Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer worldwide. The prevalence of para-aortic lymph node (PALN) metastasis in these tumors is 10% to 25%.1 The pattern of spread in cervical cancer seems orderly and predictable, from the low pelvis to the high pelvic lymph nodes (PLNs) and the PALN.2,3 Nonetheless, the most common practice for locally advanced cervical carcinoma is still pelvic radiotherapy with concurrent cisplatin. The updated results of the Radiation Therapy Oncology Group Trial 90-01 validate that decision.4
The prospective randomized study of Rotman et al5 demonstrated that prophylactic extended-field, radiation (EFRT) with elective PALN irradiation improved survival and decreased distant metastases. However, late major gastrointestinal complications increased in the EFRT arm (8% vs 4%). In contrast, a study from the European Organization for Research and Treatment of Cancer recommended against the use of prophylactic EFRT.6 More recently, cisplatin-based chemotherapy administered concurrently with pelvic irradiation improved survival among patients with locally advanced carcinoma of the cervix compared with patients treated with EFRT without concurrent chemotherapy.4 However, the 8-year PALN failure rate was 9% in the pelvic radiotherapy arm and 4% in the EFRT arm. This finding was consistent with our previous study that showed that weekly cisplatin plus pelvic radiotherapy might not completely eradicate all microscopic tumors in the PALN, particularly in high-risk subjects.3
In previous trials, EFRT targeting the PALN was delivered with conventional technique.4–14 With this technique, a large volume of healthy organs such as the gastrointestinal tract and bone marrow might be exposed to the high-dose area of the irradiation. This could increase the risk of acute or late toxicities. Currently, intensity-modulated radiotherapy (IMRT) has been shown to decrease the incidence of acute and late toxicities in cervical cancer.15 As a result, 2 retrospective studies have investigated the efficacy of EFRT with IMRT and showed extended-field IMRT (EF-IMRT) with concurrent chemotherapy can be well tolerated, with acceptable acute and early late toxicities.16,17 To optimize the therapeutic ratio, however, there are 2 main considerations. First, it is important to select suitable patients who will really benefit from EFRT because the increased toxicities in high-volume irradiation warrant careful selection. Previous risk stratification studies have indicated PLN status was frequently reported as the major determinant for survival in cervical cancer patients.18,19 Pelvic lymph node–positive patients are recognized at risk of subsequent PALN relapse.1,3,20 The second consideration is how much radiation is sufficient to eradicate microscopic or small-volume cancer cells at the PALNs when adding chemotherapy. In 3 phase 3 trials with radiation alone, a prophylactic PALN dose of 45 Gy was used,4–6 which is the dose most investigators still use in the CCRT era.7,8,10–12,14,16,17 Given that previous studies showed a lower rate of PALN recurrence following EFRT, we hypothesized that dose reduction is feasible in terms of minimizing toxicities without compromising the final outcome. Thus, this study was conducted to examine the clinical outcomes of low-dose prophylactic EFRT plus concurrent weekly cisplatin in PLN-positive and PALN-negative locally advanced cervical cancer. Because the study aimed to test the efficacy of prophylaxis, no patients had clinically involved PALN to avoid contamination of therapeutic effects in those with detectable PALN disease.
METHODS AND MATERIALS
This prospective cohort study included a cohort of 32 patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IB2-IIIB cervical cancer with positive PLN but negative PALN. All were treated with curative CCRT with EF-IMRT between 2007 and 2011 at China Medical University Hospital. All patients received comprehensive pretreatment examinations, including computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET). No patient was observed to have positive PALN or other systemic metastasis. To compare the efficacy of the prophylactic EF-IMRT, the clinical data from historical controls between 2002 and 2007 were retrieved. All PLN-positive patients in this period were included for the comparison. The characteristics of the 2 groups are listed in Table 1. In the treatment period for the control group, IMRT was not commonly applied for cervical cancer patients. For patients in the control group without pretreatment PET, criteria for lymph node involvement was based on the size and morphology of the nodes on CT.1 Except for the external beam radiotherapy technique and the proportion of patients with pretreatment FDG-PET scans, all patient- or treatment-related factors were similar. In addition, the median follow-up duration for EF-IMRT group was shorter because they were treated in the different periods. The study was approved by the institutional review board of China Medical University Hospital.
All patients underwent CT-based planning with custom immobilization. Intensity-modulated radiotherapy plans consisted of 7 coplanar fields using 10-MV photons. The prescription dose to the whole pelvis was 45 Gy in 25 fractions over 5 weeks.
