Abstract
Background: To evaluate the outcome and discover predictive factors for patients with stage IVA cervical cancer treated with definitive radiation therapy. Patients and Methods: We retrospectively reviewed 34 patients with stage IVA cervical cancer who received definitive radiation therapy between 1992 and 2009. Results: On univariate analysis, statistically significant prognostic factors for improved local control rate (LCR) were absence of pyometra (p=0.037) and equivalent dose in 2 Gy fractions (EQD2) at point A greater than 60 Gy (p=0.023). Prognostic factors for improved progression-free survival (PFS) were absence of pelvic lymph node metastasis at initial presentation (p=0.014), and EQD2 at point A greater than 60 Gy (p=0.023). Conclusion: Patients with stage IVA disease had poor median survival. However adequate radiation dose to point A produced favorable LCR and PFS, therefore efforts should be made to increase the point A dose.
Classical radiation dose distribution of intracavity brachytherapy for cervical cancer was developed to avoid the bladder and rectum as much as possible because these structures can cause severe late morbidities when large amounts of radiation are delivered. However, the dose distribution is usually extended laterally in order to cover parametrial disease spread (1, 2). The International Federation of Gynecology and Obstetrics (FIGO) stage IVA cervical cancer is defined as tumor which directly invades the mucosa of the bladder or rectum (3). Therefore, it is quite challenging to treat such locally advanced cervical cancer by classical radiation therapy techniques. There are limited reports focusing on clinical results of FIGO stage IVA cervical cancer (4-6), which are considered to be far advanced, but for which there remains a chance for cure in contrast to stage IVB disease with distant metastasis. The purpose of the current retrospective study was to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated by definitive radiation therapy.
Patients and Methods
The medical records of patients treated with definitive radiation therapy for pathologically-proven primary invasive cervical cancer at the National Cancer Center Hospital, Tokyo, Japan, between 1992 and 2009 were reviewed retrospectively. From 1992 to 2009, 407 patients with cervical cancer were treated with curative radiation therapy, with or without chemotherapy. The eligible patients for the present study consisted of cystoscopically- or colonoscopically-proven clinical stage T4A cervical cancer. Those patients who had been diagnosed with disease of less advanced than stage T4A tumor but which were revealed intra-operatively as being unresectable due to bladder wall invasion were not included in this analysis. Patients who had distant metastasis including para-aortic lymph node metastasis, who received palliative radiation therapy of less than 50 Gy, and who underwent surgery were excluded from this study. Nine patients without staging computed tomography (CT) were also excluded because status regarding pelvic and para-aorta lymph node metastasis was not obtained. A total of 34 females treated with definitive external-beam radiotherapy (EBRT), with or without high-dose-rate intracavitary brachytherapy (HDR-ICBT), were admitted to this retrospective analysis. All patients underwent pelvic examination, cystoscopy, pyeloureterography, chest X-ray/CT, pelvic CT/magnetic resonance image (MRI), and blood test. Maximum tumor diameters were measured based on the CT/MRI findings. All biopsy specimens were diagnosed at the Department of Pathology of National Cancer Center Hospital.
Treatment. Principles of management of cervical cancer at this Institute were described elsewhere (7). The treatment policy for locally advanced cervical cancer is concurrent chemoradiation therapy (cCRT) with a chemotherapy regimen of weekly cisplatin (40 mg/m2/week), cisplatin (50 mg/m2/3 weeks)-plus-oral S-1 (80-120 mg/body/day), or daily nedaplatin (10 mg/body/day). Concurrent chemoradiotherapy was not performed in patients with insufficient renal function, age over 75 years, or those treated by extended radiation fields for the whole pelvis and para-aortic lymph node (PALN) region. Supportive treatments, such as blood transfusions, were encouraged during radiotherapy.
