YGYNO-976452; No.

of pages: 6; 4C:
Gynecologic Oncology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

The effect of adjuvant radiation on survival in early stage clear cell

ovarian carcinoma
Liat Hogen a, Gillian Thomas b, Marcus Bernardini a,c, Dina Bassiouny d, Harinder Brar a, Lilian T. Gien a,e,
Barry Rosen a,c, Lisa Le f, Danielle Vicus a,e,⁎
a
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
b
Department of Radiation Oncology, Odette Cancer Centre, Toronto, Ontario, Canada
c
Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
d
Department of Anatomic Pathology, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada
e
Division of Gynecologic Oncology, Odette Cancer Centre, Toronto, Ontario, Canada
f
Department of Biostatistics, Princess Margaret Cancer Center, Toronto, Ontario, Canada

H I G H L I G H T S

• Clear cell carcinoma of the ovary is a rare subtype which is relatively resistant to platinum based chemotherapy.
• Ovarian clear cell carcinoma is frequently diagnosed at early stage, the role of adjuvant treatment is disputable.
• Our study did not demonstrate a survival benefit for adjuvant radiation in patients with ovarian clear cell carcinoma.

a r t i c l e i n f o a b s t r a c t

Article history: Objective. To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian
Received 5 June 2016 clear cell carcinoma (OCCC).
Received in revised form 27 August 2016 Methods. Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto,
Accepted 4 September 2016
between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates
Available online xxxx
were completed. The log-rank test was used to compare survival curves.
Keywords:
Results. 163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received ad-
Ovarian cancer juvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received
Clear cell carcinoma adjuvant CT and 36 had no adjuvant treatment. The 10 year progression free survival (PFS) was 65% for patients
Radiotherapy treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) pa-
Early stage tients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly
Survival associated with an increased PFS (0.85 (0.44–1.63) p = 0.63) or overall survival (OS) (0.84 (0.39–1.82) p = 0.66).
In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and
stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55–2.54) or O S(HR 1.04 (95% CI:
0.40–2.69)).
Conclusion. Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II
ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface in-
volvement and stage II patients.
© 2016 Published by Elsevier Inc.

1. Introduction incidence varies in different populations representing 3–12% of all ovar-

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian
cancer with distinctive histologic, molecular and clinical features. Its
⁎ Corresponding author at: Odette Cancer Centre, 2075 Bayview Ave., T2-018, Toronto,
Ontario, M4N 3M5, Canada.
E-mail address: danielle.vicus@sunnybrook.ca (D. Vicus).
ian cancers in North America but is far more common in Japan,
representing 20–25% of all ovarian cancers [1–6]. When compared to
the more common serous counterpart, it is frequently diagnosed at an
earlier stage; retrospective studies have shown between 47 and 81% of
OCCC are diagnosed at stage I or II [2,4,7–10].
Stage I OCCC has a relatively good prognosis with a 5-year overall
survival (OS) of 85%, and for stage IA the reported 5-year OS is

http://dx.doi.org/10.1016/j.ygyno.2016.09.006
0090-8258/© 2016 Published by Elsevier Inc.

