This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement.
A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT.
The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group.
These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings.
The spread of cervical cancer usually exhibits stepwise progression, from regional pelvic lymph nodes to para-aortic lymph nodes (PAN), followed by distant metastases with the prevalence of PAN metastases increasing progressively with stage [
The use of concurrent chemoradiotherapy (CCRT) has complicated findings regarding the efficacy and safety of EFI [
This study therefore assessed the efficacy of EFI in patients with locally advanced cervical cancer without PAN involvement.
Between January 1996 and December 2010, 241 patients with locally advanced cervical cancer underwent radiotherapy as primary treatment at Keimyung University Dongsan Medical Center. Of 241 patients, 14 patients with an incomplete course of radiotherapy, 20 patients without regular follow-up after completion of radiotherapy, and four patients with neuroendocrine carcinoma were excluded, and 203 patients were analyzed in this study. Locally advanced cervical cancer was defined according to International Federation of Gynecology and Obstetrics (FIGO) staging as stage IB2, IIA (tumor size > 40 mm or pelvic lymph node metastases), IIB, IIIA, and IIIB [
All patients received external beam radiotherapy (EBRT), followed by high dose-rate brachytherapy. EBRT was delivered with 6 to 20 mega-voltage photon beams using 4-field box techniques. Of the 203 patients, 115 (56.7%) were treated with a pelvis only field, as irradiation of the entire pelvis with the L4-L5 interspace as the superior border. The L5-S1 interspace was considered the superior border in patients who were relatively older or in poor general condition. The L3-L4 interspace was considered the superior border in patients who had extensive pelvic lymph node involvement. The remaining 88 patients (43.3%) were treated with EFI, defined as irradiation of the entire pelvis and PAN area with continuous fields using 4-field box techniques. The superior border was extended to encompass sufficient PAN spaces; 42 patients with L2-L3 interspace as the superior border, 17 patients with L1-L2 interspace and 29 patients with T12-L1 interspace. Midline shield and field size reduction were adapted after 36 to 45 Gy of EBRT. The median total EBRT dose to the pelvis was 54 Gy, ranging from 43.2 to 54 Gy. The median dose to PAN in patients treated with EFI was 45 Gy, ranging from 36 to 45 Gy. Nineteen patients received 36 Gy, one patient received 41.4 Gy, and 68 patients received 45 Gy. Dose to the PAN area was decided according to patients' condition or disease status. Following EBRT, patients were treated with high dose-rate brachytherapy using 60Co or 192Ir sources; 60Co was used until October 1998 and 192Ir was used thereafter. Under local anesthesia, tandem and ovoids were inserted and the radioisotope was applied using a remote after loading system. Patients were treated twice weekly with 5 Gy per fraction at A-point. Median brachytherapy dose to A-point was 30 Gy, ranging from 20 to 35 Gy. Combining the EBRT dose with brachytherapy dose, median total biologically equivalent dose for a 2 Gy fraction to A-point was 85.8 Gy, ranging from 77 to 90.6 Gy. The median overall treatment time was 64 days, ranging from 52 to 90 days.
Platinum based chemotherapy regimens were administered concurrently to 133 patients (65.5%). Until 2002, 37 patients received two cycles of continuous infusions of 5-fluorouracil and cisplatin every four weeks. Forty-nine patients received three cycles of paclitaxel and carboplatin or cisplatin every three weeks until 2006 and, since then, 47 patients received cisplatin every week. None of the patients received consolidation chemotherapy after completion of CCRT, but 12 patients underwent radical hysterectomy.
During treatment, each patient's performance status and complete blood count were evaluated weekly. Red blood cell transfusions were administered to patients with hemoglobin levels below 10 g/dL. When the absolute neutrophil count was below 1,000/mm3 or the platelet count was below 50,000/mm3, treatment was delayed until the blood count recovered.
In summary, four different treatment modalities were used in this study: EFI with CCRT in 62 patients (30.5%), pelvis only field with CCRT in 71 patients (35.0%), EFI without chemotherapy in 26 patients (12.8%), and pelvis only field without chemotherapy in 44 patients (21.7%).
After completion of treatment, patients were evaluated regularly by radiation oncologists and gynecologic oncologists. Responses were defined as follows: complete response (CR), disappearance of the gross tumor on pelvic examination or pelvic MRI or CT; partial response (PR), ≥ 30% reduction of the initial tumor volume; progressive disease (PD), a ≥ 20% increase in tumor volume or occurrence of a new lesion; and stable disease, neither sufficient shrinkage for PR nor sufficient increase for PD [
OS was calculated from the start of treatment to death from any cause or last follow-up visit. Disease-specific survival (DSS) was calculated from the start of treatment to death from disease or last follow-up visit. Disease-free survival (DFS) was calculated from the end of treatment to the date of disease failure or last follow-up visit. The Kaplan-Meier method was used for calculation of OS and DFS, and the log-rank test was used for evaluation of prognostic factors. The chi-square test was used for comparison of patient characteristics and other factors between two groups. A p < 0.05 was considered statistically significant. All statistical analyses were performed using IBM ver. 20.0.0 (IBM Co., Armonk, NY).
