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Chemosensitivity in ovarian metastases from gastric cancer: A case series
Clinics and Research in Hepatology and Gastroenterology (2013) 37, 289—295
Available online at
www.sciencedirect.com
ORIGINAL ARTICLE
Chemosensitivity in ovarian metastases from gastric cancer: A case series Bertrand Brieau a, Hélène Roussel b, Theofano Markoutsaki a, Olivier Dubreuil a, Isabelle Trouilloud a, Bruno Landi a, Céline Lepère a, Jean-Nicolas Vaillant a, Anne Berger c, Philippe Rougier a, Julien Taieb a, Aziz Zaanan a,∗ a
Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes, 20, rue Leblanc, 75015 Paris, France b Department of Pathology, Georges Pompidou European Hospital, 20, rue Leblanc, 75015 Paris, France c Department of Digestive Surgery, Georges Pompidou European Hospital, 20, rue Leblanc, 75015 Paris, France Available online 9 November 2012
Summary The development of ovarian metastases from gastric cancer indicates a turning point of the disease progression and is usually associated with poor prognosis. Efficacy of modern chemotherapy protocols in ovarian metastases from gastric cancer is unknown. In this case series, we have evaluated the chemosensitivity of ovarian metastases from gastric cancer in eight consecutive patients treated in our institution between January 2000 and April 2012. Median age at gastric cancer diagnosis was 48.3 years and ovarian metastases were mainly metachronous (88%). Patients were treated with FOLFOX or FOLFIRI protocols in first-line and with EOX protocol in second-line chemotherapy. These protocols of chemotherapy used in firstand second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Mean overall survival (OS) from ovarian metastases diagnosis was 14.2 months. The four patients treated by bilateral oophorectomy had a longer mean OS (16 months) than the four patients who did not experienced surgery (12.3 months). In conclusion, this case series suggests that ovarian metastases from gastric cancer are less sensitive than extraovarian metastases to modern protocol of chemotherapy. To confirm these observations, a large retrospective study is ongoing. © 2012 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. Tel.: +33 1 56 09 50 64; fax: +33 1 56 09 50 69. E-mail address: [email protected] (A. Zaanan).
Krukenberg’s tumors are uncommon ovarian metastatic tumors from gastric cancer, which were initially described by Friedrich Ernst Krukenberg in 1896 [1]. Nowadays, the Krukenberg’s tumor is generally considered as a metastatic
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.09.007
290 carcinoma derived from a primary malignancy, usually from the gastrointestinal tract, and it represents approximately 18% of all ovarian cancers [2]. Several data suggested that ovarian metastases from gastrointestinal cancer were usually resistant to chemotherapy and causing frequent locoregional complications (mainly abdominal pain or bowel obstruction) and significantly impaired patient’s quality of life [3]. Gastric cancer remains the main providers of ovarian metastases more than colon and breast cancers and represents approximately 1 to 8% of primary lesions [4,5]. Ovarian metastases are associated with poor prognostic compared with other metastases sites in patients with gastric cancer. The median overall survival (OS) varies from 8 at 13 months after the diagnosis of ovarian metastases [6—8]. Unlike ovarian metastases from colon cancer, there is no data about chemosensitivity with modern combination drug regimen in ovarian metastases from gastric cancer. Likewise, there is neither consensus on the medical or surgical management for this tumor entity. This cases series illustrates the management of patients with ovarian metastases from gastric cancer treated in our digestive oncology department between January 2000 and April 2012. Patient files were retrieved on the one hand from clinical files of digestive oncology department and on the other hand from tumor registries of pathology departments and information system medical programs, using the following key words: ‘‘ovarian adenocarcinoma’’ and ‘‘gastric adenocarcinoma’’. A total of 218 patients with ‘‘ovarian adenocarcinoma’’ (n = 79) or with ‘‘gastric adenocarcinoma’’ (n = 139) were screened. Among these patients; we identified 8 patients with ovarian metastases from gastric cancer.
Case reports
B. Brieau et al.
Figure 1 Case 1: left and right ovarian metastases from gastric cancer before chemotherapy.
Case 1 A 51-year-old Moroccan woman was admitted in our department for melena. The upper-gastrointestinal endoscopy found an ulcer in the fundus and an infiltrated appearance of the gastric antrum suggestive of gastric linitis. Biopsies revealed a poorly cohesive carcinoma with signet ring cells component. The thoracic and abdominal CT-scan showed a diffuse metastatic lymph node and heterogeneous ovarian masses measuring 65 mm on the left and 52 mm on the right, suggesting a Krukenberg syndrome (Fig. 1). Chemotherapy was started with FOLFOX regimen (oxaliplatin: 85 mg/m2 in addition to simplified LV5FU2) that leads to a partial response after four cycles with a decrease of 45% of ovarian and lymph node metastases tumors according to the RECIST criteria (Fig. 2) [9]. After four new cycles of FOLFOX (without 5FU bolus because of a poor tolerance), there was a complete disappearance of mediastinal and retroperitoneal lymph nodes. The other target lesions were stable. She is currently pursuing the same protocol of chemotherapy.