Please cite this article as: L. Hogen, et al., The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma, Gynecol Oncol
(2016), http://dx.doi.org/10.1016/j.ygyno.2016.09.006
2 L. Hogen et al. / Gynecologic Oncology xxx (2016) xxx–xxx
approximately 90% [2,4,11]. The reported survival of stage IC is variable.
While patients with stage IC due to capsule rupture alone showed
poorer survival than stage IA, their survival was better than patients
with stage IC due to positive cytology or surface involvement. A 9-year
progression free survival (PFS) of 70.7% and OS of 78.9% were reported
in a subgroup of patients with stage IC capsule rupture; a better progno-
sis than that shown in stage IC positive cytology and/or ovarian surface
involvement with a reported 9-year PFS and OS of 56.6% and 61.3%, re-
spectively [12]. A more recent study from Memorial Sloan Kettering fur-
ther demonstrates the more favorable prognosis of stage IC rupture only
when compared to IC positive cytology, with a 3-year OS of 96.2% for the
former and 71.9% for the latter (p = 0.001) [13]. Several other studies
have also demonstrated positive cytology as an adverse prognostic fac-
tor [4,9,11,14,15].
There is a paucity of data on the effectiveness of adjuvant treatment
in OCCC and hence a lack of consensus regarding the optimal manage-
ment strategy in early stage disease. This has led to variations in the
use of adjuvant treatment including observation, chemotherapy (CT)
alone or multimodality treatment with chemotherapy and radiotherapy
(RT). [11,16–21] Traditionally, CT has been recommended for all pa-
tients with OCCC, despite the relatively favorable outcome and the rela-
tive chemoresistance to standard carboplatin based regimens. Reported
response rates to chemotherapy for women with OCCC range between
11% and 56%, compared to response rates of over 70% for patients
with serous ovarian cancer. [4,11,22–24] Combining the relative good
prognosis of stage I OCCC with its relative lack of sensitivity to plati-
num-based CT, Takano et al. suggested that there is only a “mild benefi-
cial effect” of adjuvant CT for stage I patients, with similar PFS and OS
rates in the CT versus no-adjuvant CT groups [11].
Epithelial ovarian cancer is known to be a radiosensitive tumor. The
benefit of adjuvant RT in patients with early-stage epithelial ovarian
cancer has been evaluated in a series of studies [25–27]. It has been sug-
gested that the addition of RT to CT for subsets of patients may have a
broader indication [20,28,29]. In the majority of studies looking at the
effectiveness of RT, all epithelial malignancies were included. However,
for clear cell carcinomas particularly, the beneficial effect of adjuvant RT
might be more pronounced due to its unique pattern of spread with the
majority of cases being confined to the pelvis and its relative resistance
to standard CT. Nagai and associates compared adjuvant platinum-
based CT to adjuvant whole abdominal radiation (WAR) alone in 28
women with stage I to III OCCC. [28] They found a significantly higher
five-year OS and PFS; with considerably improved local regional control
in the adjuvant RT arm. Dinniwell and associates performed a prospec-
tive study of 29 patients with stage I to III epithelial ovarian cancer com-
bining surgery, CT and WAR. The subset of 11 patients with clear cell
and 5 with endometrioid histologies showed the greatest gains from
this multimodality approach [29]. Finally, a retrospective study by
Swenerton et al. reported an improved survival in patients with stage
I and II clear cell, endometrioid, and mucinous histotypes with the addi-
tion of adjuvant WAR to CT [20]. This group further published in 2012 a
study on 241 stage I-II clear cell ovarian cancer patients comparing two
groups; those treated with adjuvant CT and RT and those treated with
CT only. They demonstrated a potential beneficial effect of WAR with
a 20% increase in PFS in a subset of early stage high-risk patients defined
as: stage IC positive cytology/surface involvement and stage II [21].
The primary objective of our study was to assess the impact of adju-
vant radiotherapy in stage I and II OCCC, and in a subset of early stage
high-risk patients, in a large, North American cohort; and to determine
whether our experience was in conjunction with the aforementioned
studies.
2. Methods:
209 patients with ovarian clear cell carcinoma (OCCC) were treated
or seen in consultation at one of two tertiary cancer centers in Toronto,
