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Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer
YGYNO-976506; No. of pages: 6; 4C: Gynecologic Oncology xxx (2016) xxx–xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer Ja Young Kim a,1, Sang Jun Byun a,1, Young Seok Kim a,⁎, Joo-Hyun Nam b a b
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
H I G H L I G H T S • 60% of patients with residual tumor did not show further progression without salvage treatment. • The type of salvage treatment did not affect survival. • Initial and residual tumor sizes were significant prognostic factors for survival.
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Article history: Received 7 September 2016 Received in revised form 17 October 2016 Accepted 18 October 2016 Available online xxxx Keywords: Uterine cervical neoplasm Chemoradiotherapy Residual disease Magnetic resonance imaging
a b s t r a c t Objective. To investigate the disease course and identify prognostic factors for survival in patients with residual disease according to post-treatment magnetic resonance imaging (MRI) following definitive concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer. Methods. We reviewed clinical data from the medical records of 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics stage IB2–IVA uterine cervical cancer treated with CCRT. Post-treatment MRI was checked in all patients 3 months after CCRT completion. Out of the 545 patients, 53 with residual cervical cancer based on MRI following definitive CCRT were included in this analysis. Results. Thirty-two patients were disease-free at the last follow-up. Of them, 31 had a residual tumor size of ≤2 cm. Of these 32 women, 30 showed spontaneous regression of residual tumor during follow-up without salvage treatments, whereas the remaining two were alive with no evidence of disease after salvage surgery and chemotherapy. Disease progression was observed in 21 patients, including 7 local, 8 distant and 6 local and distant failures. Of these 21 women, 13 died of disease, 6 were alive with disease, and 2 remained diseasefree after salvage treatments. Initial and residual tumor sizes were significant prognostic factors for overall survival; only residual tumor size was significant for local progression-free survival. Conclusions. About 60% of patients with residual disease detected on post-treatment MRI remained diseasefree without further disease progression. Careful observation without immediate salvage treatments might be feasible in selected patients with a residual tumor size ≤2 cm. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Cisplatin-based concurrent chemoradiotherapy (CCRT) has become the standard treatment for bulky and locally advanced cervical cancer [1]. However, the disease course and appropriate salvage treatments of patients with residual cervical tumor following definitive CCRT
⁎ Corresponding author at: 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 Ja Young Kim and Sang Jun Byun contributed equally to this work and are considered co-first authors.
remain undefined. By reference to preoperative CCRT results due to a lack of reports after definitive CCRT, as many as 30%–65% of patients still have residual disease after preoperative CCRT [2,3]. Completion surgery following preoperative CCRT to eliminate potential residual disease and obtain better outcomes has been attempted, but the results did not indicate a survival benefit [4,5]. Another possible approach is additional chemotherapy, but its role also remains inconclusive [6]. Several imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), can be used to assess the tumor response after CCRT in cervical cancer. MRI is more effective than CT for evaluating the response and extents of disease after CCRT [7], and PET is more useful for measuring
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Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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tumor metabolism than MRI. However, the appropriate timing of the use of imaging modalities to evaluate the tumor response varies from 1 to 2 months after treatment completion, and PET is often done at 3 months post completion of treatment according to investigators at Washington university [3,8–10]. In our institution, pelvic MRI has routinely been performed as a baseline evaluation before CCRT, prior to brachytherapy, and at 3 months after the completion of CCRT. In the present study, the authors retrospectively reviewed the disease courses in women with residual disease detected by post-treatment MRI to compare the prognosis according to salvage treatment and to identify prognostic factors related to survival. 2. Methods From 1998 to 2013, 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IVA uterine cervical cancer were treated with curative radiotherapy (RT). Because 52 were lost to follow-up, post-treatment MRI data were available in 493 women. Of the 493 patients, 384 achieved a complete response, 13 had progressive disease outside of the RT field, and 96 had residual tumors. Of the 96 women with residual disease, 53 met the following inclusion criteria: (1) FIGO stage IB2–IVA invasive cervical cancer; (2) age 20–80 years; (3) cisplatin-based concurrent chemotherapy; and (4) pre-treatment work-up confirmation that the tumors were confined to the pelvic cavity with no evidence of distant metastases (including para-aortic lymph node metastasis). No patient underwent lymph node sampling or dissection prior to CCRT. This study was approved by the local institutional review board and informed consent was waived. Treatment details were summarized in a previous report [11]. In brief, planning CT was performed with each patient in the supine position with their arms on their chest using intravenous contrast agents and free breathing (AcQSim, Philips Medical System, Andover, MA and Light Speed RT, GE Healthcare, St. Giles, UK). Three-dimensional conformal RT to the pelvis was given with a daily fraction size of 1.8–2.0 Gy. After external beam radiotherapy (EBRT) of 45.0–50.4 Gy to the pelvis, patients received intracavitary brachytherapy (ICBT) twice