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Gastroentérologie Clinique et Biologique
Vol 29, N° 12  - décembre 2005
pp. 1224-1232
Doi : GCB-12-2005-29-12-0399-8320-101019-200517230
Hepatic metastases from carcinomas of unknown primary site
Experience of the Montpellier Cancer Center
 

Damien POUESSEL [1], Simon THEZENAS [1], Stéphane CULINE [1], Catherine BECHT [1], Pierre SENESSE [1], Marc YCHOU [1]
[1] Département d'Oncologie Médicale, Centre Régional de Lutte contre le Cancer Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5.

Tirés à part : M. YCHOU [1]

[1] CRLC Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5.

mychou@valdorel.fnclcc.fr

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Métastases hépatiques de carcinomes de site primitif inconnu. Expérience du centre régional de Lutte contre le Cancer de Montpellier
Objectifs

Les métastases hépatiques sont fréquemment présentes lors d'un diagnostic de carcinome de primitif inconnu (CAPI). La prise en charge diagnostique et thérapeutique de ces malades au pronostic sombre est rapportée dans cette étude.

Méthodes

Cent dix-huit malades ont été traités au Centre Régional de Lutte contre le Cancer de Montpellier de 1993 à 2002 pour un CAPI avec métastases hépatiques initiales. Leurs caractéristiques, les examens préthérapeutiques réalisés, les chimiothérapies reçues et l'évolution ont été analysés de façon rétrospective.

Résultats

Les types histologiques les plus fréquemment retrouvés étaient l'adénocarcinome, les carcinomes indifférenciés, endocrines et épidermoïdes. Dans 66 cas, les lésions hépatiques étaient révélatrices; et chez 32 malades, elles restaient isolées. Les autres sites retrouvés étaient les adénopathies, le poumon, et l'os. Lors du diagnostic, plus de 80 % des malades ont bénéficié d'un scanner thoracoabdominopelvien. Les coloscopies, gastroscopies et bronchoscopies ont été réalisées dans respectivement 58, 56 et 26 % des cas. Cent-sept patients ont reçu au moins une ligne de chimiothérapie. Les sels de platine ont été administrés chez 74 patients dont 67 en première ligne et 10 en seconde ligne. En première ligne, les taux de réponse objective après chimiothérapie avec et sans platine étaient respectivement de 19,4 et 20 %. Cent-deux des 111 décès sont imputables à la progression tumorale et sept aux chimiothérapies. La médiane de survie globale était de 6,6 mois, sans différence significative entre les groupes avec et sans sel de platine (7,8 et 4,6 mois P = 0,35). En analyse multifactorielle, deux variables indépendantes de mauvais pronostic sont retrouvées: l'élévation des lacto-déhydrogénases sériques et l'altération de l'état général. La survie des malades ayant reçu une chimiothérapie était de 7 mois.

Conclusions

Cette étude montre que des explorations parfois extensives n'ont pas permis de retrouver le site primitif des métastases hépatiques. La chimiothérapie, dont l'impact sur la survie n'est pas démontré, doit être réservée aux malades de meilleur pronostic. L'inclusion dans des essais thérapeutiques prospectifs doit être encouragée afin de déterminer la place notamment des sels de platine.

Abstract
Aim

Hepatic metastases are often present at diagnosis of carcinoma of unknown primary site (CUP). The objective of this study was to describe the diagnostic and therapeutic strategies used.

Methods

One hundred and eighteen patients were treated at the Cancer Center of Montpellier from 1993 to 2002 for CUP initially metastatic to the liver. Initial chararcteristics, diagnostic tests, chemotherapies and outcome were retrospectively recorded.

Results

The most frequent histological types observed were adenocarcinoma, undifferentiated, neuroendocrine and squamous-cell carcinomas. Hepatic metastases revealed the cancer in 66 patients and were isolated in 32 patients. Other metastatic sites involved lymph nodes, lung and bone. Pretreatment computed tomography scans of the chest, abdomen and pelvis evaluation were available for more than 80% of patients. Colonoscopy, gastroscopy and bronchoscopy were performed in 58, 56 and 26% of patients respectively. One hundred and seven patients had received at least a front-line of chemotherapy. Seventy-four patients had received platin salt-based chemotherapy, 67 in front-line treatment and 10 in second line. In first-line chemotherapy, overall response rates with or without platin were 19.4 and 20% respectively. One hundred and two of 111 deaths were due to disease progress and seven toxic-related deaths occurred. The median survival was 6.6 months, and 7.8 and 4.6 months in the with or without platin groups respectively (P = 0,35). The median survival for treated patients was 7 months. Multivariate analysis identified two prognostic factors: serum lactodehydrogenase level and performance status.