Case 2 A 50-year-old Portuguese woman had an upper endoscopy for the investigation of abdominal pain and 10 kg weight
Figure 2 Case 1: ovarian metastases response tumour after eight cycles of FOLFOX chemotherapy.
loss. Endoscopic examination found a large gastric polypoid lesion, corresponding to a poorly cohesive carcinoma. CTscan did not reveal any distant metastasis. An exploratory laparoscopy was performed and found a diffuse peritoneal carcinomatosis. The patient was treated with FOLFOX regimen that leads, after four cycles, to a stabilization of gastric
Chemosensitivity of Krukenberg gastric tumor
291
and peritoneal tumors, and to an improvement of the performance status and 4 kg weight gain. However, there were new ovarian lesions on the CT-scan (5 cm on the right and 12 cm on the left). A bilateral oophorectomy was performed and pathological results confirmed the metastatic tumor from gastric cancer. Chemotherapy was continued after surgery with FOLFIRI regimen (irinotecan: 180 mg/m2 + simplified LV5FU2). A progression disease (PD) was observed after 30 cycles motivating a resumption of FOLFOX. Currently, the patient is still undergoing FOLFOX chemotherapy because of the stable disease.
Moreover, no other primary tumor was found and these lesions were considered as gastric cancer recurrence. The patient was treated with four cycles of LV5FU2 and cisplatin (50 mg/m2 ) (J1 = J14), followed by FOLFIRI because of poor tolerance of the first protocol. CT-scan evaluation was performed after six cycles of FOLFIRI and showed a SD. The patient refused further treatment and target lesions progressed after 10 months of therapeutic break. She was then lost to follow-up.
Case 3
A 41-year-old woman treated with an antiviral combination for HIV infection presented a poorly cohesive carcinoma with signet ring cells component of the gastric antrum. A gastrectomy was performed without adjuvant therapy. Recurrence disease with liver and lung metastasis was shown on the CT-scan performed 14 months after surgery. The patient was treated with 12 cycles of LV5FU2 + cisplatin (50 mg/m2 ) (J1 = J14) that leads to a SD. After 12 months of therapeutic break, CT-scan was performed because of a bowel obstruction, which showed a mass of 9 cm on the right ovary suggesting ovarian metastases, but the size of the lung and the liver lesions did not change. Laparotomy with histological analysis confirmed the Krukenberg syndrome and found a peritoneal carcinomatosis. No further chemotherapy was prescribed because of the poor postoperative general condition.
A 39-year-old Congolese patient had an endoscopy to investigate anemia and epigastric pain. We discovered a cardia localized gastric tumor without metastasis disease in CTscan. The lesion of the cardia corresponded to a poorly cohesive carcinoma with signet ring cells component. Gastrectomy was performed followed by chemoradiotherapy and chemotherapy (seven cycles of simplified LV5FU2) due to a localized peritoneal carcinomatosis discovered during surgery. Liver, lung and right ovarian metastases appeared in less than one month after the end of LV5FU2 chemotherapy. Thus, the patient was treated with FOLFIRI, followed by EOX (epirubicin: 50 mg/m2 , oxaliplatin: 130 mg/m2 and capecitabine: 625 mg/m2 × 2/d for 14 days; J1 = J21) due to PD after six cycles of FOLFIRI. After three cycles of EOX, CT-scan showed a stable disease (SD) of all lesions except a progression of ovarian metastases. Then, the patient received three cycles of docetaxel (75 mg/m2 ) + cisplatine (75 mg/m2 ) (J1 = J21), which was discontinued due to the deterioration of general condition.
Case 4 A 56-year-old woman was admitted to control gastric ulcer after endoscopic and medical treatment. The upper endoscopy discovered an antral tumor corresponding to a poorly cohesive carcinoma with signet ring cells component, associated with a peritoneal carcinomatosis on CT-scan. The patient was treated with palliative gastrectomy followed by FOLFIRI chemotherapy. A therapeutic break was performed after ten cycles of FOLFIRI because of SD. The CT-scan performed 3 months after the therapeutic break showed a PD with ovarian right metastasis of 9 cm. Despite the resumption of FOLFIRI, peritoneal and ovarian target lesions progressed on CT-scan after five cycles. Chemotherapy was discontinued due to the deterioration of general condition and a bowel obstruction.
Case 5 A 38-year-old patient had a gastric antrum cancer diagnosed after epigastric pain. Biopsies revealed a poorly cohesive carcinoma with signet ring cells component. The patient was treated with gastrectomy alone. Fourteen years later, CTscan demonstrated peritoneal carcinomatosis and bilateral ovarian masses. Oophorectomy was performed and pathological results were compatible with Krukenberg syndrome.
Case 6
Case 7 A 41-year-old patient was treated for gastric antrum ulcer due to an infection of Helicobacter pylori. Endoscopic control with biopsies at 2 months showed a persistent ulcer corresponding to a poorly cohesive carcinoma with signet ring cells component. There was no metastatic tumor on the CT-scan. Patient had a gastrectomy followed by adjuvant radiochemotherapy (45 Gy and seven cycles of LV5FU2). Nine months later, the patient was hospitalized for bowel obstruction revealing peritoneal carcinomatosis with bilateral ovarian metastases. A palliative bilateral oophorectomy was performed and pathological results confirmed the metastatic tumor from gastric cancer. The patient died four months later without any treatment.
Case 8 A 70-year-old patient without medical history presented a gastric tumor with linitic aspect revealed by weight loss. Pathological results showed a poorly cohesive carcinoma with signet ring cells component. CT-scan found a locoregional lymph node dissemination without any other metastatic lesions. A gastrectomy was performed after 3 months of FOLFOX chemotherapy. Fourteen months later, CT-scan revealed a peritoneal carcinomatosis with a left ovarian mass measuring 10 cm. The patient was treated with 17 cycles of FOLFIRI leading to a SD. Because of a poor tolerance, FOLFIRI was switched to FOLFOX chemotherapy. This protocol was stopped after one cycle because of an oxaliplatin allergic reaction. A therapeutic break was proposed and
292 six months later, a progression of peritoneal carcinomatosis was observed on CT-scan (ovarian mass was stable). A new chemotherapy regimen based on mitomycin C was started but currently it is too early to assess its efficacy.
