Patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma.

ORIGINAL STUDY

Patterns of Recurrence and Role of Pelvic Radiotherapy in Ovarian Clear Cell Adenocarcinoma Bryan D. Macrie, MD,* Jonathan B. Strauss, MD,* Irene B. Helenowski, PhD,Þþ Alfred Rademaker, PhD,Þþ Julian C. Schink, MD,§ John R. Lurain, MD,§ and William Small, Jr, MD||

Objective(s): The aims of this study were to analyze patterns of recurrence in patients with ovarian clear cell adenocarcinoma (CCA) and to evaluate the role of pelvic radiotherapy (RT). Methods and Materials: All patients with ovarian CCA treated at a single institution between 1989 and 2012 were identified, and their medical records were reviewed. Eligibility criteria included histologic diagnosis of pure CCA of the ovary, surgical staging for International Federation of Gynecology and Obstetrics stage I-to-IIIC disease, and adjuvant or neoadjuvant chemotherapy. Selected end points were 3-, 5-, and 8-year cumulative incidence of pelvic recurrence (CIPR). Results: Fifty-six patients met eligibility criteria. Most received intravenous carboplatin and paclitaxel for a median of 6 cycles. Six patients (10.7%) received pelvic RT, and 50 (89.3%) did not. Pelvic RT patients had stage I-to-IIC disease. Median follow-up was 39 months (range, 1Y69 months). For the group as a whole, 14 patients (25%) had initial disease recurrence involving the pelvis, whereas 6 (10.7%) had first recurrence outside the pelvis. Three-, 5- and 8-year CIPR were 28.2%, 38.5%, and 43.2%, respectively. There was no significant difference in 3-, 5-, or 8-year CIPR between the group of patients receiving RT (20%, 20%, and 20%) and a group of patients with stages I to IIC who did not receive RT (9.9%, 22.4%, and 30.2%), P = 0.22. During RT, patients developed mild grade 1-to-2 side effects. After RT, 1 patient developed lower extremity lymphedema with recurrent cellulitis. One patient who developed small bowel obstruction before RT developed small bowel radiation enteritis and obstruction after RT, ultimately requiring surgical intervention. Conclusions: These findings suggest that ovarian CCA exhibits a propensity for pelvic recurrence after surgery and chemotherapy. RT, a local treatment that can effectively sterilize microscopic tumor cells, may benefit patients with this disease. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT. Key Words: Clear cell ovarian carcinoma, Adjuvant radiotherapy, Pelvic radiotherapy, Recurrence patterns Received June 17, 2014, and in revised form August 17, 2014. Accepted for publication August 19, 2014. (Int J Gynecol Cancer 2014;24: 1597Y1602)

*Department of Radiation Oncology and †Department of Preventive Medicine, Division of Biostatistics, Northwestern University Feinberg School of Medicine; ‡Robert H. Lurie Comprehensive Cancer Center and §Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Northwestern University Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000270 International Journal of Gynecological Cancer

Feinberg School of Medicine; ||Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago. Address correspondence and reprint requests to William Small Jr, MD, Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Cardinal Bernardin Cancer Center, 2160 S 1st Ave, Maguire Center, Rm 2932, Maywood, IL. E-mail: [email protected]. The authors declare no conflicts of interest.

& Volume 24, Number 9, November 2014

Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

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treatment of epithelial ovarian cancer (EOC) S tandard consists of comprehensive surgical staging, optimal

Confirmation of CCA histology was based on pathologic assessment of the tissue specimen obtained during primary surgical staging. As cell-type assignment after surgical debulking of ovarian surface epithelial carcinomas has been shown to be highly reproducible; no additional pathology review was performed for the purposes of this study.21 Dates of disease recurrence were determined by reviewing the treating physician’s written assessment of physical examination as well as laboratory and imaging findings during the follow-up period. A biopsy of recurrent disease was not required; however, equivocal imaging findings required confirmation with rising tumor markers or tissue diagnosis. Most recurrences were detected on surveillance computed tomography imaging of the chest, abdomen, and pelvis as new soft-tissue masses. For recurrences detected first by clinical examination or rising serum tumor markers, restaging scans were performed to identify all sites of recurrent disease. Pelvic recurrence was defined as disease recurrence occurring in a structure arising within the anatomic female pelvis. Multifocal recurrence was classified as a pelvic recurrence if any pelvic organ was involved. Time-to-recurrence was calculated from the date of completion of primary therapy to the date of pelvic disease recurrence, if applicable. Cumulative incidences of pelvic recurrence were estimated as described by Gooley et al22 with recurrence to other body sites treated as a competing risk. Cumulative incidence was compared between patients receiving and not receiving radiation therapy by the method of Gray.23 P values G 0.05 were considered significant.