Conclusions

According to this study, pretreatment evaluations, which were very extensive in some patients, were insufficient to identify the primary site of liver metastases. Because of the poor prognostic, chemotherapy, in absence of clinically demonstrated benefit, has to be reserved for patients with better prognosis. Prospective trials are needed to determine whether use or not of cisplatin should be proposed for standard protocols.


Introduction

Carcinoma of unknown primary site (CUP) is a difficult challenge for medical oncologists and organ specialists [1 et 2]. By definition, CUP is a malignant disease revealed by one or more metastatic localizations whose primary site remains undetermined at the time of the therapeutic decision despite clinical examination and extensive complementary explorations. Depending on the authors, CUP concerns 0.5 to 10% of malignant tumors [3]. Prognosis is poor with median survival of 6 to 11 months despite treatment [4 et 5]. The challenge is both diagnostic - how extensive should the complementary explorations be — and therapeutic — which anatomoclinical entities can be expected to respond to specific treatment and improve the patient's prognosis. Several teams have proposed diagnostic and therapeutic protocols for these complex situations [6 et 7]. Currently, four categories of CUP have been defined which warrant specific treatment [7 et 8]: metastatic axillary nodes from an adenocarcinoma in women, suggestive of breast cancer; metastatic cervical nodes from an undifferentiated or squamous-cell cancer suggestive of primary head and neck cancer; serous papillary adenoma of the peritoneum in women; neuroendocrine carcinoma of unknown primary site. For anatomoclinical presentations which do not correspond to these descriptions, no one chemotherapy scheme has been clearly established as the most appropriate standard treatment. Several non-controlled trials have been undertaken to evaluate protocols with or without platin salt-based regimens. Overall response rates have ranged from 0 to 50% with median survival of 4 to 13 months [9].

Metastasis to the liver is frequent and present in 20 to 30% of CUP [10]. After nodal metastasis, it is the second leading mode of revelation of carcinoma [11]. The debate continues as to the most appropriate diagnostic approach, particularly concerning use of endoscopic methods, for patients with CUP revealed by liver metastasis. The impact of these secondary hepatic lesions on prognosis is also a subject of debate with very different conclusions drawn from retrospective series [4, 5, 11, 12 et 13]. Nevertheless, the French Study Group on Carcinomas of Unknown Primary Site (GEFCAPI) has recently proposed a simple classification based on the WHO performance status and serum lactodehydrogenase (LDH) levels [12]. The present of hepatic metastases, retained as an element of poor prognosis by several authors [4 et 5] has less impact on prognosis than LDH [12]. Regarding chemotherapy regimens, only one trial specifically studying hepatic metastases from adenocarcinomas of unknown primary site has presented the results of a fluorouracil-adriamycin-mytocine C combination regimen (FAM) in 29 patients [14]. In two recent series, Mousseau et al. [10] and Ayoub et al. [11] demonstrated that administration of chemotherapy is a factor of better prognosis.

We report here the diagnostic and therapeutic data from 118 consecutive patients treated for CUP with liver metastases at the Montpellier Cancer Center. We aimed to identify prognostic factors in this subpopulation of CUP patients and to establish therapeutic guidelines by applying a prognostic model validated by the GEFCAPI. The effect of chemotherapy, and particularly platin salts, was also studied.

Patients and methods

Over a period of 10 years, from January 1993 to December 2002, 118 patients were treated for CUP with liver metastases at the Montpellier Cancer Center. These 118 patients were reviewed retrospectively using a standard questionnaire. Initial characteristics, complementary explorations, chemotherapy delivered, and clinical outcome were analyzed.

A specific pathology examination was necessary to establish the histological diagnosis of carcinoma and rule out another type of tumor: lymphoma, melanoma, sarcoma. For this, immunohistochemistry techniques were recommended to search for common leukocyte antigens (CD), cytokeratins (CK), endocrine markers (chromogranins, synaptophysin) and melanoma markers (S-100 and HMB-45).

The chemotherapy protocols administered in these patients were also studied in detail. The use of cisplatinium in the therapeutic regimens and its effect on prognosis were evaluated. Tumor response to chemotherapy was assessed using the WHO criteria [15].