a week using a 192Ir high-dose-rate brachytherapy unit (MicroSelectron, Nucletron, the Netherlands). In general, six sessions of ICBT were administered to point A, with a total dose of 30 Gy. During ICBT, additional 10–14 Gy of lymph node boosts for positive lymph nodes based on the pre-treatment MRI or a parametrial boost by EBRT with conventional fractionation were delivered, up to 60–65 Gy three times a week. For patients who could not receive ICBT, EBRT was boosted to the central lesion with 2.0 Gy daily, up to 66–74 Gy. ICBT was administered to 45 patients (84.9%); 8 did not undergo ICBT because of poor geometrical tumor coverage in 7 and history of uterine rupture in 1. The total radiation doses to point A in the 45 patients who received ICBT were 77.5–87.1 Gy (median, 84.5 Gy) and those to the primary tumor in 8 without ICBT were 66.0–74.0 Gy (median, 72.0 Gy) calculated to the equivalent dose in 2 Gy fractions. All patients concurrently received platinum-based chemotherapy as determined by the physician's preference. Weekly physical examinations, complete blood counts, and liver and renal function tests were performed during the RT and chemotherapy. When the absolute neutrophil count was b1000/mm3 or the platelet count was b100,000/mm3, treatments were delayed or halted until the patient's condition recovered. After treatment completion, all patients were evaluated by radiation oncologists and gynecologic oncologists at 3-month intervals for 2 years and every 6 months thereafter. The treatment response was assessed clinically and radiologically with pelvic MRI performed 3 months after the treatment. In contrast to the baseline MRI examination, intravenous contrast agent was not used on the follow-up MRI. T1, T2, and diffusion weighted sequences using body surface and/or endorectal coil were acquired on the post treatment MRI. Residual disease was defined as the lesion with higher signal intensity than surroundings on the T2 weighted
image by experienced radiologists. T1 and diffusion weighted images were used as supplementary sequences. Because all patients had residual disease based on post-treatment MRI, local progression was defined as further progression of the primary residual tumor compared with that on the 3-month follow-up MRI or any newly developed lesion within the pelvis, and distant metastasis was defined as recurrence outside the RT field. The first site of recurrence was recognized if local and distant metastases occurred simultaneously. Overall survival (OS) was calculated from the start of initial, definitive CCRT to death or last follow-up. Distant metastasis-free survival (DMFS) was counted from the start of initial, definitive CCRT to the verification of distant metastasis or last follow-up. Local progression-free survival (LPFS) was from the post-treatment MRI performed 3 months following CCRT to the identification of progressive local disease or a new lesion within the RT field or last follow-up. Patients who died with no evidence of treatment failure or who were lost to follow-up were censored at the date of death or their last follow-up. Survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used for multivariate analysis. A chi-square test was used to analyze the relationship between factors in two groups. We considered p-values b0.05 statistically significant. All statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL). 3. Results The characteristics of the 53 women analyzed in this study are listed in Table 1. Eight patients (15.1%) had non-squamous cell carcinoma: five had adenocarcinoma, one had adenosquamous, one had glassy cell carcinoma, and one had poorly differentiated carcinoma. The size of the primary tumor ranged from 2.7 to 10.0 cm (median, 5.0 cm). The characteristics of the residual disease based on post-treatment MRI are summarized in Table 2. The size of the residual tumor ranged from 0.3 to 4.6 cm (median, 1.4 cm). There was no significant relationship between the size of the initial tumor (≤6 cm vs. N 6 cm) and that of the residual tumor (≤2 cm vs. N 2 cm). With a median follow-up duration of 42 months (range, 8– 184 months), 32 out of the 53 patients were free of disease after CCRT. The residual tumor size was smaller than 2 cm in 31 of these 32 patients. Twenty-nine patients were just observed without any further treatment; all showed spontaneous regression of the residual tumor. At last follow-up, 27 patients were alive with no evidence of disease; the other 2 patients died due to other causes during observation, resulting in a 5-year OS rate of 88.9% without further salvage treatments. The remaining three underwent hysterectomy (n = 2) or hysterectomy followed by chemotherapy (n = 1). In the two patients who underwent hysterectomy only, one had no residual disease on pathologic examination and the other had a 0.8-cm-sized pathologically proven residual
Table 1 Patient characteristics. Variables Age, years Histology Primary tumor size, cm
FIGO stage
Pelvic node on initial MRI
No. of patients (%) Median (range) Squamous Non-squamous ≤5.0 N5.0 and ≤6.0 N6.0 IB2 IIA/IIB IIIA/IIIB IVA Positive Negative
54 (35–78) 45 (84.9) 8 (15.1) 29 (54.7) 13 (24.5) 11 (20.8) 4 (7.5) 1 (1.9)/30 (56.6) 1 (1.9)/6 (11.3) 11 (20.8) 24 (45.3) 29 (54.7)
FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
J.Y. Kim et al. / Gynecologic Oncology xxx (2016) xxx–xxx Table 2 Residual disease on post-treatment MRI. Variables
No. of patients (%)
Size of residual disease, cm
Residual pelvic node on MRI
≤1.0 N1.0 and ≤2.0 N2.0 Positive Negative
18 (34.0) 26 (49.1) 9 (17.0) 5 (9.4) 48 (90.6)
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for OS. These factors and their details are listed in Table 4. In multivariate analysis, among the prognostic factors with p ≤ 0.1 in univariate analysis for OS, initial tumor size (95% confidence interval, 0.07–0.72; hazard ratio, 0.22, p = 0.012) and residual tumor size (95% confidence interval, 0.08–0.86; hazard ratio, 0.26, p = 0.027) were statistically significant. Only residual tumor size (95% confidence interval, 0.03–0.39; hazard ratio, 0.10, p = 0.001) remained significant in multivariate analysis for LPFS.