METHODS AND MATERIALS

Between 1989 and 2012, 72 patients with CCA of the ovary were identified. Ten patients failed to meet eligibility criteria for the following reasons: the records of 3 patients were not available for review, 3 patients did not receive chemotherapy, 2 patients were inadequately staged, 6 patients had mixed CCA histology, and 2 patients presented with stage IV disease. In summary, 56 patients met study eligibility criteria; the characteristics of these patients are shown in Table 1. All patients received a platinum-based chemotherapy regimen except for 1 patient who received only intraperitoneal P-32. Most patients received combined intravenous carboplatin and paclitaxel. The median number of chemotherapy cycles was 6 (range, 3Y10). Forty patients (71.4%) underwent surgical assessment of lymph nodes (sampling or dissection). Six (10.7%) of the 40 patients with early-stage disease (IA-IIC) underwent adjuvant pelvic RT. Two patients received RT at other institutions, and details of their treatment were unavailable for review. The remaining 4 patients treated received 45 Gy in 25 fractions to the whole pelvis. After whole pelvic RT, 1 patient received a sequential 5.4-Gy boost in 3 fractions to a pelvic lymphocele. All patients received treatment with a 4-field technique and photon beams of 18-MV energy except for 1 patient who was treated to the pelvis with intensitymodulated RT using 6-MV energy photons. During pelvic RT, 3 patients developed grade 1 diarrhea, 1 patient developed grade 2 vulvar edema, and 1 patient developed grade 2 rectal and vaginal pain. After RT, 1 patient developed lower extremity lymphedema and recurrent cellulitis.

cytoreduction, and adjuvant platinum-based chemotherapy for stage IC and higher or high-grade stage IA to IB.1 Despite this intense therapeutic regimen, outcomes in ovarian cancer are relatively poor, and age-adjusted death rates from ovarian cancer have remained stable over time.2 As a result, ovarian cancer remains the fifth most common cause of cancer death in women.2 In many cancers, distinct biologic subtypes have been identified, and treatment has become individualized with respect to these subtypes. In EOC, treatment decisions typically reflect stage and grade only without consideration of histologic subtype. Clear cell adenocarcinoma (CCA) of the ovary is a distinct subtype of EOC that accounts for 5% to 10% of all ovarian cancers.3 By comparison with other EOC subtypes, it is characterized by gross confinement to the pelvis at diagnosis, more aggressive course, greater chemoresistance, and poorer prognosis.4Y8 Even in the setting of platinum-sensitive disease, recurrent ovarian CCA has a response rate to systemic therapy of less than 10%.9 Although recurrence patterns are established for the broader category of EOC,10Y14 limited data exist regarding tumor recurrence in ovarian CCA. Clarifying these patterns may guide new treatment strategies tailored to ovarian CCA. The role of radiotherapy (RT) in EOC is also currently poorly defined. Encouraging preliminary results for the use of RT in ovarian CCA have been reported.15Y20 The present study is a retrospective review of the patterns of tumor recurrence in patients with ovarian CCA treated at a single institution.

Patients The institutional tumor registry was used to identify all patients diagnosed with ovarian CCA seen in consultation between 1989 and 2012. For each patient, a comprehensive review of the medical record and pathology report was performed. Inclusion criteria included (1) a primary diagnosis of pure CCA of the ovary with International Federation of Gynecology and Obstetrics (FIGO) stage I-to-IIIC disease; (2) surgical staging including hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and omentectomy +/j lymph node sampling; and (3) use of adjuvant or neoadjuvant chemotherapy.

Evaluation of Acute and Late Toxicities Acute and late toxicities were graded using the Common Terminology Criteria for Adverse Events version 3.0.

Data Collection and Statistics Collected data included age at diagnosis, personal medical and surgical history, preoperative CA125, date and details of primary surgical staging, extent of residual disease, stage of disease based on 2009 FIGO criteria, histological subtype, tumor grade, type of adjuvant chemotherapy and dates of completion, details of RT if used and dates of completion, RT toxicities, date of disease recurrence or progression, site(s) of first recurrence, vital status at the date of last follow-up, and date of last contact or death.

