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Curative Chemoradiotherapy in Patients With Stage IVB Cervical Cancer Presenting With Paraortic and Left Supraclavicular Lymph Node Metastases
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Gynecologic Cancer
Curative Chemoradiotherapy in Patients With Stage IVB Cervical Cancer Presenting With Paraortic and Left Supraclavicular Lymph Node Metastases Ji-Yoon Kim, MD,* Joo-Young Kim, MD, PhD,y Jin Hee Kim, MD, PhD,z Mee Sun Yoon, MD,x Juree Kim, MD, PhD,k and Young Seok Kim, MD{ *Department of Radiation Oncology, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea; y Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; zDepartment of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea; xDepartment of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; kDepartment of Radiation Oncology, Cheil General Hospital and Women’s Healthcare Center, Kwandong University, College of Medicine, Seoul, Republic of Korea; and {Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea Received Sep 21, 2011, and in revised form Jan 13, 2012. Accepted for publication Jan 22, 2012
Summary To evaluate the efficacy and toxicity of concurrent chemoradiotherapy, the authors reviewed the clinical data of 25 patients with cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. Acute grade 3-4 hematologic toxicity was observed in 16 women. Complete response was observed in 13 patients and 3-year overall survival rate was 49%. These findings indicate that concomitant chemoradiotherapy is feasible in patients with
Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with curative intent in patients with stage IVB cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. Methods and Materials: The medical records of 25 patients with both paraortic and left supraclavicular lymph nodal metastases (group I) were reviewed and compared with those of 101 women with paraortic lymph node metastases alone (group II). Group I received a mean 59.4 Gy to the paraortic and left supraclavicular areas and 50.4 Gy to the pelvis, followed by 30 Gy of high-dose-rate brachytherapy in 6 fractions. Group II received the same dose to the paraortic area and pelvis followed by intracavitary brachytherapy. All patients received platinum-based chemotherapy simultaneously. Results: Of the 25 patients in group I, 16 (64%) experienced acute grade 3-4 hematologic toxicities, and 1 had a late grade 3 genitourinary toxicity. Complete responses, including the primary mass and pelvic, paraortic, and left supraclavicular lymph nodes, were observed in 13 patients (52%). At a median follow-up of 32 months for surviving patients, 3 experienced in-field failure, 6 showed distant failure, and 9 showed both. The 3-year overall and disease-free survival rates were 49% and 33%, respectively. In comparison, of the 101 patients in group II, 16 showed infield failure, 14 experienced distant failure, and 11 showed both. The 3-year overall and diseasefree survival rates were 69% and 57%, respectively. Conclusions: Curative CCRT is feasible in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph nodal metastases, with acceptable late toxicity and high response rates, despite high rates of acute hematologic toxicity. Ó 2012 Elsevier Inc.
Reprint requests to: Young Seok Kim, MD, Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea. Tel: þ82 2 3010 5614; Fax: þ82 2 3010 6950 E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 84, No. 3, pp. 741e747, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.070
AcknowledgmentdThis work is supported by grant no. 1110540 and NCC 1010100-3 from National Cancer Center, Goyang, Republic of Korea.
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distant lymph node metastases, even in left supraclavicular nodes.
Keywords: Uterine cervical cancer, Radiotherapy, Chemotherapy, Lymph node metastasis, Prognosis
Introduction The staging system of the International Federation of Gynecology and Obstetrics (FIGO) for uterine cervical cancer has classified patients with distant lymph node (LN) involvement, including the paraortic LN (PALN) and left supraclavicular LN (SCLN), as stage IVB. Patients with stage IVB cervical cancer have a 5-year survival rate of only 9% (1) and are usually considered candidates for systemic chemotherapy or are treated with palliative radiotherapy for specific symptom control. A recent phase III trial of cisplatin-based doublet combination chemotherapy in patients with stage IVB, recurrent, or persistent cervical cancer yielded disappointing results, with a response rate of 22%-36% and a median survival time of 9.7-12.8 months (2, 3). Patients initially diagnosed with FIGO stage IVB cervical cancer include those with distant nodal metastases or metastases to other hematogenous visceral organs. Although considered beyond the indications for curative radiation therapy, patients with limited distant nodal metastases, such as those to the PALN and/or left SCLN, may be candidates for radiotherapy with curative intent by extending the radiation field. Because of advances in radiotherapy techniques, curative doses of extended-field radiotherapy (EFRT) and concurrent chemotherapy can be safely delivered to patients with FIGO IVB cervical cancer presenting with only PALN metastasis, using 3dimensional conformal radiotherapy (3D CRT) or intensitymodulated radiotherapy (IMRT). Increasing the radiation dose to the involved paraortic area to 55-60 Gy, plus concurrent chemotherapy, resulted in acute grade 3-4 gastrointestinal toxicity rates of 9%-11% (4-6). Of these patients, 85%-100% completed their planned treatment, and the 5-year overall survival (OS) rate was 47%-77% (4-6). In contrast to the established role of the extended-field concurrent chemoradiotherapy (CCRT) in patients with cervical cancer involving PALN metastases, its role in patients with both PALN and SCLN metastases remains undefined. We therefore performed this retrospective analysis (1) to evaluate the efficacy and toxicity of CCRT in patients presenting with cervical cancer and pelvic, PALN and SCLN metastases and (2) to compare these findings with those in patients with PALN without SCLN metastases who received extended-field CCRT.
Methods and Materials Patients The records of patients with carcinoma of the cervix treated at four institutions in Korea from 1998-2010 were retrospectively evaluated. Patients were included if they had biopsy-proven carcinoma of the cervix with evidence of PALN and left SCLN metastases on imaging or surgical sampling at initial diagnosis and received CCRT with curative intent. Patients were excluded from this analysis if they had histologic evidence of small cell or clear cell carcinoma,
distant metastases other than PALN or left SCLN, had received radiotherapy alone, or had received sequential chemoradiation treatment. To compare the efficacy and toxicity of chemoradiotherapy in patients with PALN and SCLN metastases (group I, n Z 25), we also collected the records of women with PALN but without SCLN metastases (group II, n Z 101). All patients underwent physical and pelvic examinations, routine laboratory testing, chest radiography, intravenous pyelography, cystoscopy, sigmoidoscopy, and magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT). Any PALN or SCLN showing discrepancies on MRI and PET-CT was investigated surgically.
