Pattern of cancer recurrence in 320 patients after radical vaginal trachelectomy.

ORIGINAL STUDY

Pattern of Cancer Recurrence in 320 Patients After Radical Vaginal Trachelectomy Mandy Mangler, MD, Malgorzata Lanowska, MD, Christhardt Ko¨hler, MD, Filiberto Vercellino, MD, Achim Schneider, MD, and Dorothee Speiser, MD Objective: The oncological outcome regarding disease-free survival and overall survival after radical vaginal trachelectomy (RVT) is the same as the rates after radical hysterectomy. We aim to analyze predictive and risk factors and death in patients with cervical cancer undergoing fertility preservation by laparoscopic lymphadenectomy and RVT. Methods: Three hundred twenty patients with cervical cancer underwent RVT between March 1995 and February 2013. In our study, we examined recurrence rates analyzed by risk factors. We classified the presence of lymphovascular space invasion, depth of tumor infiltration, tumor size, and tumor grading as risk factors. The mean follow-up time was 48 months. Results: Ten of the 320 patients had cancer recurrence. Recurrence appeared at a mean time of 26.1 months (3Y108 months) after RVT. Five patients died within 8.8 months (4Y15 months) after recurrence was diagnosed. Two of these 5 patients had distant metastasis at the time of recurrence. Five patients were treated successfully by surgery, and 4 patients were treated successfully by chemotherapy. The mean follow-up after the recurrence of these 5 patients is 76 months (6Y120 months). None of the 10 patients with recurrences in our series showed significant high-risk factors. Conclusion: There seems to be no pattern in the recurrence of cancer after RVT. It is strictly mandatory to follow up the patients closely every 3 months after RVT to diagnose recurrence at an early stage so therapeutic options such as chemoradiation are still available. Once distant metastasis occurs, prognosis is not good. Key Words: Recurrence rate in cervical cancer, Early cervical cancer, Radical vaginal trachelectomy, Pattern of cervical cancer recurrence Received July 12, 2013, and in revised form August 27, 2013. Accepted for publication August 27, 2013. (Int J Gynecol Cancer 2014;24: 130Y134)

cervical cancer is a common malignant disease above E arly all in young women who still seek motherhood. 1Y3

Forty-one percent of women with cervical cancer are affected between 20 and 44 years, thus within their reproductive age period.3Y5

Department of Gynecology, Charite´YUniversity Medicine Berlin, Berlin, Germany. Address correspondence and reprint requests to Mandy Mangler, MD, Department of Gynecology, Charite´ Universita¨tsmedizin Berlin, Campus Mitte, Charite´platz 1, 10117 Berlin, Germany. E-mail: [email protected]. Achim Schneider receives honoraria for counseling and support for his fellowship program from Karl Storz, Tuttlingen, Germany. The other authors declare no conflicts of interest. Copyright * 2013 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000012

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It became of increasing interest to these young women to consider optimal oncologic treatment in conjunction with fertility preservation. Nine of 10 young women with cervical cancer will still be treated by hysterectomy. The inability to have children will alter their quality of life.6 Radical vaginal trachelectomy (RVT), as introduced by Daniel Dargent in 1994, is a therapeutic option for young women with cervical cancer in early stage (tumor G2 cm, International Federation of Gynecology and Obstetrics [FIGO] stages IA1 to IB1, V0, pN0) who still wish to have children.1,7Y9 Radical vaginal trachelectomy is always combined with laparoscopic removal of pelvic lymph nodes either as sentinel node biopsy in studies or complete lymphadenectomy.10Y13 Inclusion criteria for radical trachelectomy have to be strictly followed to avoid recurrent disease. Therefore, cancer size should not be more than 2 cm in diameter, as cervical cancer bigger than 2 cm treated by trachelectomy will have a

International Journal of Gynecological Cancer

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Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.