MRI, magnetic resonance imaging.
4. Discussion disease but had no evidence of disease at last follow-up. The remaining patient who underwent surgery followed by chemotherapy is also alive with no evidence of disease. Disease progression was observed in 21 (39.6%). Of the 21 patients with disease progression, 15 developed within 1 year from the initiation of treatment and the residual tumor size was larger than 2 cm in 8 of the 21 patients. Seven patients (13.2%) had local progression only, another eight (15.1%) had distant progression only, and six (11.3%) had both local and distant. Of the 7 patients with local progression only, all showed the local failure in their primary tumors and the disease courses of the seven patients are summarized in Table 3. Of the seven patients with local progression only, one (No. 4) showed second local recurrence, 5 months after salvage surgery. In the two patients who underwent both salvage surgery and chemotherapy, one patient (No. 5) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, six cycles of chemotherapy, and remained disease-free for 9 months until recurrence at the stump was found, which was salvaged again. The other patient (No. 3) died due to rapid local progression despite total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by five cycles of chemotherapy. Finally, there were 15 (28%) patients who died during the follow-up periods including 2 patients who died without evidence of cervical cancer. Of remaining 13 patients, 3 showed local progressions, 5 distant metastases and 6 local and distant progressions in spite of systemic chemotherapy. There was no statistically significant difference in OS according to the type of salvage treatment in patients with further local progression (p = 0.942). Six patients had both local progression and distant metastasis: one underwent salvage radiotherapy to lesions in the pelvic wall and para-aortic lymph node area with chemotherapy including gemcitabine and cisplatin and remained with no evidence of disease for 79 months; the other five died of the disease progression without any salvage treatments (n = 2), with salvage chemotherapy (n = 2), and with salvage surgery followed by chemotherapy (n = 1). Of the 21 patients with local or distant progression, 13 (61.9%) died of disease, 6 (28.6%) were alive with disease, and the remaining 2 (9.5%) remained disease free. Of the 13 patients who died of disease, 10 (76.9%) had distant failures. The 3-year OS, LPFS, and DMFS rates were 76.3%, 74.6%, and 74.9%, respectively (Fig. 1 (a)). In univariate analysis, patient age, initial hemoglobin level, initial and residual tumor size, initial and post-treatment pelvic lymph node status, and ICBT were significant prognostic factors
In the present study, we analyzed the disease courses and patterns of failure in cervical cancer patients with residual disease on post-treatment MRI, finding that about 60% of patients remained progression free. In patients with disease progression after CCRT, the incidences of local and distant progression were similar. Furthermore, more than half of further disease progression occurred within 1 year from the initial CCRT. Although salvage surgery may be helpful to evaluate pathologic diagnosis as well as to eradicate residual tumor, it seems that careful observation without immediate salvage treatments is a feasible option in selected groups, specifically patients with residual tumor size ≤2 cm. Based on our results, use of salvage surgery may also not be appropriate for patients with residual tumor larger than 2 cm because these tumors tend to show rapid progression or recurrence and metastasis to distant sites. For patients with local progression only, there was no statistically significant difference among the types of salvage treatments. The most significant prognostic factors for survival were the sizes of the post-treatment residual disease and the primary disease on MRI. The few studies to perform MRI evaluation of residual disease after CCRT found that the diagnostic performance of post-treatment MRI was not satisfactory [3,9,12]. Hequet et al. [3] evaluated the impact of residual disease after CCRT in 144 locally advanced cervical cancer patients. They assessed residual disease with clinical examination and pelvic MRI 4 to 6 weeks after CCRT completion and compared the findings with the pathologic results of completion surgery 8 to 10 weeks after CCRT. MRI showed worse sensitivity (77.8%) and specificity (41.7%) than pathologic examination. Another study assessing residual disease in 44 cervical cancer patients showed that the sensitivity and specificity of residual tumor evaluation were 80% and 55%, respectively [9]. In that study, MRI evaluations were performed between 3 and 8 weeks after radiotherapy completion. For the better evaluation of post-treatment status, functional methods such as PET and diffusion-weighted MRI have been widely investigated as noninvasive tests [13]. Because PET maps tumors based on their need for constituents to maintain growth and increased metabolism, PET scans after RT could supplement the weak point of MRI in terms of low specificity, therefore, could provide better diagnostic performance than MRI or CT in the context of defining tumor viability. Diffusionweighted MRI is also sensitive to the motion of water molecules and reflects water diffusion properties of the specific tissue [14]. It has been reported that the apparent diffusion coefficient of tumors increases after effective treatment, which is associated with lowered
Table 3 Disease courses of seven patients with local progression only. Patient no.
