Vito Lorusso

It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6–11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21–81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m2 on days 1 and 2 and FM iv 100 mg/m2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients. We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status. This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed. EUDRACT 2009–016487-36l ; date of registration 23 June 2010.

9574 Background: In the pigmentation of hair and skin a key role is played by the MC1R gene whose inherited variations are linked with a higher melanoma risk. In melanoma cells, MC1R has a central role because of its interaction with several intracellular signaling cascades such as the MAPK or mTOR pathways. Little heed has been paid to the role of its genetic polymorphisms in the management of metastatic melanoma. Our aim was to evaluate the effects of MC1R variants on the clinical outcomes of BRAF mutated patients treated with BRAF inhibitors. Methods: Fifty-three consecutive patients were evaluated according to their MC1R status (21 wild type and 32 with minor/major functional variants). First we explored eventual association between MC1R status and basal patient features. Than we evaluated the influence of MC1R status on therapeutic outcomes to anti BRAF inhibitors (ORR, PFS, OS). Finally, we studied the effect of vemurafenib in 2 BRAF V600 melanoma cell lines with and without MC1R variant. Results: Regarding the baseline patient features, we only found an association between MC1R polymorphisms and bone metastases (p 0.017). Moreover, MC1R variants were significantly associated with worse outcomes to BRAF inhibitors compared with MC1R wild type in terms of both ORR (59% vs 95% [p 0.011 in univariate, p 0.028 in multivariate analysis]) and PFS shorter than 6 months (72% vs 33% [p 0.012 in univariate, p 0.027 in multivariate analysis]). No significant difference was found in OS, probably due to the influence of further treatments. Data in vitro demonstrated a significantly different phosphorylation of Erk1/2 and p38 MAPK before and after treatment, associated with a greater increase of vemurafenib IC50 in cases of MC1R variant. Conclusions: Our data document, for the first time, detrimental effects of MC1R variants on BRAF inhibitor therapy. Moreover, these evidences concur to understand the resistance mechanisms to targeted therapy and may help to pinpoint new therapeutic strategies.

To assess the predictive role of lactate dehydrogenases (LDH) and fibrinogen (FBG) serum levels in metastatic colorectal cancer (mCRC) patients receiving a first-line bevacizumab-based therapy.The aim of the present analysis was to retrospectively evaluate the role of basal and post-treatment LDH and FBG serum levels in predicting the clinical outcome of 139 mCRC patients receiving first-line chemotherapy in combination with bevacizumab.A statistically significant association between high pre-treatment LDH and FBG levels and progressive disease was observed with respect to low basal LDH and FBG patients. Furthermore, median progression-free survival was 7.3 versus 10.8 months and 7.3 versus 9.4 months for high and low LDH and FBG levels, respectively. Within the high LDH group, we observed a statistically significant reduction of LDH mean value compared with pre-treatment values in patients with objective response rate and stable disease.High LDH and FBG levels correlated with prognosis. A significant correlation between bevacizumab-based chemotherapy-induced reduction in LDH serum levels and response to treatment was observed within the high LDH group. These results, if confirmed in larger prospective studies, could be helpful for early identification of patients responsive to bevacizumab-based chemotherapy or candidate to more aggressive treatments.

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox’ multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

This study aimed to increase the understanding of health resource utilization (HRU) associated with skeletal-related events (SREs) occurring in patients with bone metastases secondary to advanced prostate cancer. A total of 120 patients from Germany, Italy, Spain and the United Kingdom were enrolled in this observational study. They had bone metastases secondary to prostate cancer and had experienced at least one SRE in the 97 days before giving informed consent. HRU data were collected retrospectively for 97 days before enrolment and prospectively for up to 18–21 months. HRU, including the number and duration of inpatient hospitalizations, number of outpatient and emergency department visits and procedures, was independently attributed by investigators to an SRE. Of the 222 SREs included in this analysis, 26% were associated with inpatient stays and the mean duration per SRE was 21.4 days (standard deviation (SD) 17.8 days). Overall, 174 SREs (78%) required an outpatient visit and the mean number of visits per SRE was 4.6 (SD 4.6). All SREs are associated with substantial HRU. Preventing SREs in patients with advanced prostate cancer and bone metastases may help to reduce the burden to both patients and European healthcare systems.

Desmoplastic small round cell tumour (DSRCT) is a rare and aggressive cancer that usually develops in the peritoneal cavity of young males. Its prognosis is dismal, with current treatment options including the combination of multi-agent chemotherapy, aggressive surgery, radiation therapy, and autologous stem cell transplantation. Hyperthermic intraperitoneal chemotherapy (HIPEC) may also be an option. Herein we report the administration of the marine-derived multi-target antineoplastic agent, trabectedin, in a patient with DSRCT, heavily pre-treated with conventional multi-agent chemotherapy, HIPEC, and surgery. The patient achieved a prolonged partial response and an extended period of stable disease with third-line trabectedin, following disease progression after conventional multi-agent chemotherapy, HIPEC, and surgery. Trabectedin may be a treatment option in multimodal therapy for the management of DSRCT and warrants further research to explore the impact of trabectedin in the treatment of this disease.