Discussion In this case series, we observed that ovarian metastases from gastric cancer are poorly sensitive to modern chemotherapy regimen. Mean OS from ovarian metastases diagnosis was 14.2 months. Ovarian metastases chemosensitivity was evaluated for five patients, including one patient assessed for two lines of treatment (case 3). The diagnosis of Krukenberg syndrome was based on the histological results for patients who underwent ovarian surgery or on the clinical examination associated with abdominal and pelvic CT-scan for patients who did not undergo surgery. As proposed by the French recommendations of ‘‘Thesaurus National de Cancérologie Digestive’’ (http://www.tncd.org/) for advanced gastric cancer treatment, patients included in this case series were treated with FOLFOX regimen in first-line treatment [10] in two cases, FOLFIRI in first-line [11,12] in three cases, and EOX in second-line [13] in one case (Table 1). CT-scan evaluations showed discordant response in two cases with SD (in first-line FOLFOX and second-line EOX chemotherapy) for extraovarian metastases while ovarian metastases size increased (Table 1). In other cases, CTscan showed concordant evaluation results from ovarian and extraovarian metastases: PD for two cases (in first-line FOLFIRI chemotherapy), SD for one case (in first-line FOLFIRI chemotherapy) and objective response (OR) for one case (in first-line FOLFOX chemotherapy). In summary, for ovarian metastases, disease control rate (DCR) (DCR = OR + SD) was observed in two of five patients in first-line but not for the patient treated in second-line chemotherapy. In contrast, for extraovarian metastases, DCR was observed in three of five patients treated in first-line and for the patient treated in second-line chemotherapy. Thus, modern chemotherapy protocols used in first and second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Although this series was based on small number of patients, these results suggest that ovarian metastases are poorly sensitive to chemotherapy. Most studies have reported that ovarian metastases are less sensitive to chemotherapy than other metastatic lesions. These studies were limited by including Krukenberg tumors from various organs such as gastric, colon, rectal or breast cancers and evaluating them all together without any discrimination. Chemosensitivity of ovarian metastases specifically from gastric cancer was not or little evaluated. A retrospective study has evaluated the clinical outcome of 26 patients with Krukenberg syndrome and treated by bilateral oophorectomy associated with chemotherapy [14]. The primary tumor was identified in 20 cases, including 18 cases of gastric cancer. Protocols of chemotherapy were not specified but drugs used were 5-fluorouracil, cyclosphamide, adriamycin and cisplatin. Among the 26 patients treated with chemotherapy, authors observed no complete response and OR in eight cases. However, only eight patients had received chemotherapy before bilateral oophorectomy and response
B. Brieau et al. to chemotherapy in ovarian metastases was not specified. Another retrospective work has evaluated OS among 54 patients with exclusive ovarian metastases from gastric cancer. Of these patients, 33 underwent ovarian metastasectomy while 21 have been treated with either palliative chemotherapy (n = 16) or supportive care (n = 5). The median OS in the resection group was 17 months, which was significantly longer than in the non resection group (3 months) [8]. In the same perspective, Kobayashi et al. observed in a retrospective study of 21 patients with ovarian metastases from gastric cancer that oophorectomy increased OS compared to the no surgery group [15]. Authors of these studies suggested that bilateral oophorectomy for Krukenberg tumours from gastric cancer should be performing in absence of an obvious distant metastasis. In our case series, patients treated by oophorectomy had a longer mean OS (16 months) than patients who did not experienced surgery (12.3 months). In colorectal cancer, a monocentric retrospective study evaluated the chemosensitivity in 23 patients with ovarian metastases [16]. Chemotherapy treatment resulted in tumor control of measurable extraovarian metastases in 65% of cases. On the contrary, no OR of ovarian metastases was observed, SD was obtained in only three patients (13%), and PD or occurrence of new ovarian metastases were observed in 20 patients (87%). Because of chemotherapy resistance and symptoms induced by ovarian metastases, some authors suggested that surgical resection should always be considered for ovarian metastases from colorectal cancer, even in case of associated extra ovarian metastases [16—18]. Moreover, for patients with ovarian metastases from colorectal cancer, a retrospective study suggested that oophorectomy significantly prolonged OS compared to non-oophorectomy [19]. Interestingly, two retrospective studies showed that patients with Krukenberg tumors from colorectal cancer experienced a better benefit of oophorectomy than those from gastric cancer [6,20]. However, a prospective randomized trial included 155 patients with Dukes Stage B or C colorectal cancer failed to demonstrate any benefit of prophylactic oophorectomy on OS [21]. To date, there is no prospective study evaluated OS for patients treated by oophorectomy versus chemotherapy alone in ovarian metastatic treatment from gastric or colorectal cancer. Clinical characteristics of ovarian metastases from gastric cancer are not well known, but several features emerge in the literature. Li Qiu et al. resume the main characteristics of Krukenberg tumors from a retrospective study concerning 102 patients with gastrointestinal cancer [5]. The median age at diagnosis was around 40 years, with a majority of premenopausal status (about 80%). The main clinical characteristics were ascite, abdominal mass and change of bowel habits. Few patients were asymptomatic. The disease tended to be bilateral in approximately 70% of cases [5]. Otherwise, histological characteristics of gastric tumors with ovarian metastases were most frequently poorly differentiated with signet ring cells [15]. In our series, median age of gastric cancer diagnosis was 48.3 years and ovarian metastases were more often metachronous (88%) (Table 1). A majority of patients had a poorly cohesive carcinoma with signet ring cells component, including two patients with gastric linitis plastic (Table 1). Gastric linitis platic is defined by macroscopic aspect (diffuse and rigid infiltration of stomach associated with thickened gastric
Characteristics of eight cases of patients with ovarian metastasis from gastric cancer. Age at gastric cancer diagnosis (years)
Histological gastric tumor results
Ovarian metastasis
Protocol of chemotherapy
Ovarian tumor response
Extraovarian response tumor
Oophorectomy
Case 1
51
Synchronous
FOLFOX (L1)
OR
OR
No
6
Case 2
50
Metachronous
FOLFOX (L1)
PD
SD
Yes
18
Case 3
39
Metachronous
FOLFIRI (L1) EOX (L2)
PD PD
PD SD
No
10
Case 4
56
Metachronous
FOLFIRI (L1)
PD
PD
No
Case 5
38
Metachronous
—
—
—
Yes
16
Case 6
41
Metachronous
—
—
—
Yes
26
Case 7
41
Metachronous
—
—
—
Yes
4
Case 8
70
Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component
Metachronous
FOLFIRI (L1)
SD
SD
No
30
Survival from metastasis ovarian diagnosis (months)
Chemosensitivity of Krukenberg gastric tumor
Table 1
3.5
L1: first-line chemotherapy; L2: second-line chemotherapy; OR: objective response; PD: progression disease; SD: stable disease.