significantly higher recurrence rate than tumors smaller than 2 cm.13 If patients with tumors bigger than 2 cm insist on fertility preservation, neoadjuvant chemotherapy can be applied to reduce tumor size; this concept should only be applied either in studies or after thoroughly informing the patients about the experimental modus and its concomitant risks.10,14,15 Trachelectomy was observed initially in retrospective and later in prospective observational studies to verify its oncologic validity.7,9,16 In the past 2 decades, many different studies showed that this operation, performed by a skilled surgeon, is equivalent to radical hysterectomy relating to oncologic safety.4,11,16Y18 Trials prospectively randomizing RVT versus radical hysterectomy do not exist and are, in practice, hard to carry out.19 Although a high percentage of patients may not seek motherhood immediately after the operation, the preservation of fertility and childbearing function is of great importance to the patients concerned.6Y8 Fertility does not seem to be significantly reduced by radical trachelectomy, with pregnancy rates of up to 75%.9,11,20,21 Patients who have infertility after trachelectomy already presented impaired fertility before the operation in most of the patients.5,21 Pregnancy after RVT is associated with an elevated risk of preterm birth. One third of deliveries occur before the gestational week 32, of which another one third take place before the gestational week 28.11,20 By following special recommendations5 with intense supervision and medical care during pregnancy, the rate of preterm births can be decreased.5,20Y22 All previously released data showed a low risk of recurrence after RVT. Therefore, it seems reasonable to take a therapeutic approach for young women with low-risk early cervical cancer. Even after strict adherence to the inclusion criteria in our cohort of 320 patients treated by RVT in the last 18 years, we observed a total of 10 relapses of invasive disease. All 10 relapses occurred in patients in whom inclusion criteria were strictly respected. In different studies, low- and high-risk factors for recurrence of cervical cancer based on histopathologic analysis have been described.23 However, to date, no clear explanation can be given to patients as to why some cases of early cervical cancer reoccur whereas most do not. In our study, we analyzed the histopathologic patterns of patients with cancer recurrence among our patients.

MATERIALS AND METHODS The study was approved by the Ethics Commission of the Charite´. Informed consent to collect their data was given by all patients. Three hundred twenty patients with cervical cancer underwent RVT between March 1995 und February 2013. Data were recorded prospectively. Before surgery, we performed a complete medical history. - All patients met the inclusion criteria for RVT: - seeking motherhood prospectively, - cervical cancer FIGO stage IA1, lymphovascular space invasion, - cervical cancer FIGO stage IA2 or IB1 G2 cm.

Cancer Recurrence After Trachelectomy

Patients were excluded if the cancer was bigger than 2 cm or if neuroendocrine or other rare tumors were observed and if pelvic lymph nodes were positive for cancer. In all patients with cervical cancer, the pelvic lymph nodes were taken out and examined as a first step either as a complete lymphadenectomy or as sentinel node biopsy, if patients were enrolled in studies. Pelvic lymph nodes were sent for frozen section and had to be free of cancer to proceed with radical trachelectomy during the same procedure. The technique of RVT has been described before.1,4,10 All patients treated by RVT were followed up using a special follow-up protocol5 in our clinic; thus, we had access to all relevant data concerning the patient and the tumor. Prognostic factors independently leading to a poorer prognosis are capillary-lymphatic space involvement, depth of invasion and tumor size, parametrial involvement, and age. Patients with high-risk factors such as positive surgical margins, pathologically confirmed involvement of the pelvic lymph nodes, and microscopic involvement of the parametrium were not included in our study. We classified the presence of lymphovascular space invasion, depth of tumor infiltration, tumor size, and tumor grading as intermediate risk factors in compliance with the guidelines.24Y26 Cancer recurrence was diagnosed either by gynecological examination or magnetic resonance imaging and always confirmed histologically. All metric data are given in median and range. P G 0.05 was considered statistically significant. Differences between both groups (patients with and without recurrence) were analyzed for metric data using the t test as statistical hypothesis test. For comparison of categorical data, the Fisher exact test was used. Data were collected pseudonymously, entered into a database, and evaluated using the statistical program SPSS version 18 (SPSS Inc, Chicago, IL).

