research article

Complementary and Salvage Surgeries in the Treatment of Cervical Cancer Persistent Following Chemo Radiation. Experience with 105 Patients.

Alfonso Torres Lobaton1*, Rosalva Barra Martinez2, Maria Yicel Bautista Hernandez5, Carla America Suarez Juarez4, Mónica Alejandra Matta Martínez3, Fred Morgan Ortiz6, Juan Carlos Oliva Posada7, Isidro Siañez Rodriguez8

1Surgeon Oncologist, Technical consultant, Oncology Gynaecology Unit, Surgical procedures, Database and prepared the manuscript, Mexico

2Surgeon Oncologist, Master of Science, Head of Unit of Skin Cancer / Melanomas / Soft Tissue Sarcomas and Bone tumours, Database and revision of the manuscript, Mexico

3Head of the Radiotherapy Unit, Treatment planning, Mexico

4Gynecologist Oncologist, Database, translation and editing, Mexico

5Gynecologist Oncologist, Database and translation, Mexico

6Obstetrician gynaecologist, Master of Science, Health Sciences Research Center, Autonomous University of Sinaloa, Mexico, Statistical analysis, Mexico

7Head Surgeon Oncologist of the Oncological Gynaecology Unit, Surgical procedures, Mexico

8Gynecologist Oncologist, Database, Mexico

*Corresponding author: Alfonso Torres Lobaton, Surgeon Oncologist, Technical consultant, Oncology Gynaecology Unit, Surgical procedures, Database and prepared the manuscript, Mexico

Received Date: 27 September 2022

Accepted Date: 29 September 2022

Published Date: 04 October 2022

Citation: Torres LA, Barra MA, Bautista HMY, Matta MMA, et al (2022) Complementary and Salvage Surgeries in the Treatment of Cervical Cancer Persistent Following Chemo Radiation, Experience with 105 Patients, Ann Case Report 7: 973, DOI: https://doi.org/10.29011/2574-7754.100973

Abstract

Objective: The purpose of this review is to show results of surgical treatment performed 6-12 weeks after chemo radiation, with or without brachytherapy, in patients with locally advanced cervical cancer with documented or suspected tumour.

Material and Methods: This was a retrospective study of patients with cervical cancer treated in the Oncology Service of Hospital General of Mexico during the period 2008-2018 who underwent surgery to perform complementary or salvage surgery due to actual or perceived tumour persistence.

Results: Patients had a median age of 46.5 years (range= 25-71) and underwent 105 surgeries which included 75 hysterectomies with or without lymphadenectomy (71.4%) and 30 pelvic exenterations (28.5%). Major complications occurred in 7/75 (9.3%) of hysterectomies and 9/30 (30.0%) exenterations. In this series, there was no postoperative mortality. In 105 hysterectomies and pelvic exenterations, the Kaplan Meier curves were generated for disease-free survival (DFS) and overall survival (OS) with a median follow-up of 20 months and 24.0 months respectively. Common variables for the 105 hysterectomies and exenterations demonstrated by univariate analysis for (DFS) and (OS) significant differences for age < 35 years (p=0.031 and p=0.051), adenocarcinoma (p=0.023 and p=0.019) and for the absence of lymph vascular infiltration on surgical specimens (p=0.003 and p=0.001). The multivariate analysis for DFS and OS only showed significant differences for the absence vs presence of lymph vascular invasion (p=0.001 and p=0.002). Seventy -five patients treated with hysterectomies had DFS with a mean of 29.4 months and OS of 32.4 months. In the multivariate analysis, Log Rank test showed significant differences for the DFS and OS in favour of class 3 hysterectomy (p<0.0001 and p=0.003) and DFS for the absence of lymph node metastases (p = 0.059). In patients with exenterations, the multivariate analysis for OS demonstrated a significant difference with parametrial infiltration (p=0.012). In this series 13 of 105 (12.5%) patients developed recurrences with 53.8% % being distant.

Conclusions: Post chemo radiation surgery in patients with suspected or documented persistent cervical cancer showed better prognosis for adenocarcinoma as compared to squamous carcinoma and less morbidity in the absence of brachytherapy. The high number of distant metastases in patients with tumour recurrence suggests the importance of administering adjuvant chemotherapy to these at-risk patients.