293
294 wall) and histological criteria (poorly cohesive carcinoma). The new nomenclature of gastric cancer in the last WHO classification, updated in 2010, defines the ‘‘poorly cohesive carcinoma’’ as a neoplastic cells that are isolated or arranged in small aggregates [22]. This entity could include a signet ring cells component, which is one of the variant, and corresponds to the previous description of ‘‘independent carcinoma’’, ‘‘poorly differenciated carcinoma’’, and ‘‘diffuse carcinoma’’, encountered in the literature [22]. Chemoresistance of Krukenberg syndrome was unclear justifying the term of ‘‘metastatic sanctuaries’’. Histological characteristic of gastric adenocarcinoma with signet ring cells confers a poor prognosis associated with higher rates of diffuse peritoneal carcinomatosis [23]. This pathological characteristic is also probably a predictive factor of chemotherapy resistance for gastric cancer [24]. Indeed, a large and recent retrospective study suggests that perioperative chemotherapy does not provide any survival benefits for patients who underwent surgery for gastric signet ring cell adenocarcinoma [24]. However, this observation does not explain why ovarian metastases would be more resistant to chemotherapy than other metastatic locations. Interestingly, some data suggested that primary cancer of ovary with mucinous histological subtype is more resistant to cytotoxic chemotherapy than other histological subtypes [25]. Likewise, ovarian metastases from gastric adenocarcinoma with signet ring cells, histologically defined as malignant cells containing intracytoplasmic mucins, could be less sensitive to chemotherapy like primary mucinous ovarian tumors. These observations suggest that ovarian mucinous tumors (primary or metastasis) have limited vascular penetration of systemic chemotherapy. In conclusion, we observed that ovarian metastases from gastric cancer appear to be poorly sensitive to modern protocol of chemotherapy. Surgical resection of ovarian metastases must be discussed even in the palliative setting. However, the published data are obviously not sufficient to recommend a specific medical or surgical management of Krukenberg tumor from gastric cancer. For this purpose, a large retrospective study is ongoing to evaluate the chemosensitivity and the clinical outcomes of patients treated with modern regimen of chemotherapy for ovarian metastases from gastric cancer.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Krukenberg FE. Fibrosarcoma ovarii mucocellulare (carcinomatodes). Arch Gynakol 1896;50:287—321. [2] Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol 1987;6:166—75. [3] Ayhan A, Guvenal T, Salman MC, Ozyuncu O, Sakinci M, Basaran M. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries. Gynecol Oncol 2005;98:235—41.