Treatment Before radiation treatment, all patients underwent CT simulation using intravenous contrast agents. The abdomino-pelvic field encompasses a volume that included the primary mass, the entire uterus, the paracervical, parametrial, and uterosacral regions; and the external iliac, hypogastric, obturator, and paraortic LNs. The superior border of the abdomino-pelvic field was usually the T12-L1 interface, but was adjusted based on the position of the positive PALNs. The left supraclavicular field encompassed the positive SCLNs and supraclavicular lymphatics. The median daily fraction of EBRT was 1.8 Gy (range, 1.5-2.0 Gy), administered once daily, 5 times per week using 3D CRT (n Z 25 in group I, n Z 94 in group II) or IMRT with a linear accelerator or a helical tomotherapy machine. Proton therapy was included as a boost for 1 patient in group II. All patients received median doses of 59.4 Gy to the PALN and 50.4 Gy to the entire pelvis, and patients in group I also received a median dose of 59.4 Gy to the left SCLN region simultaneously. At the end of external beam radiation therapy (EBRT), high-dose-rate intracavitary brachytherapy was administered with Fletcher-Suit after-loading applicators. Six to seven fractions of 4-5 Gy were delivered to point A, twice or three times per week, with no EBRT treatment on the same day of brachytherapy. Parametrial boosts were integrated between brachytherapy sessions. All patients were prescribed platinum-based chemotherapy, as determined by each physician, concurrently with EBRT. Chemotherapy regimens included cisplatin weekly (n Z 11 in group I, n Z 76 in group II); fluorouracil plus cisplatin monthly (n Z 8 in group I, n Z 14 in group II); paclitaxel plus cisplatin at 3-week intervals (n Z 6 in group I, n Z 9 in group II); and paclitaxel plus carboplatin at 3-week intervals (n Z 2 in group II).
Follow-up and statistical analysis During treatment, patients were evaluated weekly for toxicity and tumor response. After completion of therapy, patients were evaluated 1 month after the completion of chemoradiotherapy, every 3 months for the next 2 years, every 6 months for 3 years, and yearly thereafter. History taking and pelvic examination were
Volume 84 Number 3 2012 performed on every visit. Imaging studies were routinely done for surveillance to every patient, not limited to patients who complained of any symptoms. At 3 months after the completion of chemoradiotherapy, magnetic resonance imaging (MRI) and/or PET-CT was done to evaluate the response to treatment. PET-CT was checked further once a year for the first 2 years, and a CT scan was performed yearly thereafter. If a patient complained of any symptoms or a physician suspected recurrence, additional imaging studies were done as appropriate. Acute toxicities, measured from the initiation of treatment to 3 months after chemoradiotherapy, were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Late toxicities were graded according to the Radiation Therapy Oncology Group late toxicity scale. A complete response was defined as the complete clinical or radiologic disappearance of gross disease, based on MRI 3 months after the completion of treatment. Local failure was defined as either persistent disease or any recurrence of disease within the radiation field and distant failure a distant metastasis outside the radiation field. Disease-free survival (DFS) was calculated from the date of start of radiotherapy to the date of local or distant failure or death from any cause. Any recurrence or relapse, or death from any cause, was regarded as an event. Overall survival (OS) was calculated from the date of start of treatment to the date of death or last follow-up. Baseline characteristics and responses to treatment in the two groups were compared using the c2 test, Fisher’s exact test, and independent samples t tests, as appropriate. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. All P values were twosided, and P values less than .05 were considered statistically significant. All statistical analyses were performed using SPSS v. 19 (SPSS Inc, Chicago, IL).
Results Patient and treatment characteristics A review of medical records of patients treated between 1998 and 2010 identified 25 patients in group I and 101 in group II. Patient characteristics are shown in Table 1. Among the listed variables, only median age differed significantly between the two groups (47 vs 52 years, PZ.02). Although all patients in group I did not undergo staging laparotomy for histological confirmation of PALNs, SCLNs were histologically identified in 18 patients (72%). In group II, 1 patient had an involved LN around the hepatoduodenal ligament and 1 showed involvement of the splenic hilum; all of these involved LNs were included in the radiation field and received the same dose of 59.4 Gy. Treatment characteristics are shown in Table 2. The only variable that differed significantly in the two groups was median overall duration of radiation treatment, being 65 and 61 days in groups I and II, respectively. Three (12%) and 17 (17%) patients in groups I and II, respectively, did not complete the full course of chemotherapy because of grade 3-4 hematologic toxicities. Moreover, 2 (8%) and 9 (9%) patients, respectively, did not complete the planned doses of EBRT or brachytherapy because of grade 3-4 hematologic toxicities, diminished performance status, or patient refusal. There was no statistically significant difference in compliance with chemotherapy (PZ.55) and radiotherapy (PZ.86) between two groups.
Chemoradiotherapy for stage IVB cervical cancer Table 1
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Patient characteristics
Characteristic
Group I (%)
Age (y) Median 47 Range 31-66 ECOG performance status 1 22 (88) 2 3 (12) Pathologic findings SCC 23 (92) Adenocarcinoma 1 (4) Others* 1 (4) Primary tumor size (cm) 5 13 (48) >5 12 (52) NA 0 Parametrial involvement None 5 (20) Unilateral 13 (52) Bilateral 7 (28) Pretreatment hemoglobin >10 (g/dL) 19 (76) 10 (g/dL) 5 (20) NA 1 (4) Pretreatment SCC Ag 2.0 (ng/mL) 3 (12) >2.0 (ng/mL) 21 (84) NA 1 (4)
Group II (%)
P value
52 27-76
.02y
81 (80) 20 (20)
.56z
94 (93) 3 (3) 4 (4)
.97x
45 (45) 54 (53) 2 (2)
.56x
14 (14) 45 (44) 42 (42)
.43x
72 (71) 29 (29) 0
.44x
17 (17) 83 (82) 1 (1)
.76z
Abbreviations: ECOG Z Eastern Cooperative Oncology Group; NA Z not available; SCC Ag Z squamous cell carcinoma antigen; SCC Z squamous cell carcinoma. Group I: 25 patients with PALN and left SCLN. Group II: 101 patients with PALN. * Including 4 patients with adenosquamous cell carcinoma and 1 with poorly differentiated carcinoma (in group II). y Independent samples t test. z Fisher’s exact test. x c2 test.