Keywords: Complementary Salvage Surgeries; Persistent; Cervical Cancer; Chemo radiation

Abbreviations: RT: Pelvic radiation; EBRT: External Beam Radiotherapy; ICBT: Intracavitary Brachytherapy; CT: Chemotherapy; CCRT: Concurrent chemo radiation; EBRTCT: External beam radiotherapy/Chemotherapy; GHM: General Hospital of Mexico; DFS: Disease-free Survival; FIGO: International Federation of Gynaecology and Obstetrics; OS: Overall Survival; PET: Positron Emission Tomography; Gy: Radiation Treatment Unit; SCC: Squamous Cell Carcinoma; AC: Adenocarcinoma

Introduction

Cervical cancer is a serious health problem in developing countries due to its presentation in advanced stages and is the leading cause of death from gynaecological neoplasms [1-3]. The World Health Organization (WHO) estimated in 2020 there will be 105,963 new cases of cancer in women in Mexico, of which 20,691 (19.5%) appeared in the genital tract. Cervical cancer leads the list of gynaecologic cancers in terms of incidence and mortality, with 9,439 new cases (45.6%) and 4,395 deaths (49.6%) [4]. In Mexican institutions such as the National Cancer Institute and the General Hospital of Mexico (GHM) [5,6], the number of affected patients with cervical cancer is only surpassed by those with breast cancer. Cervical cancer is predominantly diagnosed in advanced stages of the disease for which the treatment of choice is a combination of pelvic radiation with concomitant platinum agent-based chemotherapy followed by the application of Intracavitary Brachytherapy (ICBT) [7,8]. Although Chemo radiation (CCRT) maintains its validity for the management of locally advanced cervical cancer, therapeutic schemes have been published that include adjuvant surgery for some of these patients [12-14]. This increases the possibility of adapting the established treatments in order to improve specific oncologic results with conventional therapy. In 2003, the Gynaecologic Oncology Group of the United States of America [12] published data that patients with tumours of 4-6 cm limited to the cervix benefited from better local control of the disease when hysterectomy was added to the pelvic radiation (RT). In 2010, Houvenaeghel et al [13] published data on 35 patients with advanced lesions operated with hysterectomies or pelvic exonerations after receiving concurrent chemo radiotherapy (CCRT). Loco regional control was obtained in 88.6% of patients with a 10-year disease-free survival (DFS) of 66.4%. The authors concluded that adjuvant surgery reduces the risk of local recurrences and increases DFS. Fanfani et al [14] compared the results obtained with CCRT vs. CCRT plus hysterectomies in patients with stage III CC and reported a significant increase in local recurrences in the first group (p = 0.0210), a lower number of deaths in patients undergoing surgery (p = 0.021) and a 3-year DFS of 62.9% and 68.3% respectively (p = 0.0686). Failure to administer intracavitary brachytherapy represents incomplete treatment for patients undergoing CCRT. This deficiency constitutes a reason to consider increasing the external beam radiotherapy (EBRT) dose or to evaluate complementary surgical treatment. Walji et al [8] evaluated both treatments in 19/208 patients in whom incomplete ICBT was administered. Fourteen received an EBRT overdose (7 recurrent and 6 died of tumour activity) and five underwent hysterectomies class 1 or 3, all of whom experienced DFS at 5 years [15]. Recently the radiotherapy unit of our institution underwent a remodelling process during which it was not possible to administer ICBT in patients with cervical cancer who required concurrent chemo radiotherapy (CCRT). Some were channelled to other hospitals to complete their treatment and other patients were considered for complementary surgeries to conclude their treatment. In this setting, we present our experience in 62 patients who underwent surgery which included 56 hysterectomies with or without pelvic lymphadenectomy, 3 exenterations and 3 laparotomies for unresectable tumours. In 3/62 (4.8%) patients, there was a major complication with no operative mortality. An average follow-up of 30 months without tumour recurrence was obtained in 76.2% of all cases. In a subgroup analysis, a 30-month DFS period was obtained in 34/40 (85%) patients vs. 8/13 (61.5%) patients in whom there was a report of tumour activity (p = 0.03). DFS was noted in 12/13 (92.3%) patients in clinical stage I, 27/33 (81.8%) in stage II and 7/14 (50%) in stage III. It was concluded that surgery can be used as an alternative adjuvant treatment for patients with cervical cancer who require CCRT for its management and who cannot receive ICBT [16]. The aim of this publication is to present the results of surgical treatment in 127 patients with locally advanced cervical cancer whose tumour persistence was documented by biopsy, incomplete chemo radiation treatment due to lack of brachytherapy, clinical suspicion and/or by imaging studies when these were available after CCRT or with histopathology of poor prognosis (advanced stage adenocarcinomas) [17-19].