Time to progression
Salvage treatment
Response
Status (M)
1 2 3 4 5 6 7
3 3 8 3 3 3 3
Chemotherapy Chemotherapy Hysterectomy, chemotherapy Hysterectomy Hysterectomy, chemotherapy Chemotherapy Chemotherapy
DP DP DP Second local recurrence, 5 M after salvage surgery Second local recurrence, 9 M after salvage surgery PR PR
Died of disease (13 M) Died of disease (23 M) Died of disease (10 M) Alive with disease (8 M) Alive with disease (35 M) Alive with disease (9 M) Alive with disease (15 M)
M M M M M M M
M, month; DP, disease progression; PR, partial response.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Table 4 Univariate analysis of prognostic factors for OS, LPFS, and DMFS. Variables Age Hydronephrosis Initial HGB Initial tumor Initial pelvic lymph node ICBT Residual tumor Post-RT pelvic LN
b55 ≥55 Absent Present ≤11.0 g/dL N11.0 g/dL ≤6 cm N6 cm Absent Present Yes No ≤2 cm N2 cm Absent Present
No. (%)
3 Y OS
p-Value
3 Y LPFS
p-Value
3 Y DMFS
p-Value
28 (52.8) 25 (47.2) 40 (75.5) 13 (24.5) 20 (37.7) 33 (62.3) 42 (79.2) 11 (20.8) 24 (45.3) 29 (54.7) 45 (84.9) 8 (15.1) 44 (83.0) 9 (17.0) 48 (90.6) 5 (9.4)
69.7% 83.3% 81.4% 60.6% 60.0% 86.7% 84.9% 40.9% 87.1% 66.9% 77.4% 66.7% 83.6% 33.9% 76.6% 66.7%
NS
70.4% 79.1% 77.1% 69.2% 68.6% 78.3% 80.5% 53.0% 95.8% 57.3% 81.8% 37.5% 88.5% 11.1% 80.9% 20.0%
NS
63.4% 87.8% 76.7% 69.2% 54.0% 87.8% 83.0% 45.5% 79.2% 70.7% 75.1% 75.0% 77.1% 66.7% 74.6% 80.0%
0.044
0.075 0.035 b0.001 NS NS 0.005 NS
NS NS 0.018 0.002 0.005 b0.001 0.002
NS 0.009 0.006 NS NS NS NS
Y, year; OS, overall survival; LPFS, local progression-free survival; DMFS, distant metastasis-free survival; NS, not significant; HGB, hemoglobin; ICBT, intracavitary brachytherapy; RT, radiotherapy; LN, lymph node.
tissue cellularity and cell membranes disintegration, resulting in changes in water molecular mobility [15]. The presence and size of residual disease have been identified as prognostic factors for disease-free survival and OS [2–4,16–18]. In a prospective study of 184 patients with locally advanced cervical cancer treated with CCRT, the investigators observed that patients with no residual disease had a significantly longer disease-free survival than patients with microscopic or macroscopic disease after completion surgery [2]. Hequet et al. and Touboul et al. also reported that patients with pathologic residual disease larger than 10 mm had poorer disease-free survival and OS [3,19]. In our results, about 71% of patients with residual tumor size ≤ 2 cm had no further disease progression, whereas just 11% of the patients with residual tumor N2.0 cm had no further progression. In our study, the only significant prognostic factor for local recurrence was residual disease N 2.0 cm on MRI and the only factor correlating with residual disease N 2.0 cm was use of ICBT, suggesting that a higher RT dose to the tumor is important for local control. Previously, Potter et al. [20] performed a prospective study of MRI-guided adaptive brachytherapy (4 doses of 7 Gy, high-dose-rate) combined with 3D conformal RT in patients with locally advanced cervical cancer. In their study, 85%–90% local control rates were reported in large/poorly responsive (IIB/III/IV) cervical cancer patients with moderate rates of treatment-related morbidity and a relative pelvic recurrence reduction of 65%–70% compared with the previous Vienna series results. When compared with 3D brachytherapy, conventional 2D brachytherapy showed inferior local control rates [21]. Therefore, a higher RT dose to the primary tumor, such as via MRI-guided adaptive brachytherapy, should be considered for patients with bulky/poorly responsive cervical cancer for better pelvic control. There are several limitations to our study, including its retrospective design, small number of patients, and uneven FIGO stage distribution. There was also heterogeneity in the chemotherapeutic regimens, although cisplatin-based concurrent chemotherapy was administered to all patients. However, as a single-center study, we reviewed all patients who underwent this regimen to minimize the selection bias. Patients also underwent radiotherapy in a consistent manner. Because the interpretation of residual disease by MRI can be influenced by differences in experience and technique at individual institutions, external validation studies are crucial to confirm our findings.
In conclusion, of patients with residual disease on 3-month followup MRI, about 60% were alive at last follow-up without further disease progression. Residual disease size N2.0 cm was the most significant poor prognostic factor for LPFS and OS. Primary tumor size N6.0 cm was also the most significant poor prognostic factor for OS. Careful observation with close follow-up without the need for salvage treatment of the residual tumor may be feasible in selected patients with a residual tumor size ≤2 cm. Conflict of interest statement The authors have no conflict of interest to report.
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Fig. 1. (a). Overall survival (diamonds), local progression-free survival (squares), and distant metastasis-free survival curves (triangles). The 3-year survival rates of each curve are shown. (b). Local progression-free survival curves according to initial tumor size, ≤ 6 cm (diamonds) and N6 cm (squares). The 3-year survival rates of each curve are shown. (c). Local progressionfree survival curves according to residual tumor size, ≤ 2 cm (diamonds) and N2 cm (squares). The 3-year survival rates of each curve are shown.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer Ja Young Kim a,1, Sang Jun Byun a,1, Young Seok Kim a,⁎, Joo-Hyun Nam b a b
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
H I G H L I G H T S • 60% of patients with residual tumor did not show further progression without salvage treatment. • The type of salvage treatment did not affect survival. • Initial and residual tumor sizes were significant prognostic factors for survival.
