Adjuvant therapy for patients with stage I papillary serous endometrial cancer

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Theodore Lawrence
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1 EJSO 32 (2006) For Debate Adjuvant therapy for patients with stage I papillary serous endometrial cancer A. Alobaid a, I. Bruchim b, H. Verkooijen c, P. Gauthier a, P. Petignat a,d, * a Gynecologic Oncology Service, Centre hospitalier de l Université de Montréal (CHUM), Hôpital Notre-Dame, Montreal, Que., Canada b Gynecologic Oncology Service, McGill University, Montreal, Que., Canada c Geneva Cancer Registry, Institute for Social and Preventive Medicine, Geneva University, Geneva, Switzerland d Gynecologic Oncology and Senology Service, University Hospitals of Geneva, Geneva, Switzerland Accepted 7 December 2005 Available online 18 January 2006 Abstract Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer characterized by a high recurrence rate and poor prognosis. Several studies have demonstrated that UPSC has a tendency to manifest with extra-uterine disease, even for tumors which appear to be limited to the endometrium. The data on adjuvant chemotherapy for stage I UPSC are limited, and the available studies are generally under-powered to assess if chemotherapy improves survival. However, we believe that, patients with UPSC should receive complete surgical staging, including omentectomy and peritoneal biopsies, and then until the results of larger series or randomized controlled trials will be available, we feel that combined radiotherapy and chemotherapy is justified for all stage I UPSC. q 2005 Elsevier Ltd. All rights reserved. Keywords: Adjuvant therapy; Early stage; Surgical staging; Papillary serous endometrial Introduction Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer characterized by a high recurrence rate and poor prognosis. UPSC represents 3 10% of all endometrial cancers, but accounts for 25% of the disease mortality. 1 3 Like papillary serous adenocarcinoma of the ovaries, UPSC has a tendency to spread over the peritoneal surfaces and, therefore, often presents at a more advanced stage at diagnosis than other uterine carcinomas. 4 Whereas 15 20% of patients with endometrial carcinoma have extrauterine disease at diagnosis, up to 87% of UPSC patients manifest with advanced disease. 5 7 As a result, the prognosis of UPSC compares unfavorably to the whole group of endometrial cancer. But even if we look at the different stages separately, UPSC behaves in a more aggressive manner. For patients with FIGO stage I disease (endometrial cancer limited to the uterus), overall 5-year * Corresponding author. Address: CHUM, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Que., Canada H2L 4M1. Tel.: C address: patrick.petignat@hcuge.ch (P. Petignat). survival is 80 90% for patients with endometrioid cancer compared to only 45 78% for UPSC patients (Table 1) Standard treatment for patients with stage I uterine cancer (except grade I endometrioid adenocarcinoma) includes pelvic washings, total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), pelvic (PLN) and para-aortic lymphadenectomy (PALN). 11 Until now, major controversy still exists over the optimal surgical and adjuvant treatment of stage I UPSC. For this debate, we conducted a search of the literature to identify all relevant articles published in the period 1966-September 2005 in Medline (PubMed, Ovid). We conducted a variety of searches using a combination of the following medical terms and MeSH headings: serous papillary and endometrial cancer and early stage. In addition, potentially relevant publications were identified from the reference lists of identified articles and from review articles. No attempt was made to identify unpublished studies. Variables of interest considered for the present debate were the surgical and adjuvant treatments of patients with stage I UPSC. The aim of our debate is to discuss the evidence available at the present time from the literature regarding the management of stage I UPSC. For this purpose the following questions will be addressed separately: /$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi: /j.ejso

2 A. Alobaid et al. / EJSO 32 (2006) Table 1 Survival rate in patients with FIGO stage I uterine papillary serous endometrial cancer treated by surgery (with or without adjuvant radiotherapy) Author (Ref.) Patients Adjuvant XRT Outcome Median FU Turner et al XRT GCHM 45 95% 5-year OS 47 months Huh et al GXRT 59 66% 5-year OS 30 months Slomovitz et al GXRT 62.9% 5-year OS NA Kwon et al XRT 78% 5-year OS 71 months Creasman et al GXRT 66 74% 5-year NA Kelly et al GXRT 5-year % DFS months Note: series with less than 20 patients have not been included. OS, overall survival; DFS, disease free survival; XRT, radiotherapy (including pelvic radiotherapy and/or whole abdominal radiotherapy and/or brachytherapy); CHM, chemotherapy for seven patients; NA, not