Canada. Of those, 71 patients with no macroscopic extra-ovarian spread
Please cite this article as: L. Hogen, et al., The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma, Gynecol Oncol
(2016), http://dx.doi.org/10.1016/j.ygyno.2016.09.006
underwent full surgical staging including; hysterectomy, bilateral
salpingo-oophorectomy, pelvic and para-aortic lymph node dissection
and omental biopsy. 11 patients were found to have positive lymph
nodes, however, in 4 out of the 11 there was also microscopic involve-
ment of the omentum. A total of 163 patients were found to have
stage I or II ovarian clear cell carcinoma (OCCC) and they are the subject
of this manuscript: 101 patients seen at Princess Margaret Cancer Cen-
ter treated between 1995 and 2014 and 62 patients at Sunnybrook
Health Sciences Center between 2000 and 2014. At Princess Margaret
Cancer Center, the institutional tumor registry was used to identify
the patients, and at Sunnybrook Health Sciences Center the patients
were identified using the pathology registry. For each patient, a compre-
hensive review of the electronic medical record was performed includ-
ing operative, pathology and radiology reports and outpatient clinic
notes. Only patients with pure ovarian clear cell carcinomas FIGO
stage I (confined to the ovary) or FIGO stage II (extra ovarian spread
confined to the pelvis) were included. A gynecologic pathologist
reviewed all slides. Patients with adhesions that were biopsied and
were negative for malignancy or if a biopsy was not taken from the ad-
hesions were considered as stage I rather than stage II.
The high-risk population was defined as patients with stage IC pos-
itive cytology, surface involvement or stage II. Patients identified as
stage IC based on rupture only in which cytology was unknown were in-
cluded in the low risk group; as were patients with stage IA/IB and un-
known cytology.
All patients underwent surgery: laparotomy, laparoscopy or robotic
assisted. Most surgeries included a hysterectomy, bilateral salpingo-oo-
phorectomy and omentectomy. Cytology, as well as lymph node dissec-
tion, was optional, and performed at the surgeon's discretion. When
performed, pelvic lymph node dissection included all lymph tissue sur-
rounding the external iliac, internal iliac and obturator vessels, from the
common iliac bifurcation to the circumflex iliac vein. The para-aortic
lymph node dissection included removal off all lymph barring tissue
surrounding the inferior vena cava and aorta, from the common iliac bi-
furcation to the origin of the renal vessels.
Adjuvant treatment differed according to the institutional guidelines
and physician preference. Chemotherapy was predominantly a plati-
num based doublet, with carboplatin (AUC = 5–6) and paclitaxel
(175 mg/m2) every 3 weeks, for 3–6 cycles. Radiation included pelvic
and/or WAR. The RT dosage and number of fractions were in keeping
with the standard protocols: abdominopelvic RT usually began 4–
6 weeks after chemotherapy, the parallel opposed pair technique was
used to deliver 2300 cGy in 100 cGy 23 daily fractions. Posterior kidney
shields were introduced at 1500 cGy to maintain the total kidney dose
at b 2000 cGy. No hepatic shielding was used. The pelvis received a con-
current boost of 1150 cGy in 23 fractions and a further 1050 cGy in 7
fractions after completion of the abdominal treatment. The total pelvic
dose was 4500 cGy in 150 cGy daily fractions. In cases of pelvic radiation
only, the four-field-box technique was used to deliver a total pelvic dose
of 4500 cGy, in 25 daily fractions of 180 cGy.
Not all patients with a pelvic mass that do not present with additional
symptoms undergo imaging for staging purposes prior to surgery at our
institutions. Post-operative imaging is left to the discretion of the treating
physician, however, the majority of patients either receive adjuvant
treatment or have assessment of their nodal status surgically. At time of
recurrence all patients are assessed with the most appropriate imaging.
Variables included in the univariate analysis were: age, stage, Asian
race, endometriosis, cytology, surgical staging, adjuvant chemotherapy
and adjuvant RT. In addition to adjuvant radiation, three pre-selected
variables: age, stage, and adjuvant CT were included in the multivariable
analysis.
3. Statistics
Patient demographics and baseline characteristics were summarized
using descriptive statistics. OS was calculated from the date of surgery
 L. Hogen et al. / Gynecologic Oncology xxx (2016) xxx–xxx 3