Bone complications or skeletal‑related events (SREs), typically defined as radiation to bone, pathological fractures, surgery to bone and spinal cord compression, occur frequently in patients with bone metastases. As the survival of patients with advanced lung cancer improves, preventing SREs is becoming increasingly clinically relevant. The aim of this analysis was to assess the impact of SREs on health resource utilisation (HRU) in European lung cancer patients with bone metastasis. This multinational, observational study included patients who had at least one SRE in the 97 days prior to enrolment, a life expectancy of ≥6 months and an Eastern Cooperative Oncology Group performance status of 0‑2. Data on HRU were retrospectively collected for up to 97 days prior to enrolment with a planned prospective follow‑up for up to 18‑21 months. The HRU measures included the number and length of inpatient hospitalisations and the number of outpatient visits and procedures. The investigators determined whether each HRU was attributable to a SRE. In total, 135 patients with lung cancer, enrolled at centres in Germany, Italy, Spain and the United Kingdom, contributed 214 SREs to this analysis. The median length [quartile (Q)1, Q3] of follow‑up ranged from 1.5 (0.7, 3.3) to 5.6 (2.0, 8.2) months across the countries. Overall, 41% of the SREs required an inpatient stay, with a median (Q1, Q3) duration of 19.0 (6.0, 28.0) days. Spinal cord compression and surgery to bone were the SRE types most frequently requiring inpatient stays. Radiation to bone was associated with the largest number of outpatient visits and procedures. All the SREs resulting from bone metastases in patients with lung cancer contribute considerably to HRU and efforts to minimise the incidence of bone complications in these patients through appropriate treatments may help reduce this burden.

We present the case of a 58-year-old woman with breast cancer metastasizing to the liver after adjuvant chemotherapy. A liver biopsy confirmed metastatic lesions from breast cancer that were immunohistochemically positive for estrogen/progesterone receptors and HER2. After first-line treatment with trastuzumab and vinorelbine, the patient commenced therapy with capecitabine (1000 mg/m2 twice daily, days 1-14) and lapatinib (1250 mg/day). Three months after the administration of this combination therapy, the liver metastases had shrunk substantially. Lapatinib may have the potential to convert trastuzumab-refractory tumors to trastuzumab-sensitive tumors in HER2-positive breast cancer by upregulation of the cell surface expression of HER2. Further study will be needed to evaluate in the clinic the combination of lapatinib and an m-TOR inhibitor as a treatment approach in HER2 overexpressing breast cancer that shows a poor response to trastuzumab.

Gefitinib is the current first-line treatment for advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutations. The possibility of using gefitinib as neoadjuvant therapy is interesting because of the low toxicity profile of tyrosine kinase inhibitors. Here we report the case of a 67-year-old nonsmoking woman affected by locally advanced lung adenocarcinoma, in whom one-year treatment with gefitinib rendered the tumor amenable to surgical removal. The results of ongoing clinical trials exploring the ability of preoperative gefitinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of EGFR mutations are urgently awaited.

Background: Rhabdomyolysis is an uncommon side effect of trabectedin which is used for the second line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. This side effect may be due to pharmacokinetic interactions caused by shared mechanisms of metabolism involving the cytochrome P450 (CYP) system in the liver. Here, for the first time in literature, we describe the unexpected onset of heavy toxicity, including rhabdomyolysis, after the fourth course of trabectedin in a patient with retroperitoneal liposarcoma who at the same time was taking an alternative herbal medicine suspected of triggering this adverse event. Case presentation: This is the case of a 56 year old Caucasian man affected by a relapsed de-differentiated liposarcoma who, after the fourth cycle of second-line chemotherapy with trabectedin, complained of sudden weakness, difficulty walking and diffuse muscle pain necessitating complete bed rest. Upon admission to our ward the patient showed grade (G) 4 pancytopenia and a marked increase in liver lytic enzymes, serum levels of myoglobin, creatine phosphokinase (CPK) and lactate dehydrogenase. No cardiac or kidney function injuries were present. Based on these clinical and laboratory features, our conclusive diagnosis was of rhabdomyolysis induced by trabectedin. The patient did not report any trauma or muscular overexertion and no co-morbidities were present. He had not received any drugs during treatment with trabectedin, but upon further questioning the patient informed us he had been taking a folk medicine preparation of chokeberry (Aronia melanocarpa) daily during the last course of trabectedin and in the 2 subsequent weeks. One week after hospitalization and cessation of intake of chokeberry extract, CPK and other markers of myolysis slowly returned to standard range, and the patient noted a progressive recovery of muscle strength. The patient was discharged on day 14 when a blood transfusion and parenteral hydration gradually lowered general toxicity. Progressive mobilization of the patient was obtained as well as a complete normalization of the laboratory findings. Conclusions: The level of evidence of drug interaction leading to the adverse event observed in our patient was 2 (probable). Thus our case underlines the importance of understanding rare treatment-related toxicities such as trabectedin-induced rhabdomyolysis and the possible role of the drug-drug interactions in the pathogenesis of this rare side effect. Furthermore, this report draws attention to a potential problem of particular concern, that of nutritional supplements and complementary and alternative drug interactions. These are not widely recognized and can cause treatment failure.