available; meaning that specific data of these subgroups were not presented; FU, follow-up. (1) Is surgical staging essential for all patients with UPSC? (2) What defines adequate surgical staging? (3) What is optimal adjuvant therapy? (4) Should all patients with stage I disease receive adjuvant therapy? Is surgical staging essential for all patients with UPSC? Several studies have demonstrated the importance of complete surgical staging in apparently early stage disease. Goff et al. 7 observed extrauterine disease in 72% of 50 patients with clinical stage I UPSC at the time of surgery. Gehrig et al. 5 reported on a series of 16 patients with non-invasive tumours (apparent stage IA), and found that six had true stage IA, 10 had metastatic disease and two of them, have isolated omental disease. Chan et al. 12 performed complete surgical staging, including omentectomy, in 12 patients with non-invasive UPSC and noted that half of them had extrauterine disease. Moreover, in this study, 25% of the patients with no invasive uterine lesion and no intraoperative evidence of macroscopic omental involvement had microscopic isolated omental metastasis. 12 Slomovitz et al. 13 observed that 13 (38%) of 32 patients with UPSC superficial disease had extrauterine spreading. In 69% of these patients, the disease involved the omentum, and 19% had lymph-node metastases. Although all series had a limited number of patients, they clearly demonstrate that UPSC has a tendency to manifest with extrauterine disease, even for tumours which appear to be limited to the endometrium. Consequently, incomplete surgical staging would understage a significant number of UPSC patients, who would then be incorrectly managed as having stage I disease. What defines adequate surgical staging? As in epithelial ovarian cancer, microscopic omental or peritoneal implants may be the only evidence of extrauterine disease in UPSC. Therefore, UPSC patients should undergo similar surgical staging procedures as patients with ovarian cancer, and traditional endometrial cancer staging including peritoneal cytology, TAH, BSO, PLN and PALN, should be completed with omentectomy and multiple peritoneal biopsies. 6,12 The latter two procedures are easy to perform and carry a limited risk of surgical morbidity. At present, there is no evidence that complete surgical staging, including omentectomy and peritoneal biopsies, reduces mortality. However, until this evidence will be available, we believe that complete surgical staging should be performed, to define the extent of the disease and to correctly identify patients whose survival may be improved by adjuvant therapy. This information allows more appropriate patient counseling and permits the accurate identification of patients for participation in clinical trials. What is optimal adjuvant therapy? The role of adjuvant radiotherapy Radiotherapy is most commonly used for the adjuvant and salvage treatment of endometrial cancer. As UPSC has a propensity to recur in the upper part of the abdomen, whole abdominal radiotherapy has been investigated in a few reports. Kwon et al. 14 reported on 23 patients with stage I UPSC treated with abdominopelvic radiotherapy (only one patient received chemotherapy in addition to radiotherapy). After a median follow-up of 71 months, they found that 18 patients had no evidence of disease, one died of an unrelated cause, and four died of the disease. 14 As they did not include a control group (i.e. UPSC patients without radiotherapy), this report allows no definitive conclusions on the effectiveness of adjuvant radiotherapy for early stage UPSC. Lim et al. 15 described a retrospective series of 58 stage I III UPSC patients treated with adjuvant whole abdominal radiotherapy. The 5-year disease-specific survival of these patients was 75% compared to 41% (pz0.04) of 20 patients with no adjuvant treatment. 15 Steed et al. 16 retrospectively studied 108 patients with stage I III UPSC, who received either adjuvant whole abdominal radiotherapy (nz57), adjuvant whole abdominal radiotherapy and chemotherapy (carboplatin/paclitaxel) (nz19), chemotherapy alone (nz8) or no adjuvant treatment (nz24). After 3.6 years of follow-up, patients receiving whole abdominal radiotherapy showed a poorer