Qualitative data were expressed in percent of mean of the contingency tables and compared with chi-square tests. Quantitative data were expressed as median, range, mean, and standard deviation, and compared with Student's t test (mean). The Kaplan-Meier method was used to draw the survival curves which were compared between groups with the log-rank test.

Stepwise Cox regression models were applied to study predictive factors using the initial characteristics of the patients and biological data such as administration of platinium salts or not. Relative risk and the 95% interval of confidence (95%IC) were presented.

Two-way statistical tests were performed and P ≪ 0.05 was considered significant. Statistical analysis was performed with STATA 7.0.

Results
Patient characteristics

One hundred eighteen patients, 68 men and 50 women, who presented liver metastases from CUP were retained for this study. Median age was 61 years, range 22 - 86 (table I). Adenocarcinomas predominated (N = 68, 57.6%) and differentiation was available for 53 of them: 19 poor, 26 intermediary, and 8 well-differentiated tumors. Sixteen patients had a neuroendocrine tumor. Other histological types were: undifferentiated carcinoma (N = 23), clear-cell carcinoma (N = 4), squamous-cell carcinoma (N = 4). The diagnosis of malignant disease was confirmed on needle aspiration biopsies in three patients but the histological type could not be determined. General health status was preserved in 68.1% of patients with a performance status of 0 or 1.

For 66 patients (55.9%) liver metastases revealed the malignant disease. For 20/118 patients (16.9%), the hepatic lesion was the only secondary localization. For 32 patients (31.1%) the search for extension was negative. Twenty-seven patients had two metastatic sites and 59 others had three or more metastatic sites. Lymph node, lung, and bone metastases predominated (55.9%, 38.1% and 36.4% respectively).

The patients were classified into two groups using a recently validated prognostic model [12] based on the performance score and serum LDH level, . Forty-eight patients with a performance score of 0 or 1 and normal serum LDH were assigned to the “good prognosis” group. Seventy patients with a performance score ≥ 2 and elevated or unknown serum LDH were assigned to the “poor prognosis” group. LDH assay was not available for 23 patients.

Complementary examinations performed

For each patient, we recorded the complementary examinations performed before making the therapeutic decision. Thirty-one different examinations were identified (table II). By definition, none of these explorations enabled identification of the primary tumor site.

Computed tomography (CT) scans of the thorax, abdomen and pelvis was performed in 80% of patients in order to search for the primary site and determine extension. Colonoscopy, gastroscopy and bronchial fibroscopy were performed in 69 (58.5%), 67 (56.8%) and 31 (26.3%) patients respectively. Diagnostic mammography and thyroid ultrasound were performed in 32 and 22 patients. Mean time from histological diagnosis to administration of first-line chemotherapy was 28.4 days (range 1-350). Bone scintigraphy (N = 63 patients) and brain scans (N = 28 patients) were also performed to search for extension. Bone metastases were identified in 43 patients and brain metastases in 6.

Serum tumor markers

None of the studied tumor markers were elevated in 30 patients. Carcinoembryonic antigen (CAE) was elevated in 43 patients (48.9%) and CA 19-9, Cyfra 21, CA 125 and CA 15-3 in 38, 33, 30 and 28 patients respectively (table III).

Therapeutic management

Among the 118 patients in the study population, 11 were not given specific chemotherapy either because of early death before the therapeutic decision, or because chemotherapy was considered incompatible with the patient's general status. Hepatectomy was performed in three patients. In the first patient, hepatectomy was diagnostic and enabled confirmation of the histological type. In the second, hepatectomy was performed three months after initiating therapeutic management. The third patient underwent hepatectomy 4.5 years after the initial diagnosis of a neuroendocrine tumor. Chemotherapy was delivered in 107 patients. Sixty received a first-line protocol alone, 34 also received a second-line protocol, and 13 received a third (or more) protocol(s) (table IV). A median of 3 cycles were administered per patient for the first-, second-, and third-line protocols. Median time between lines 1 and 2 was 4.7 months (range 0.7-36.0). Cisplatin was included in the first-line protocol for 62.6% of patients, in the second-line for 21.3% and the third line for 15.4%. Among the 107 patients who received chemotherapy, 74-69.2%) were given platin salts (cisplatin or carboplatin) at least once. The platin salt was administered in the first-line protocol in 67 patients, in the second line in 10 and in the third line in 2.