Material and Methods

This is a retrospective study of patients treated in the Oncology Unit of GHM during the period from January 2008 to December 2018 with the diagnosis of locally advanced cervical cancer (either squamous cell carcinoma (SCC) or adenocarcinoma) who received treatment with conventional or incomplete CCRT: External Beam Radiation Therapy 50-54 Gy with linear accelerator: Intensity-modulated radiation therapy (IMRT) or volumetric arc therapy (VMAT) + chemotherapy with Cisplatin or carboplatin at conventional doses. Intracavitary radiotherapy (brachytherapy30 Gy) high 3D rate with Iridium 192 or low dose rate with Cesium 137, or Tele therapy 50-54 Gy plus Chemotherapy with Cisplatin or Carboplatin weekly. The patients were laparotomies 6-12 weeks after concomitant chemo radiation treatment was completed under the following criteria: 1. chemo radiation without brachytherapy, 2. the presence of residual tumour in the cervix and or vagina documented by biopsy, 3. residual tumour in parametria by imaging studies (CT and PET), when available, 4. a clinical suspicion of residual tumour in parametria made by the specialty's professors in the absence of imaging studies; 5. reports of adenocarcinomas in advanced stages in which a less favourable response to conventional treatment has been documented [17-19]. Surgeries were performed according to the following preoperative and trans operative findings [9-15]. Extra facial hysterectomy class 1, [9,12] on suspicion of residual tumour in the cervix and / or vagina for not having received brachytherapy; Class 2 hysterectomy, (Stage IB1:FIGO-2018, in treatment-virgin patients) [3]: central persistence < 2 cm with resection of the internal third of the parametrium without pelvic lymphadenectomy and no suspicion of lymph node metastases or lymphadenectomy with suspected lymph node activity; Class 3 hysterectomy, [9,10,14] advanced stage neoplasia with infiltrating central residual tumour of 3 or >4 cm. Pelvic exenteration for neoplasms with residual tumour in the parametrium or with inability to separate the vesicovaginal or rectovaginal septa in central neoplasms. Pelvic exenterations (PE) were divided as follows: anterior (with Bricker duct), posterior (with resection of the rectum plus definitive colostomy) or total (with Bricker duct or sigmoid duct plus definitive colostomies). The major surgical morbidity was considered to be the complications obtained during the first 30 days following surgery. This included anastomosis dehiscence, bladder dysfunction, pneumonia and intestinal obstruction. The variables analysed included age, type of surgery performed, history of having received chemo radiation (CCRT), clinical stage and pathology reports with or without local or regional residual disease in the surgical specimen (cervix, vagina, uterine body, parametrium), metastases to the adnexa and report of lymph node metastases. For pelvic exenterations, the following variables were also analysed: report of central residual tumour defined as tumour limited to the remains of the cervix and/or vagina, diagnosis of parametrical invasion with or without infiltration to the pelvic wall, histologic evidence of invasion of the bladder or rectum and report of hydronephrosis previously observed through preoperative imaging studies. For age, we selected the analysis of the groups 35 years old and under and 36 years old and greater because a previous publication on prognostic factors for pelvic exenterations for cervical cancer demonstrated that patients aged 35 years and younger had a better prognosis [20]. The clinical classification used was that of the International Federation of Gynaecology and Obstetrics (FIGO) in its 2018 version [3] with consideration for stage I, IB2 and IB3 lesions, Stage II, IIA and IIB lesions and for stage III, IIIA and IIIB neoplasms. For the analysis of the variables, descriptive statistics were used with calculation of means and proportions for numerical and categorical variables. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were assessed using the log-range test. Univariate and multivariate Cox proportional hazards models were used to identify variables that correlated with DFS and overall survival (OS) with 95% confidence intervals being calculated for the odds ratio. All statistical analyses were performed with the SPSS 22.0 statistical program.