to the date of death or censored at the date of last follow-up. PFS was treatment. In the CT group, the median number of CT cycles was 6
calculated from the date of surgery to the date of recurrence or to the (range 2–8): 99 of 120 (82.5%) patients had 6 cycles of CT. There was
date of death; otherwise censored at the date of last follow-up. Recur- a higher rate of comprehensive surgical staging in those with no adju-
rence was determined based on either imaging and/or biopsy. OS and vant RT compared to those with adjuvant RT (40.3% vs. 20.5%, p = 0.03)
PFS probabilities were obtained using the Kaplan-Meier method and Baseline characteristics including age, stage, Asian race, endometri-
the log-rank test was used to compare survival curves. Univariate and osis, positive cytology and adjuvant CT were not found to differ between
multivariable analyses were performed using Cox proportional hazards patients treated to those not treated with adjuvant RT.
regression model. A p-value b 0.05 was considered statistically The median follow up time was 6.2 years (95% CI: 5.0–7.0 years).
significant. Rates of recurrence were not statistically different between the two
Research ethics board approval was obtained at both institutions groups; those that received adjuvant RT and those that did not. A total
prior to initiating the study. of 41 patients recurred; 29 of the 119 (24.3%) patients who were not
treated with adjuvant RT, and 12 of the 44 (27.2%) patients who were
4. Results treated with adjuvant RT. The median PFS for all patients was
13.9 years. (95% CI: 12.4 – NA). The 5-year PFS was 70% in both groups
163 patients with stage I or II ovarian clear cell carcinoma were in- (RT and no RT). The 10 year PFS was 59% (95% CI: 47–75%) in those not
cluded in our study. Patient demographics and baseline characteristics treated with adjuvant RT and 65% (95% CI: 51–84%) in those treated
are summarized in Table 1. The median age was 54.6 years; 58 patients with RT (Fig. 1). There was a total of 34 deaths; 25 (21%) in the no adju-
were stage IA, 3 patients stage IB, 87 stage IC and 15 stage II. vant RT group, and 9 (20.5%) in the RT group. 27 were disease specific
All patients underwent surgery. 152 patients underwent at least a deaths and 7 died without disease recurrence. Median OS for all patients
hysterectomy, bilateral salpingo-oophorectomy and omentectomy. 8 was 14.5 years (95% CI: 13.9–NA). The 5-year OS was 82% in those not
patients did not have an omentectomy and 3 patients had fertility spar- treated with adjuvant RT and 81% in those treated with RT. The
ing surgery, in which 2 retained their uterus and one ovary and one pa- 10 year OS was 70% in both groups (Fig. 2). 12/44 (27%) patients that
tient retained the uterus only. 95 (58%) had documented cytology were treated with RT recurred: 2 (16.5%) had a distant recurrence
(peritoneal washing or fluid). 80 (49%) patients had a lymph node dis- only, 2 (16.5%) had recurrence limited to para-aortic lymph nodes
section: 57 patients had comprehensive surgical staging which includ- only, 1 (8%) recurred only in the pelvis, and 7 (58%) had a pelvic and dis-
ed: a hysterectomy, bilateral salpingo-oophorectomy, omental biopsy tant recurrence. Total pelvic failure rate was 64%. 29/119 (24%) patients
and pelvic and para-aortic lymph node dissection, (at least unilateral). that had no-RT recurred: 12 (42%) had a distant recurrence only, 4
Patients that were found to have stage I disease after “comprehensive (14%) had recurrence limited to para-aortic lymph nodes only, 7
surgical staging” are referred to as “surgical stage I”. 23 patients had pel- (24%) recurred solely in the pelvis, and 6 (21%) recurred both distant
vic or para-aortic lymphadenectomy and were not considered “surgical- and in the pelvis. Total pelvic failure rate was 45%. This difference was
ly staged”. not found to be statistically significant (p = 0.24).
44 (27%) patients were treated with adjuvant RT and 119 (73%) had Three patients were lost to follow up after recurrence and were cen-
no adjuvant RT. Of the forty-four patients who received adjuvant RT: 20 sored at the analysis. Eleven patients were successfully treated at time
patients had pelvic RT, 8 patients had WAR and 15 patients had a com- of recurrence: 4 patients who received prior adjuvant RT and 7 who
bination of both treatments. Of the 44 patients that had adjuvant RT, 37 did not. Three patients were salvaged: two of them with RT (1 vaginal
(84.1%) also received CT, and 7 (15.9%) patients had RT only. Adjuvant vault recurrence and 1 pelvic recurrence), one with CT (complete re-
CT was administered in 120 (73.1%) patients: 37 in the RT group, and sponse of abdominal spread). Eight patients had multiple sites of dis-
83 in the no-RT group. 36 patients in our cohort received no adjuvant ease and a multimodality approach was applied with partial response,
they are alive with disease at the time of analysis. We calculated the
5-year PFS in subgroups by stage: there were 61 patients with stage
Table 1 IA/B, and 15 patients with stage IC rupture alone with confirmed nega-
Patient demographics and baseline characteristics.
tive cytology. Eight out of the 61 stage IA/B patients recurred; only 1 out
Variable All patients No adjuvant RT1 Adjuvant RT p value of the 8 patients who recurred (12.5%) had confirmed negative cytology.
N = 163 (%) N = 119 (%) N = 44 (%) The 5-year PFS in this group was 83%. 3 out of 15 (20%) patients
Age, in years 0.27
Median (range) 54.6(32.7–81.6) 54.7(32.7–81.6) 54.5(35.6–74.4)
St Stage 0.18
IA/IB 61 (37.4%) 47 (39.5%) 14 (31.8%)
IC 87 (53.4%) 61 (51.3%) 26 (59.1%)
II 15 (9.2%) 11 (9.2%) 4 (9.1%)
Asian 0.29
No 98 (72.1%) 72 (75.0%) 26 (65.0%)
Yes 38 (27.9%) 24 (25.0%) 14 (35.0%)
Adjuvant 0.07
chemotherapy
No 43 (26.4%) 36 (30.3%) 7 (15.9%)
Yes 120 (73.6%) 83 (69.7%) 37 (84.1%)
Endometriosis 0.37
No 36 (24.7%) 25 (22.5%) 11 (31.4%)
Yes 110 (75.3%) 86 (77.5%) 24 (68.6%)
Stage IC Cytology 0.24
status2
Negative 23 (26.4%) 18 (29.5%) 5 (19.2%)
Positive 29 (33.3%) 18 (29.5%) 11 (42.3%)
Pelvic and PA LND3 0.03
No 106 (65.0%) 71 (59.7%) 35 (79.5%)
Yes 57 (35.0%) 48 (40.3%) 9 (20.5%)
1
RT: radiotherapy.
2
% were calculated from total of 87 stage IC patients.
3
PA LND: Para-aortic lymph node dissection. Fig. 1. Kaplan-Meier plot of progression free survival by radiation treatment.

