Analysis of treatment failures in stage IB–IIA squamous cell carcinoma of the uterine cervix following surgery

Joanna Terlikiewicz Received: 31.01.2017 Accepted: 19.05.2017 Published: 31.05.2017 © Curr Gynecol Oncol 2017, 15 (1), p. 54–67 DOI: 10.15557/CGO.2017.0005 Analiza niepowodzeń leczenia chorych na raka płaskonabłonkowego szyjki macicy w stopniu IB–IIA po leczeniu operacyjnym Analysis of treatment failures in stage IB–IIA squamous cell carcinoma of the uterine cervix following surgery


MATERIAŁ I METODY
Badaniem retrospektywnym objęto 338 chorych na raka płaskonabłonkowego szyjki macicy leczonych na Oddziale Ginekologii Onkologicznej Centrum Onkologii w Bydgoszczy od marca 2002 do września 2015 roku.W celu oceny stopnia zaawansowania choroby nowotworowej pacjentki były poddawane badaniu ginekologicznemu INTRODUCTION C ervical cancer is the second most common malignant neoplasm in the developing countries, while in the developed countries it is the eleventh most frequent one.In Poland, according to the National Cancer Registry data of 2010, cervical cancer is the sixth most common malignant neoplasm in women, following breast cancer, colon cancer, lung cancer, endometrial and ovarian cancer (1,2) .Over the last 10 years the incidence of cervical cancer in Poland has been gradually decreasing.However, the standardized mortality ratio has still been high, which is associated with the diagnosis of a large number of cases of advanced-stage cervical cancer in Poland.The 5-year relative survival rate of cervical cancer patients is 67% in Europe and only 54% in Poland (3)(4)(5) .The use of radical hysterectomy with pelvic and paraaortic lymphadenectomy is a widely accepted method of treatment in stage IB-IIA cervical cancer.The assessment of prognosis takes into account such factors as tumor size, the presence of metastases in the lymph nodes, tumor differentiation grade as well as stromal, lymphovascular and parametrial invasion.If the analysis of postoperative material reveals the presence of recurrence risk factors, adjuvant radiotherapy or radiochemotherapy is used to improve treatment outcomes (3,4,(6)(7)(8) .In patients with pelvic lymph node metastases found in postoperative material the overall survival rates fall by approximately 20-30% compared to patients for whom no nodal spread is found in postoperative material (5)(6)(7)(8) .Despite the use of radical treatment the recurrence rate following surgery with adjuvant radiochemotherapy has been constant -approximately 10-20% (6,7,9,10) .

AIM OF THE STUDY
The aim of the study was to analyze the treatment outcomes of stage IB-IIA cervical cancer patients treated with surgery and subsequent radiochemotherapy.
was used in patients with high recurrence risk factors such as tumor size of >4 cm and pelvic and/or paraaortic lymph node metastases.Teleradiotherapy dosed at 45-50.4 Gy in 25-28 fractions was applied using X-radiation of 15 MV and was combined with HDR brachytherapy dosed at 15 Gy in 2 fractions.Cisplatin-based chemotherapy was used once a week during the whole course of radiation and was dosed at 40 mg/m 2 .Local recurrence was confirmed with imaging and/or histopathological examination in every case.Distant metastases and nodal recurrences were confirmed with imaging in every case.Overall survival was measured from the date of cancer diagnosis to the date of death.Disease-free interval was defined as the time from cancer diagnosis to treatment failure.Overall survival and disease-free interval was predicted using the Kaplan-Meier method.Differences between the curves were described using the log-rank test.