Results

During the 11 years analysed, 105 surgical interventions were performed which included 75 (71.4%) complementary or rescue hysterectomies (17 class 1, 46 class 2 and 12 class 3), 30 exenterations, (28.5%):13 total, 14 anterior and 3 posterior. The clinic pathologic characteristics of the 105 patients are shown in Table 1.

Variable

Mean o N

DE o %

Age (years)

46.5

9.8

Age group

   

<35 years

14

13.3

>35 years

91

86.7

Clinical stage

   

 I

17

16.2

IIA

2

1.9

IIB

60

57.1

IIIA

3

2.9

IIIB

20

19.0

IVA

2

1.9

Not Classified

1

1.0

Histologic type

   

Squamous cell carcinoma

57

54.3

Adenocarcinoma

48

45.7

Previous treatment

   

RT+CT (CCRT)

74

70.5

TLT+CT

31

29.5

Surgical specimen with nodes

   

No

80

76.2

Yes

25

23.8

Number of nodes resected (n=63)

2.0

2.9

Lymph node metastasis

   

No

101

96.2

Yes

4

3.8

Central tumor

   

No

54

51.4

Yes

51

48.6

Histopathologic report of tumor in the surgical specimen

   

No

46

43.8

Yes

59

56.1

Lymph vascular infiltration

   

No

88

83.8

Yes

17

16.2

Parametrial infiltration

   

No

102

97.1

Yes

3

2.9

Rectal invasion

   

No

100

95.2

Yes

5

4.8

Invasion of the Uterine body

   

No

103

98.1

Yes

2

1.9

Postoperative recurrence in months(n=35)

12.3

7.5


Table 1: General characteristics of 105 patients with cervical cancer following chemo radiotherapy.

Residual Tumour

Forty-six of 105 (43.8%) patients who were operated upon for curative purposes had a complete response to radiotherapy without residual tumour in the surgical samples. The figures without residual tumour included 39/75 (52.0%) of the hysterectomies: 13/17 (72.4%) class 1, 22/46 class 2 (47.8%) and 4/12 (33.3%) class 3. For pelvic exenterations, the figures were 7 out of 30 patients (23.3%).

Surgical morbidity and mortality

An evaluation of postoperative complications was recorded according to the treatment prior to the surgery and the surgical procedures performed. For the patients who received concurrent chemo radiotherapy, the figures were 15/83 (18.0%) and 1/22 (4.5%) for those with chemo radiation without brachytherapy (p = 0.2912). Major complications were present in 7/75 (9.3%) hysterectomies and 9/30 (30.0%) exenterations. In this series, there was no postoperative mortality.

Complementary or salvage hysterectomies

Seven of 75 patients (9.3%) who had received CCRT had major postoperative complications. Of these, 4/12 (33.3%) were present in class 3 hysterectomies (2 rectovaginal fistulas that required a definitive colostomy, 1 ureterovaginal fistula conservatively managed and 1 with bladder dysfunction which resolved with conservative therapy). In addition, 1 of 46 (2.3%) class II hysterectomies experienced an intestinal obstruction requiring surgery and 2/17 (11.7%) patients with class 1 hysterectomies developed rectovaginal and vesicovaginal fistula requiring a colostomy and ileal duct respectively.

Pelvic exenterations

Major complications occurred in 9/30 (30.0%) patients. Eight of 21 (38.0%) had previously received CCRT and 1/9 (11.1%) tele therapy plus CT. Findings included 5 ureterovaginal fistulas (2 resolved with surgical reoperations, 2 conservatively managed and 1 with nephrostomy), 1 rectovaginal fistula in one anterior exoneration that required a definitive colostomy, 1 dehiscence of the intestinal anastomosis managed conservatively, 1 intestinal obstruction surgically resolved and a medically resolved pneumonia.

Results of surgical treatment

The Kaplan Meier curves for DFS and OS in the 105 hysterectomies and pelvic exenterations showed a median follow up of 20 months and 24.0 months respectively Figure 1.