3 360 A. Alobaid et al. / EJSO 32 (2006) Table 2 Outcome and survival rate in patients with FIGO stage I uterine papillary serous endometrial cancer treated with adjuvant chemotherapy (with or without adjuvant radiotherapy) Author (Ref.) Study years Patients Adjuvant CHM Outcome Rosenberg et al XRTCP/E 8 NED (median FU 32 mo) Price et al XRTCP/A/C 6 NED (median FU 21 mo) Chambers et al P i.p./a/c No DOD (FU mo) Bancher-Todesca et al XRTCP or P/C 4 NED (median FU 39 mo) Turner et al XRTCP/A/C No DOD (FU NA) Huh et al GXRTCP/C or P/A or P/T 8 NED (mean FU 32 mo) Chan et al P/T or P/A 3 NED (FU ) Kelly et al GXRTCP of P/A or P/A/C 5-year 100% (FU mo) Low et al P/E or P/T or G/T 5-year 72% (median FU 28 mo) Note: P, platinum-based chemotherapy (including either cisplatin or carboplatin); C, cyclophosphamide; G, gemcitabine; T, taxane; A, doxorubicin; E, epirubicin; i.p., intraperitoneal; XRT, radiotherapy (including pelvic radiotherapy and/or whole abdominal radiotherapy and/or brachytherapy); DOD, died of disease; NED, no evidence of disease; FU, follow-up. survival over whole abdominal radiotherapy and chemotherapy (hazard ratio 6.1; 95% CI: ; pz0.02). The study suggests that combined radiotherapy and chemotherapy could be the most effective treatment option for this patient category. However, the number of patients investigated was limited, and, due to the nonrandomized design, selection bias might have influenced the results. In addition, the study provided no data on toxicity and long-term follow-up. It has been suggested that UPSC responds poorly to radiotherapy. Among patients with stage III or IV disease, who received curative treatment, recurrences in the treatment field are common. 14,17 Martin et al. 18 retrospectively studied the pathologic response rate in hysterectomy specimens of endometrial cancer patients who had undergone preoperative radiotherapy. They observed a complete pathologic response in 24 (39%) out of 62 specimens. However, none of the seven UPSC cases displayed a complete response, indicating that UPSC could be less radiosensitive than non- UPSC. 18 In short, the available literature suggests that adjuvant radiotherapy for stage I UPSC may contribute to improved local control (as in non-upsc), but there is still no proof that it increases survival. 16 The role of chemotherapy Chemotherapy for UPSC has been tested in several studies, but most of them included patients with metastatic or recurrent disease. Trials on the effectiveness of chemotherapy as adjuvant primary treatment for stage I UPSC are rare. Paclitaxel has been associated with favorable response rates either as a single agent or in combination with platinumbased chemotherapy. Zanotti et al. 19 performed a retrospective study of 24 UPSC patients treated with platinum-based chemotherapy and paclitaxel in an adjuvant setting or for recurrence. Eight patients had surgical stage I disease. The reported response rate was 89% (8/9) in patients treated for residual disease after initial surgery, and 64% (7/ 11) for those with recurrent disease, although more specific outcomes for the stage I subgroup were not presented. Rosenberg et al. 20 investigated the use of combination chemotherapy in eight clinical stage I patients after radical surgery; pelvic radiotherapy was followed by cisplatin/ epirubicin. No recurrences were seen at 32 months of followup (Table 2). Bancher-Todesca et al. 21 reported on four patients with clinical stage I UPSC given combination platinum-based chemotherapy and pelvic irradiation therapy. All patients were alive with no recurrences after a median follow-up duration of 39 months (Table 2). Low et al. 22 treated nine stage I patients with chemotherapy (cisplatin/epirubicin, carboplatin/paclitaxel or gemcitabine/ carboplatin) followed by pelvic and/or vaginal brachytherapy. Only 1 recurrence (lung) was reported after a median follow-up of 28 months (Table 2). 22 In summary, the data on adjuvant chemotherapy for stage I UPSC are limited, and the available studies are generally under-powered to assess if chemotherapy improves survival and which chemotherapeutic regimen is the most beneficial. Should all patients with stage I disease receive adjuvant therapy? Grice et al. 17 and Craighead et al. 23 suggested that surgical stage IA UPSC patients should not receive adjuvant treatment. However, as discussed above, several reports have pointed out that the lack of myometrial invasion does not necessarily correlate with the absence of tumour extension or metastasis. 3,7,24 Kelly et al. 3 defined two groups of stage IA disease: (i) patients with no cancer in hysterectomy specimens (defined as no residual uterine disease), and (ii) patients with cancer in hysterectomy specimens (defined as residual uterine disease). Stage IA patients with no residual uterine disease had no recurrences, regardless of adjuvant therapy (nz12). Among the patients with residual disease (nz13), six received chemoradiation (concomitant brachytherapy and platinum-based chemotherapy), and seven received adjuvant radiation or no therapy. No recurrence was observed in the first group, but two patients had recurrent disease in the second group. In a commentary by Zheng and

