Docetaxel and Cisplatin in First Line Treatment of Patients with Unknown Primary Cancer : A Multicenter Study of the Anatolian Society of Medical Oncology

Cancer of unknown primary (CUP) accounts for 2-10% of all malignancies and accepted as metastatic cancer (Fizzazi et al., 2011; Pavlidis et al., 2012; Greco et al., 2012). Incidence of CUP is decreased secondary to advances of pathology and imaging methods (Greco et al., 2012; Hemminki et al., 2012). In many patients, pathologic diagnosis is adenocarcinoma and the disease is on the multimetastatic sites. Except selected patients, survival benefit of the treatments are limited and the intent of treatment is palliative. The prognosis of CUP is poor, response rate (RR) is 20-35%, median overall survival (OS) is 6-12 months and one year OS is 15-35% (Fizzazi et al., 2011; Greco et al., 2012; Pavlidis et al., 2012). Although different chemotherapy regimens were evaluated, there is no standard treatment, currently. Platin based regimens are mostly used and the results of phase II


Introduction
Cancer of unknown primary (CUP) accounts for 2-10% of all malignancies and accepted as metastatic cancer (Fizzazi et al., 2011;Pavlidis et al., 2012;Greco et al., 2012).Incidence of CUP is decreased secondary to advances of pathology and imaging methods (Greco et al., 2012;Hemminki et al., 2012).In many patients, pathologic diagnosis is adenocarcinoma and the disease is on the multimetastatic sites.Except selected patients, survival benefit of the treatments are limited and the intent of treatment is palliative.The prognosis of CUP is poor, response rate (RR) is 20-35%, median overall survival (OS) is 6-12 months and one year OS is 15-35% (Fizzazi et al., 2011;Greco et al., 2012;Pavlidis et al., 2012).Although different chemotherapy regimens were evaluated, there is no standard treatment, currently.Platin based regimens are mostly used and the results of phase II taxane studies are promising in patients with CUP (Poussel et al., 2004;Adenis et al., 2010;Hainsworth et al., 2010).
Here-in, we evaluated our multicentric retrospective experience for CUP administering docetaxel and cisplatin in combination therapy.

Materials and Methods
Between 2007 and 2010, totally 29 patients that were pathologically confirmed subtypes of CUP was evaluated in the five institutions, retrospectively.The treatment naive patient has pathologically confirmed CUP and although detailed examinations (physical examination, chest graphy, thoraco-abdominal computarized tomography (CT), mammography, if necessary pozitron emission tomography/ computarized tomography-PET/CT) and diagnostic sample, the primary was unable to identify.Female patient with alone axillary lymph node involvement and adenocarcinoma of the peritoneal cavity, midline carcinoma that suspected with germ cell tumor and patient with SCC at single site involvement were not included the study.
The patients were treated with the combination of docetaxel (75 mg/m 2 , day 1) and cisplatin (75 mg/m 2 , day 1) every 21 days.The evaluation for the treatment response in CUP was assessed by both clinical and radiological criteria using Response Evaluation Criteria in Solid Tumors (RECIST) (Eisenhauer et al., 2009).Toxicities were recorded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Data were expressed with median values with range.While progression free survival (PFS) is defined from the initial day of treatment to first progression, OS is defined from the initial of treatment to last control or death.All statistical analyses were based on 'intent to treat'.The Kaplan Meier survival estimates were calculated.Survival curve were compared with logrank test.A p-value was accepted statistically significant if the value less than 0.05.SPSS 15 was used for statistical analysis.
In a prospective phase II study, combination of docetaxel and either cisplatin or carboplatin, 90% of the patients were adenocarcinoma and undifferantiated histology and majority were multimetastatic.In docetaxelcisplatin arm, 26% of the patients showed major response and median OS and one year OS were 8 months and 42% respectively.In 7 patients treatment discontinued because of grade 3/4 gastrointestinal toxicities (Mukai et al., 2010).A study evaluated different doses of the combination of docetaxel (60mg/m 2 /d) and cisplatin (80 mg/m 2 /d).The median age was 56.5 years of 45 patients and 14 patients (33%) had visceral disease.The overall response rate was 65.1%.The median time to progression and median OS were 5.0 months and 11.8 months.However there is no differences in terms of OS and RR with present study (Lazaridis et al., 2008).While median age and PS of the patients similar to present study, 60% of the patients with presented with lymph node metastases.RR (58.6% vs 65%) and PFS (6 months vs 5 months) are similar however OS was superior (16 months vs 11.8 months) in our study.The result may explained with our patients were treated with more second line treatment on progression and low incidence of liver involvement.An overall response rate of 62.5% was seen in Japanese patients with CUP who were treated same combination.The RR and survival were superior than present study.The median DFS and OS were 8.7 months and 22.7 months respectively (Yakushiji et al., 2010).Another trial had a response rate of 57.1% and the median OS was 13.2 months with same combination (Greco et al., 2000).
Recent study that has the patients mostly adenocarcinoma, showed that lymph node metastatic patients has better outcome compare to visceral involvement; median OS was 8 months vs 3 months and one year OS were 41% vs 17%, respectively (Greco et al., 2012).In a recent study evaluated to 49 patients with liver metastatic CUP, similar to our patients that majority male and adenocarcinoma histology.In this study 62% of the patients multimetastatic thus the study results, ORR and median OS were 12% and 10 months respectively, were inferior than our results.Age and extrahepatic disease were detected as a prognostic factor (Culine et al., 2002).Another study, median age was 67 and 64.5% of the patients with multimetastatic CUP.Median OS and 1 year OS were 2.5 months and 24.5% (Lazaridis et al., 2008).
In present study there was no treatment related death.Although the treatment generally well tolerated, most common toxicities were nonhematological.Serious toxicities were low reported in present study because of retrospective nature.In previous studies, serious hematological toxicities (12-17%) and nonhematological (3-30%) were reported and there were no toxic death (Fernandez-Cotarelo et al., 2010;Hainsworth et al., 2010).There are several prognostic factors such as multiple metastatic sites, liver metastasis, elevated lactate dehydrogenase level (Culine et al., 2002;Seve et al., 2006).However there is no effect sex, age, PS and number of metastatic sites on survival in present study.The study drawbacks are retrospective nature, limited sample size and lack of quality of life evaluation.
Most of the patients with CUP have unfavourable prognosis and treatment of patient with CUP is designed histopathologic and clinical features of individual.Combination of cisplatin and docetaxel is a valuable option for selected patients with CUP

Figure
Figure 1.A) Progression Free Survival and B) Overall Survival by Kaplan-Meier