RESULTS
Cancer (squamous cell carcinoma) was confirmed histologically in all patients.The mean age of the patients was 58 years (22-83) and median follow-up lasted 60 months (11-119) The 5-year overall survival rate of patients with FIGO stage IB and IIA cervical cancer was 87% and 70%, respectively.The 10-year overall survival rate for FIGO stage IB cancer was 82% and 70% for stage IIA.These differences were statistically significant (log-rank test: p = 0.0022) (Fig. 1).The chance of 5-and 10-year recurrence-free survival depending on FIGO stage was 83.5% and 81%, respectively,

Ryc. 5. Czas przeżycia całkowitego w badanej grupie chorych w zależności od wielkości guza
Chance of survival (%) Five-and 10-year recurrence-free survival rates in the group of patients with no pelvic lymph node metastases were 86% and 82%, respectively, while in the group of patients with pelvic lymph node metastases the figures were 70% and 70%.These differences were statistically significant (log-rank test: p = 0.0049) (Fig. 4).The chance of 5-and 10-year overall survival in the group of patients with a tumor of <4 cm was 87.5% and 84.5%, respectively.In the group of patients with a tumor of >4 cm the chance of 5-and 10-year overall survival was 74.5% and 74.5%, respectively.These differences were statistically significant (log-rank test: p = 0.0064) (Fig. 5).
In 99 out of 338 (29.3%) patients treatment failure was observed.In 54/99 (54.5%) patients with treatment failure nodal recurrence was diagnosed.In 29/99 (29.2%) subjects the recurrence was found in paraaortic lymph nodes and in 25/99 (25.3%) the recurrence was found in pelvic lymph nodes.In 26/99 (26.3%) patients local pelvic recurrence was diagnosed (Fig. 7).Median time to nodal recurrence was 14 months (paraaortic recurrence -range of 6-102 months, pelvic lymph node recurrence -range of 5-97 months).Median time to central recurrence was 13 months (range of 6-100 months) (Fig. 8).Distant metastases were found in 19/99 (26.3%) patients.These metastases were located in 10 cases in the bones, in 8 cases in the lungs and in 1 case in the liver (Fig. 7).Median time to distant metastases was 21 months.The range of time to bone metastases was 3-110 months, for lung metastases it was 9-122 months and for liver metastasis it was 48 months from treatment completion (Fig. 8).

Piśmiennictwo / References
IA-IIA cervical cancer patients who underwent radical hysterectomy and pelvic lymph node dissection with adjuvant radiotherapy.In a group of 636 patients with squamous cell carcinoma of the uterine cervix the authors recorded a 5.7% treatment failure rate.Locoregional recurrence was observed in 27.8% of patients, nodal recurrence in 50% and distant metastases (in the lungs, liver, other organs) in 22.2% (37) .Please note that although the recurrence rate reported by Lee et al. is significantly lower than in the studied group, the percentage distribution of failures are similar in both studies.
In the analyzed group of patients median time to nodal recurrence was 14 months, time to central recurrence was 13 months and time to distant metastases was 21 months.
In the study by Rotman et al. 82% of all recurrences were observed within 3 years of treatment completion, while 94% of recurrences were found within 5 years.In the group of patients who underwent adjuvant radiotherapy, 66.6% of recurrences appeared within the first 15 months, further 16,6% occurred within 4 years and the remaining recurrences appeared after 4 years from the completion of treatment.In 79% of recurrences a locoregional lesion occurred and 16.6% of recurrences were located beyond the pelvis (36) .

CONCLUSIONS
The results of the analysis confirm the influence of FIGO stage and tumor size on the overall survival of patients with cervical cancer and the influence of pelvic lymph node status on the recurrence-free survival in this group of patients.

Fig. 3 .Ryc. 4 .
Overall survival in the studied group of patients depending on the status of pelvic lymph nodes Czas przeżycia wolnego od wznowy nowotworu w badanej grupie chorych w zależności od stanu węzłów chłonnych miednicznych Fig.4.Recurrence-free survival in the studied group of patients depending on the status of pelvic lymph nodes

Fig. 5 .
Overall survival in the studied group of patients depending on the tumor size . Based on the International Federation of Gynecology and The chance of 5-and 10-year recurrence-free survival in the group of patients with a tumor of <4 cm was 84.5% and 84.5%, while in the group of patients with a tumor of Ryc.8.Mediana czasu wystąpienia niepowodzeń leczenia w badanej grupie chorych (w miesiącach) Fig.8.Median time to treatment failure in the studied group of patients(months) de Putte et al. for a group of patients with stage IB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy with adjuvant radiochemotherapy.