Please cite this article as: L. Hogen, et al., The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma, Gynecol Oncol
(2016), http://dx.doi.org/10.1016/j.ygyno.2016.09.006
4 L. Hogen et al. / Gynecologic Oncology xxx (2016) xxx–xxx

Fig. 2. Kaplan-Meier plot of overall survival by radiation treatment.
recurred in the IC confirmed negative cytology group, and 5-year PFS in
this subgroup was 75%. All 3 patients were not comprehensively staged.
The influence of various patient characteristics and adjuvant treat-
ments on progression free and overall survival was assessed and the
results are shown in Table 2. Stage (IA/IB versus IC/II), positive cytology
and adjuvant CT were significantly associated with a longer PFS on
univariate analysis; however, stage and adjuvant CT were the only sig-
nificant factors on multivariable analysis.
Furthermore, when assessing the influence of these factors on OS
only stage was found to be significant both on univariate and multivar-
iable analyses. Adjuvant RT was not associated with a difference in PFS
or OS.
In order to investigate the effect of CT, we further analyzed our pop-
ulation: There were 57 patients that had comprehensive surgical stag-
ing with confirmed surgical stage I. 30 of surgical stage I patients had
no adjuvant chemotherapy, 27 had adjuvant chemotherapy. We found
that for patients with surgical stage IA, adjuvant chemotherapy did
not significantly alter survival (5y PFS 100% vs 81%, p = 0.3; 5y OS
100% vs 89%, p = 0.36). However, for stage IC patients, chemotherapy
significantly improved OS, and there was a trend in PFS (5y OS 90% VS
48%, p = 0.04 and 5y PFS 82% vs 57%, p = 0.06).
Based on the results from previous studies, and aiming to better
comprehend the nature of disease and effect of RT in a “high risk popu-
lation”, we divided our cohort into two groups: “low risk cohort” includ-
ing stages IA/IB and IC rupture only (n = 104) and “high risk cohort”
including stage IC positive cytology and/or surface involvement and
stage II (n = 59) [20,21]. In the high-risk cohort, 20 (33.9%) patients
had adjuvant RT (16 patients were also treated with CT, and 4 patients
with RT only). 39 patients in this high-risk group did not receive RT
(34 patients were treated with CT alone and 5 patients had no adjuvant
treatment). In this high-risk group, there were a total of 22 (37.3%) re-
currences: 9 out of the 20 (45%) patients in the RT group recurred,
and 13 out of the 39 (33%) in the no-RT group recurred. The effect of
RT in this high-risk cohort was not found to be significantly associated
with recurrence or survival: PFS: HR 1.07 (95% CI: 0.47–2.43), OS: HR
0.81 (95% CI: 0.28–2.33).
In our series, we had 43 patients with stage IC based on rupture only.
However, only 15 of them had confirmed negative cytology. For the 15
that had stage IC with confirmed negative cytology, only 3 received ad-
juvant RT, none of the 3 recurred. 3 of the 12 (25%) patients that did not
have RT recurred, however, 2 of them did not receive adjuvant CT. No
inferences regarding the effect of RT can be made due to the limited
size of this subgroup.
In our cohort, there was diversity in treatments prescribed including
43 patients that did not receive adjuvant CT. Therefore, by excluding
these patients, we also calculated the effect of RT only in the 120 pa-
tients that had adjuvant CT; PFS and OS of 37 patients that had RT and
CT were compared to those of 83 patients that had CT only. We found
both PFS and OS not to significantly differ between the two groups, albe-
it; the numbers were small (PFS: HR 0.89 (95% CI: 0.41–1.93), p = 0.76,
OS: HR 1.07 (95% CI: 0.46–2.48), p = 0.88).
5. Discussion
In our study, we did not find a progression free or overall survival
benefit for adjuvant RT in patients with stage I or II clear cell ovarian
cancer. We also did not find a beneficial effect of adjuvant RT in a
“high-risk cohort” of 57 patients with stage IC positive cytology or sur-
face involvement and stage II disease.
The effect of adjuvant RT in ovarian clear cell carcinoma (OCCC) has
been previously described in retrospective studies, predominantly in
studies with a mixed patient population including both early and ad-
vanced stage patients. Nagai et al. showed an advantage in OS and PFS
for adjuvant RT in 16 OCCC patients, stage IC-III treated with WAR in
comparison to 12 patients from a historical cohort that received post-
surgical platinum based CT [28]. They reported a significantly improved
5-year OS in the RT group of 81.8% vs. 33.3% and improved 5-year PFS of
81.2% in the RT group vs. 25% in the CT group. However, in his cohort,
the numbers are very small, stages IA/IB were excluded and stage III
was included. Additionally, 5 year OS and PFS of the CT group were
33.3% and 24% respectively; considerably lower than expected for stages
IC-II. Swenerton et al. explored the influence of ovarian cancer histotype
on the effectiveness of adjuvant RT. [20] Out of 703 patients with epithe-
lial ovarian cancer in their study, 197 had stage I-III OCCC; 97 received
adjuvant CT and 100 were treated with a combination of CT and RT.
For those with apparent stage I and II tumors, the cohort including
375 patients with clear cell, endometrioid and mucinous subtypes
who were treated with a combination of CT and RT showed a 40% reduc-
tion in disease-specific mortality and a 43% reduction in overall mortal-
ity in comparison to those treated with CT only. This has influenced