Acute and late toxicities The most common acute toxicities were hematologic (Table 3). Grade 3-4 acute hematologic toxicities were observed in 16 (64%) group I and 57 (56%) group II patients, with 2 patients in group II dying of hematologic toxicities (pancytopenia). In all, 17 patients (68%) and 64 patients (63%) in groups I and II, respectively, experienced grade 2 acute gastrointestinal toxicities, which were transient and controlled with supportive care, and 1 and 3 patients, respectively, had grade 3 acute gastrointestinal toxicities. No patient in group I died of treatment-related toxicities. Late toxicity was evaluable in 25 patients in group I and 96 in group II, with 5 patients in the latter group being lost to followup or experiencing early death. One woman in group I experienced a late grade 3 genitourinary toxicity (hydronephrosis) requiring surgical intervention. One patient in group II experienced radiation cystitis requiring transfusion and transurethral coagulation of the bladder; and 8 patients (8%) reported grade 3 late gastrointestinal toxicities, such as rectovaginal fistula and
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Table 2
Treatment characteristics Group I (%)
Group II (%)
P value
Radiotherapy 3D CRT 23 (92) 94 (93) .70* 3D CRT þ IMRT 1 (4) 5 (5) boost IMRT 1 (4) 1 (1) 3D CRT þ proton 0 1 (1) boost EBRT dose to pelvis (Gy) Median (range) 50.4 (41.4-62.9) 50.4 (30-74) .74y Total dose to PALN (Gy) Median (range) 59.4 (45-63) 59.4 (30-68) .52y Total dose to SCLN (Gy) Median (range) 59.7 (39.6-66) ICR Yes 22 (88) 86 (85) 1.00z No 3 (12) 15 (15) Total dose of ICR (Gy) Median (range) 30 (15-40) 30 (5-35) .21y RT duration (d) Median (range) 65 (54-152) 61 (31-116) .01y Abbreviations: 3D CRT Z 3-dimensional conformal radiotherapy; ICR Z intracavitary radiation; IMRT Z intensity modulated radiation therapy; PALN Z paraortic lymph node; RT Z radiotherapy; SCLN Z supraclavicular lymph node. Group I: 25 patients with PALN and left SCLN. Group II: 101 patients with PALN. * c2 test. y Independent samples t test. z Fisher’s exact test.
rectal bleeding, requiring transfusion and/or argon plasma coagulation.
Treatment outcomes
Discussion
All 25 patients in group I and 96 in group II were evaluable for response, based on physical and imaging examinations, 3 months after radiotherapy. The primary cervical mass, pelvic LN, PALN,
Table 3
and SCLN were listed separately (Table 4) and patients who achieved a complete response (CR) inside all treated fields were considered to have achieved overall CR. We found that 13 of the 25 (52%) patients in group I and 79 of the 101 (78%) in group II achieved overall CR (P<.01). During the follow-up period, 18 patients (72%) in group I experienced treatment failures, including 1 woman with liver metastasis who was treated with stereotactic body radiotherapy and salvaged successfully. At the time of analysis, 8 patients (32%) in group I showed no evidence of disease. Three patients experienced local failure only, 1 patients with persistent disease and 2 patients with local recurrences, 1 each in the PALN and pelvic wall. Six patients had distant metastases outside the radiation field, and 9 had failures both inside and outside of the treatment field. Of the 15 patients who developed distant metastasis with or without local failure, 8 had only visceral organ metastases, 6 had only LN metastases in other than the treated areas, and the other had combined features. The sites of visceral organ metastasis included the lungs, peritoneum, bones, liver, and gallbladder, in decreasing order. Of the 101 patients in group II, 16, 14, and 11 experienced local, distant, and local plus distant failures, respectively. The median follow-up duration was 23 months (range, 6-108 months) for all patients and 32 months for surviving patients. Of the 25 patients in group I, 14 (56%) were alive, the other 11 died of cervical cancer. Of the 14 surviving patients, 6 had persistent or recurrent cervical cancer. Patients in group I had a median survival time of 32 months and 3-year OS and DFS rates of 49% and 33%, respectively (Fig). The 3-year OS was 68% for the 13 patients who achieved overall CR, and 29% for the 12 patients who did not (PZ.01). The 3-year OS rate was similar for the 13 patients in group I and the 79 in group II who achieved overall CR (68% vs 76%, PZ.98). Group II had significantly better 3-year local recurrence-free survival (53% vs 70%, PZ.03) and distant metastasis-free survival (41% vs 73%, P<.01) rates than group I. The overall 3-year DFS rate was significantly higher in group II than in group I (33% vs 57%, P<.01), but the difference in 3-year OS rate did not reach statistical significance (49% vs 69%, PZ.24).
Median survival of 32 months in group I patients of current study is far better than those of others (Table 5). The authors attribute
Treatment-related acute and late toxicities Group I (Grade)
Acute: Hematologic Gastrointestinal Genitourinary Skin and soft tissue Late: Hematologic Gastrointestinal Genitourinary Skin and soft tissue
Group II (Grade)
1-2 (%)
3 (%)
4 (%)
5 (%)
1-2 (%)
5 23 8 1
(20) (92) (32) (4)
8 (32) 1 (4) -
8 (32) -
-
35 90 28 4
1 7 1 2
(4) (28) (4) (8)
1 (4) -
-
-
1 25 15 2
3 (%)
4 (%)
5 (%)
(36) (94) (29) (4)
35 (36) 3 (3) -
22 (23) -
2 (2) -
(1) (26) (16) (2)
6 (6) 8 (8) 2 (2) -
8 (8) 1 (1) -
-
Group I: 25 patients with PALN and left SCLN. Group II: 96 evaluable patients among 101 with PALN.
Volume 84 Number 3 2012 Table 4
Chemoradiotherapy for stage IVB cervical cancer
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Response after treatment
Primary mass Group I Group II Pelvic LN Group I Group II PALN Group I Group II SCLN Group I Group II
CR (%)
PR (%)
SD (%)
PD (%)
20 (80) 77 (80)
5 (20) 16 (17)
0 0
0 3 (3)
16 (64) 82 (85)
8 (32) 13 (14)
0 0
1 (4) 1 (1)
20 (80) 85 (89)
4 (16) 9 (9)
0 1 (1)
1 (4) 1 (1)
22 (88) -
3 (12) -
0 -
0 -
Abbreviations: CR Z complete response; LN Z lymph node; PALN Z paraortic lymph node; PD Z progressive disease; PR Z partial response; SCLN Z supraclavicular lymph node; SD Z stable disease. Group I: 25 patients with PALN and left SCLN. Group II: 96 evaluable patients among 101 with PALN.