RESULTS In 10 (3.1%) of 320 patients, cancer recurrence was observed. The patients were operated on between March 1995 and February 2013. The median follow-up of all patients was 48 months (range, 0Y216 months). Patients had a mean age of 31.8 years (range, 21Y48 years) at the time of surgery. Patients with recurrence were at a median of 31.1 years old (range, 25Y37 years). All patients met the inclusion criteria for RVT as mentioned previously. The distribution of characteristics between the group of patients with and without recurrence is presented in Table 1. Two hundred fifteen patients (69.4 %) had a diagnosis of squamous cell carcinoma, and 93 patients (30%) had a diagnosis of adenocarcinoma. Adenosquamous cancer was found in 4 women (1.3%). Of the cancers, 13.2% were graded as G1, 60% as G2, and 19.4% as G3. Twenty-nine percent of the patients had an invasion of the lymphovascular space. Three percent showed invasion of the vascular space. Parametrial involvement was not observed. Ten patients who met the inclusion criteria for RVT had a recurrence of cancer (Table 2). The mean follow-up time after cancer recurrence was 76 months (range, 6Y120 months). Recurrence appeared at a mean time of 26.1 months (range, 3Y108 months) after RVT.

* 2013 IGCS and ESGO


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TABLE 1. Distribution of characteristics in 320 patients after RVT Characteristics

Data of Recurrence n = 10

Age, yrs FIGO stage IA1 IA2 IB1 G2 cm Histological type Squamous cell cancer Adenocarcinoma Adenosquamous Grading G1 G2 G3 LVSI Follow-up, months

P

Data of Primary Diagnosis n = 310

31.8 (21Y48)

31.1 (25Y37)

0.325*

0 2/10 (20%) 8/10 (80%)

46/310 (14.8%) 66/310 (21.3%) 199/310 (64.2%)

0.367* 1* 0.729*

5/10 (50%) 4/10 (40%) 1/10 (10%)

215/310 (69.4%) 93/310 (30%) 4/310 (1.3%)

0.295* 0.497* 0.147*

1/10 7/10 2/10 4/10 76

41/310 186/310 60/310 90/310 48

1* 0.745* 1* 0.487*

(10%) (70%) (20%) (40%) (6Y120)

(13,2%) (60%) (19.4%) (29%) (0Y216)

*Not significant. LVSI, Lymphovascular space invasion.

TABLE 2. Data of patients with recurrence after RVT Recurrence, No. Patients 1

Recurrence/*Death (m) 4

2

25/*29

3

34

4

7/*22

5

11/*19

6

3

7

40

8

5/*16

9

108

10

24/*30

Stage

Site

Treatment

Adenosquamous pT1a2pN0G2L0V0 Squamous pT1b1pN0G2L0V0 Adenocarcinoma pT1b1pN0G2L1V0 Squamous pT1b1pN0G2L0V0 Adenocarcinoma pT1b1pN0G2L0V0 Adenocarcinoma pT1b1pN0G2L0V0 Squamous pT1b1pN0G2L1V0 Squamous pT1a2pN0G3L0V0 Adenocarcinoma pT1b1pN0G1L1V0 Squamous pT1b1pN0G3L1V0

Cervix

HE, RCT

Cervix

Rad HE, RCT

Cervix

Rad HE

Cervix/Corpus

Exenteration, RCT

Pelvic side wall

Rad HE, RCT

Cervix

HE, RCT

Pelvic side wall

Rad HE, RCT

Pelvic side wall

Rad HE, RCT

Cervix

Rad HE, RCT

Cervix and distant

Chemotherapy

L, Lymphovascular space invasion (0, negative; 1, positive). V, Vascular space invasion (0, negative; 1, positive). HE, hysterectomy; RCT, chemoradiation; and rad HE, radical hysterectomy.