Table 2
Univariable and multivariable analysis of overall and progression free survival.

Overall Survival Progression free survival

Variable Univariable Multivariable Univariable Multivariable

HR(95% CI) p-Value HR(95% CI) p-Value HR(95% CI) p-Value HR(95% CI) p-Value

Age 1.02 (0.99–1.05) 0.25 1.02 (1.00–1.05) 0.12

Stage IA/IB 0.40 (0.17–0.97) 0.04 0.36 (0.15–0.88) 0.03 0.36 (0.17–0.77) 0.009 0.33 (0.14–0.75) 0.009
Adjuvant CT* 0.65 (0.30–1.41) 0.28 0.56 (0.25–1.22) 0.14 0.40 (0.22–0.73) 0.003 0.35 (0.18–0.65) 0.001
Asian 0.82 (0.33–2.06) 0.67 0.86 (0.42–1.77) 0.68
EM` 1.70 (0.69–4.21) 0.25 1.22 (0.60–2.49) 0.58
Cytology, positive 1.46 (0.69–3.10) 0.32 1.97 (1.07–3.63) 0.03 1.73 (0.90–3.32) 0.10
Adjuvant Radiation 0.90 (0.42–1.93) 0.78 0.84 (0.39–1.82) 0.66 0.90 (0.48–1.71) 0.76 0.85 (0.44–1.63) 0.63
Staged^ 0.69 (0.31–1.52) 0.35 0.76 (0.40–1.43) 0.39

*CT = chemotherapy, ~EM = endometriosis, ^Staged = patients that had pelvic and/or para-aortic lymph node dissection.