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RESULTS

* 2014 IGCS and ESGO




TABLE 1. Patient characteristics Characteristic

Value

Age at diagnosis, years Median (range) Stage at initial diagnosis IA IC IIA IIB IIC IIIA IIIB IIIC Grade at initial diagnosis 1 2 3 Unknown Chemotherapy cycles Median (range)

51 (34Y76) 10 16 1 3 10 2 2 12 0 2 42 12 6 (3Y10)

One patient, who developed a small bowel obstruction while receiving adjuvant chemotherapy, experienced small bowel symptoms and repeat obstruction after RT requiring laparotomy, enterolysis, and resection of the ileum. Median follow-up was 39 months (range, 1Y269 months). Seven (17.5%) of the 40 early-stage (IA-IIC) patients and 7 (43.75) of the 16 advanced-stage (III) patients recurred. For the group as a whole, 8 patients (14.2%) recurred locally within the pelvis, and 6 patients (10.7%) experienced pelvic recurrence as a component of first failure. Six patients (10.7%) experienced a first recurrence outside the pelvis. One of the 6 patients receiving pelvic RT had a multifocal recurrence of disease involving the upper abdomen and pelvis. The remaining 5 RT patients had no evidence of disease at the last follow-up. Characteristics of the recurrences are described in Table 2, and the specific subsites of initial recurrence are listed in Table 3. For the group as a whole, cumulative incidence of pelvic recurrence (CIPR) at 3, 5, and 8 years was 28.2%, 38.5%, and 43.2%, respectively. There was no significant difference in 3-, 5-, or 8-year CIPR between the group of patients receiving RT (20.0%, 20.0%, and 20.0%) and a comparable group of stage I-to-IIC patients who did not receive RT (9.9%, 22.4%, and 30.2%), P = 0.22.

DISCUSSION In the present study, 7 (17.5%) of the 40 patients with FIGO IA-to-IIC disease and 7 (43.8%) of the 16 patients with FIGO IIIA-to-IIIC disease developed a tumor recurrence. Seven (87.5%) of the 8 early-stage recurrences and 7 (58.3%) of the 12 recurrences in advanced-stage patients involved the pelvis. There was a CIPR at 8 years of 43.2% for all patients, including 30.2% for stage I-to-IIC patients not treated with

Ovarian Clear Cell Carcinoma Recurrence

adjuvant pelvic RT compared with 20.0% for stage I-to-IIC patients treated with adjuvant pelvic RT. Our results are generally in agreement with recurrence rates from representative series of ovarian CCA shown in Table 4.24,25 Patterns of ovarian CCA recurrence from the British Columbia Cancer Agency database are described by Hoskins et al,20 who noted a pelvic component of first relapse after combined modality treatment in their series of 76% of all cases of recurrent disease. Representative EOC series are shown in Table 5.26 Rates of first recurrence involving the pelvis seen in this study are higher than those seen in earlystage EOC where initial failure more commonly occurs outside the pelvis (Table 5). This difference supports the concept that CCA of the ovary has a predilection for pelvic failure that exceeds that of other EOC histologies and is consistent with the observation that CCA often presents as a large pelvic mass without distant spread.6,27 In this series, the median time-to-recurrence for stage I-to-IIC patients was 33.4 months (range, 4.6-91 months). This finding is consistent with other series of ovarian CCA. A limited analysis of relapses in the British Colombia series showed a relapse-free interval of 26 months for IC and 18 months for IIC ovarian CCA patients treated with surgery and chemotherapy alone.28 Similarly, Sugiyama et al7 found a median time-to-recurrence of 12.2 months in patients with stage I/II ovarian CCA. These findings are also consistent with early-stage EOC studies where a median interval to recurrence of 11 to 29 months is described.10,29 Historically, ovarian cancers have been conceptualized as a single entity, and tumor cell type has not been used as a prognostic marker or a predictor of treatment efficacy. New data, however, suggest that tumor cell type defines biologically distinct entities within EOC. Kobel et al30 have demonstrated that a panel consisting of 3 immunohistochemical markers can reproducibly distinguish ovarian CCA from other subtypes.