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Article history: Received 7 September 2016 Received in revised form 17 October 2016 Accepted 18 October 2016 Available online xxxx Keywords: Uterine cervical neoplasm Chemoradiotherapy Residual disease Magnetic resonance imaging
a b s t r a c t Objective. To investigate the disease course and identify prognostic factors for survival in patients with residual disease according to post-treatment magnetic resonance imaging (MRI) following definitive concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer. Methods. We reviewed clinical data from the medical records of 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics stage IB2–IVA uterine cervical cancer treated with CCRT. Post-treatment MRI was checked in all patients 3 months after CCRT completion. Out of the 545 patients, 53 with residual cervical cancer based on MRI following definitive CCRT were included in this analysis. Results. Thirty-two patients were disease-free at the last follow-up. Of them, 31 had a residual tumor size of ≤2 cm. Of these 32 women, 30 showed spontaneous regression of residual tumor during follow-up without salvage treatments, whereas the remaining two were alive with no evidence of disease after salvage surgery and chemotherapy. Disease progression was observed in 21 patients, including 7 local, 8 distant and 6 local and distant failures. Of these 21 women, 13 died of disease, 6 were alive with disease, and 2 remained diseasefree after salvage treatments. Initial and residual tumor sizes were significant prognostic factors for overall survival; only residual tumor size was significant for local progression-free survival. Conclusions. About 60% of patients with residual disease detected on post-treatment MRI remained diseasefree without further disease progression. Careful observation without immediate salvage treatments might be feasible in selected patients with a residual tumor size ≤2 cm. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Cisplatin-based concurrent chemoradiotherapy (CCRT) has become the standard treatment for bulky and locally advanced cervical cancer [1]. However, the disease course and appropriate salvage treatments of patients with residual cervical tumor following definitive CCRT
⁎ Corresponding author at: 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 Ja Young Kim and Sang Jun Byun contributed equally to this work and are considered co-first authors.
remain undefined. By reference to preoperative CCRT results due to a lack of reports after definitive CCRT, as many as 30%–65% of patients still have residual disease after preoperative CCRT [2,3]. Completion surgery following preoperative CCRT to eliminate potential residual disease and obtain better outcomes has been attempted, but the results did not indicate a survival benefit [4,5]. Another possible approach is additional chemotherapy, but its role also remains inconclusive [6]. Several imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), can be used to assess the tumor response after CCRT in cervical cancer. MRI is more effective than CT for evaluating the response and extents of disease after CCRT [7], and PET is more useful for measuring
http://dx.doi.org/10.1016/j.ygyno.2016.10.032 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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tumor metabolism than MRI. However, the appropriate timing of the use of imaging modalities to evaluate the tumor response varies from 1 to 2 months after treatment completion, and PET is often done at 3 months post completion of treatment according to investigators at Washington university [3,8–10]. In our institution, pelvic MRI has routinely been performed as a baseline evaluation before CCRT, prior to brachytherapy, and at 3 months after the completion of CCRT. In the present study, the authors retrospectively reviewed the disease courses in women with residual disease detected by post-treatment MRI to compare the prognosis according to salvage treatment and to identify prognostic factors related to survival. 2. Methods From 1998 to 2013, 545 consecutive women with biopsy-proven, International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IVA uterine cervical cancer were treated with curative radiotherapy (RT). Because 52 were lost to follow-up, post-treatment MRI data were available in 493 women. Of the 493 patients, 384 achieved a complete response, 13 had progressive disease outside of the RT field, and 96 had residual tumors. Of the 96 women with residual disease, 53 met the following inclusion criteria: (1) FIGO stage IB2–IVA invasive cervical cancer; (2) age 20–80 years; (3) cisplatin-based concurrent chemotherapy; and (4) pre-treatment work-up confirmation that the tumors were confined to the pelvic cavity with no evidence of distant metastases (including para-aortic lymph node metastasis). No patient underwent lymph node sampling or dissection prior to CCRT. This study was approved by the local institutional review board and informed consent was waived. Treatment details were summarized in a previous report [11]. In brief, planning CT was performed with each patient in the supine position with their arms on their chest using intravenous contrast agents and free breathing (AcQSim, Philips Medical System, Andover, MA and Light Speed RT, GE Healthcare, St. Giles, UK). Three-dimensional conformal RT to the pelvis was given with a daily fraction size of 1.8–2.0 Gy. After external beam radiotherapy (EBRT) of 45.0–50.4 Gy to the pelvis, patients received intracavitary brachytherapy (ICBT) twice a week using a 192Ir high-dose-rate brachytherapy unit (MicroSelectron, Nucletron, the Netherlands). In general, six sessions of ICBT were administered to point A, with a total dose of 30 Gy. During ICBT, additional 10–14 Gy of lymph node boosts for positive lymph nodes based on the