Please cite this article as: L. Hogen, et al., The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma, Gynecol Oncol
(2016), http://dx.doi.org/10.1016/j.ygyno.2016.09.006
 L. Hogen et al. / Gynecologic Oncology xxx (2016) xxx–xxx
practice and provoked radiation oncologists to reconsider the role of ad-
juvant RT in women with ovarian cancer, a practice that had lost popu-
larity over the past two decades. However, as in all retrospective studies
this study has its limitations: the cohort included patients with clinical
stage I-II disease; the percentage of patients that underwent surgical
staging was not reported. The role of RT in this study is perceived to
be in the adjuvant setting but if an unknown percentage had retroperi-
toneal spread the actual question answered could be different. Further-
more, the reported incidence of clear cell histology in this study was
higher than expected in a North American population (28%) whereas
the serous subgroup comprised only 40% of the patient population, a
distribution similar to that expected in studies originating in Japan, po-
tentially limiting the generalizability of the results. Finally, the analysis
that showed improved survival with RT was calculated for clear cell,
mucinous and endometrioid together; hence the effect of RT specifically
on stage I-II clear cell ovarian carcinoma remains unknown. Hoskins et
al., the same group from British Columbia, Canada, retrospectively ana-
lyzed 241 patients with early stage OCCC, approximately half had 3 cy-
cles of adjuvant CT followed by RT, and half of the patients had 6 cycles
of adjuvant CT without RT. The clinical characteristics were generally
well balanced. By using a multivariate decision tree analysis, they iden-
tified cytologic positivity as the most important adverse factor, and sur-
face involvement in addition to cytologic positivity resulted in a
particularly poor outcome. While the decision tree analysis results dem-
onstrated an effect of RT in patients who were cytologically negative or
unknown, no benefit from RT in patients with stage IA or stage IC with
rupture only, (negative cytology and no surface involvement) was iden-
tified. They concluded that RT seemed to improve the outcome for some
of the patients with macroscopic or occult extraovarian spread (identi-
fied by positive cytology and/or ovarian surface involvement within
stage IC) , presumably those with spread limited to the pelvis.
In our study, RT was not found to improve survival (PFS or OS) in the
entire cohort or in a high risk cohort of patients defined similarly to the
description by Hoskins et al. [21].
The explanation for this discrepancy probably lies in a combination
of factors, such as the differences between the patient populations, sur-
gical aspects, variations in treatment protocols and unidentified con-
founders due to the retrospective nature of these studies. In the
Hoskins study, the treatment choices were made based upon different
policies at institutions contributing patients to the study cohort. This
could potentially reduce part of a confounding bias in their study. In
our series, the decision towards giving adjuvant radiation was based
upon the physician's preferences and this was found to be consistent
over time. Although there was not a uniform institution based protocol,
in one site more patients underwent comprehensive surgical staging
and received less adjuvant treatment; both CT and RT. There was not
an abrupt historical change in policy, with even distribution of patients
having adjuvant RT throughout the years. While this provides some ex-
planation towards the guiding principles towards patient selection for
adjuvant radiation, it cannot entirely exclude selection bias.
The Hoskins study results show that patients with both cytologic
and surface positivity have a very high chance of recurrence, and sug-
gested that RT improves the outcome for some patients in this group,
presumably those with their spread limited to the pelvis. In our cohort,
patients with “high risk” features did not seem to benefit from adjuvant
radiation. In the no-RT group, 33% recurred and in the RT group 45% re-
curred. (PFS: HR 1.07 (95% CI: 0.47–2.43), OS: HR 0.81 (95% CI: 0.28–
2.33)). However, the specific statistical model that Hoskins used to
identify patients at risk for only pelvic recurrence was not applicable
in our smaller cohort.
In our study, 35% of patients had confirmed early stage disease, and
half of the patients underwent at least a partial staging procedure. Fur-
thermore, in our cohort only 4 patients (2.5%) had residual disease at