Mean: 22.6 months (CI 95%: 19.2 – 26.0)

Median: 20.0 months (CI 95%: 14.5 – 25.4)


Mean: 26.3 months (CI 95%: 23.1 – 29.4)

Median: 24.0 months (CI 95%: 20.9 – 27.0)

Figure 1: Kaplan Meier curves for DFS and OS in 105 hysterectomies and pelvic exenterations.

Ninety-two patients (87.6%) had follow-up from 1 to 79 months without evidence of tumour activity at their last evaluation. At 60 months, the figures for DFS and OS were 8.6% and 9.6%, respectively. For DFS and OS, the univariate analysis showed significant differences in favour of age < 35 years (p=0.031 and p=0.051), adenocarcinoma (p=0.023 and p=0.019), and the absence of lymph vascular infiltration (p=0.003 and p=0.001). Tables 2A and 2B. The multivariate analysis for DFS and OS only demonstrated significant differences for the absence vs presence of lymph vascular invasion (p=0.001 and p=0.002) Tables 3A and 3B.

Variable

N

Media

DE

P Value

Age group

     

0.031

<35 years

14

34.86

28.379

 

>35 years

91

22.91

17.258

 

Histologic type

     

0.023

Squamous carcinoma

57

20.58

18.902

 

Adenocarcinoma

48

29.17

19.061

 

Lymph vascular infiltration

     

0.003

No

88

26.9

19.7

 

Yes

17

12.0

11.2

 

Parametria infiltration

     

0.343

No

102

24.8

19.5

 

Yes

3

14.0

8.6

 

Lymph node metastasis

     

0.134

No

101

25.07

19.512

 

Yes

4

10.25

5.500

 

Previous treatment

     

0.080

CCRT

74

26.65

20.592

 

TLT+CT

31

19.39

15.165

 

Table 2A: Univariate analysis of disease-free survival (DFS) for different variables in 105 patients with cervical cancer.

Variable

N

Mean

SD

P value

Age group

     

0.051

<35 years

14

37.07

28.824

 

>35 years

91

26.24

17.276

 

Histologic type

     

0.019

Squamous carcinoma

57

23.65

18.933

 

Adenocarcinoma

48

32.48

19.007

 

Lymph vascular infiltration

     

0.003

No

88

30.1

19.6

 

Yes

17

15

11.5

 

Previous treatment

     

0.112

RT+CT

74

29.64

20.651

 

TLT+CT

31

23.03

15.276

 

Survival analysis was performed using the Kaplan-Meier method. Differences between groups were assessed by using the log-rank test.

Table 2B: Univariate analysis of overall survival (OS) for different variables in 105 patients with cervical cancer.

Variable included in the model

B

SE

Wald

RM (IC 95%)

P value

Age group

0.448

0.314

2.033

1.56 (0.845 - 2.897)

0.154

Histological type

-0.309

0.204

2.302

0.734 (0.492 - 1.09 )

0.129

Previous treatment

0.367

0.223

2.691

1.44 (0.931 - 2.23)

0.101

Lymph vascular infiltration

0.918

0.280

10.736

2.50 (1.44 - 4.33)

0.001

Only variables that were statistically significant in the univariate analysis were analysed in multivariate Cox regression models.

Table 3A: Multivariate analysis of disease-free survival (DFS) for different variables in 105 patients with cervical cancer (Cox Regression).

Variable included in the model

B

SE

Wald

OR (CI 95%)

P value

Age group

0.506

0.310

2.660

1.65 (0.903 - 3.04)

0.103

Histologic type

-0.313

0.203

2.377

0.731 (0.491 - 1.08)

0.123

Lymph vascular infiltration

0.853

0.278

9.433

2.34 (1.36 - 4.04)

0.002

Only variables that were statistically significant in the univariate analysis were analysed in multivariate Cox regression models.

Table 3B: Multivariate analysis of overall survival (OS) for different variables in 105 patients with cervical cancer (Cox regression models).

DFS and OS analysis for histopathologic reports: the presence or absence of tumour activity in these 105 patients showed no statistically significant differences. (P=0.428 and P=0.311).

Complementary or salvage hysterectomies

General characteristics of 75 patients undergoing hysterectomies are shown in Table 4.