Radiotherapy. The common EBRT portals included the cervix, as well as the parametrium, the upper part of vagina down to the level of lower border of the obturator foramens, and the draining pelvic lymph nodes up to the level of the common iliac (L4/5 junction). If the primary lesion involved the lower third of the vagina, inguinal regions were also included in the EBRT fields. Patients with inguinal lymph node involvement were excluded from this study. The initial 30-40 Gy was delivered to the whole pelvis with a 4-field box or the anterior-posterior technique and then pelvic irradiation was administered with a central shield (CS) being employed to reduce exposure of organs at risk (OARs). The dose of the whole pelvic irradiation was dependent upon tumor shrinkage, with late responding tumors being irradiated to a higher dose by whole pelvic irradiation. The total pelvic side wall dose was 50 Gy in 25 fractions. Two-dimensional conventional radiotherapy (2DCRT) was employed between 1992 and 2005, and three-dimensional conformal radiotherapy (3DCRT) was used between 2005 and 2009. After the CS was inserted, high-dose rate intracavitary brachytherapy (HDR-ICBT) was performed in 1-2 sessions/week, but EBRT and HDR-ICBT were not carried out on the same day. All brachytherapy was carried out by 192Ir remote after loading system (RALS, MicroSelectron HDR™; Nucletron, Veennendaal, the Netherlands). ICBT with tandem and ovoid applicators was performed with a prescribed dose of 6 Gy in point A using the Manchester method. For dose calculation of ICBT, Plato® (Nucletron) was used. A tandem-cylinder was used only in cases with a vaginal involvement of more than one-third of the total vaginal length or with an extraordinarily narrow vagina. Advanced tumors which did not shrink adequately to initiate HDR-ICBT after whole-pelvic EBRT were usually treated solely by EBRT with shrunk boost fields up to 60-66 Gy.
Follow-up. All patients were evaluated weekly during radiotherapy through physical examination and blood tests. CT and/or MRI scans and cytology were performed 1-3 months after radiotherapy, and physical examination and blood tests were performed regularly every 1-6 months. Disease progression was defined by the response evaluation criteria in solid tumors (RECIST) version 1.1 (8).
Statistical analysis. Information on potential prognostic factors, such as age, initial tumor diameter, vaginal invasion, parametrial invasion, uterine corpus invasion, pyometra, pelvic lymph node metastasis, PALN metastasis, hydronephrosis, tumor pathology, use of concurrent chemotherapy, type of radiation therapy applied, total treatment time, and total point A dose was retrieved from medical charts and CT/MRI findings. Overall survival (OS) rate was estimated from the start of radiation therapy to the date of death, or of the last follow-up. Progression-free survival (PFS) rate was estimated to the date of any disease relapse considered as an event. Patients without relapse who died of another disease or were still alive were censored at the time of death or last follow-up. Local failure includes central and parametrial relapses. The local control rate (LCR) was censored at the time of local failure, death, non-local relapse, or last follow-up. OS, PFS, and LCR were calculated by the Kaplan–Meier method. As a measure of radiotherapeutic intensity, we used the equivalent dose in 2 Gy fractions (EQD2) calculated from the total irradiated dose (D) and each dose (d) with α/β for 10 Gy using the following formula (9);
The survival curves were compared by the log-rank test. For univariate analysis, all of the variables were dichotomized at the median. Statistical significance was set to less than 0.05. All statistical analyses were performed using SPSS Statistics version 18.0 (SAS Institute, Tokyo, Japan).
Patients' characteristics.