B. Brieau et al. [4] Petru E, Pickel H, Heydarfadai M, Lahousen M, Haas J, Schaider H, et al. Nongenital cancers metastatic to the ovary. Gynecol Oncol 1992;44:83—6. [5] Qiu L, Yang T, Shan XH, Hu MB, Li Y. Metastatic factors for Krukenberg tumor: a clinical study on 102 cases. Med Oncol 2011;28:1514—9. [6] Jiang R, Tang J, Cheng X, Zang RY. Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors. Eur J Surg Oncol 2009;35:92—7. [7] Kim HK, Heo DS, Bang YJ, Kim NK. Prognostic factors of Krukenberg’s tumor. Gynecol Oncol 2001;82:105—9. [8] Cheong JH, Hyung WJ, Chen J, Kim J, Choi SH, Noh SH. Survival benefit of metastasectomy for Krukenberg tumors from gastric cancer. Gynecol Oncol 2004;94:477—82. [9] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205—16. [10] Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26:1435—42. [11] Bouche O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study–FFCD 9803. J Clin Oncol 2004;22:4319—28. [12] Guimbaud R, Louvet C, Bonnetain F, Viret F, Samalin E, Gornet J. Final results of the intergroup FFCD-GERCORFNCLCC 03-07 phase III study comparing two sequences of chemotherapy in advanced gastric cancer. Ann Oncol 2010;21(Suppl. 8):abst8010. [13] Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36—46. [14] Savey L, Lasser P, Castaigne D, Michel G, Bognel C, Colau JC. Krukenberg tumors. Analysis of a series of 28 cases. J Chir (Paris) 1996;133:427—31. [15] Kobayashi O, Sugiyama Y, Cho H, Tsuburaya A, Sairenji M, Motohashi H, et al. Clinical and pathological study of gastric cancer with ovarian metastasis. Int J Clin Oncol 2003;8:67—71. [16] Goere D, Daveau C, Elias D, Boige V, Tomasic G, Bonnet S, et al. The differential response to chemotherapy of ovarian metastases from colorectal carcinoma. Eur J Surg Oncol 2008;34:1335—9. [17] Morrow M, Enker WE. Late ovarian metastases in carcinoma of the colon and rectum. Arch Surg 1984;119:1385—8. [18] Rayson D, Bouttell E, Whiston F, Stitt L. Outcome after ovarian/adnexal metastectomy in metastatic colorectal carcinoma. J Surg Oncol 2000;75:186—92. [19] Lee SJ, Lee J, Lim HY, Kang WK, Choi CH, Lee JW, et al. Survival benefit from ovarian metastatectomy in colorectal cancer patients with ovarian metastasis: a retrospective analysis. Cancer Chemother Pharmacol 2010;66:229—35. [20] Li WH, Wang HY, Wang J, Lv FF, Zhu XD, Wang ZH. Ovarian metastases resection from extragenital primary sites:outcome and prognostic factor analysis of 147 patients. BMC Cancer 2012;12:278. [21] Young-Fadok TM, Wolff BG, Nivatvongs S, Metzger PP, Ilstrup DM. Prophylactic oophorectomy in colorectal carcinoma: pre-
Chemosensitivity of Krukenberg gastric tumor liminary results of a randomized, prospective trial. Dis Colon Rectum 1998;41:277—83 [discussion 83—5]. [22] Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumors of the digestive system. 4th ed Lyon: IARC; 2010. [23] Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg 2009;250: 878—87.
295 [24] Messager M, Lefevre JH, Pichot-Delahaye V, Souadka A, Piessen G, Mariette C. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg 2011;254:684—93 [discussion 93]. [25] Hess V, A’Hern R, Nasiri N, King DM, Blake PR, Barton DP, et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004;22:1040—4.
Available online at
www.sciencedirect.com
ORIGINAL ARTICLE
Chemosensitivity in ovarian metastases from gastric cancer: A case series Bertrand Brieau a, Hélène Roussel b, Theofano Markoutsaki a, Olivier Dubreuil a, Isabelle Trouilloud a, Bruno Landi a, Céline Lepère a, Jean-Nicolas Vaillant a, Anne Berger c, Philippe Rougier a, Julien Taieb a, Aziz Zaanan a,∗ a
Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes, 20, rue Leblanc, 75015 Paris, France b Department of Pathology, Georges Pompidou European Hospital, 20, rue Leblanc, 75015 Paris, France c Department of Digestive Surgery, Georges Pompidou European Hospital, 20, rue Leblanc, 75015 Paris, France Available online 9 November 2012
Summary The development of ovarian metastases from gastric cancer indicates a turning point of the disease progression and is usually associated with poor prognosis. Efficacy of modern chemotherapy protocols in ovarian metastases from gastric cancer is unknown. In this case series, we have evaluated the chemosensitivity of ovarian metastases from gastric cancer in eight consecutive patients treated in our institution between January 2000 and April 2012. Median age at gastric cancer diagnosis was 48.3 years and ovarian metastases were mainly metachronous (88%). Patients were treated with FOLFOX or FOLFIRI protocols in first-line and with EOX protocol in second-line chemotherapy. These protocols of chemotherapy used in firstand second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Mean overall survival (OS) from ovarian metastases diagnosis was 14.2 months. The four patients treated by bilateral oophorectomy had a longer mean OS (16 months) than the four patients who did not experienced surgery (12.3 months). In conclusion, this case series suggests that ovarian metastases from gastric cancer are less sensitive than extraovarian metastases to modern protocol of chemotherapy. To confirm these observations, a large retrospective study is ongoing. © 2012 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. Tel.: +33 1 56 09 50 64; fax: +33 1 56 09 50 69. E-mail address: [email protected] (A. Zaanan).
Krukenberg’s tumors are uncommon ovarian metastatic tumors from gastric cancer, which were initially described by Friedrich Ernst Krukenberg in 1896 [1]. Nowadays, the Krukenberg’s tumor is generally considered as a metastatic
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2012.09.007
290 carcinoma derived from a primary malignancy, usually from the gastrointestinal tract, and it represents approximately 18% of all ovarian cancers [2]. Several data suggested that ovarian metastases from gastrointestinal cancer were usually resistant to chemotherapy and causing frequent locoregional complications (mainly abdominal pain or bowel obstruction) and significantly impaired patient’s quality of life [3]. Gastric cancer remains the main providers of ovarian metastases more than colon and breast cancers and represents approximately 1 to 8% of primary lesions [4,5]. Ovarian metastases are associated with poor prognostic compared with other metastases sites in patients with gastric cancer. The median overall survival (OS) varies from 8 at 13 months after the diagnosis of ovarian metastases [6—8]. Unlike ovarian metastases from colon cancer, there is no data about chemosensitivity with modern combination drug regimen in ovarian metastases from gastric cancer. Likewise, there is neither consensus on the medical or surgical management for this tumor entity. This cases series illustrates the management of patients with ovarian metastases from gastric cancer treated in our digestive oncology department between January 2000 and April 2012. Patient files were retrieved on the one hand from clinical files of digestive oncology department and on the other hand from tumor registries of pathology departments and information system medical programs, using the following key words: ‘‘ovarian adenocarcinoma’’ and ‘‘gastric adenocarcinoma’’. A total of 218 patients with ‘‘ovarian adenocarcinoma’’ (n = 79) or with ‘‘gastric adenocarcinoma’’ (n = 139) were screened. Among these patients; we identified 8 patients with ovarian metastases from gastric cancer.