After platin salt-based first-line protocols, complete or partial response was observed in 12 patients, giving a rate of objective response of 19.4% (95%CI, 10.7-30.8). After chemotherapy without platin salts, the rate of objective response was 20% (95%CI, 9.0-35.6) (8 partial responses) (table V). For second-line protocols, the rates of objective response with and without platin salts were 10 [95%CI, 0.2-44.5] and 2.8% [95%CI, 0.1-14.5] respectively. Thereafter, no responses were recorded irrespective of the drug used.

Survival

Among the 118 patients studied, 111 (94.1%) had died at the time of this analysis. In 102, the cause of death was directly related to tumor progression. Seven patients died from toxic causes (6.3%), including 5 after platin salt chemotherapy. Two patients died from another cause. Among the 7 surviving patients, two had achieved sustained remission 10 and 13 months after diagnosis. The first had a neuroendocrine tumor and the other isolated hepatic metastases from an adenocarcinoma. The five other survivors presented tumor progression 7, 8, 9, 18, and 34 after diagnosis.

Median overall survival was 6.6 months. The survival rates at 6 months, one year and three years were 52%, 32% and 3% respectively (figure 1). Among the 107 patients given chemotherapy, median survival was not significantly different between those given and not given platin salts (P = 0.35). Median survival was 4.6 months in the group not given platin salts and 7.8 months in the group given platin salts.

Prognostic factors

Unifactorial analysis of the clinical and biological data was used to search for prognostic factors. Results are given in table VI. Five variables had a statistically significant negative effect on survival: performance status > 1, liver metastasis revealing the malignant disease, and elevated serum CA 19-9, alkaline phosphates, and LDH. Inversely, presence of a neuroendocrine CUP and administration of chemotherapy were linked with better prognosis.

At multivariate analysis, independent factors linked with poor prognosis were elevated serum LDH and altered performance status: odds ratios 2.4 [95%CI, 1.5-3.8] and 2.4 [95%CI, 1.540.8] respectively. Administration of chemotherapy was found to be an independent factor of good prognosis: odds ratio 0.07 [95%CI, 0.02-0.21] (table VII).

Discussion

The liver is a common site for mestastases from CUP. Hepatic metastases are found in 20 — 30% of cases. In our retrospective analysis, we searched for both therapeutic and prognostic elements among patients treated at the Montpellier Cancer Center over a 10-year period. Among the 118 patients studied, we observed the commonly reported characteristics of CUP, i.e. median age 60 years, male predominance, adenocarcinoma the most frequent histological type (50%), most common metastatic sites (lymph nodes, lung, bone) [1, 4 et 5]. Many complementary explorations were performed in our patients, and some had undergone an impressive number of examinations. More than 80% of the patients had a thoracoabdominopelvic CT-scan and nearly 60% upper and lower gastrointestinal endoscopic explorations. All of these examinations remained, by definition, negative. Mousseau et al. [10] performed systematic endoscopic procedures in 30 patients with revealing liver metastases and failed to identify the primary site in all 30  [10]. During the period of this study, access to certain imaging techniques progressed with their development at our center, possibly leading to a certain variability in our retrospective data. Considering current assess to imaging techniques, standardized diagnostic protocols have been defined and evaluated [6 et 7] in order to avoid retarded delivery of treatment and limit explorations to those having a specific influence on prognosis. Two elements have a determining effect: the fact that identifying the primary site has no effect on prognosis (excepting a few subtypes), and the low yield (1% per exploration) of examinations other than the basic work-up performed without a clinical indication [6, 16 et 17]. In general, the standard procedure for patients with CUP is to perform a thorough physical examination (digital examination of the pelvic orifices, dermatological examination, palpation of the thyroid gland and the testicles. Current recommendations [7] propose complementary exploration using thoracoabdominal CT, pelvic imaging (ultrasound or CT), and mammography in women with an adenocarcinoma or an undifferentiated carcinoma. It is advisable to limit assay of serum tumor markers to prostate-specific antigen, alpha-fetoprotein, and gonadotrope chorionic hormone when the clinical picture is compatible with a germ-cell or prostatic tumor [6, 8 et 18]. Colonoscopy would not be recommended unless there is a clinical indication. In patients free of clinical symptoms, particularly in those with liver metastases, colonoscopy nevertheless could be a valid option because of the emergence of medicosurgical strategies resulting from the recent development of chemotherapy protocols improving the prognosis of metastatic colorectal cancer. There would be no indication for any other complementary examination without a clearly demonstrated clinical orientation [7].