Three months after completion of treatment, 197 patients (97.0%) achieved CR and six (3.0%) achieved PR, with similar response rates in patients treated with EFI and pelvis only field (p=0.615). The median follow-up period was 60 months (range, 4 to 184 months). At the time of the last follow-up, 133 patients (65.5%) were alive without evidence of disease, three (1.5%) were alive with disease, 46 (22.7%) had died from cervical cancer, and 21 (10.3%) had died from other causes.
Disease failure was observed in 51 patients (25.1%).
The 2- and 5-year OS rates were 87.8% and 73.5%, respectively. The 2- and 5-year DSS rates were 89.6% and 78.7%, respectively. The 2- and 5-year DFS rates were 81.7% and 75.0%, respectively. Patients treated with EFI had 2- and 5-year OS rates of 87.0% and 71.7%, whereas patients treated with pelvis only field had 2- and 5-year OS rates of 88.4% and 74.8%, respectively (p=0.699) (
When analyzed patients treated with radiotherapy alone without concurrent chemotherapy, the 2- and 5-year OS rates were 92.1% and 72.1% in patients treated with EFI, and 75.0% and 60.5%, respectively, in patients treated with pelvis only field (p=0.056) (
In patients treated with CCRT, however, treatment field had no significant effect on OS or DFS. The 2- and 5-year OS rates were 84.9% and 72.3% in patients treated with EFI, and 97.1% and 84.3%, respectively, in patients treated with pelvis only field (p=0.140) (
A summary of acute and late grade 3-4 toxicities is shown in
No significant differences in the rates of acute or late grade 3-4 toxicities were observed between patients treated with EFI and pelvis only field. Late toxicities occurred in the entire pelvic field, not in the PAN area. Treatment with CCRT had no significant effect on toxicity rates.
In recent decades, radiotherapy has become the standard treatment for patients with locally advanced cervical cancer. EBRT followed by intracavitary brachytherapy was the standard treatment until the 1990s; since then, CCRT has become the standard treatment method [
The results observed in the absence of concurrent chemotherapy were similar to these earlier findings. Higher 5-year OS rates were observed in patients treated with EFI than in patients treated with pelvic irradiation alone (72.1% vs. 60.5%). In the absence of concurrent chemotherapy, although the difference was marginally significant (p=0.056), prophylactic irradiation of the PAN area may be effective if toxicity is not a concern. However, in a previous randomized trial, the cumulative incidence of grade 4 and 5 toxicities was higher in patients treated with EFI (8% vs. 4%), with the difference being much greater in patients who had surgical staging or had undergone previous abdominal surgery [
A trial comparing EFI without chemotherapy and pelvis only field with CCRT using 5-fluorouracil and cisplatin in patients with locally advanced cervical cancer found that OS and DFS were longer in the latter group, with 5-year OS rates of 52% and 73%, respectively [
The toxicity findings in patients treated with EFI plus CCRT are conflicting [
Patients in this study were treated with four different treatment modalities: EFI with or without concurrent chemotherapy, pelvis only field with or without concurrent chemotherapy. Significantly lower OS was observed in patients treated with pelvis only field without chemotherapy than in the other three groups. These results suggest that EFI may be reliable in the absence of chemotherapy by reducing the risk of systemic metastases. When combined with CCRT, however, the efficacy of EFI seems to be decreased, because chemotherapy has cytotoxic effects in controlling micrometastases of PAN and has radiation sensitizing effects in controlling pelvic disease [
This study was designed to show the efficacy of EFI and the results shed much light on the use of EFI. However, there were still some limitations, including the retrospective design. Because this study was not prospective, patients were not well matched in the treatment field groups and CCRT groups. Patients treated with EFI tended to be younger, positive for pelvic node metastases, and to have large-sized tumors. Patients treated with CCRT also tended to be younger and positive for pelvic node metastases. In addition, each group included a different number of patients, making comparisons difficult. In addition, chemotherapeutic regimens differed. From January 2001 to December 2002, 37 patients were treated with 5-fluorouracil and cisplatin. From January 2003 to December 2006, 49 patients were treated with paclitaxel and carboplatin or cisplatin after several studies demonstrated the advantages of these regimens [
We found that EFI did not have a significant impact on survival outcomes in locally advanced cervical cancer patients without PAN involvement. Although this study was conducted retrospectively and had some limitations, these results may be useful when determining the optimal radiation treatment fields in patients. In the absence of CCRT, EFI may be appropriate; however, in patients administered concurrent chemotherapy, EFI may not be effective. Conduct of well-designed prospective or case matched studies will be necessary in order to confirm these results.
Conflict of interest relevant to this article was not reported.
Overall survival curves according to treatment field. EFI, extended field irradiation.