The clinical target volume (CTV) included the gross disease, cervix, parametrium, uterus, superior half of the vagina, cardinal ligament, presacral region, and regional lymph nodes (common, internal, and external iliac). The CTV delineation was similar to that in the recent consensus guidelines on CTV delineation.21 The planning target volume (PTV) was extended from the CTV to account for organ motion and setup uncertainty. We applied a 15-mm planning margin around the cervix, a 10-mm margin around the uterus and vagina, and an 8-mm margin around the remainder of the CTV.
The prophylactic PALN field, consisting of the PALN chain from the superior border of L1 to the L4/L5 interface, was irradiated concurrently with pelvic IMRT with a standard dose of 40 Gy in 25 fractions (dose per fraction = 1.6 Gy). A radiobiological equivalent dose in 2-Gy fractions was 38.7 Gy. To avoid prolongation of the overall treatment time, irradiation of the prophylactic PALN field was withheld if any ≥ grade 4 leukopenia or thrombocytopenia was observed, or the patient was unable to tolerate treatment-related adverse effects assessed during weekly checkups. In choosing a dose of 40 Gy, we hypothesized that an approximate 10% reduction in the prescribed dose of 45 Gy used in 3 phase 3 trials might be feasible for the prophylactic dose in chemoradiotherapy.4–6 Target planning constraints were standardized as follows: (1) more than 97% of the PTV received more than 97% of the prescription dose, (2) less than 1% of the PTV received less than 93% of the prescription dose, and (3) less than 5% of the PTV received more than 107% of the prescription dose. When prescribing a dose of 45 Gy to the whole pelvis, normal tissue planning constraints were consistent and were as follows: (1) less than 50% of the volume of the rectum received greater than 45 Gy, (2) less than 50% of the volume of the bladder received greater than 45 Gy, (3) less than 10% of the volume of the nonrectal bowel received greater than 45 Gy, (4) the spinal cord received a maximum dose less than 40 Gy, and (5) the kidney dose was less than 35% at 16 Gy. No special constraint was used for the adjacent bone or bone marrow.
Following EF-IMRT, the bilateral parametrium was boosted to 50.4 to 54 Gy via the anterior and posterior parallel field technique with rectangular central shielding 4 cm wide. Thereafter, the involved PLNs were sequentially boosted with an external beam dose up to 60 Gy for PLNs with maximal diameters of less than 2 cm and 64 Gy for maximal diameters ≥2 cm.
Conventional External Beam Radiotherapy
For the historical controls, the whole pelvis was treated with 10-MV x-rays via the anterior and posterior parallel opposed fields or box fields. We prescribed a radiation dose of 45 Gy in 25 fractions to the whole pelvis. Generally, a field margin of at least 1.5 cm around the gross tumor was used, as described previously.22 Then, the doses in patients with bilateral parametrial disease and those for the involved PLN were boosted to the same technique as mentioned previously.
After adequate tumor regression, high-dose-rate intracavitary brachytherapy was performed using an iridium Ir 192 remote after-loading technique at 1-week intervals, concurrently with pelvic irradiation or parametrial boosting.22 The standard prescribed dose for each brachytherapy was 6.0 Gy to point A for 4 sessions. The point A dose was reduced to 5.0 Gy for those with higher reference doses to the rectum or bladder, or whose age was older than 70 years. The total prescribed point A doses (external beam radiotherapy + brachytherapy) of a radiobiological equivalent dose in 2-Gy fractions ranged from 69.3 to 84.3 Gy (median, 76.3 Gy).
Chemotherapy consisted of cisplatin delivered weekly at a dose of 40 mg/m2 intravenously, for a maximal dose of 60 mg. The detailed drug administration protocol was described in our previous study.22 Chemotherapy was withheld if any hematologic toxicities of grade 3 or greater were found.
The follow-up protocol was consistent between the 2 different treatment periods. After completion of radiotherapy, patients received regular follow-up every 1 to 2 months for the first year and then every 3 months afterward. A pelvic examination was performed during each follow-up; in addition, tumor markers (squamous cell carcinoma antigen and carcinoembryonic antigen) were checked. A radiographic examination was carried out every 3 to 6 months. Routine urine and stool examinations were done every 6 to 12 months to assess the possibilities of late complications. The Common Terminology Criteria for Adverse Events version 3.0 was used to score the maximum acute and late adverse effects,23 including gastrointestinal, genitourinary, and hematologic toxicities.