The second important step in the therapeutic decision making process is to identify prognostic factors. Data in the literature are limited to retrospective series of small numbers of patients (57 to 927) treated for CUP [4, 13, 16, 19 et 20]. Conclusions have varied greatly. The most commonly described factors of poor prognosis are poor general health status, more than three metastatic sites, presence of liver metastases, elevated serum alkaline phosphatases, male gender, and adenocarcinoma. Search for prognostic factors in our population enabled us to identify WHO performance status and serum LDH as independent factors. These findings are in line with another recently published study [12] which validated a simple prognostic model easy to apply in clinical practice:i) patients with a performance status of 0 or 1 and normal serum LDH level had a good prognosis with a median survival of 11.7 months;ii) patients with a performance status > 1 or elevated serum LDH had a poor prognosis with a median survival of 3.9 months. It is noteworthy that the presence of liver metastases, retained as an element of poor prognosis by several authors [4 et 5] was found in the multifactorial analysis reported by Culine et al. [12] but disappeared when LDH level was considered. This prognostic model, which has been validated for all CUP considered together, is thus found in our subpopulation of patients with liver metastases. A third variable, chemotherapy, appears to have a favorable effect on survival. This element has been emphasized by Ayoub et al. [11]. However, the significance of chemotherapy is not univocal because it is not often delivered in patients in poor general status. Presence of a neuroendocrine histology was also found to be a factor of better prognosis. This has been reported by several authors [11 et 20]. One retrospective study of 365 patients treated for hepatic metastases from a CUP reported a median survival of 7.2 months and identified three prognostic factors: neuroendocrine tumor, patient age, and number of metastatic sites [11].

The overall objective response after first-line chemotherapy was 19.6% in our patients who had a short median survival of 6.6 months, which is similar to other retrospective series (4 and 7.2 months for Mousseau and Ayoub respectively) [10 et 11]. Furthermore, the rate of objective response after first-line treatment was 19.4% and 20% in patients given and not given platin, with median survivals of 7.8 and 4.6 months respectively. However a wide range of chemotherapy protocols were delivered and the difference in survival was not statistically significant. It should be noted that the objective response observed in our patients occurred after first-line chemotherapy in all patients except two. Beyond the first-line protocols, only tumor stabilization was observed. In the literature, there is no consensus on a standard chemotherapy protocol and the only beneficial effect of chemotherapy in terms of survival has been demonstrated in one of three randomized studies using cisplatin [21, 22 et 23]. Very few studies have specifically examined second-line protocols. In two series reported, results were disappointing (0 and 8% objective response respectively) [24 et 25]. In a third, we obtained encouraging results with the gemcitabin-docetaxel combination after escape under cisplatin in a small number of selected patients [26]. In the absence of a consensual standard protocol, it appears advisable to propose inclusion in a prospective therapeutic trial. If such a trial is not available, and considering the current data in the literature [21, 22 et 23] and the limitations of our retrospective analysis, bitherapy, with or without cisplatin, could be proposed for patients with good prognosis, even though there are no current data on its potential impact on quality-of-life.

Toxicity attributable to treatment must remain low in these patients whose life expectancy rarely exceeds one year. For the “poor prognosis” patients, there is no evidence currently available demonstrating a clinical benefit of chemotherapy given as symptomatic treatment.

CUPs include a wide range of tumors with poorly elucidated biology. When revealed by a liver metastasis, it is advisable to perform a basic search for primary sites whose identification could have an impact on the therapeutic strategy and prognosis. The therapeutic decision remains difficult, but the use of prognostic models to select patients who could be expected to benefit from chemotherapy appears to be a logical solution. The decision requires a multidisciplinary collaboration, particularly for certain presentations such as unique or resectable liver metastases. The emergence of new molecular therapeutic targets such as tyrosine kinases and VEGF should offer new perspectives for these patients. Better knowledge of this heterogeneous group of carcinomas is indispensable before employing these new therapeutic targets alone or in combination with chemotherapy. Nevertheless, Fizazi et al. [27] reported over-expression of HER-2, EGFR and c-kit in less than 10% of CUP and an absence of correlation between this over-expression and differentiation, response to chemotherapy, and clinical outcome.

More widely, for patients with a suspected liver metastasis, the debate continues concerning the pertinence of upper and lower gastrointestinal endoscopy. A prospective trial would be useful to better determine the contribution of these invasive examinations. The study could be designed to undertake colonoscopy in patients with liver metastasis revealing a CK7-negative and CK20-positive adenocarcinoma.

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