the superior survival rate to the aggressive chemoradiotherapy using higher dose irradiation administered with modern technologies. In one study, CCRT was administered to only 7 of 14 patients with SCLN metastasis (7). Moreover, SCLN was included in the radiation field in only 2 of 7 patients, and the total dose to the PALN and SCLN was limited to 45 Gy, a dose insufficient to control the gross disease. Although none of these patients developed pelvic recurrence, all showed disease persistence or progression. The median survival was 8 months and none survived beyond 16 months. In another study, of 33 women with SCLN metastases, reporting a median survival of 15 months, the patients received 45 Gy to PALN which was also insufficient dose (8). Factors prognostic of better OS in these patients included serum squamous cell carcinoma antigen <15 ng/mL at diagnosis and staging/restaging including PET. All long-term survivors with no evidence of disease (range, 23-84 months) received CCRT. Of our 18 group I patients who experienced failure after CCRT, 15 (83%) had distant failure outside the treated fields, either with or without local failure. In comparison, 25 of the 41 group II patients (61%) who experienced failure outside the treated fields had a distant failure component, with or without local failure. These findings suggest a need for additional or maintenance chemotherapy with novel systemic agents after primary chemoradiotherapy and close follow-up using PET-CT. Recently, adjuvant gemcitabine plus cisplatin was demonstrated to improve 3-year OS and progression-free survival (9) when compared with standard treatment. In addition, the “OUTBACK,” a phase III trial, which is designed to determine whether the addition of adjuvant chemotherapy to standard cisplatin-based chemoradiation improves overall survival is currently underway. Among cervical cancer patients with histologically confirmed metastases to the PALNs, 7%-28% had metastases to the left SCLN, as shown by biopsy samples of the left scalene fat pad as part of routine pretreatment evaluation (10, 11). PET may be equal or superior to morphologic MRI in detecting metastatic LNs in patients with cervical cancer (8, 12). During the staging of cervical cancer, the overall frequency of occult SCLN metastases identified by PET was 8%-12% (7, 13, 14). This frequency
Fig. Kaplan-Meier estimates of overall survival (A) and disease-free survival (B) rates in groups I and II. Group I included 25 patients with paraortic and left supraclavicular lymph node metastases. Group II included 101 patients with paraortic lymph node metastases. increases with more advanced stage cancers, being 7% in stage IIA patients, 4% in stage IIB, 25% in stage IIIA, and 50% in stage IVB (14). Another study evaluating patients with clinical FIGO stage IIIB disease found that 15% of patients had SCLN involvement, including 40% of patients with abnormal uptake in PALNs (7). The use of PET at initial staging or for restaging at the time of relapse would have detected many asymptomatic distant metastases. Patient prognosis, including survival and site of failure, was correlated with PET findings of distant LN metastases (12, 14, 15). The FIGO staging system classifies cervical cancer patients with PALN and SCLN metastases as having distant metastases. However, patients with limited numbers and sites of metastatic tumors could be considered as having an intermediate state of metastases, termed oligometastases. Localized treatments could therefore eradicate several metastatic sites along with the primary tumor, thus improving patient survival (16, 17). It is noteworthy that among the patients who achieved overall CR, there was no significant difference in OS between two treatment groups. We delivered a high radiation dose (median, 59.4 Gy) to metastatic PALNs and SCLNs, showing that cervical cancer accompanied by
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Table 5
Results of previous studies of treatment of patients with supraclavicular lymph nodal metastasis
First author
n
SCLN PET biopsy (n) (n)
Treatment (n)
Primary tumor (Gy)
PALN SCLN (Gy) (Gy)
Brandt (1981) 11 Tran (2003) 14
11 14
0 14
CCRT (7)
EBRT 60.8
45
Qiu (2007)
33
33
10
EBRT 45 þ ICR 25.8
45
Chao (2008) Kim (2010)
12 13
12 NA
12 NA
Present study (2011)
25
18
25
CCRT (24) RT (9) CCRT (12) CCRT (9) Chemo (4) CCRT (25)
EBRT 45 þ ICR 25.8 45 EBRT þ ICR 81-91 50-70 EBRT 50.4 þ ICR 30
59.4
Response
Survival
45
Median 12 mo No pelvic recurrence, Median 8 mo All distant metastases 30-60 Median 15 mo 3-y OS Z 17% 30-60 2-y OS Z 25% 59-72 Median 14 mo 2-y OS Z 36% 59.4 CR (n Z 13) Median 32 mo 3-y OS Z 49%
Abbreviations: CCRT Z concurrent chemoradiotherapy; CR Z complete response; EBRT Z external beam radiation therapy; ICR Z intracavitary radiation; NA Z not available; PALN Z paraortic lymph node; PET Z positron emission tomography; OS Z overall survival; SCLN Z supraclavicular lymph node.
SCLN metastases is relevant to the concept of oligometastases and curable by chemoradiotherapy with increased radiation doses. Advances in imaging techniques, such as PET-CT, may result in a more accurate determination of whether this aggressive combination treatment is beneficial for individual patients. The type of spread (lymphatic vs hematogenous) was evaluated as a prognostic factor in 30 patients with metastatic cervical cancer (18). Of the 13 patients with lymphatic including SCLN metastases, 9 were treated with CCRT and 4 received only chemotherapy, with 3 of the 9 patients who received curative CCRT surviving over 2 years. Moreover, these 13 patients with only lymphatic metastases had a higher 2-year OS rate than the 17 patients with hematogenous metastases (75% vs 7%). These findings suggest that CCRT should be considered in stage IVB cervical cancer patients, even with positive left SCLN metastases, after complete examination (ie, including PET-CT). This study had several limitations, including its retrospective design, which may have introduced potential biases, the small patient sample size, not a perfectly well-balanced study across the two groups, and the heterogeneity of treatments. Because of the low incidence of this disease and little awareness of CCRT for this situation, it seems not to be easy to conduct large-scale, prospective studies. Despite these limitations, however, this study was the first to evaluate the feasibility and efficacy of CCRT with curative intent for patients presenting with PALN and SCLN metastases and to compare these findings with those in patients presenting with PALN metastases.
Conclusion Curative treatment may be feasible in patients with FIGO stage IVB cervical cancer, if the disease is limited to PALN and/or SCLN metastasis. Limited distant LN metastases can be cured by CCRT using high-dose 3D CRT or IMRT. Although acute toxicities, especially hematologic toxicities, were frequently observed after this aggressive treatment, late severe toxicities were uncommon. Large scale, prospective trials are necessary to determine the efficacy and toxicity of chemoradiotherapy in patients with limited distant LN metastases and to determine subgroups that would most benefit from this strategy.
References 1. Quinn MA, Benedet JL, Odicino F, et al. Carcinoma of the cervix uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95(S1):S43-S103. 2. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 2004;22:3113-3119. 3. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2009;27:4649-4655. 4. Kim YS, Kim JH, Ahn SD, et al. High-dose extended-field irradiation and high-dose-rate brachytherapy with concurrent chemotherapy for cervical cancer with positive para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 2009;74:1522-1528. 5. Beriwal S, Gan GN, Heron DE, et al. Early clinical outcome with concurrent chemotherapy and extended-field, intensity-modulated radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2007; 68:166-171. 6. Chung Y, Jian JJ, Cheng SH, et al. Extended-field radiotherapy and high-dose-rate brachytherapy with concurrent and adjuvant cisplatinbased chemotherapy for locally advanced cervical cancer: a phase I/II study. Gynecol Oncol 2005;97:126-135. 7. Tran BN, Grigsby PW, Dehdashti F, et al. Occult supraclavicular lymph node metastasis identified by FDG-PET in patients with carcinoma of the uterine cervix. Gynecol Oncol 2003;90:572-576. 8. Qiu JT, Ho KC, Lai CH, et al. Supraclavicular lymph node metastases in cervical cancer. Eur J Gynaecol Oncol 2007;28:33-38. 9. Duenas-Gonzalez A, Zarba JJ, Patel F, et al. Phase III, openlabel, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 2011;29: 1678-1685. 10. Brandt B 3rd, Lifshitz S. Scalene node biopsy in advanced carcinoma of the cervix uteri. Cancer 1981;47:1920-1921. 11. Stehman FB, Bundy BN, Hanjani P, et al. Biopsy of the scalene fat pad in carcinoma of the cervix uteri metastatic to the periaortic lymph nodes. Surg Gynecol Obstet 1987;165:503-506. 12. Chao A, Ho KC, Wang CC, et al. Positron emission tomography in evaluating the feasibility of curative intent in cervical cancer patients with limited distant lymph node metastases. Gynecol Oncol 2008;110: 172-178.