4 A. Alobaid et al. / EJSO 32 (2006) Schwartz, 25 one option is to treat all stage IA UPSC patients with chemotherapy (carboplatin/paclitaxel) and radiotherapy (vaginal cuff radiation), and patients whose hysterectomy specimens lack residual disease, no additional therapy. However, as reported recently in an editorial by Goff, the presence or absence of residual disease after endometrial biopsy is probably a function of the aggressiveness of pre-operative endometrial curettage rather than an independent prognostic factor of recurrence. 26 Discussion UPSC is associated with a high rate of recurrence compared to non-upsc after surgical treatment alone; therefore, the need for effective adjuvant therapy is apparent. However, currently, no randomized data have determined if adjuvant chemotherapy improves the outcome and what is the optimal adjuvant treatment. Unfortunately, in most published works there is imprecision in the proportion of patients who underwent complete surgical staging, and confusion about what should be considered as complete surgical staging. Some authors believe that complete staging includes standard endometrial staging, but for others, complete staging should also comprise omentectomy and randomized peritoneal biopsies. Therefore, it is possible that in some reports, occult stage IV may have been included as presumed stage I and, hence, under-evaluated the efficacy of adjuvant therapy. This paper illustrate that we urgently need appropriate powered, randomized, controlled trials with completely staged patients to determine the optimal adjuvant treatment for UPSC. However, due to the rareness of the disease, it will not be easy to recruit patients, and only multicenter trials will definitively define optimal adjuvant treatment of UPSC. Based on the available scientific evidence, we believe that, firstly, patients with UPSC should receive complete surgical staging, including omentectomy and peritoneal biopsies. Secondly, until the results of larger series or randomized controlled trials will be available, we feel that combined radiotherapy (pelvic or vaginal cuff) and chemotherapy (platinum-based and paclitaxel) is justified for all stage I UPSC. References 1. Rose PG. Endometrial Carcinoma. N Engl J Med 1996;335: Creasman WT, Odicino F, Maisonneuve P, Beller U, Benedet JL, Heintz AP, et al. Carcinoma of the corpus uteri. Int J Gynaecol Obstet 2003;83(Suppl 1): Kelly MG, O Malley DM, Hui P, McAlpine J, Yu H, Rutherford TJ, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol 2005;98: Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6: Gehrig PA, Groben PA, Fowler Jr WC, Walton LA, Van Le L. Noninvasive papillary serous carcinoma of the endometrium. Obstet Gynecol 2001;97: Podratz KC, Mariani A. Uterine papillary serous carcinomas: the exigency for clinical trials. Gynecol Oncol 2003;91: Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 1994;54: Creutzberg CL, van Putten WLJ, Koper PCM, Lybeert MLM, Jobsen JJ, Warlam-Rodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. Lancet 2000;355: Creasman WT, Kohler MF, Odicino F, Maisonneuve P, Boyle P. Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium. Gynecol Oncol 2004;95: Kelly MG, O Malley D, Hui P, McAlpine J, Dziura J, Rutherford TJ, et al. Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation. Gynecol Oncol 2004;95: ACOG practice bulletin, clinical management guidelines for obstetrician gynecologists, number 65, 2005: management of endometrial cancer. Obstet Gynecol 2005;106: Chan JK, Loizzi V, Youssef M, Osann K, Rutgers J, Vasilev SA, et al. Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium. Gynecol Oncol 2003;90: Slomovitz BM, Burke TW, Eifel PJ, Ramondetta LM, Silva EG, Jhingran A, et al. Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases. Gynecol Oncol 2003;91: Kwon J, Ackerman I, Franssen E. The role of abdominal-pelvic radiotherapy in the management of uterine papillary serous carcinoma. Int J Radiat Oncol Biol Phys 2004;59: Lim P, AlKushi A, Gilks B, Wong F, Aguino-Parson C. 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5 362 A. Alobaid et al. / EJSO 32 (2006) Carcangiu ML, Chambers JT. Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecol Oncol 1992;47: Zheng W, Schwartz PE. Serous EIC as an early form of uterine papillary serous carcinoma: recent progress in understanding its pathogenesis and current opinions regarding pathologic and clinical management. Gynecol Oncol 2005;96: Goff BA. Uterine papillary serous carcinoma: what have we learned over the past quarter century? Gynecol Oncol 2005;98: Turner BC, Knisely JP, Kacinski BM, Haffty BG, Gumbs AA, Roberts KB, et al. Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. Int J Radiat Oncol Biol Phys 1998; 40: Huh WK, Powell M, Leath 3rd CA, Straughn Jr JM, Cohn DE, Gold MA, et al. Uterine papillary serous carcinoma: comparisons of outcomes in surgical stage I patients with and without adjuvant therapy. Gynecol Oncol 2003;91: Price FV, Chambers SK, Carcangiu ML, Kohorn EI, Schwartz PE, Chambers JT. Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC). Gynecol Oncol 1993;51: Chambers JT, Chambers SK, Kohorn EI, Carcangiu ML, Schwartz PE. Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide. Gynecol Oncol 1996;60:

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