Results
Patients' characteristics are summarized in Table I. Between 1992 and 2009, nine patients were clinically diagnosed with tumors of less than T4A but surgically of T4A because of direct tumor invasion of the bladder wall. These patients were excluded from the current study. Thirty-four patients were all diagnosed clinically as having T4A tumor either by cystoscopy or colonoscopic findings without distant metastasis. In the current study, the frequency of cases with bladder invasion was much higher than those with rectal invasion (32 vs. 2). All the patients had parametrial invasion, and most had vaginal and corpus invasion. Twenty-three patients had hydronephrosis at the time of diagnosis and four patients required urinary tract diversion during radiotherapy because of bilateral hydronephrosis. One patient had vesicovaginal fistula at initial presentation. Treatment characteristics are shown in Table II. Eight patients were treated solely by EBRT because tumor shrinkage was inadequate to start HDR-ICBT or because the external os of the uterus could not be found for ICBT. Tandem ovoid applicators were used in the majority of patients (18 out of 26 patients) treated by a combination of EBRT and HDR-ICBT. Concurrent chemotherapy was used in 17 patients who were under 75 years old and with adequate kidney function and good performance status; in these, the combined chemotherapeutic agents used were cisplatin in 12 patients (70.6%), cisplatin-plus-oral S-1 in two (11.8%), and nedaplatin in three (17.6%). Follow-up period was calculated from the start of radiation therapy. After a median follow-up period of 50.9 months (range: 35.7-191 months) for those who were alive at the time of the analysis (November 2012), 5-year OS, PFS, and LCR were 48.3%, 29.1% and 58.7%, respectively. The median survival time (MST) was estimated to be 49 months (95% confidence interval, 7.9-90.1, Figure 1). At the time of analysis, 11 patients were still alive and seven were alive without disease recurrence, while 21 patients had died from recurrent disease and 2 from other causes. Twenty-six out of 34 patients (76.5%) experienced persistent disease or disease recurrence after definitive radiotherapy. Local failure was the most common reason for disease progression, with 15 out of 34 patients (44.1%) experiencing local failure. Regional lymph node failure was rare (3/34, 8.9%), with distant metastasis being more frequent (8/34, 23.5%) than regional failure. Among 15 patients who experienced local treatment failure, eight patients required urinary tract diversion because of direct tumor invasion of the base of the bladder, and three and one patient experienced vesicovaginal and rectovaginal fistula, respectively.
Treatment details.
Kaplan–Meier curves for local control rate (LCR), progression-free survival (PFS) and overall survival (OS).
Univariate analysis was performed on eight different variables to evaluate their potential effect on LCR, PFS, and OS after radiotherapy (Table III). On univariate analysis, statistically significant prognostic factors for improved LCR were absence of pyometra (p=0.037) and EQD2 at point A greater than 60 Gy (p=0.023). The prognostic factors for improved PFS were absence of pelvic lymph node metastasis at initial presentation (p=0.014), and EQD2 at point A greater than 60 Gy (p=0.023). None of the variables was found to be a significant prognostic factor predicting OS, but a trend towards a favorable OS was noted for EQD2 at point A greater than 60 Gy (p=0.078). Figure 2 shows a boxplot of the EQD2 of point A stratified by event for LCR, PFS and OS.
Treatment-related toxicities. Toxicities during and after radiotherapy are listed in Table IV. Hematological toxicity was relatively mild and there was only one case of grade 4 leukopenia. One patient developed sigmoidal colon rupture one month after radiotherapy and required colostomy but is still alive without disease recurrence. One patient died due to obstruction of the gastrointestinal tract. This patient first developed local recurrence in the lower part of the vagina four months after radiotherapy and local relapse was controlled by further HDR-ICBT of 30 Gy in five fractions using a vaginal cylinder. This patient again developed secondary local recurrence in the uterine cervix and was salvaged by a third treatment with HDR-ICBT of 24 Gy in four fractions. This patient developed ileus 44 months after the third HDR-ICBT and died without evidence of disease relapse. One patient developed grade 4 cystitis four months after radiotherapy but anti-coagulant for deep vein thrombosis was used, therefore there is a possibility that such medication might exacerbate the severity of cystitis. After the cessation of anti-coagulant, cystitis subsided by itself. There was no radiation-related vesicovaginal or rectovaginal fistula formation.
Results of univariate analysis for local control rate, progression-free survival, and overall survival.