A comparison of the categorical variables between the study and control groups was performed using the χ2 test. Student t test was used to compare differences in continuous variables in the 2 groups. Overall survival (OS), disease-free survival (DFS), pelvic relapse-free survival, and distant metastasis–free survival (DMFS) were calculated using the Kaplan-Meier method to compare preliminary results for the 2 treatment regimens. A 2-sided P < 0.05 was considered statistically significant. Patient survival was measured from the date of initiation of radiotherapy to the last follow-up. All statistical analyses were performed using a commercial software package (SPSS 13.0 for Windows; SPSS Inc, Chicago, IL).
Patient Compliance and Treatment-Related Toxicities
Thirty-one patients (97%) completed allocated EF-IMRT, and all finished the planned pelvic IMRT and brachytherapy. The prophylactic PALN irradiation was suspended for 1 patient at a cumulative dose of 25.6 Gy because of grade 3 gastrointestinal toxicities. The acute and late toxicities in EF-IMRT patients are summarized in Table 2. Acute gastrointestinal and genitourinary toxicities and myelotoxicities of grade 3 or greater were seen in 2, 1, and 18 patients, respectively. Eighteen patients (56%) developed hematologic toxicities of grade 3 or greater (n = 18, leukopenia; n = 4, thrombocytopenia). All events were observed after the fifth week of chemoradiotherapy. At this time, most patients had completed the prophylactic PALN irradiation. The total length of treatment including brachytherapy ranged from 44 to 72 days (median, 51 days). Four patients had treatment courses protracted more than 8 weeks because of adverse effects (n = 1, urinary tract infection; n = 1, pneumonia; n = 2, grade 4 thrombocytopenia). The treatment breaks occurred mainly at 6 to 8 weeks. However, the allocated external beam boost to the involved PLN and brachytherapy could be completed with appropriate medical care. All treatment-related toxicities recovered gradually within 1 month after radiotherapy. After a median follow-up duration of 35 months (range, 10–61 months), 1 patient had a late grade 3 gastrointestinal complication (ileus), and another patient had a grade 3 genitourinary toxicity (radiation cystitis). None had ≧ grade 2 hematologic or other late toxicities.
Comparison With Historical Controls
In the EF-IMRT group, 3 patients died of recurrent tumors at the time of analysis. Two patients experienced cervical recurrences, 1 had infield PLN relapse, and 5 patients developed out-field distant recurrences (n = 2, lung; n = 1, liver and bone; n = 1, lower neck lymph node; n = 1, peritoneal carcinomatosis). None had concurrent or isolated PALN relapse. The failure pattern and proportion of distant metastasis changed compared with those in the historical controls, as summarized in Table 3. The incidence of out-field metastasis for the EF-IMRT and control group was 15.6% and 51.1%, respectively. Eighteen patients (38%) in the control group had clinical PALN relapse. The 3-year actuarial OS, DFS, and DMFS for the study cohort and historical controls were 87% versus 62% (P = 0.02), 82% versus 54% (P = 0.02), and 79% versus 57% (P = 0.01), respectively. The curves are depicted in Figures 1, 2, and 3. In contrast, the 3-year pelvic relapse-free survival was similar in the 2 groups (90% vs 86%, P = 0.57). Late gastrointestinal/genitourinary complications of grade 3 or greater in the study and control cohorts were 3.1%/3.1% and 6.4%/4.3%, respectively.
Lymph nodal metastasis in women with locally advanced cervical cancer, together with clinical stage, is the strongest prognostic factor for survival.18,19 The use of pretreatment FDG-PET to detect tumor-containing lymph nodes cannot exclude the existence of micrometastasis in the PALN because of limited resolution of the gamma camera.20,24 In addition, subsequent PALN relapse might be observed after pelvic irradiation with concurrent chemotherapy if occult tumor foci are not completely eradicated by the drugs.3,4 However, the selection criteria for EFRT plus concurrent chemotherapy should be meticulous to avoid unacceptable toxicity from the combined treatment. Previous reports show that patients with PLN-positive cervical cancer should undoubtedly be considered a major high-risk group in developing subsequent PALN relapse and can be selected for EFRT trials.1,3,9,18,20
This is the first prospective study to investigate the prophylactic efficacy of integrating EF-IMRT, high-dose rate brachytherapy, and concurrent weekly cisplatin for PLN-positive and PALN-negative cervical cancer. Given the acceptable toxicities in the study group, our current irradiation strategy for positive PLNs is applicable for this patient setting. In the CCRT era, Malfetano et al11 first reported the efficacy of weekly cisplatin with prophylactic EFRT and low-dose-rate brachytherapy in a cohort of 67 women with no suspicious radiographic PALN. Seventy-five percent were alive without evidence of disease at a mean follow-up of 47.5 months. Comparisons between that study and the present one are not straightforward because our study cohort was confined to PLN-positive patients. In addition, all nodal disease was confirmed by PET scan, which seems to be more sensitive than magnetic resonance imaging or CT for detection of PLN.25 This is because CT and magnetic resonance imaging cannot differentiate metastatic nodes from hyperplastic nodes of similar size. Because patients with observable PALN are more vulnerable to synchronous or subsequent systemic disease, the therapeutic gain for the PALN field would be blurred when reporting the final outcome. In several studies of EFRT plus concurrent chemotherapy,7–10,12–14,16,17 the experimental cohort was usually composed of some patients with detectable PALN disease. Thus, EFRT would be considered a therapeutic method instead of a prophylactic approach, as in our study and other trials.4–6,11