Volume 84 Number 3 2012 13. Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745-3749. 14. Kidd EA, Siegel BA, Dehdashti F, et al. Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis. J Clin Oncol 2010;28:2108-2113. 15. Singh AK, Grigsby PW, Dehdashti F, et al. FDG-PET lymph node staging and survival of patients with FIGO stage IIIb
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cervical carcinoma. Int J Radiat Oncol Biol Phys 2003;56:489493. 16. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995; 13:8-10. 17. Weichselbaum R, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8:378-382. 18. Kim K, Cho SY, Kim BJ, et al. The type of metastasis is a prognostic factor in disseminated cervical cancer. J Gynecol Oncol 2010;21:186-190.
Radiation Oncology biology
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Clinical Investigation: Gynecologic Cancer
Curative Chemoradiotherapy in Patients With Stage IVB Cervical Cancer Presenting With Paraortic and Left Supraclavicular Lymph Node Metastases Ji-Yoon Kim, MD,* Joo-Young Kim, MD, PhD,y Jin Hee Kim, MD, PhD,z Mee Sun Yoon, MD,x Juree Kim, MD, PhD,k and Young Seok Kim, MD{ *Department of Radiation Oncology, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea; y Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; zDepartment of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea; xDepartment of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; kDepartment of Radiation Oncology, Cheil General Hospital and Women’s Healthcare Center, Kwandong University, College of Medicine, Seoul, Republic of Korea; and {Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea Received Sep 21, 2011, and in revised form Jan 13, 2012. Accepted for publication Jan 22, 2012
Summary To evaluate the efficacy and toxicity of concurrent chemoradiotherapy, the authors reviewed the clinical data of 25 patients with cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. Acute grade 3-4 hematologic toxicity was observed in 16 women. Complete response was observed in 13 patients and 3-year overall survival rate was 49%. These findings indicate that concomitant chemoradiotherapy is feasible in patients with
Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with curative intent in patients with stage IVB cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. Methods and Materials: The medical records of 25 patients with both paraortic and left supraclavicular lymph nodal metastases (group I) were reviewed and compared with those of 101 women with paraortic lymph node metastases alone (group II). Group I received a mean 59.4 Gy to the paraortic and left supraclavicular areas and 50.4 Gy to the pelvis, followed by 30 Gy of high-dose-rate brachytherapy in 6 fractions. Group II received the same dose to the paraortic area and pelvis followed by intracavitary brachytherapy. All patients received platinum-based chemotherapy simultaneously. Results: Of the 25 patients in group I, 16 (64%) experienced acute grade 3-4 hematologic toxicities, and 1 had a late grade 3 genitourinary toxicity. Complete responses, including the primary mass and pelvic, paraortic, and left supraclavicular lymph nodes, were observed in 13 patients (52%). At a median follow-up of 32 months for surviving patients, 3 experienced in-field failure, 6 showed distant failure, and 9 showed both. The 3-year overall and disease-free survival rates were 49% and 33%, respectively. In comparison, of the 101 patients in group II, 16 showed infield failure, 14 experienced distant failure, and 11 showed both. The 3-year overall and diseasefree survival rates were 69% and 57%, respectively. Conclusions: Curative CCRT is feasible in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph nodal metastases, with acceptable late toxicity and high response rates, despite high rates of acute hematologic toxicity. Ó 2012 Elsevier Inc.
Reprint requests to: Young Seok Kim, MD, Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea. Tel: þ82 2 3010 5614; Fax: þ82 2 3010 6950 E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 84, No. 3, pp. 741e747, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.070
AcknowledgmentdThis work is supported by grant no. 1110540 and NCC 1010100-3 from National Cancer Center, Goyang, Republic of Korea.
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distant lymph node metastases, even in left supraclavicular nodes.
Keywords: Uterine cervical cancer, Radiotherapy, Chemotherapy, Lymph node metastasis, Prognosis
Introduction The staging system of the International Federation of Gynecology and Obstetrics (FIGO) for uterine cervical cancer has classified patients with distant lymph node (LN) involvement, including the paraortic LN (PALN) and left supraclavicular LN (SCLN), as stage IVB. Patients with stage IVB cervical cancer have a 5-year survival rate of only 9% (1) and are usually considered candidates for systemic chemotherapy or are treated with palliative radiotherapy for specific symptom control. A recent phase III trial of cisplatin-based doublet combination chemotherapy in patients with stage IVB, recurrent, or persistent cervical cancer yielded disappointing results, with a response rate of 22%-36% and a median survival time of 9.7-12.8 months (2, 3). Patients initially diagnosed with FIGO stage IVB cervical cancer include those with distant nodal metastases or metastases to other hematogenous visceral organs. Although considered beyond the indications for curative radiation therapy, patients with limited distant nodal metastases, such as those to the PALN and/or left SCLN, may be candidates for radiotherapy with curative intent by extending the radiation field. Because of advances in radiotherapy techniques, curative doses of extended-field radiotherapy (EFRT) and concurrent chemotherapy can be safely delivered to patients with FIGO IVB cervical cancer presenting with only PALN metastasis, using 3dimensional conformal radiotherapy (3D CRT) or intensitymodulated radiotherapy (IMRT). Increasing the radiation dose to the involved paraortic area to 55-60 Gy, plus concurrent chemotherapy, resulted in acute grade 3-4 gastrointestinal toxicity rates of 9%-11% (4-6). Of these patients, 85%-100% completed their planned treatment, and the 5-year overall survival (OS) rate was 47%-77% (4-6). In contrast to the established role of the extended-field concurrent chemoradiotherapy (CCRT) in patients with cervical cancer involving PALN metastases, its role in patients with both PALN and SCLN metastases remains undefined. We therefore performed this retrospective analysis (1) to evaluate the efficacy and toxicity of CCRT in patients presenting with cervical cancer and pelvic, PALN and SCLN metastases and (2) to compare these findings with those in patients with PALN without SCLN metastases who received extended-field CCRT.
Methods and Materials Patients The records of patients with carcinoma of the cervix treated at four institutions in Korea from 1998-2010 were retrospectively evaluated. Patients were included if they had biopsy-proven carcinoma of the cervix with evidence of PALN and left SCLN metastases on imaging or surgical sampling at initial diagnosis and received CCRT with curative intent. Patients were excluded from this analysis if they had histologic evidence of small cell or clear cell carcinoma,
distant metastases other than PALN or left SCLN, had received radiotherapy alone, or had received sequential chemoradiation treatment. To compare the efficacy and toxicity of chemoradiotherapy in patients with PALN and SCLN metastases (group I, n Z 25), we also collected the records of women with PALN but without SCLN metastases (group II, n Z 101). All patients underwent physical and pelvic examinations, routine laboratory testing, chest radiography, intravenous pyelography, cystoscopy, sigmoidoscopy, and magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT). Any PALN or SCLN showing discrepancies on MRI and PET-CT was investigated surgically.
