Departments of 1 Gynecologic Surgery, 2 Biostatistics, 3 Oncology and 4 Radiotherapy, Institut Gustave Roussy, Villejuif, France
Received 16 June 2003; accepted 9 September 2003
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ABSTRACT |
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The aim of this study was to determine the value of routine follow-up for the detection of recurrence in patients treated for cervical cancer.
Patients and methods:
From 1986 to 1998, 583 women with stage I and II cervical carcinoma were treated with combined surgeryradiation therapy. After treatment, follow-up was based on clinical examination, a systematic Pap smear and radiography (chest X-ray and abdomino-pelvic ultrasonography).
Results:
Forty-five patients had recurrence observed with a delay 6 months following the end of treatment. Thirty-eight patients had symptoms and seven were asymptomatic at the time of their recurrence. Among asymptomatic patients only two recurrences were diagnosed following routine examinations. Survival is similar in asymptomatic and symptomatic recurrent patients.
Conclusions:
In conclusion, follow-up of patients treated for cervical cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrence and does not increase survival.
Key words: cervical cancer, chest X-ray, follow-up, pap smears, recurrence
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Introduction |
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The aim of this retrospective study, based on a large series of 583 consecutive patients, was to evaluate the usefulness of routine follow-up procedures for the detection of recurrent disease following treatment of stage I/II cervical carcinoma.
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Patients and methods |
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Briefly, for patients with stage IB or II tumors of 4 cm in diameter, the treatment consisted of pre-operative utero-vaginal brachytherapy (60 Gy) approximately 6 weeks prior to the operation. Up until 1995, patients with bulky tumors (
5 cm) received pre-operative external pelvic irradiation (20 Gy) followed by vaginal brachytherapy (40 Gy); since 1996, the treatment has been external radiation therapy (45 Gy) with concomitant chemotherapy (cisplatin 40 mg/m2/weekly) for patients with stage >IB2 and/or tumor size >4 cm. Young patients (<40 years) with a small tumor (<2 cm) underwent initial surgery with ovarian conservation and transposition, followed, in most cases, by brachytherapy (60 Gy). Post-operative pelvic irradiation (4045 Gy) was delivered to patients with histologically proven pelvic node involvement (in absence of pre-operative external radiation therapy). Pelvic irradiation (4045 Gy) and cisplatin-containing chemotherapy (40 mg/m2/weekly) were given to patients with metastatic common iliac and/or para-aortic nodes. Post-operative para-aortic irradiation was not performed after complete para-aortic lymphadenectomy.
Women with no residual tumor after the completion of treatment were followed up according to the protocol of our institution. A clinical examination, consisting of a gynecological examination and a Pap smear of the vaginal cuff, was performed every 3 months during the first year, every 4 months during the second year, every 6 months during the third year, and every year thereafter. Chest X-ray and abdomino-pelvic ultrasonography were performed annually until 1995 and thereafter for patients with unfavorable prognostic factors (nodal involvement). Squamous cell carcinoma (SCC) antigen determination and magnetic resonance imaging (MRI) examinations were not routinely used during the period of this study.
Recurrence was defined as the reappearance of cervical cancer 6 months after the end of treatment. Patients with recurrence occurring within 6 months of the completion of their treatment were not included in the present series. Each recurrence that developed in the patients considered as cured was reviewed. The clinical examination, radiographic studies and the histological and cytological specimens were analyzed. The duration of symptoms before detection of recurrence, the site and treatment of recurrences and survival were also studied. Prognostic factors for the occurrence of recurrence were not studied in the present series because they have been precisely defined previously [19].
Statistical analysis
Survival curves were calculated using the KaplanMeier method. Medians were compared using the WilcoxonRank test.
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Results |
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The location of the recurrence was as follows: local pelvic, 25 patients (with pelvic and/or paraortic nodal metastases); distant metastases (except para-aortic node), 13 patients; and local plus metastatic, seven patients. Thirty-two patients had local recurrence and 20 patients a distant metastasis. Patients with local pelvic recurrence had histological confirmation of the recurrent disease. The location of 32 local recurrences was as follows: pelvic alone, 21 patients (centropelvic, 10; lateropelvic, three and extensive pelvic infiltration, eight); nodal metastases (three pelvic and three para-aortic), six patients; and centropelvic plus pelvic nodes, five patients. In 10 patients with centropelvic extension, six had a vaginal tumor, two vaginal with extension to the vulva and perineum, one had a recurrence on the vulva, and one rectal involvement. Of 20 patients with metastases, 12 had isolated metastases (chest, six; supra-clavicular nodes, three; inguinal nodes, two; and in one patient a superior mesenteric node was invaded) and eight multiple metastases (chest, four; liver, four; bone, three; splenic, one; peritoneum, one; skin, one; mediastinal, one; distant nodes, two).