pre-treatment MRI or a parametrial boost by EBRT with conventional fractionation were delivered, up to 60–65 Gy three times a week. For patients who could not receive ICBT, EBRT was boosted to the central lesion with 2.0 Gy daily, up to 66–74 Gy. ICBT was administered to 45 patients (84.9%); 8 did not undergo ICBT because of poor geometrical tumor coverage in 7 and history of uterine rupture in 1. The total radiation doses to point A in the 45 patients who received ICBT were 77.5–87.1 Gy (median, 84.5 Gy) and those to the primary tumor in 8 without ICBT were 66.0–74.0 Gy (median, 72.0 Gy) calculated to the equivalent dose in 2 Gy fractions. All patients concurrently received platinum-based chemotherapy as determined by the physician's preference. Weekly physical examinations, complete blood counts, and liver and renal function tests were performed during the RT and chemotherapy. When the absolute neutrophil count was b1000/mm3 or the platelet count was b100,000/mm3, treatments were delayed or halted until the patient's condition recovered. After treatment completion, all patients were evaluated by radiation oncologists and gynecologic oncologists at 3-month intervals for 2 years and every 6 months thereafter. The treatment response was assessed clinically and radiologically with pelvic MRI performed 3 months after the treatment. In contrast to the baseline MRI examination, intravenous contrast agent was not used on the follow-up MRI. T1, T2, and diffusion weighted sequences using body surface and/or endorectal coil were acquired on the post treatment MRI. Residual disease was defined as the lesion with higher signal intensity than surroundings on the T2 weighted
image by experienced radiologists. T1 and diffusion weighted images were used as supplementary sequences. Because all patients had residual disease based on post-treatment MRI, local progression was defined as further progression of the primary residual tumor compared with that on the 3-month follow-up MRI or any newly developed lesion within the pelvis, and distant metastasis was defined as recurrence outside the RT field. The first site of recurrence was recognized if local and distant metastases occurred simultaneously. Overall survival (OS) was calculated from the start of initial, definitive CCRT to death or last follow-up. Distant metastasis-free survival (DMFS) was counted from the start of initial, definitive CCRT to the verification of distant metastasis or last follow-up. Local progression-free survival (LPFS) was from the post-treatment MRI performed 3 months following CCRT to the identification of progressive local disease or a new lesion within the RT field or last follow-up. Patients who died with no evidence of treatment failure or who were lost to follow-up were censored at the date of death or their last follow-up. Survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used for multivariate analysis. A chi-square test was used to analyze the relationship between factors in two groups. We considered p-values b0.05 statistically significant. All statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL). 3. Results The characteristics of the 53 women analyzed in this study are listed in Table 1. Eight patients (15.1%) had non-squamous cell carcinoma: five had adenocarcinoma, one had adenosquamous, one had glassy cell carcinoma, and one had poorly differentiated carcinoma. The size of the primary tumor ranged from 2.7 to 10.0 cm (median, 5.0 cm). The characteristics of the residual disease based on post-treatment MRI are summarized in Table 2. The size of the residual tumor ranged from 0.3 to 4.6 cm (median, 1.4 cm). There was no significant relationship between the size of the initial tumor (≤6 cm vs. N 6 cm) and that of the residual tumor (≤2 cm vs. N 2 cm). With a median follow-up duration of 42 months (range, 8– 184 months), 32 out of the 53 patients were free of disease after CCRT. The residual tumor size was smaller than 2 cm in 31 of these 32 patients. Twenty-nine patients were just observed without any further treatment; all showed spontaneous regression of the residual tumor. At last follow-up, 27 patients were alive with no evidence of disease; the other 2 patients died due to other causes during observation, resulting in a 5-year OS rate of 88.9% without further salvage treatments. The remaining three underwent hysterectomy (n = 2) or hysterectomy followed by chemotherapy (n = 1). In the two patients who underwent hysterectomy only, one had no residual disease on pathologic examination and the other had a 0.8-cm-sized pathologically proven residual
Table 1 Patient characteristics. Variables Age, years Histology Primary tumor size, cm
FIGO stage
Pelvic node on initial MRI
No. of patients (%) Median (range) Squamous Non-squamous ≤5.0 N5.0 and ≤6.0 N6.0 IB2 IIA/IIB IIIA/IIIB IVA Positive Negative
54 (35–78) 45 (84.9) 8 (15.1) 29 (54.7) 13 (24.5) 11 (20.8) 4 (7.5) 1 (1.9)/30 (56.6) 1 (1.9)/6 (11.3) 11 (20.8) 24 (45.3) 29 (54.7)
FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
J.Y. Kim et al. / Gynecologic Oncology xxx (2016) xxx–xxx Table 2 Residual disease on post-treatment MRI. Variables
No. of patients (%)
Size of residual disease, cm
Residual pelvic node on MRI
≤1.0 N1.0 and ≤2.0 N2.0 Positive Negative
18 (34.0) 26 (49.1) 9 (17.0) 5 (9.4) 48 (90.6)
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for OS. These factors and their details are listed in Table 4. In multivariate analysis, among the prognostic factors with p ≤ 0.1 in univariate analysis for OS, initial tumor size (95% confidence interval, 0.07–0.72; hazard ratio, 0.22, p = 0.012) and residual tumor size (95% confidence interval, 0.08–0.86; hazard ratio, 0.26, p = 0.027) were statistically significant. Only residual tumor size (95% confidence interval, 0.03–0.39; hazard ratio, 0.10, p = 0.001) remained significant in multivariate analysis for LPFS.
