP (median 0.5, range 0.1-5.7, p<0.001 and median 0.5, range 0.1-4.5, p=0.024, respectively) compared to NEDP (median 1.7, range 0.4-8.9 and median 0.8, range 0.2-3.8, respectively), regardless of the number and type of bone lesions or the presence of visceral metastases. The area under the ROC curve (NEDP vs. BMP) was higher for OPG (82.5, 95% CI 74.5-90.6) than for RANK-L (69.2, 95% CI 59.0-79.40). Specificity for OPG was 87.7% (95% CI 75.7-94.2) and sensitivity was 74.1% (95% CI 60.4-85.0), both values increasing when considered together with CEA and CA15-3. For VMP, OPG and RANK-L were expressed in only one patient. Our results highlight the potentially important role of circulating OPG in the diagnosis of bone metastases. A confirmatory study on a larger case series is ongoing.

Pathogenesis of osteoblastic bone metastases from prostate cancer.

Prostate cancer is the second leading cause of cancer-related death in men. A typical feature of this disease is its ability to metastasize to bone. It is mainly osteosclerotic, and is caused by a relative excess of osteoblast activity, leading to an abnormal bone formation. Bone metastases are the result of a complex series of steps that are not yet fully understood and depend on dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment, and bone matrix (osteoblasts and osteoclasts). Prostate cancer cells from primary tissue undergo an epithelial-mesenchymal transition to disseminate and acquire a bone-like phenotype to metastasize in bone tissue. This review discusses the biological processes and the molecules involved in the progression of bone metastases. Here we focus on the routes of osteoblast differentiation and activation, the crosstalk between bone cells and tumor cells, and the molecules involved in these processes that are expressed by both osteoblasts and tumor cells. Furthermore, this review deals with the recently elucidated role of osteoclasts in prostate cancer bone metastases. Certainly, to better understand the underlying mechanisms of bone metastasis and so improve targeted bone therapies, further studies are warranted to shed light on the probable role of the premetastatic niche and the involvement of cancer stem cells.

Adjuvant immunotherapy with tumor infiltrating lymphocytes and interleukin-2 in patients with resected stage III and IV melanoma.

Adoptive immunotherapy with tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 is reasonably effective in the treatment of patients with advanced melanoma. However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (resected stages III and IV). In a preliminary study, 25 patients (aged 23-72 years) with stage III-IV melanoma who underwent resection of metachronous metastases were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 x 10 IU/m ) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) evaluable patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) rates were 44% and 37%, respectively, at 2 years, and 52% and 45% at 3 years. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 x 10 versus 86 x 10 IU/m, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. Analysis of tumor immunosuppression factors in lymphocytes inside the tumor (TCR zeta and epsilon chains, p56, FAS, and FAS-ligand) confirmed that the immunologic potential of TIL, depressed at the time of metastasectomy, was significantly restored after in vitro culture with IL-2. Adoptive immunotherapy with TIL and IL-2 could improve DFS and OS, although further work is required to determine its role in the treatment of patients with high-risk melanoma.

Adjuvant, adoptive immunotherapy with tumor infiltrating lymphocytes plus interleukin-2 after radical hepatic resection for colorectal liver metastases: 5-year analysis.

BACKGROUND AND OBJECTIVES: Conventional chemotherapy has not proven effective in improving long-term results of surgery for liver metastases from colorectal cancer. We assessed the usefulness of immunotherapy with tumor infiltrating lymphocytes (TIL) plus Interleukin-2 (IL-2) as adjuvant treatment. METHODS: Between 1995 and 1998, 47 patients were enrolled onto a prospective protocol; 25 entered the treatment group (A) and 22 entered the control group (B). All patients had undergone radical liver resection. TIL obtained from surgical specimens from group A patients were cultured and activated in vitro with IL-2, then reinfused into the patients with IL-2. We investigated pre- and post-IL-2 stimulation expression of T cell receptor (TCR) zeta- and epsilon-chains, p56(lck), Fas, and Fas-L by TIL immunostaining. RESULTS: Fourteen patients from group A (56%) received immunotherapy; 14 from group B (60%) underwent conventional chemotherapy, and the remaining 19 patients did not receive any treatment. No significant differences between the two groups were found in the actuarial and disease-free survival (DSF) rates after 1, 3, and 5 years. After IL-2 exposure, TCR zeta-chain expression significantly increased (P = 0.001); An increase in TCR epsilon-chain expression (P = 0.04), and p56(lck) (P = 0.03) was detected; TCR epsilon-chain expression was significantly increased in disease-free patients compared to those who relapsed (P = 0.04). Fas-L expression was correlated with the TCR epsilon-chain and p56(lck) levels (P = 0.05). CONCLUSIONS: Our data suggest that we are still a long way from being able to propose TIL + IL-2 treatment as an effective adjuvant therapy. However, the results confirm that the biological indicators examined could play an important role in modulating immunitary response against tumor cells.

Relationship between plasma concentrations of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil and toxicity of 5-fluorouracil infusions in cancer patients.

This study investigated the relationship among the pharmacokinetics of 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU); the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells; and treatment-related toxicity in 26 patients with surgically resected colorectal cancer treated with short daily infusions of 5-FU adjuvant chemotherapy, each cycle consisting of 5 consecutive days every 4 weeks. After the first chemotherapeutic cycle, severe stomatitis and diarrhea occurred in 5 patients and were related to the variations in the systemic disposition of the drug rather than to DPD activity. These patients showed a significant decrease in 5-FU clearance, and an increase in the 5-FU/5-FDHU area under the time-concentration curve (AUC) ratio, as compared with patients who experienced mild toxicities, whereas a low DPD activity was observed in only 2 patients. In conclusion, the results of this study demonstrate that the alterations in 5-FU and 5-FDHU pharmacokinetics are related to severe toxicities in patients treated with short intravenous infusion of 5-FU.

Immunosuppression in renal cancer: differential expression of signal transduction molecules in tumor-infiltrating, near-tumor tissue, and peripheral blood lymphocytes.

Alterations in the expression of signal activation molecules, such as the T-cell receptor (TCR) zeta and epsilon chains and p56lck tyrosine kinase, are described in tumor-infiltrating lymphocytes (TIL). The aim of this study was to ascertain if such molecules were present in near-tumor-tissue lymphocytes (NTTL) and peripheral blood lymphocytes (PBL), as well as TIL, of renal cell carcinoma patients, to verify whether this tumor induces immunosuppression only locally or affects distant lymphocytes as well. Tissue from the tumor and from healthy nearby sites, as well as blood samples, were obtained from 27 consecutive patients who had undergone radical nephrectomy for renal cell carcinoma. Phenotype analysis and immunohistochemical staining of the TCR zeta and epsilon chains and p56lck were performed with standard techniques on TIL, NTTL, and PBL, and values were compared for each patient. Low expression of the TCR zeta chain and an almost complete absence of TCR epsilon chain and p56lck expression was observed in TIL (median values: 10% for zeta chain and 0% for epsilon and p56lck). In NTTL, these signal transduction molecules were expressed by a higher percentage of cells (60%, 50%, and 60%, respectively; p=0.000 vs. TIL), whereas PBL showed an almost normal expression of zeta and epsilon chains (80% and 90%, respectively; p=0.000 vs. TIL). Conversely, p56lck was detected in a greater proportion of NTTL than PBL (50% vs. 10%; p=0.001). The absence or the very low expression of signaling activation molecules in TIL compared with NTTL and PBL in renal cancer patients suggest that tumor-induced immunosuppression generally occurs or starts locally.