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Five patients died after cancer recurred. Death after cancer recurrence occurred at a mean of 8.8 months (range, 4Y15 months). In one woman, cancer recurred after 108 months. The specimens were compared and matched the initial tumor. Tumor size was equally distributed within the group of patients with recurrence: 4 of 5 patients with recurrence who did not die showed an initial tumor size of FIGO IB1, and 1 of 5 patients showed an initial tumor size of FIGO IA2; exactly the same distribution was found in patients who died owing to cancer recurrence. In comparison to the initial tumor size, cervical cancer FIGO IB1 was slightly but not significantly overrepresented with 80% in the group of recurrences (64.2% in patients with primary diagnosis). P = 0.729. Five patients have not experienced recurrence to date. They were treated by (radical) hysterectomy (n = 5) and/or chemoradiation (n = 4). Patients with a recurrent tumor showed G3 tumors in 20%, capillary-lymphatic space involvement in 40%, and parametrial involvement in 0%. Thus, independent risk factors were not overrepresented. No significant differences were found between the 2 groups.

Cancer Recurrence After Trachelectomy

tumor. Independent risk factors for poorer prognosis were capillary-lymphatic space involvement, depth of invasion and parametrial involvement and age.23Y26 In the first Gynecologic Oncology Group trial evaluating prognostic factors pelvic lymph node metastasis, tumor diameter, deep stromal invasion, capillary lymphatic space tumor invasion, parametrial invasion, and positive resection margins have been identified as independent risk factors most frequently.24,25 The therapy of cervical cancer becomes less locally advanced; some authors recommend not to resect the parametrium and to do either cone resections or simple trachelectomies.13,17 Our long-term results show that recurrences in these young patients occur and have a tragic outcome in 50%. The need to resect the parametrium of patients with tumors bigger than pT1a1 is also based on the findings of lymph nodes in the parametrium.29 These lymph nodes could cause a local recurrence, thus leading to distant metastasis. Therefore, in our experience, it is still recommended to resect the parametrium. Morbidity due to parametrial resection needs to be evaluated in further studies.

SUMMARY

Comment In our cohort of 320 patients treated by RVT in the past 18 years, we observed a total of 10 relapses of the disease. Not all patients who undergo RVTwant to have children in the long term.5,20Y22,27 Therefore, a strict selection of patients including detailed information about the risks after RVT should be offered. The recurrence rate of 3.13% in a mean time period of 48 months (range, 0Y216 months) is similar as described in literature.11,28 Patients for RVT are selected carefully and closely followed up every 3 months after the operation to detect recurrent disease as early as possible. Early discovery of recurrence might lead to a better outcome. If recurrences are detected locally at an early stage or even as precancer lesions, various therapeutic options can be offered, whereas once distant metastasis occurs, therapeutic options are only palliative. In our group of patients with recurrence after RVT, G3 tumors were observed in 20% (2/10). Two patients with G3 carcinoma died of the tumor 16 and 30 months after recurrence. Adenocarcinomas are overrepresented, with 40% in the recurrence list compared to 29% at the date of first diagnosing the cancer. Nevertheless, no deaths after adenocarcinoma have occurred so far. Future patients with G3 tumors and adenosquamous or adenocarcinoma should be informed that the grading and histological type of the tumor might be risk factors for recurrence. There seems to be no clear pattern as to which patients show recurrence after RVT. No special risk factors other than the tendency to slight overrepresentation of high grading and adenocarcinoma in the list of patients with recurrences could be found. Thus, it seems even harder to advice patients with early cervical cancer who wish to preserve fertility. The Gynecologic Oncology Group 49 trial evaluated five risk factors showing a more aggressive tumor spread: depth of invasion, parametrial involvement, capillary-lymphatic space invasion, tumor grade, and gross versus occult primary

Patients with cervical cancer and their family must be extensively advised about the advantages and disadvantages of RVT. Patients should carefully consider whether radical trachelectomy is the best choice of therapy for them and if they want to have children in the future. It seems to be very important to follow up the patients closely to further reduce the recurrence rate. Fifty percent of patients with recurrent cervical cancer died in our study. Once distant metastasis occurs, outcome is not good. If recurrence is found at an early stage, therapeutic options range from operative strategies, such as radical hysterectomy, to chemoradiation, depending on the location and size of the recurrent tumor.

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