Treatment Before radiation treatment, all patients underwent CT simulation using intravenous contrast agents. The abdomino-pelvic field encompasses a volume that included the primary mass, the entire uterus, the paracervical, parametrial, and uterosacral regions; and the external iliac, hypogastric, obturator, and paraortic LNs. The superior border of the abdomino-pelvic field was usually the T12-L1 interface, but was adjusted based on the position of the positive PALNs. The left supraclavicular field encompassed the positive SCLNs and supraclavicular lymphatics. The median daily fraction of EBRT was 1.8 Gy (range, 1.5-2.0 Gy), administered once daily, 5 times per week using 3D CRT (n Z 25 in group I, n Z 94 in group II) or IMRT with a linear accelerator or a helical tomotherapy machine. Proton therapy was included as a boost for 1 patient in group II. All patients received median doses of 59.4 Gy to the PALN and 50.4 Gy to the entire pelvis, and patients in group I also received a median dose of 59.4 Gy to the left SCLN region simultaneously. At the end of external beam radiation therapy (EBRT), high-dose-rate intracavitary brachytherapy was administered with Fletcher-Suit after-loading applicators. Six to seven fractions of 4-5 Gy were delivered to point A, twice or three times per week, with no EBRT treatment on the same day of brachytherapy. Parametrial boosts were integrated between brachytherapy sessions. All patients were prescribed platinum-based chemotherapy, as determined by each physician, concurrently with EBRT. Chemotherapy regimens included cisplatin weekly (n Z 11 in group I, n Z 76 in group II); fluorouracil plus cisplatin monthly (n Z 8 in group I, n Z 14 in group II); paclitaxel plus cisplatin at 3-week intervals (n Z 6 in group I, n Z 9 in group II); and paclitaxel plus carboplatin at 3-week intervals (n Z 2 in group II).
Follow-up and statistical analysis During treatment, patients were evaluated weekly for toxicity and tumor response. After completion of therapy, patients were evaluated 1 month after the completion of chemoradiotherapy, every 3 months for the next 2 years, every 6 months for 3 years, and yearly thereafter. History taking and pelvic examination were
Volume 84 Number 3 2012 performed on every visit. Imaging studies were routinely done for surveillance to every patient, not limited to patients who complained of any symptoms. At 3 months after the completion of chemoradiotherapy, magnetic resonance imaging (MRI) and/or PET-CT was done to evaluate the response to treatment. PET-CT was checked further once a year for the first 2 years, and a CT scan was performed yearly thereafter. If a patient complained of any symptoms or a physician suspected recurrence, additional imaging studies were done as appropriate. Acute toxicities, measured from the initiation of treatment to 3 months after chemoradiotherapy, were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Late toxicities were graded according to the Radiation Therapy Oncology Group late toxicity scale. A complete response was defined as the complete clinical or radiologic disappearance of gross disease, based on MRI 3 months after the completion of treatment. Local failure was defined as either persistent disease or any recurrence of disease within the radiation field and distant failure a distant metastasis outside the radiation field. Disease-free survival (DFS) was calculated from the date of start of radiotherapy to the date of local or distant failure or death from any cause. Any recurrence or relapse, or death from any cause, was regarded as an event. Overall survival (OS) was calculated from the date of start of treatment to the date of death or last follow-up. Baseline characteristics and responses to treatment in the two groups were compared using the c2 test, Fisher’s exact test, and independent samples t tests, as appropriate. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. All P values were twosided, and P values less than .05 were considered statistically significant. All statistical analyses were performed using SPSS v. 19 (SPSS Inc, Chicago, IL).
Results Patient and treatment characteristics A review of medical records of patients treated between 1998 and 2010 identified 25 patients in group I and 101 in group II. Patient characteristics are shown in Table 1. Among the listed variables, only median age differed significantly between the two groups (47 vs 52 years, PZ.02). Although all patients in group I did not undergo staging laparotomy for histological confirmation of PALNs, SCLNs were histologically identified in 18 patients (72%). In group II, 1 patient had an involved LN around the hepatoduodenal ligament and 1 showed involvement of the splenic hilum; all of these involved LNs were included in the radiation field and received the same dose of 59.4 Gy. Treatment characteristics are shown in Table 2. The only variable that differed significantly in the two groups was median overall duration of radiation treatment, being 65 and 61 days in groups I and II, respectively. Three (12%) and 17 (17%) patients in groups I and II, respectively, did not complete the full course of chemotherapy because of grade 3-4 hematologic toxicities. Moreover, 2 (8%) and 9 (9%) patients, respectively, did not complete the planned doses of EBRT or brachytherapy because of grade 3-4 hematologic toxicities, diminished performance status, or patient refusal. There was no statistically significant difference in compliance with chemotherapy (PZ.55) and radiotherapy (PZ.86) between two groups.
Chemoradiotherapy for stage IVB cervical cancer Table 1
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Patient characteristics
Characteristic
Group I (%)
Age (y) Median 47 Range 31-66 ECOG performance status 1 22 (88) 2 3 (12) Pathologic findings SCC 23 (92) Adenocarcinoma 1 (4) Others* 1 (4) Primary tumor size (cm) 5 13 (48) >5 12 (52) NA 0 Parametrial involvement None 5 (20) Unilateral 13 (52) Bilateral 7 (28) Pretreatment hemoglobin >10 (g/dL) 19 (76) 10 (g/dL) 5 (20) NA 1 (4) Pretreatment SCC Ag 2.0 (ng/mL) 3 (12) >2.0 (ng/mL) 21 (84) NA 1 (4)
Group II (%)
P value
52 27-76
.02y
81 (80) 20 (20)
.56z
94 (93) 3 (3) 4 (4)
.97x
45 (45) 54 (53) 2 (2)
.56x
14 (14) 45 (44) 42 (42)
.43x
72 (71) 29 (29) 0
.44x
17 (17) 83 (82) 1 (1)
.76z
Abbreviations: ECOG Z Eastern Cooperative Oncology Group; NA Z not available; SCC Ag Z squamous cell carcinoma antigen; SCC Z squamous cell carcinoma. Group I: 25 patients with PALN and left SCLN. Group II: 101 patients with PALN. * Including 4 patients with adenosquamous cell carcinoma and 1 with poorly differentiated carcinoma (in group II). y Independent samples t test. z Fisher’s exact test. x c2 test.