Overall survival curves according to treatment field in patients treated with radiotherapy alone. EFI, extended field irradiation.
Overall survival curves according to treatment field in patients treated with radiotherapy alone. EFI, extended field irradiation.
Overall survival curves according to four different treatment modalities. EFI, extended field irradiation; CCRT, concurrent chemoradiotherapy.
Baseline demographic and clinical characteristics
Total (n=203) | EFI (n=88) | Pelvis only (n=115) | p-value | |
---|---|---|---|---|
Median age (range, yr) | 59 (28-83) | 55 (28-77) | 64 (34-83) | < 0.001 |
< 60 | 107 | 59 (67.0) | 48 (41.7) | |
≥ 60 | 96 | 29 (33.0) | 67 (58.3) | |
ECOG performance status | 0.754 | |||
0 | 145 | 61 (69.3) | 84 (73.0) | |
1 | 55 | 26 (29.5) | 29 (25.2) | |
2 | 3 | 1 (1.1) | 2 (1.7) | |
Initial hemoglobin (g/dL) | 0.462 | |||
≤ 12 | 121 | 55 (62.5) | 66 (57.4) | |
> 12 | 82 | 33 (37.5) | 49 (42.6) | |
Pathology | 0.255 | |||
SqCC | 179 | 75 (85.2) | 104 (90.4) | |
Others | 24 | 13 (14.8) | 15 (9.6) | |
FIGO stage | 0.019 | |||
I B2 | 11 | 6 (6.8) | 5 (4.3) | |
II A | 14 | 8 (9.1) | 6 (5.2) | |
II B | 139 | 50 (56.8) | 89 (77.4) | |
III B | 39 | 24 (27.3) | 15 (13.0) | |
Pelvic LN involvement | < 0.001 | |||
Present | 93 | 59 (67.0) | 34 (29.6) | |
Absent | 110 | 29 (33.0) | 81 (90.4) | |
Tumor size (mm) | 0.002 | |||
≤ 40 | 80 | 23 (26.1) | 57 (49.6) | |
> 40 | 108 | 59 (67.1) | 49 (42.6) | |
Unknown | 15 | 6 (6.8) | 9 (7.8) |
Values are presented as number (range or %). EFI, extended field irradiation; ECOG, Eastern Cooperative Oncology Group; SqCC, squamous cell carcinoma; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph nodes.
Patterns of failure
Total (n=203) | EFI (n=88) | Pelvis only (n=115) | |
---|---|---|---|
Locoregional failure | 22 | 8 (9.1) | 14 (12.2) |
Distant metastases | 24 | 7 (8.0) | 17 (14.8) |
Both LRF and DM | 5 | 5 (5.7) | 0 (0.0) |
Values are presented as number (%). EFI, extended field irradiation; LRF, locoregional failure; DM, distant metastases.
Univariate analyses of prognostic factors for overall survival (OS) and disease-free survival (DFS)
OS |
DFS |
|||
---|---|---|---|---|
5-year OS (%) | p-value | 5-year DFS (%) | p-value | |
Age (yr) | 0.293 | 0.716 | ||
< 60 | 73.3 | 73.2 | ||
≥ 60 | 73.6 | 77.1 | ||
ECOG performance status | 0.003 | 0.075 | ||
0 | 76.2 | 75.8 | ||
1 | 69.1 | 75.6 | ||
2 | 0.0 | 0.0 | ||
Pathology | 0.201 | 0.018 | ||
SqCC | 74.8 | 77.4 | ||
Others | 62.9 | 55.7 | ||
FIGO stage | 0.043 | 0.097 | ||
I | 88.9 | 90.9 | ||
II | 75.5 | 77.6 | ||
III | 62.1 | 60.9 | ||
Pelvic LN involvement | 0.949 | 0.583 | ||
Present | 70.0 | 77.5 | ||
Absent | 76.0 | 73.4 | ||
Tumor size (mm) | 0.940 | 0.970 | ||
≤ 40 | 75.4 | 73.0 | ||
> 40 | 72.9 | 76.7 | ||
Concurrent chemotherapy | 0.001 | 0.035 | ||
Yes | 78.8 | 79.4 | ||
No | 64.6 | 67.7 |
ECOG, Eastern Cooperative Oncology Group; SqCC, squamous cell carcinoma; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph nodes.
Acute and late grade 3-4 toxicities
Total (n=203) | EFI (n=88) | Pelvis only (n=115) | p-value | |
---|---|---|---|---|
Acute | ||||
Hematologic | 9 | 3 (3.4) | 6 (5.2) | 0.535 |
Gastrointestinal | 2 | 1 (1.1) | 1 (0.9) | 0.849 |
Genitourinary | 0 | 0 (0.0) | 0 (0.0) | |
Late | ||||
Gastrointestinal | 2 | 1 (1.1) | 1 (0.9) | 0.849 |
Genitourinary | 4 | 2 (2.3) | 2 (1.7) | 0.786 |
Values are presented as number (%). EFI, extended field irradiation.