the end of surgery as per the operative report, and in 4 (2.5%) cases doc-
umentation regarding the extent of disease at the completion of surgery
was missing. However, post-operative imaging was not mandated and
Please cite this article as: L. Hogen, et al., The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma, Gynecol Oncol
(2016), http://dx.doi.org/10.1016/j.ygyno.2016.09.006
5
left to the discretion of the treating physician. Previous studies have re-
ported that complete surgical resection to no residual macroscopic dis-
ease was the only independent prognostic factor, and that prognosis
was significantly inferior in those with OCCC and residual disease,
even if it was of small volume [11,30]. It is reasonable to hypothesize,
that in patients with postoperative residual disease, there may be a ben-
eficial effect from adjuvant radiation for local control.
Patterns of recurrence in OCCC patients have not been well de-
scribed. Jenison et al. described in 25 OCCC patients 40% with distant
organ involvement (liver, lung, bone, brain and others), 40% retroperi-
toneal and 72% with diffuse abdominal and peritoneal spread [31]. Our
data suggests a minority of recurrences localized to the pelvis, (8/41,
20%) potentially salvageable with RT. The majority of recurrences (33/
41, 80%) are multi-focal including distant. As such, adding postoperative
RT to the pelvis or even WAR, will most likely not prevent the distant
metastases nor improve the overall survival.
Our results suggest a potential benefit of adjuvant chemotherapy in
decreasing recurrence although this did not translate into an improved
overall survival (PFS: HR = 0.38, 95% CI 0.2–0.72, p = 0.004, OS: HR =
0.68, 95% CI 0.3–1.52, p = 0.34).
While OCCC is not as chemosensitive as the more common high-
grade serous ovarian cancer there is very limited data as to the actual
clinical benefit of chemotherapy in early stage OCCC patients. In
MITO9, a multivariable analysis showed that front-line chemotherapy
of cisplatinum with versus without taxane was not significant in im-
proving PFS or OS in stage I OCCC patients [32]. Takano et al., did not
demonstrate a benefit of chemotherapy in a retrospective series of
254 patients with surgical stage I OCCC, in which only 12 declined treat-
ment [18]. More data is needed to further clarify the benefit of adjuvant
chemotherapy in this patient population.
Our study has limitations, mostly due to its retrospective nature. It
covers a 20-year period, during which there were changes in adjuvant
CT and RT protocols as well as trends in the surgical approach. Although
the treatment groups were statistically similar, as patients were not ran-
domized we cannot exclude the possibility of selection bias. Further-
more, the number of patients that underwent comprehensive surgical
staging in the no-RT group was significantly higher than in those who
were treated with adjuvant RT (p = 0.03). This probably represents
more aggressive use of adjuvant treatment in those not fully staged.
When we looked at our database including all stages of OCCC we
found that 9.8% were upstaged from clinical stage I to surgical stage III
based on positive lymph-nodes only. (unpublished data). Hence we
can estimate that an out of the 35 patients in the radiation group that
were not fully staged, 3–4 patients probably had undetected stage III
disease. We also acknowledge that more patients in the radiation
group had positive cytology (42% vs 30%), albeit not statistically signif-
icant (p = 0.24). However, more patients in the RT group were given
adjuvant CT (84% vs 70%), and CT was shown to have a beneficial effect
on survival in our study population. While RT did not significantly effect
PFS or OS in our study, [HR 0.84 (0.39–1.82) and 0.85 (0.44–1.63)], we
do acknowledge that the numbers are limited and cannot exclude po-
tential benefit.
Despite these limitations, our study is a large cohort for this uncom-
mon disease, with only one previous study that assessed this question in
a similar cohort.
Based on the studies above, it seems that RT can be an effective treat-
ment modality for OCCC. However, the indications for adjuvant use of
this modality for early stage OCCC patients remain unclear and further
research is warranted to delineate the most appropriate treatment par-
adigm for this patient population.
Disclosures of potential conflicts of interest
Authors' disclosure of potential conflict of interest:
The authors indicated no potential conflicts of interest.
6 L. Hogen et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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