Acute and late toxicities The most common acute toxicities were hematologic (Table 3). Grade 3-4 acute hematologic toxicities were observed in 16 (64%) group I and 57 (56%) group II patients, with 2 patients in group II dying of hematologic toxicities (pancytopenia). In all, 17 patients (68%) and 64 patients (63%) in groups I and II, respectively, experienced grade 2 acute gastrointestinal toxicities, which were transient and controlled with supportive care, and 1 and 3 patients, respectively, had grade 3 acute gastrointestinal toxicities. No patient in group I died of treatment-related toxicities. Late toxicity was evaluable in 25 patients in group I and 96 in group II, with 5 patients in the latter group being lost to followup or experiencing early death. One woman in group I experienced a late grade 3 genitourinary toxicity (hydronephrosis) requiring surgical intervention. One patient in group II experienced radiation cystitis requiring transfusion and transurethral coagulation of the bladder; and 8 patients (8%) reported grade 3 late gastrointestinal toxicities, such as rectovaginal fistula and
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Table 2
Treatment characteristics Group I (%)
Group II (%)
P value
Radiotherapy 3D CRT 23 (92) 94 (93) .70* 3D CRT þ IMRT 1 (4) 5 (5) boost IMRT 1 (4) 1 (1) 3D CRT þ proton 0 1 (1) boost EBRT dose to pelvis (Gy) Median (range) 50.4 (41.4-62.9) 50.4 (30-74) .74y Total dose to PALN (Gy) Median (range) 59.4 (45-63) 59.4 (30-68) .52y Total dose to SCLN (Gy) Median (range) 59.7 (39.6-66) ICR Yes 22 (88) 86 (85) 1.00z No 3 (12) 15 (15) Total dose of ICR (Gy) Median (range) 30 (15-40) 30 (5-35) .21y RT duration (d) Median (range) 65 (54-152) 61 (31-116) .01y Abbreviations: 3D CRT Z 3-dimensional conformal radiotherapy; ICR Z intracavitary radiation; IMRT Z intensity modulated radiation therapy; PALN Z paraortic lymph node; RT Z radiotherapy; SCLN Z supraclavicular lymph node. Group I: 25 patients with PALN and left SCLN. Group II: 101 patients with PALN. * c2 test. y Independent samples t test. z Fisher’s exact test.
rectal bleeding, requiring transfusion and/or argon plasma coagulation.
Treatment outcomes
Discussion
All 25 patients in group I and 96 in group II were evaluable for response, based on physical and imaging examinations, 3 months after radiotherapy. The primary cervical mass, pelvic LN, PALN,
Table 3
and SCLN were listed separately (Table 4) and patients who achieved a complete response (CR) inside all treated fields were considered to have achieved overall CR. We found that 13 of the 25 (52%) patients in group I and 79 of the 101 (78%) in group II achieved overall CR (P<.01). During the follow-up period, 18 patients (72%) in group I experienced treatment failures, including 1 woman with liver metastasis who was treated with stereotactic body radiotherapy and salvaged successfully. At the time of analysis, 8 patients (32%) in group I showed no evidence of disease. Three patients experienced local failure only, 1 patients with persistent disease and 2 patients with local recurrences, 1 each in the PALN and pelvic wall. Six patients had distant metastases outside the radiation field, and 9 had failures both inside and outside of the treatment field. Of the 15 patients who developed distant metastasis with or without local failure, 8 had only visceral organ metastases, 6 had only LN metastases in other than the treated areas, and the other had combined features. The sites of visceral organ metastasis included the lungs, peritoneum, bones, liver, and gallbladder, in decreasing order. Of the 101 patients in group II, 16, 14, and 11 experienced local, distant, and local plus distant failures, respectively. The median follow-up duration was 23 months (range, 6-108 months) for all patients and 32 months for surviving patients. Of the 25 patients in group I, 14 (56%) were alive, the other 11 died of cervical cancer. Of the 14 surviving patients, 6 had persistent or recurrent cervical cancer. Patients in group I had a median survival time of 32 months and 3-year OS and DFS rates of 49% and 33%, respectively (Fig). The 3-year OS was 68% for the 13 patients who achieved overall CR, and 29% for the 12 patients who did not (PZ.01). The 3-year OS rate was similar for the 13 patients in group I and the 79 in group II who achieved overall CR (68% vs 76%, PZ.98). Group II had significantly better 3-year local recurrence-free survival (53% vs 70%, PZ.03) and distant metastasis-free survival (41% vs 73%, P<.01) rates than group I. The overall 3-year DFS rate was significantly higher in group II than in group I (33% vs 57%, P<.01), but the difference in 3-year OS rate did not reach statistical significance (49% vs 69%, PZ.24).
Median survival of 32 months in group I patients of current study is far better than those of others (Table 5). The authors attribute
Treatment-related acute and late toxicities Group I (Grade)
Acute: Hematologic Gastrointestinal Genitourinary Skin and soft tissue Late: Hematologic Gastrointestinal Genitourinary Skin and soft tissue
Group II (Grade)
1-2 (%)
3 (%)
4 (%)
5 (%)
1-2 (%)
5 23 8 1
(20) (92) (32) (4)
8 (32) 1 (4) -
8 (32) -
-
35 90 28 4
1 7 1 2
(4) (28) (4) (8)
1 (4) -
-
-
1 25 15 2
3 (%)
4 (%)
5 (%)
(36) (94) (29) (4)
35 (36) 3 (3) -
22 (23) -
2 (2) -
(1) (26) (16) (2)
6 (6) 8 (8) 2 (2) -
8 (8) 1 (1) -
-
Group I: 25 patients with PALN and left SCLN. Group II: 96 evaluable patients among 101 with PALN.
Volume 84 Number 3 2012 Table 4
Chemoradiotherapy for stage IVB cervical cancer
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Response after treatment
Primary mass Group I Group II Pelvic LN Group I Group II PALN Group I Group II SCLN Group I Group II
CR (%)
PR (%)
SD (%)
PD (%)
20 (80) 77 (80)
5 (20) 16 (17)
0 0
0 3 (3)
16 (64) 82 (85)
8 (32) 13 (14)
0 0
1 (4) 1 (1)
20 (80) 85 (89)
4 (16) 9 (9)
0 1 (1)
1 (4) 1 (1)
22 (88) -
3 (12) -
0 -
0 -
Abbreviations: CR Z complete response; LN Z lymph node; PALN Z paraortic lymph node; PD Z progressive disease; PR Z partial response; SCLN Z supraclavicular lymph node; SD Z stable disease. Group I: 25 patients with PALN and left SCLN. Group II: 96 evaluable patients among 101 with PALN.