Our study disclosed several novel findings. First, a prescribed dose of 40 Gy in 25 fractions can effectively eradicate microscopic disease at the PALN when integrating pretreatment FDG-PET. All subsequent systemic failures were located beyond the prophylactic PALN field. Currently, the most commonly adopted dose for prophylactic PALN irradiation is 45 Gy, with a reported infield failure rate generally lower than 5%. Kodaira et al9 conducted a prospective trial with a cohort of 40 patients with stage III/IVA disease or stage IB/II with high-risk factors (primary tumor diameter >50 mm or positive lymph node). Prophylactic (36 Gy/20 fractions) or definitive (45–56 Gy) irradiation for PALN was initiated at 6 to 7 weeks after pelvic irradiation. However, this study did not report the details of failure patterns. Thus, the therapeutic effect of 36 Gy in the prophylactic PALN area cannot be compared directly. Because early and late toxicities can be minimized by dose reduction, there is a need to conduct more validation studies using similar dose levels to promote therapeutic gains.
Second, although most previous studies have suggested the majority of patients can achieve good compliance with EFRT plus chemotherapy, our study disclosed acute hematologic toxicities are the major concern in the last half of the entire EF-IMRT period. Thus, careful monitoring of the blood count is essential during this period. In addition, we planned to suspend prophylactic field irradiation or concurrent chemotherapy if any high-grade myelotoxicity was found; the planned pelvic IMRT and brachytherapy were not withheld in any patients. Only 1 patient failed to complete prophylactic PALN irradiation because of intolerable gastrointestinal discomfort. Furthermore, 4 patients (13%) had a protracted treatment course longer than 8 weeks. The patient compliance seemed comparable with previous EFRT studies. In EF-IMRT trials using weekly cisplatin, Gerszten et al16 reported that 2 of 22 patients experienced short treatment breaks because of marrow toxicities. Beriwal et al17 reported that 10 patients (27.8%) experienced myelotoxicities of grade 3 or greater.
Third, failure patterns have changed substantially by integrating EF-IMRT, and the experimental cohort showed a superior OS, DFS, and DMFS compared with the PLN-positive historical controls. Despite the median follow-up duration was 3 years for the study cohort, the trend suggested this approach can be tested or applied widely for this patient setting. With the growing popularity of IMRT for gynecologic cancer in the CCRT era, a phase 3 trial should be conducted to investigate the differences between pelvic IMRT and EF-IMRT for patients with high-risk features, such as those with positive PLN or bulky tumors.
This study had some weakness, such as the limited sample size and follow-up duration in the experimental cohort. Furthermore, our comparative study used a retrospective and historical control. There were several biases in the survival comparison because of variations in the external beam radiotherapy technique, proportion of patients with PET scans, and follow-up duration. Given a lower sensitivity rate in predicting positive lymph nodes on CT compared with that on PET (57.5% vs 74.7%),25 the potential impact of only 53% of women in the control group undergoing pretreatment PET should be taken into account. Accordingly, some proportion of cases in the control group might have detectable PALNs on PET, and the risk of subsequent PALN relapse would be higher if all cancer cells could not be eradicated by weekly cisplatin. Of course, future EF-IMRT studies should comprise a large patient sample with longer follow-up duration, particularly enrolling more patients with high-risk features besides positive PLN.
In summary, EF-IMRT of 40 Gy to the PALN plus concurrent cisplatin can effectively eradicate microscopic disease at the PALN and improve short-term outcomes for patients with PLN-positive stage IB2-IIIB cervical cancer. Despite the major limitation of acute myelotoxicities in the last half of the treatment period, most patients had good compliance. In view of the excellent outcome compared with that of historical controls, this approach can be applied in this patient setting.
The authors thank the Taiwan Department of Health, Cancer Research Centers for Excellence, and the International Research-Intensive Centers of Excellence in Taiwan for grant support.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Carcinoma of the cervix; Extended-field; Radiation; Intensity-modulated radiotherapy; Para-aortic lymph node