MRI, magnetic resonance imaging.
4. Discussion disease but had no evidence of disease at last follow-up. The remaining patient who underwent surgery followed by chemotherapy is also alive with no evidence of disease. Disease progression was observed in 21 (39.6%). Of the 21 patients with disease progression, 15 developed within 1 year from the initiation of treatment and the residual tumor size was larger than 2 cm in 8 of the 21 patients. Seven patients (13.2%) had local progression only, another eight (15.1%) had distant progression only, and six (11.3%) had both local and distant. Of the 7 patients with local progression only, all showed the local failure in their primary tumors and the disease courses of the seven patients are summarized in Table 3. Of the seven patients with local progression only, one (No. 4) showed second local recurrence, 5 months after salvage surgery. In the two patients who underwent both salvage surgery and chemotherapy, one patient (No. 5) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, six cycles of chemotherapy, and remained disease-free for 9 months until recurrence at the stump was found, which was salvaged again. The other patient (No. 3) died due to rapid local progression despite total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by five cycles of chemotherapy. Finally, there were 15 (28%) patients who died during the follow-up periods including 2 patients who died without evidence of cervical cancer. Of remaining 13 patients, 3 showed local progressions, 5 distant metastases and 6 local and distant progressions in spite of systemic chemotherapy. There was no statistically significant difference in OS according to the type of salvage treatment in patients with further local progression (p = 0.942). Six patients had both local progression and distant metastasis: one underwent salvage radiotherapy to lesions in the pelvic wall and para-aortic lymph node area with chemotherapy including gemcitabine and cisplatin and remained with no evidence of disease for 79 months; the other five died of the disease progression without any salvage treatments (n = 2), with salvage chemotherapy (n = 2), and with salvage surgery followed by chemotherapy (n = 1). Of the 21 patients with local or distant progression, 13 (61.9%) died of disease, 6 (28.6%) were alive with disease, and the remaining 2 (9.5%) remained disease free. Of the 13 patients who died of disease, 10 (76.9%) had distant failures. The 3-year OS, LPFS, and DMFS rates were 76.3%, 74.6%, and 74.9%, respectively (Fig. 1 (a)). In univariate analysis, patient age, initial hemoglobin level, initial and residual tumor size, initial and post-treatment pelvic lymph node status, and ICBT were significant prognostic factors
In the present study, we analyzed the disease courses and patterns of failure in cervical cancer patients with residual disease on post-treatment MRI, finding that about 60% of patients remained progression free. In patients with disease progression after CCRT, the incidences of local and distant progression were similar. Furthermore, more than half of further disease progression occurred within 1 year from the initial CCRT. Although salvage surgery may be helpful to evaluate pathologic diagnosis as well as to eradicate residual tumor, it seems that careful observation without immediate salvage treatments is a feasible option in selected groups, specifically patients with residual tumor size ≤2 cm. Based on our results, use of salvage surgery may also not be appropriate for patients with residual tumor larger than 2 cm because these tumors tend to show rapid progression or recurrence and metastasis to distant sites. For patients with local progression only, there was no statistically significant difference among the types of salvage treatments. The most significant prognostic factors for survival were the sizes of the post-treatment residual disease and the primary disease on MRI. The few studies to perform MRI evaluation of residual disease after CCRT found that the diagnostic performance of post-treatment MRI was not satisfactory [3,9,12]. Hequet et al. [3] evaluated the impact of residual disease after CCRT in 144 locally advanced cervical cancer patients. They assessed residual disease with clinical examination and pelvic MRI 4 to 6 weeks after CCRT completion and compared the findings with the pathologic results of completion surgery 8 to 10 weeks after CCRT. MRI showed worse sensitivity (77.8%) and specificity (41.7%) than pathologic examination. Another study assessing residual disease in 44 cervical cancer patients showed that the sensitivity and specificity of residual tumor evaluation were 80% and 55%, respectively [9]. In that study, MRI evaluations were performed between 3 and 8 weeks after radiotherapy completion. For the better evaluation of post-treatment status, functional methods such as PET and diffusion-weighted MRI have been widely investigated as noninvasive tests [13]. Because PET maps tumors based on their need for constituents to maintain growth and increased metabolism, PET scans after RT could supplement the weak point of MRI in terms of low specificity, therefore, could provide better diagnostic performance than MRI or CT in the context of defining tumor viability. Diffusionweighted MRI is also sensitive to the motion of water molecules and reflects water diffusion properties of the specific tissue [14]. It has been reported that the apparent diffusion coefficient of tumors increases after effective treatment, which is associated with lowered
Table 3 Disease courses of seven patients with local progression only. Patient no.