TABLE 2. Details of recurrence Time to Recurrence (Months) Early Stage

Advanced Stage

Median (range)

33.4 (4.6Y91) 6.3 (1Y38.3) Recurrence by initial stage IA 2 IC 4 IIA 1 IIB 1 IIIA 1 IIIB 1 IIIC 10 Sites of first recurrence, n (%) Early Stage Advanced Stage Total Pelvic 5 (8.1) 3 (4.8) 8 (12.9) Pelvic + extrapelvic 2 (3.2) 4 (6.5) 6 (9.7) Extrapelvic 1 (1.6) 5 (8.1) 6 (9.7)



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TABLE 3. Subsites of initial recurrence Stage

Type of Initial Recurrence

IA IA IC IC

P P P PEP

IC IC

P PEP

IIA IIB IIIA IIIB IIIC IIIC IIIC IIIC IIIC IIIC

P EP EP EP EP P P PEP EP PEP

IIIC IIIC IIIC

PEP EP PEP

IIIC

P

Involved Subsites Pelvis, nonvaginal cuff Pelvis, nonvaginal cuff Pelvis, nonvaginal cuff Vaginal cuff, intraperitoneal chemotherapy port site Pelvis, nonvaginal cuff Vaginal cuff with diffuse involvement of peritoneum, liver serosa, omentum, mesentery Right iliac lymph nodes Liver dome, hepatic flexure Liver and omentum Liver, omentum, small bowel Para-aortic lymph nodes Iliac lymph nodes Pelvis, nonvaginal cuff Vaginal cuff and liver Unknown* Lungs, liver, pleura, diaphragm, spleen, pelvis (nonvaginal cuff ) Liver, vaginal cuff Liver Presacral lymph nodes, lower abdominal peritoneum Pelvis, nonvaginal cuff

*Recurrence diagnosis made outside the hospital; subsites are not available. P, pelvic only; EP, extrapelvic; PEP, pelvic and extrapelvic.


is especially chemoresistant. A subset analysis of GOG 157, a trial that randomized women with early-stage high-risk EOC to 3 versus 6 cycles of carboplatin and paclitaxel, found that additional chemotherapy conferred a lower risk for recurrence in serous carcinoma (hazard ratio, 0.33) but no risk reduction for CCA (hazard ratio, 0.90).32 Takano et al identified 219 patients with stage I ovarian CCA treated surgically, 195 of whom received adjuvant chemotherapy and 24 of whom declined chemotherapy. Although positive cytology was identified as a risk factor for recurrence on multivariate analysis, the receipt of chemotherapy had no prognostic value. Pectasides et al4 reported the experience of the Hellenic Cooperative Oncology Group, finding that patients with ovarian CCA had an overall response rate of 45% as compared with 81% in other histologic subtypes of EOC. Crotzer et al9 reported the experience of MD Anderson Cancer Center and found that most patients with ovarian CCA were resistant to first-line platinum chemotherapy and that these patients exhibited almost no response to gemcitabine in the second line. Similarly, Takano et al8 report that response rates for second-line chemotherapy in CCA are exceedingly low. In vitro analyses suggest that, although ovarian CCA is relatively insensitive to chemotherapy, it may be a radiosensitive tumor. Saga et al33 derived a new cell line (TAYA) from an ovarian CCA that showed a very high 50% growth inhibitory concentration to a variety of common chemotherapeutic agents. However, the same cell line revealed 50% growth inhibitory radiation dose of 1.8 Gy in culture. A similar in vitro analysis by Suzuki et al34 found a 50% growth inhibitory radiation dose of 1.2 Gy. Several clinical series have also demonstrated that adjuvant RT seems to be of greater value in ovarian CCA than EOC of other histologies. A review by Hoskins et al20 examined 241 patients with ovarian CCA treated with surgery followed by platinum-based chemotherapy (n = 125) or chemotherapy and abdominopelvic RT (n = 116). They identified no discernible difference in 5-year disease-free survival for patients with stages IA and IC (with capsule rupture) with the addition of RT. TABLE 4. Recurrence in early-stage ovarian CCA studies

Accurate identification of tumor subtype may be of considerable importance given data from Gilks et al suggesting that it is a more powerful prognostic marker than tumor grade.21 The biological underpinnings of the differences in clinical behavior between CCA and other EOCs are beginning to be elucidated. An in vitro analysis of ovarian tumor cells demonstrates that, unlike serous ovarian tumors, CCA cell lines remain attached to the mesothelial cell layer in an adhesive pattern whereas all other EOCs displayed an invasive growth pattern. In a murine model, the difference in adhesive versus invasive behavior correlated with a reduced tendency of CCA to disseminate throughout the peritoneum.31 These laboratory findings further suggest that the extent of disease in CCA of the ovary is more likely to be limited to the pelvis. As such, addressing the pelvic reservoir of disease may assume greater importance in treatment with curative intent. Ovarian CCA also differs from other EOC in its chemosensitivity. Many clinical series report that, among EOCs, CCA

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Author Sugiyama et al7

Timmers et al24 Hoskins et al20 Takano et al25 Present study

Stage (n)

Adjuvant Therapy

IAYC (49) CT II (10) CT III (31) CT IAYIIA (63) Observation or CT IAYIIC (125) CT IAYIIC (116) CT and WART I (195) CT I (24) Observation IAYIIC (40) CT and PRT* III (16) CT

Recurrence Rate, % 29 30 62 25.4 39.2 30.2 18.0 4 17.5 43.8

*Only 6 patients treated with RT. CT, platinum chemotherapy; PRT, pelvic RT.