Among the patients with recurrence seven patients were asymptomatic (Table 1; patients 17). In four patients, recurrent disease was discovered at the time of the routine follow-up consultation. Two asymptomatic patients (Table 1; patients 2 and 4) had pelvic recurrences diagnosed during clinical examination (with normal pap smears). Only two asymptomatic patients had recurrence diagnosed using cytological or radiological examinations: the first one had an abnormal pap smear (with a normal clinical examination of the vagina; Table 1, patient 1) and the other had metastases following a routine chest X-ray (Table 1; patient 7). In three asymptomatic patients (Table 1, patients 3, 5 and 6), recurrences (chest, one; upper pelvic cavity, one; and para-aortic nodes, one) were fortuitously diagnosed during a radiological examination (chest X-ray, one; abdominal CT scan, two) performed for other reasons (before a surgical procedure for a pathology not related to the initial cancer). Thirty-eight were seen for various symptoms before their scheduled follow-up consultation. Characteristics of these patients are given in Table 2 (patients with isolated local recurrence) and Table 3 (patients with distant ± local recurrence). The most common symptom was pain (Tables 2 and 3). In eight other patients symptoms included vaginal bleeding (n = 5), cough (n = 3), two with self-detection of mass (supra-clavicular and inguinal nodes: Table 3, patients 30 and 44).
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The median disease-free interval (DFI) (delay between the end of treatment and the discovery of recurrence) was 16 months (range 2128). The DFI of asymptomatic and symptomatic patients were 13 (range 742) and 16 (range 2128) months, respectively (NS). The DFI of patients with distant metastasis and local recurrences were 34 (range 767) and 15 months (range 2128) (NS). Five patients (11%) (all with symptoms) had a recurrence diagnosed after a DFI >5 years (Tables 2 and 3, patients 9, 13, 19, 41 and 42). Location of the recurrent disease in these five patients was as follows: centropelvic, one; lateropelvic, one; pelvic and para-aortic nodes, one; and supra-clavicular nodes, two.
Treatment of patients with asymptomatic recurrence is detailed in Table 1. Treatment of patients with symptomatic recurrences is detailed in Tables 2 and 3 and comprised surgery (14 patients), radiation therapy (seven patients), chemotherapy (22 patients) and radiation therapy (external and/or brachytherapy) (eight patients). In 12 patients more than one modality was combined.
Overall survival for all patients at 2 and 3 years after diagnosis of the recurrence was 25% [95% confidence interval (CI) 14% to 41%] and 11% (95% CI 4% to 25%), respectively. Only three patients (with local recurrences) were alive after 3 years: one of them died at 68 months, the other currently has progressive disease at 56 months and one is alive without apparent disease 44 months after the treatment of nodal pelvic and para-aortic recurrence with chemotherapy. An exploratory laparotomy was performed in this last patient and confirmed remission of the recurrent disease.
The median survival is similar in asymptomatic and symptomatic patients (14 months; Figure 1). All seven patients with asymptomatic recurrence died (within 26 months following the discovery of the recurrence). Only two symptomatic patients (nos 19 and 23) are currently alive (one of them, patient 23, with evolutive disease).
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Discussion |
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The most recent large series by Bodurka-Bevers et al., suggests that surveillance could improve survival by detecting recurrence earlier [17]. The median survival from recurrence of asymptomatic versus symptomatic patients was 42 versus 11 months (P <0.001) [17]. Samlal et al. reached similar conclusions [14]. Furthermore, in the series of Bodurka-Bevers et al., the median survival of asymptomatic patients with pulmonary recurrence (eight patients) was substantially improved (3 years versus 1 year in symptomatic patients) [17]. Both these authors, along with Soisson et al., recommend the inclusion of a routine chest X-ray in follow-up programs [12, 17]. Nevertheless, in our series the median survival of asymptomatic and symptomatic patients is identical (14 months; Figure 1). All four asymptomatic patients with recurrence diagnosed during a radiological examination died. Those results seem to suggest, as in endometrial cancer, that routine radiology should not be performed in asymptomatic patients. But perhaps, in the near future, PET imaging could be helpful in detecting early recurrent disease [20].
Recent studies suggest that serum SCC measurements could be useful in optimizing treatment and detecting recurrences in patients treated for cervical cancer [21]. In the series of Bolli et al., SCC levels were elevated in 81% of recurrences and the delay between elevation and the clinical diagnosis of recurrence was 7 months [22]. Post-treatment follow-up of this marker could therefore be a predictor of recurrence. In a recent paper, even if recurrence was detected earlier, monitoring of SCC levels did not increase survival [22, 23]. Thus, this marker does not seem to be a cost-effective procedure [24]; nevertheless, it could be helpful in the subgroup of patients with important fibrosis and a potential differential diagnosis of recurrent disease.
In conclusion, clinical examination is the most effective method for follow-up of patients with cervical carcinoma treated by radio-surgical combination (with radical hysterectomy). In addition, this follow-up should be performed after 5 years following the end of treatment because late recurrences are observed (11% in present series) [24]. Routine vaginal cytology and radiological studies do not permit earlier detection of recurrences. In the future, the development of new techniques (PET imaging) may be helpful in the follow-up of patients treated for cervical carcinoma.
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FOOTNOTES |
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