Time to progression
Salvage treatment
Response
Status (M)
1 2 3 4 5 6 7
3 3 8 3 3 3 3
Chemotherapy Chemotherapy Hysterectomy, chemotherapy Hysterectomy Hysterectomy, chemotherapy Chemotherapy Chemotherapy
DP DP DP Second local recurrence, 5 M after salvage surgery Second local recurrence, 9 M after salvage surgery PR PR
Died of disease (13 M) Died of disease (23 M) Died of disease (10 M) Alive with disease (8 M) Alive with disease (35 M) Alive with disease (9 M) Alive with disease (15 M)
M M M M M M M
M, month; DP, disease progression; PR, partial response.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Table 4 Univariate analysis of prognostic factors for OS, LPFS, and DMFS. Variables Age Hydronephrosis Initial HGB Initial tumor Initial pelvic lymph node ICBT Residual tumor Post-RT pelvic LN
b55 ≥55 Absent Present ≤11.0 g/dL N11.0 g/dL ≤6 cm N6 cm Absent Present Yes No ≤2 cm N2 cm Absent Present
No. (%)
3 Y OS
p-Value
3 Y LPFS
p-Value
3 Y DMFS
p-Value
28 (52.8) 25 (47.2) 40 (75.5) 13 (24.5) 20 (37.7) 33 (62.3) 42 (79.2) 11 (20.8) 24 (45.3) 29 (54.7) 45 (84.9) 8 (15.1) 44 (83.0) 9 (17.0) 48 (90.6) 5 (9.4)
69.7% 83.3% 81.4% 60.6% 60.0% 86.7% 84.9% 40.9% 87.1% 66.9% 77.4% 66.7% 83.6% 33.9% 76.6% 66.7%
NS
70.4% 79.1% 77.1% 69.2% 68.6% 78.3% 80.5% 53.0% 95.8% 57.3% 81.8% 37.5% 88.5% 11.1% 80.9% 20.0%
NS
63.4% 87.8% 76.7% 69.2% 54.0% 87.8% 83.0% 45.5% 79.2% 70.7% 75.1% 75.0% 77.1% 66.7% 74.6% 80.0%
0.044
0.075 0.035 b0.001 NS NS 0.005 NS
NS NS 0.018 0.002 0.005 b0.001 0.002
NS 0.009 0.006 NS NS NS NS
Y, year; OS, overall survival; LPFS, local progression-free survival; DMFS, distant metastasis-free survival; NS, not significant; HGB, hemoglobin; ICBT, intracavitary brachytherapy; RT, radiotherapy; LN, lymph node.
tissue cellularity and cell membranes disintegration, resulting in changes in water molecular mobility [15]. The presence and size of residual disease have been identified as prognostic factors for disease-free survival and OS [2–4,16–18]. In a prospective study of 184 patients with locally advanced cervical cancer treated with CCRT, the investigators observed that patients with no residual disease had a significantly longer disease-free survival than patients with microscopic or macroscopic disease after completion surgery [2]. Hequet et al. and Touboul et al. also reported that patients with pathologic residual disease larger than 10 mm had poorer disease-free survival and OS [3,19]. In our results, about 71% of patients with residual tumor size ≤ 2 cm had no further disease progression, whereas just 11% of the patients with residual tumor N2.0 cm had no further progression. In our study, the only significant prognostic factor for local recurrence was residual disease N 2.0 cm on MRI and the only factor correlating with residual disease N 2.0 cm was use of ICBT, suggesting that a higher RT dose to the tumor is important for local control. Previously, Potter et al. [20] performed a prospective study of MRI-guided adaptive brachytherapy (4 doses of 7 Gy, high-dose-rate) combined with 3D conformal RT in patients with locally advanced cervical cancer. In their study, 85%–90% local control rates were reported in large/poorly responsive (IIB/III/IV) cervical cancer patients with moderate rates of treatment-related morbidity and a relative pelvic recurrence reduction of 65%–70% compared with the previous Vienna series results. When compared with 3D brachytherapy, conventional 2D brachytherapy showed inferior local control rates [21]. Therefore, a higher RT dose to the primary tumor, such as via MRI-guided adaptive brachytherapy, should be considered for patients with bulky/poorly responsive cervical cancer for better pelvic control. There are several limitations to our study, including its retrospective design, small number of patients, and uneven FIGO stage distribution. There was also heterogeneity in the chemotherapeutic regimens, although cisplatin-based concurrent chemotherapy was administered to all patients. However, as a single-center study, we reviewed all patients who underwent this regimen to minimize the selection bias. Patients also underwent radiotherapy in a consistent manner. Because the interpretation of residual disease by MRI can be influenced by differences in experience and technique at individual institutions, external validation studies are crucial to confirm our findings.
In conclusion, of patients with residual disease on 3-month followup MRI, about 60% were alive at last follow-up without further disease progression. Residual disease size N2.0 cm was the most significant poor prognostic factor for LPFS and OS. Primary tumor size N6.0 cm was also the most significant poor prognostic factor for OS. Careful observation with close follow-up without the need for salvage treatment of the residual tumor may be feasible in selected patients with a residual tumor size ≤2 cm. Conflict of interest statement The authors have no conflict of interest to report.
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Fig. 1. (a). Overall survival (diamonds), local progression-free survival (squares), and distant metastasis-free survival curves (triangles). The 3-year survival rates of each curve are shown. (b). Local progression-free survival curves according to initial tumor size, ≤ 6 cm (diamonds) and N6 cm (squares). The 3-year survival rates of each curve are shown. (c). Local progressionfree survival curves according to residual tumor size, ≤ 2 cm (diamonds) and N2 cm (squares). The 3-year survival rates of each curve are shown.
Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032
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Please cite this article as: J.Y. Kim, et al., Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.10.032