Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study.

BACKGROUND: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. METHODS: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. FINDINGS: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). INTERPRETATION: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. FUNDING: AstraZeneca.

[A CR case of amylase-producing tumor treated by hyperthermochemotherapy].

A 64-year-old female who was diagnosed with an amylase-producing tumor of unknown origin was treated by hyperthermochemotherapy. The patient was admitted with a complaint of abdominal fullness due to ascites. Laboratory examination showed high levels of serum amylase and tumor markers, including CA15-3, CA 125 and CA 72-4. Laparotomy showed peritoneal dissemination with histological findings of adenocarcinoma of unknown origin. After laparotomy, she was given hyperthermia combined with chemotherapy using carboplatin (CBDCA), mitomycin C (MMC) and doxifluridine (5'-DFUR). Hyperthermia (13.56 MHz radiofrequency for 40-50 min) was performed a total of six times within one and a half months. The total doses of CBDCA and MMC were 450 mg and 24 mg, respectively, and 600 mg of 5'-DFUR was orally administered every day. By these combined treatments, ascites disappeared and serum levels of amylase and all tumor markers were decreased and normalized. MRI and echo examination also showed complete disappearance of peritoneal metastasis. Two and a half years after the treatment, the patient is alive without any evidence of recurrence, which suggests that this combined therapy is one of the useful modalities for peritoneal dissemination as well as an inoperable tumor itself.

Matrix metalloproteinases in carcinoma of unknown primary.

BACKGROUND: The purpose was to study proteolysis-related molecules, matrix metalloproteinase-2 (MMP-2) and MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1), in carcinoma of unknown primary (CUP). METHODS: Paraffin-embedded tumor material from 75 patients diagnosed with CUP was used. Tumor histologies were adenocarcinoma (77%), undifferentiated carcinoma (19%), and squamous cell carcinoma (4%) and patients were categorized into favorable (62%) and unfavorable (38%) subsets. The tissue expression of MMP-2, MMP-9, and TIMP-1 was assessed by use of specific monoclonal antibodies and evaluated by means of a visual staining score. The expression of molecules studied was analyzed against clinicopathological data. RESULTS: MMP-2 was found expressed in 69% (strong expression in 49%), MMP-9 in 49% (strong in 36%), and TIMP-1 in 79% (strong in 44%) of studied cases. The expression of MMP-2 correlated positively with MMP-9. TIMP-1 was significantly higher in unfavorable compared with favorable tumors and was associated with a shorter survival of patients (7.5 vs. 12 mos). No other associations were detected. CONCLUSIONS: MMP-2, MMP-9, and TIMP-1 are widely expressed in CUP, suggesting an essential role of proteolysis in these tumors. TIMP-1 may be considered a possible marker of poor prognosis in CUP patients.

Identification of primary tumour site by immunolocalization of progastricsin in metastatic adenocarcinoma.

The aspartic proteinase zymogen, progastricsin, which occurs in normal gastroduodenal mucosa and prostate, has been localized by the immunogold-silver method in formalin-fixed, paraffin-embedded sections of metastatic adenocarcinoma in lymph nodes and liver, the primary site being known in each case. Progastricsin was demonstrated in 16 of 84 lymph node metastases, including 7 of 17 from stomach, 2 of 2 from prostate, and 7 of 65 from other sites. Progastricsin was also found in 19 of 98 hepatic metastases, including 8 of 22 from stomach, 6 of 24 from pancreas, and 5 of 52 from other sites. The presence of progastricsin in a metastasis correlated well with a primary tumour in the stomach or prostate or, less significantly, pancreas. Immunolocalization of progastricsin in a histological section of metastatic adenocarcinoma may help to locate the primary site.