Case reports
B. Brieau et al.
Figure 1 Case 1: left and right ovarian metastases from gastric cancer before chemotherapy.
Case 1 A 51-year-old Moroccan woman was admitted in our department for melena. The upper-gastrointestinal endoscopy found an ulcer in the fundus and an infiltrated appearance of the gastric antrum suggestive of gastric linitis. Biopsies revealed a poorly cohesive carcinoma with signet ring cells component. The thoracic and abdominal CT-scan showed a diffuse metastatic lymph node and heterogeneous ovarian masses measuring 65 mm on the left and 52 mm on the right, suggesting a Krukenberg syndrome (Fig. 1). Chemotherapy was started with FOLFOX regimen (oxaliplatin: 85 mg/m2 in addition to simplified LV5FU2) that leads to a partial response after four cycles with a decrease of 45% of ovarian and lymph node metastases tumors according to the RECIST criteria (Fig. 2) [9]. After four new cycles of FOLFOX (without 5FU bolus because of a poor tolerance), there was a complete disappearance of mediastinal and retroperitoneal lymph nodes. The other target lesions were stable. She is currently pursuing the same protocol of chemotherapy.
Case 2 A 50-year-old Portuguese woman had an upper endoscopy for the investigation of abdominal pain and 10 kg weight
Figure 2 Case 1: ovarian metastases response tumour after eight cycles of FOLFOX chemotherapy.
loss. Endoscopic examination found a large gastric polypoid lesion, corresponding to a poorly cohesive carcinoma. CTscan did not reveal any distant metastasis. An exploratory laparoscopy was performed and found a diffuse peritoneal carcinomatosis. The patient was treated with FOLFOX regimen that leads, after four cycles, to a stabilization of gastric
Chemosensitivity of Krukenberg gastric tumor
291
and peritoneal tumors, and to an improvement of the performance status and 4 kg weight gain. However, there were new ovarian lesions on the CT-scan (5 cm on the right and 12 cm on the left). A bilateral oophorectomy was performed and pathological results confirmed the metastatic tumor from gastric cancer. Chemotherapy was continued after surgery with FOLFIRI regimen (irinotecan: 180 mg/m2 + simplified LV5FU2). A progression disease (PD) was observed after 30 cycles motivating a resumption of FOLFOX. Currently, the patient is still undergoing FOLFOX chemotherapy because of the stable disease.
Moreover, no other primary tumor was found and these lesions were considered as gastric cancer recurrence. The patient was treated with four cycles of LV5FU2 and cisplatin (50 mg/m2 ) (J1 = J14), followed by FOLFIRI because of poor tolerance of the first protocol. CT-scan evaluation was performed after six cycles of FOLFIRI and showed a SD. The patient refused further treatment and target lesions progressed after 10 months of therapeutic break. She was then lost to follow-up.
Case 3
A 41-year-old woman treated with an antiviral combination for HIV infection presented a poorly cohesive carcinoma with signet ring cells component of the gastric antrum. A gastrectomy was performed without adjuvant therapy. Recurrence disease with liver and lung metastasis was shown on the CT-scan performed 14 months after surgery. The patient was treated with 12 cycles of LV5FU2 + cisplatin (50 mg/m2 ) (J1 = J14) that leads to a SD. After 12 months of therapeutic break, CT-scan was performed because of a bowel obstruction, which showed a mass of 9 cm on the right ovary suggesting ovarian metastases, but the size of the lung and the liver lesions did not change. Laparotomy with histological analysis confirmed the Krukenberg syndrome and found a peritoneal carcinomatosis. No further chemotherapy was prescribed because of the poor postoperative general condition.
A 39-year-old Congolese patient had an endoscopy to investigate anemia and epigastric pain. We discovered a cardia localized gastric tumor without metastasis disease in CTscan. The lesion of the cardia corresponded to a poorly cohesive carcinoma with signet ring cells component. Gastrectomy was performed followed by chemoradiotherapy and chemotherapy (seven cycles of simplified LV5FU2) due to a localized peritoneal carcinomatosis discovered during surgery. Liver, lung and right ovarian metastases appeared in less than one month after the end of LV5FU2 chemotherapy. Thus, the patient was treated with FOLFIRI, followed by EOX (epirubicin: 50 mg/m2 , oxaliplatin: 130 mg/m2 and capecitabine: 625 mg/m2 × 2/d for 14 days; J1 = J21) due to PD after six cycles of FOLFIRI. After three cycles of EOX, CT-scan showed a stable disease (SD) of all lesions except a progression of ovarian metastases. Then, the patient received three cycles of docetaxel (75 mg/m2 ) + cisplatine (75 mg/m2 ) (J1 = J21), which was discontinued due to the deterioration of general condition.
Case 4 A 56-year-old woman was admitted to control gastric ulcer after endoscopic and medical treatment. The upper endoscopy discovered an antral tumor corresponding to a poorly cohesive carcinoma with signet ring cells component, associated with a peritoneal carcinomatosis on CT-scan. The patient was treated with palliative gastrectomy followed by FOLFIRI chemotherapy. A therapeutic break was performed after ten cycles of FOLFIRI because of SD. The CT-scan performed 3 months after the therapeutic break showed a PD with ovarian right metastasis of 9 cm. Despite the resumption of FOLFIRI, peritoneal and ovarian target lesions progressed on CT-scan after five cycles. Chemotherapy was discontinued due to the deterioration of general condition and a bowel obstruction.