Discussion
Stage IVA cervical cancer is infrequent and according to the FIGO annual report 2006 only 3.1% of patients were diagnosed as stage IVA (10, 11). Limited literature exists specifically dealing with stage IVA cervical cancer. In the current study, we evaluated 34 patients with stage IVA disease who were treated with definitive radiation therapy between 1992 and 2009. The MST of 49 months of the entire patient cohort was poor and only seven out of 34 patients were alive without disease progression at the time of analysis (November 2012). As was also shown in the literature (4-6), most stage IVA tumors were diagnosed based on bladder involvement in this study. Patients with stage IVA disease not only had disease directly invading neighboring organs, but they also had several poor prognostic factors, such as parametrial invasion, corpus invasion and hydronephrosis (Table I). It can be considered that the poor prognosis of patients with stage IVA disease was not only due to direct invasion to neighboring organs, but also to the co-existence of such prognostic factors. In this study, local recurrence was the most frequent pattern of disease progression. Therefore, improvement in the initial local therapy might contribute to prolongation of OS. The presence of pyometra at the time of diagnosis was found to be a predictive factor for unfavorable LCR (p=0.037, Table III). Pyometra was considered to be an adverse factor for radiation therapy (12) because hypoxic region surrounding inflammation were found to be radioresistant, therefore quick and adequate drainage is imperative for prompt recovery from inflammation. A cumulative EQD2 of point A greater than 60 Gy was also found to be a predictive factor for favorable LCR and PFS. Although the majority of patients received the combination of EBRT and ICBT, the cumulative EQD2 of point A is relatively low at 63 Gy (range=50-74 Gy) presumably because of the lack of experience using high dose ICBT in the past, the total dose of ICBT was slightly lower than the one used in recent years. Although prognosis of stage IVA cervical cancer is devastating, unlike stage IVB disease, some of patients with tumor stage IVA can be cured with definitive radiation therapy. Therefore it is important to deliver an adequate dose.
A boxplot of the equivalent dose in 2 Gy fractions (EQD2) of point A stratified by event for local control rate (LCR), progression-free survival (PFS) and overall survival (OS).
Toxicity during and after radiotherapy.
Stage IVA cervical carcinoma is associated with fistula formation (5, 6). In this study, there was no fistula formation for patients whose disease was controlled by radiation therapy; however among 15 patients who experienced local recurrence, three and one patient experienced vesicovaginal and rectovaginal fistula, respectively. In addition, eight out of 15 patients required urinary tract diversion because of direct tumor invasion of the base of the bladder. Therefore in order to achieve local control, an adequate radiation dose is necessary for stage IVA disease. Pinn-Bingham et al. reported an excellent local control for advanced cervical carcinoma, including seven cases of stage IVA using HDR interstitial brachytherapy (ISBT) with a LCR for the entire patient cohort of 85.3% (13). Patients with locally advanced cervical carcinoma for whom ICBT is unsuitable should be treated by HDR-ISBT in order to deliver an adequate dose. However, there are patients whose disease does not respond well to EBRT and even HDR-ISBT is unsuitable because of bulky disease. In such patients, an EBRT boost over 60 Gy should be delivered. Matsuura et al. reported favorable local control of stage IVA cervical cancer treated by only EBRT with a 3-year LCR of 57.1% (14). The National Cancer Center Institute Alert of 1999 recommended cisplatin-based cCRT for patients requiring primary radiation therapy for cervical carcinoma. This was based on the results of five randomized trials that evaluated cisplatin-based chemotherapy with radiation for various stages of cervical carcinoma (15-19). Improvement in local control was demonstrated in all of these studies. However, whether addition of chemotherapy will be beneficial for patients with stage IVA disease has not been validated. No impact of cisplatin-based chemotherapy on the outcome of the patients with stage IVA disease was observed in this study. This was presumably due to the small sample size (4, 10). Patients with stage IVA disease had a poor prognosis, with only 3-year survival of only 55.7%. However, an adequate radiation dose to point A confers favorable LCR and PFS, therefore efforts must be made to deliver as great a dosage as possible.
Acknowledgements
Part of this study was financially supported by the Cancer Research and Development Fund 23-A-13 of the National Cancer Center, Tokyo, Japan.
- Received September 1, 2013.
- Revision received October 10, 2013.
- Accepted October 14, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