the superior survival rate to the aggressive chemoradiotherapy using higher dose irradiation administered with modern technologies. In one study, CCRT was administered to only 7 of 14 patients with SCLN metastasis (7). Moreover, SCLN was included in the radiation field in only 2 of 7 patients, and the total dose to the PALN and SCLN was limited to 45 Gy, a dose insufficient to control the gross disease. Although none of these patients developed pelvic recurrence, all showed disease persistence or progression. The median survival was 8 months and none survived beyond 16 months. In another study, of 33 women with SCLN metastases, reporting a median survival of 15 months, the patients received 45 Gy to PALN which was also insufficient dose (8). Factors prognostic of better OS in these patients included serum squamous cell carcinoma antigen <15 ng/mL at diagnosis and staging/restaging including PET. All long-term survivors with no evidence of disease (range, 23-84 months) received CCRT. Of our 18 group I patients who experienced failure after CCRT, 15 (83%) had distant failure outside the treated fields, either with or without local failure. In comparison, 25 of the 41 group II patients (61%) who experienced failure outside the treated fields had a distant failure component, with or without local failure. These findings suggest a need for additional or maintenance chemotherapy with novel systemic agents after primary chemoradiotherapy and close follow-up using PET-CT. Recently, adjuvant gemcitabine plus cisplatin was demonstrated to improve 3-year OS and progression-free survival (9) when compared with standard treatment. In addition, the “OUTBACK,” a phase III trial, which is designed to determine whether the addition of adjuvant chemotherapy to standard cisplatin-based chemoradiation improves overall survival is currently underway. Among cervical cancer patients with histologically confirmed metastases to the PALNs, 7%-28% had metastases to the left SCLN, as shown by biopsy samples of the left scalene fat pad as part of routine pretreatment evaluation (10, 11). PET may be equal or superior to morphologic MRI in detecting metastatic LNs in patients with cervical cancer (8, 12). During the staging of cervical cancer, the overall frequency of occult SCLN metastases identified by PET was 8%-12% (7, 13, 14). This frequency
Fig. Kaplan-Meier estimates of overall survival (A) and disease-free survival (B) rates in groups I and II. Group I included 25 patients with paraortic and left supraclavicular lymph node metastases. Group II included 101 patients with paraortic lymph node metastases. increases with more advanced stage cancers, being 7% in stage IIA patients, 4% in stage IIB, 25% in stage IIIA, and 50% in stage IVB (14). Another study evaluating patients with clinical FIGO stage IIIB disease found that 15% of patients had SCLN involvement, including 40% of patients with abnormal uptake in PALNs (7). The use of PET at initial staging or for restaging at the time of relapse would have detected many asymptomatic distant metastases. Patient prognosis, including survival and site of failure, was correlated with PET findings of distant LN metastases (12, 14, 15). The FIGO staging system classifies cervical cancer patients with PALN and SCLN metastases as having distant metastases. However, patients with limited numbers and sites of metastatic tumors could be considered as having an intermediate state of metastases, termed oligometastases. Localized treatments could therefore eradicate several metastatic sites along with the primary tumor, thus improving patient survival (16, 17). It is noteworthy that among the patients who achieved overall CR, there was no significant difference in OS between two treatment groups. We delivered a high radiation dose (median, 59.4 Gy) to metastatic PALNs and SCLNs, showing that cervical cancer accompanied by
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Table 5
Results of previous studies of treatment of patients with supraclavicular lymph nodal metastasis
First author
n
SCLN PET biopsy (n) (n)
Treatment (n)
Primary tumor (Gy)
PALN SCLN (Gy) (Gy)
Brandt (1981) 11 Tran (2003) 14
11 14
0 14
CCRT (7)
EBRT 60.8
45
Qiu (2007)
33
33
10
EBRT 45 þ ICR 25.8
45
Chao (2008) Kim (2010)
12 13
12 NA
12 NA
Present study (2011)
25
18
25
CCRT (24) RT (9) CCRT (12) CCRT (9) Chemo (4) CCRT (25)
EBRT 45 þ ICR 25.8 45 EBRT þ ICR 81-91 50-70 EBRT 50.4 þ ICR 30
59.4
Response
Survival
45
Median 12 mo No pelvic recurrence, Median 8 mo All distant metastases 30-60 Median 15 mo 3-y OS Z 17% 30-60 2-y OS Z 25% 59-72 Median 14 mo 2-y OS Z 36% 59.4 CR (n Z 13) Median 32 mo 3-y OS Z 49%
Abbreviations: CCRT Z concurrent chemoradiotherapy; CR Z complete response; EBRT Z external beam radiation therapy; ICR Z intracavitary radiation; NA Z not available; PALN Z paraortic lymph node; PET Z positron emission tomography; OS Z overall survival; SCLN Z supraclavicular lymph node.
SCLN metastases is relevant to the concept of oligometastases and curable by chemoradiotherapy with increased radiation doses. Advances in imaging techniques, such as PET-CT, may result in a more accurate determination of whether this aggressive combination treatment is beneficial for individual patients. The type of spread (lymphatic vs hematogenous) was evaluated as a prognostic factor in 30 patients with metastatic cervical cancer (18). Of the 13 patients with lymphatic including SCLN metastases, 9 were treated with CCRT and 4 received only chemotherapy, with 3 of the 9 patients who received curative CCRT surviving over 2 years. Moreover, these 13 patients with only lymphatic metastases had a higher 2-year OS rate than the 17 patients with hematogenous metastases (75% vs 7%). These findings suggest that CCRT should be considered in stage IVB cervical cancer patients, even with positive left SCLN metastases, after complete examination (ie, including PET-CT). This study had several limitations, including its retrospective design, which may have introduced potential biases, the small patient sample size, not a perfectly well-balanced study across the two groups, and the heterogeneity of treatments. Because of the low incidence of this disease and little awareness of CCRT for this situation, it seems not to be easy to conduct large-scale, prospective studies. Despite these limitations, however, this study was the first to evaluate the feasibility and efficacy of CCRT with curative intent for patients presenting with PALN and SCLN metastases and to compare these findings with those in patients presenting with PALN metastases.
Conclusion Curative treatment may be feasible in patients with FIGO stage IVB cervical cancer, if the disease is limited to PALN and/or SCLN metastasis. Limited distant LN metastases can be cured by CCRT using high-dose 3D CRT or IMRT. Although acute toxicities, especially hematologic toxicities, were frequently observed after this aggressive treatment, late severe toxicities were uncommon. Large scale, prospective trials are necessary to determine the efficacy and toxicity of chemoradiotherapy in patients with limited distant LN metastases and to determine subgroups that would most benefit from this strategy.
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Volume 84 Number 3 2012 13. Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745-3749. 14. Kidd EA, Siegel BA, Dehdashti F, et al. Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis. J Clin Oncol 2010;28:2108-2113. 15. Singh AK, Grigsby PW, Dehdashti F, et al. FDG-PET lymph node staging and survival of patients with FIGO stage IIIb
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cervical carcinoma. Int J Radiat Oncol Biol Phys 2003;56:489493. 16. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995; 13:8-10. 17. Weichselbaum R, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8:378-382. 18. Kim K, Cho SY, Kim BJ, et al. The type of metastasis is a prognostic factor in disseminated cervical cancer. J Gynecol Oncol 2010;21:186-190.