Case 5 A 38-year-old patient had a gastric antrum cancer diagnosed after epigastric pain. Biopsies revealed a poorly cohesive carcinoma with signet ring cells component. The patient was treated with gastrectomy alone. Fourteen years later, CTscan demonstrated peritoneal carcinomatosis and bilateral ovarian masses. Oophorectomy was performed and pathological results were compatible with Krukenberg syndrome.
Case 6
Case 7 A 41-year-old patient was treated for gastric antrum ulcer due to an infection of Helicobacter pylori. Endoscopic control with biopsies at 2 months showed a persistent ulcer corresponding to a poorly cohesive carcinoma with signet ring cells component. There was no metastatic tumor on the CT-scan. Patient had a gastrectomy followed by adjuvant radiochemotherapy (45 Gy and seven cycles of LV5FU2). Nine months later, the patient was hospitalized for bowel obstruction revealing peritoneal carcinomatosis with bilateral ovarian metastases. A palliative bilateral oophorectomy was performed and pathological results confirmed the metastatic tumor from gastric cancer. The patient died four months later without any treatment.
Case 8 A 70-year-old patient without medical history presented a gastric tumor with linitic aspect revealed by weight loss. Pathological results showed a poorly cohesive carcinoma with signet ring cells component. CT-scan found a locoregional lymph node dissemination without any other metastatic lesions. A gastrectomy was performed after 3 months of FOLFOX chemotherapy. Fourteen months later, CT-scan revealed a peritoneal carcinomatosis with a left ovarian mass measuring 10 cm. The patient was treated with 17 cycles of FOLFIRI leading to a SD. Because of a poor tolerance, FOLFIRI was switched to FOLFOX chemotherapy. This protocol was stopped after one cycle because of an oxaliplatin allergic reaction. A therapeutic break was proposed and
292 six months later, a progression of peritoneal carcinomatosis was observed on CT-scan (ovarian mass was stable). A new chemotherapy regimen based on mitomycin C was started but currently it is too early to assess its efficacy.
Discussion In this case series, we observed that ovarian metastases from gastric cancer are poorly sensitive to modern chemotherapy regimen. Mean OS from ovarian metastases diagnosis was 14.2 months. Ovarian metastases chemosensitivity was evaluated for five patients, including one patient assessed for two lines of treatment (case 3). The diagnosis of Krukenberg syndrome was based on the histological results for patients who underwent ovarian surgery or on the clinical examination associated with abdominal and pelvic CT-scan for patients who did not undergo surgery. As proposed by the French recommendations of ‘‘Thesaurus National de Cancérologie Digestive’’ (http://www.tncd.org/) for advanced gastric cancer treatment, patients included in this case series were treated with FOLFOX regimen in first-line treatment [10] in two cases, FOLFIRI in first-line [11,12] in three cases, and EOX in second-line [13] in one case (Table 1). CT-scan evaluations showed discordant response in two cases with SD (in first-line FOLFOX and second-line EOX chemotherapy) for extraovarian metastases while ovarian metastases size increased (Table 1). In other cases, CTscan showed concordant evaluation results from ovarian and extraovarian metastases: PD for two cases (in first-line FOLFIRI chemotherapy), SD for one case (in first-line FOLFIRI chemotherapy) and objective response (OR) for one case (in first-line FOLFOX chemotherapy). In summary, for ovarian metastases, disease control rate (DCR) (DCR = OR + SD) was observed in two of five patients in first-line but not for the patient treated in second-line chemotherapy. In contrast, for extraovarian metastases, DCR was observed in three of five patients treated in first-line and for the patient treated in second-line chemotherapy. Thus, modern chemotherapy protocols used in first and second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Although this series was based on small number of patients, these results suggest that ovarian metastases are poorly sensitive to chemotherapy. Most studies have reported that ovarian metastases are less sensitive to chemotherapy than other metastatic lesions. These studies were limited by including Krukenberg tumors from various organs such as gastric, colon, rectal or breast cancers and evaluating them all together without any discrimination. Chemosensitivity of ovarian metastases specifically from gastric cancer was not or little evaluated. A retrospective study has evaluated the clinical outcome of 26 patients with Krukenberg syndrome and treated by bilateral oophorectomy associated with chemotherapy [14]. The primary tumor was identified in 20 cases, including 18 cases of gastric cancer. Protocols of chemotherapy were not specified but drugs used were 5-fluorouracil, cyclosphamide, adriamycin and cisplatin. Among the 26 patients treated with chemotherapy, authors observed no complete response and OR in eight cases. However, only eight patients had received chemotherapy before bilateral oophorectomy and response
B. Brieau et al. to chemotherapy in ovarian metastases was not specified. Another retrospective work has evaluated OS among 54 patients with exclusive ovarian metastases from gastric cancer. Of these patients, 33 underwent ovarian metastasectomy while 21 have been treated with either palliative chemotherapy (n = 16) or supportive care (n = 5). The median OS in the resection group was 17 months, which was significantly longer than in the non resection group (3 months) [8]. In the same perspective, Kobayashi et al. observed in a retrospective study of 21 patients with ovarian metastases from gastric cancer that oophorectomy increased OS compared to the no surgery group [15]. Authors of these studies suggested that bilateral oophorectomy for Krukenberg tumours from gastric cancer should be performing in absence of an obvious distant metastasis. In our case series, patients treated by oophorectomy had a longer mean OS (16 months) than patients who did not experienced