Ovarian Clear Cell Carcinoma Recurrence


TABLE 5. Patterns of tumor recurrence in EOC studies Site of First Recurrence, n (%) Author Bolis et al12 Trope et al13 Trimbos et al14 Gadducci et al10 Gadducci et al11 Firat et al26

Subjects, Stage (n)

Adjuvant Therapy

Recurrence Rate, %

Pelvic

Pelvic and Extrapelvic

Extrapelvic

IAYIB (41) IAYIC (77) I (162) IYIIA (224) I (224) IIIYIV (192) IYIII (71)

CT CT Observation or CT CT Observation or CT CT WAR

17.1 15.6 24 18 17.4 48.9 47

2 (4.9) 6 (7.8) 6 (3.7) 14 (6) 10 (4.5) 45 (23.4) 4 (6)

Y Y Y 6 (3) 11 (4.9) Y Y

5 (12.2) 6 (7.8) 33 (20.3) 20 (9) 18 (8) Y Y

CT, platinum chemotherapy; WAR, whole abdomen RT.

However, for patients with stage II or IC (with cytologic positivity or surface involvement), there was an improvement in disease-free survival of 20% at 5 years with the addition of RT. Skirnisdottir et al15 treated 215 women with stage IA-to-IIC EOC with adjuvant whole abdominal or lower abdominopelvic RT after primary surgical tumor debulking. The subset of patients with CCA exhibited favorable 5-year cancer-specific survival rate of 80% compared with 68% for the cohort as a whole. Nagai et al16 compared the outcomes of a cohort of 16 women with ovarian CCA treated with whole abdomen RT (WAR) after surgery to historical controls treated with platinumbased chemotherapy. Five-year overall survival and disease-free survival in the women receiving WAR were 81.8% and 81.2% versus 33.3% and 25% in historical control patients (Ps = 0.031 and 0.006, respectively). Locoregional control was similarly24 superior after WAR; only 1 of the 16 women presented with a locoregional recurrence after WAR versus 7 of the 12 women after chemotherapy. Dinniwell et al18 reported a series of 29 patients with EOC treated with surgery and adjuvant carboplatin and paclitaxel chemotherapy followed by WAR. This treatment strategy resulted in 4-year disease-free survival in patients with CCA, endometrioid, or other nonserous histologies of 77% versus 27% in patients with serous histology (P = 0.01). Finally, case reports are available, which demonstrate long-term diseasefree survival in women with chemotherapy-insensitive recurrent ovarian CCA after salvage RT.17,34 In the present study, the use of pelvic RT yielded a trend toward reduction in CIPR at 5 and 8 years. Although by no means definitive, these data contribute to a growing body of literature supporting the clinical use of adjuvant RT in the management of ovarian CCA. Patients treated with RT in this study received 45 Gy to the whole pelvis, a dose that is commonly used to sterilize microscopic tumor in the treatment of many other pelvic malignancies. A 5.4-Gy boost was given to 1 patient with a lymphocele felt to be at risk for harboring additional disease. The authors feel that this approach to RT could be used in protocols that prospectively examine the value of adjuvant RT for CCA. The present study is a single-institution retrospective review, and consequently, there are caveats to the interpretation of these findings. Given the rarity of ovarian CCA, a 23-year period of review was required to optimize sample

size. Important advances in the treatment of EOC have been made during this time, and as a result, there was heterogeneity of surgical management and chemotherapeutic regimens. We consider this report to be hypothesis generating and await prospective validation of these findings.

CONCLUSIONS The present study suggests that ovarian CCA has a greater tendency to recur in the pelvis than other subtypes of EOC. These findings are consistent with other reports that ovarian CCA seems less prone to peritoneal dissemination, suggesting a role for RT in the management of ovarian CCA. Larger prospective studies assessing the role of RT in ovarian CCA are needed for the validation of these findings.

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