surgery (12.3 months). In colorectal cancer, a monocentric retrospective study evaluated the chemosensitivity in 23 patients with ovarian metastases [16]. Chemotherapy treatment resulted in tumor control of measurable extraovarian metastases in 65% of cases. On the contrary, no OR of ovarian metastases was observed, SD was obtained in only three patients (13%), and PD or occurrence of new ovarian metastases were observed in 20 patients (87%). Because of chemotherapy resistance and symptoms induced by ovarian metastases, some authors suggested that surgical resection should always be considered for ovarian metastases from colorectal cancer, even in case of associated extra ovarian metastases [16—18]. Moreover, for patients with ovarian metastases from colorectal cancer, a retrospective study suggested that oophorectomy significantly prolonged OS compared to non-oophorectomy [19]. Interestingly, two retrospective studies showed that patients with Krukenberg tumors from colorectal cancer experienced a better benefit of oophorectomy than those from gastric cancer [6,20]. However, a prospective randomized trial included 155 patients with Dukes Stage B or C colorectal cancer failed to demonstrate any benefit of prophylactic oophorectomy on OS [21]. To date, there is no prospective study evaluated OS for patients treated by oophorectomy versus chemotherapy alone in ovarian metastatic treatment from gastric or colorectal cancer. Clinical characteristics of ovarian metastases from gastric cancer are not well known, but several features emerge in the literature. Li Qiu et al. resume the main characteristics of Krukenberg tumors from a retrospective study concerning 102 patients with gastrointestinal cancer [5]. The median age at diagnosis was around 40 years, with a majority of premenopausal status (about 80%). The main clinical characteristics were ascite, abdominal mass and change of bowel habits. Few patients were asymptomatic. The disease tended to be bilateral in approximately 70% of cases [5]. Otherwise, histological characteristics of gastric tumors with ovarian metastases were most frequently poorly differentiated with signet ring cells [15]. In our series, median age of gastric cancer diagnosis was 48.3 years and ovarian metastases were more often metachronous (88%) (Table 1). A majority of patients had a poorly cohesive carcinoma with signet ring cells component, including two patients with gastric linitis plastic (Table 1). Gastric linitis platic is defined by macroscopic aspect (diffuse and rigid infiltration of stomach associated with thickened gastric
Characteristics of eight cases of patients with ovarian metastasis from gastric cancer. Age at gastric cancer diagnosis (years)
Histological gastric tumor results
Ovarian metastasis
Protocol of chemotherapy
Ovarian tumor response
Extraovarian response tumor
Oophorectomy
Case 1
51
Synchronous
FOLFOX (L1)
OR
OR
No
6
Case 2
50
Metachronous
FOLFOX (L1)
PD
SD
Yes
18
Case 3
39
Metachronous
FOLFIRI (L1) EOX (L2)
PD PD
PD SD
No
10
Case 4
56
Metachronous
FOLFIRI (L1)
PD
PD
No
Case 5
38
Metachronous
—
—
—
Yes
16
Case 6
41
Metachronous
—
—
—
Yes
26
Case 7
41
Metachronous
—
—
—
Yes
4
Case 8
70
Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component Poorly cohesive carcinoma with signet ring cells component
Metachronous
FOLFIRI (L1)
SD
SD
No
30
Survival from metastasis ovarian diagnosis (months)
Chemosensitivity of Krukenberg gastric tumor
Table 1
3.5
L1: first-line chemotherapy; L2: second-line chemotherapy; OR: objective response; PD: progression disease; SD: stable disease.
293
294 wall) and histological criteria (poorly cohesive carcinoma). The new nomenclature of gastric cancer in the last WHO classification, updated in 2010, defines the ‘‘poorly cohesive carcinoma’’ as a neoplastic cells that are isolated or arranged in small aggregates [22]. This entity could include a signet ring cells component, which is one of the variant, and corresponds to the previous description of ‘‘independent carcinoma’’, ‘‘poorly differenciated carcinoma’’, and ‘‘diffuse carcinoma’’, encountered in the literature [22]. Chemoresistance of Krukenberg syndrome was unclear justifying the term of ‘‘metastatic sanctuaries’’. Histological characteristic of gastric adenocarcinoma with signet ring cells confers a poor prognosis associated with higher rates of diffuse peritoneal carcinomatosis [23]. This pathological characteristic is also probably a predictive factor of chemotherapy resistance for gastric cancer [24]. Indeed, a large and recent retrospective study suggests that perioperative chemotherapy does not provide any survival benefits for patients who underwent surgery for gastric signet ring cell adenocarcinoma [24]. However, this observation does not explain why ovarian metastases would be more resistant to chemotherapy than other metastatic locations. Interestingly, some data suggested that primary cancer of ovary with mucinous histological subtype is more resistant to cytotoxic chemotherapy than other histological subtypes [25]. Likewise, ovarian metastases from gastric adenocarcinoma with signet ring cells, histologically defined as malignant cells containing intracytoplasmic mucins, could be less sensitive to chemotherapy like primary mucinous ovarian tumors. These observations suggest that ovarian mucinous tumors (primary or metastasis) have limited vascular penetration of systemic chemotherapy. In conclusion, we observed that ovarian metastases from gastric cancer appear to be poorly sensitive to modern protocol of chemotherapy. Surgical resection of ovarian metastases must be discussed even in the palliative setting. However, the published data are obviously not sufficient to recommend a specific medical or surgical management of Krukenberg tumor from gastric cancer. For this purpose, a large retrospective study is ongoing to evaluate the chemosensitivity and the clinical outcomes of patients treated with modern regimen of chemotherapy for ovarian metastases from gastric cancer.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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