Variable

Mean (SD) or Percentage (n)

Age (years)

46.3 (9.2)

Age Groups (years)

 

35 years or minor

13.3 (10)

>35 years

 86.7 (65)

Clinical Stage

 

 I

21.3 (16)

 IIA

61.3 (46)

 IIB

2.7 (2)

 IIIA

12.0 (9)

IIIB

1.3 (1)

No classified

1.3 (1)

Histologic type

 

Squamous carcinoma

45.3 (34)

Adenocarcinoma

54.7 (41)

Previous treatment

 

Radiotherapy plus Chemotherapy (RT + CT)

70.7 (53)

Tele therapy plus Chemotherapy (TLT+CT)

29.3 (22)

Surgical specimen with nodes

 

Yes

21.3 (16)

No

78.7 (59)

Number of lymph nodes resected

5.0 (1.6)

Lymph node metastasis

 

Yes

4.0 (3)

No

96.0 (72)

Central tumour

 

Yes

42.7 (32)

No

57.3 (43)

Tumour in the surgical specimen

 

Yes

48.0 (36)

No

52.0 (39)

Lymph vascular infiltration

 

Yes

4.0 (3)

No

96 (72)

Parametria infiltration

 

Yes

1.3 (1)

No

98.7 (74)

Invasion to the uterine body

 

Yes

1.3 (1)

No

98.7 (74)

Tumour persistence (months)

2.81 (0.99)

Postsurgical recurrence of the tumour (months)

12.5 (8.1)

Table 4: General characteristics of 75 patients undergoing hysterectomies.

Sixty-seven /75 patients (89.3.0%) had a follow-up of one to 60 months without evidence of disease. The mean DFS was 29.4 months and 33 (44.0%) patients had a follow-up of >25 months without evidence of disease. Figure 2.

The mean OS was 32.4 months and 38 (56.7%) patients had an OS of >25 months without evidence of disease. Figure 2.


Figure 2: Disease-free survival and overall survival. 67 Hysterectomies, (29.4 and 32.4 months respectively).

For DFS, the univariate analysis had significant differences for patients aged 35 and under (p=0.004) and for class 3 hysterectomies (p=0.003) Table 5A.

Variable

N

Media

DE

P value

Age Groups (years)

     

0.004

35 years or minor

10

44.0

27.5

 

>35 years

65

25.1

16.8

 

Type of surgery performed

     

0.003

Class 3 Radical Hysterectomy

12

36.7

23.1

 

Class 2 Radical Hysterectomy

46

21.7

15.2

 

Simple Hysterectomy

17

37.4

21.7

 

Table 5A: Univariate analysis of disease-free survival for different variables in 75 patients undergoing hysterectomies.

In the univariate analysis for OS, the following variables were statistical significance: age equal to or less than 35 years (p=0.007) and class 3 hysterectomies (p=0.003) Table 5B.

Variable

N

Media

DE

P value

Age Groups (years)

     

0.007

35 years or minor

10

46.2

28.185

 

>35 years

65

28.7

16.790

 

Type of surgery performed

     

0.003

Class 3 Radical Hysterectomy

12

39.4

22.7

 

Class 2 Radical Hysterectomy

46

25.1

15.3

 

Simple Hysterectomy

17

41.2

21.4

 

Table 5B: Univariate analysis of Overall survival for different variables in 75 patients undergoing hysterectomies.

In multivariate analysis for DFS significant differences were found when comparing class 2 (p<0.0001) and class 3 (p=0.001) hysterectomies vs. class 1 hysterectomies Table 6A.

Variable included in the model

B

SE

Wald

OR (IC 95%)

P value

Type of surgery performed

   

14.778

 

0.001

Class 3 Radical hysterectomy

0.748

0.628

1.42

2.11 (0.617 - 7.2) 3

0.233

Class 2 Radical hysterectomy

1.43

0.378

14.29

4.18 (1.99 - 8.77)

P<0.0001

Surgical specimen with lymph nodes

-0.362

0.568

0.406

0.696 (0.229 - 2.12)

0.524

Lymph nodes metastasis

1.734

0.919

3.559

5.66 (0.935 - 34.33)

0.059

Table 6A: Multivariate analysis for disease-free survival in 75 patients undergoing hysterectomies (Cox Regression).

For the multivariate analysis for OS, statistical significance was noted for age equal to or less than 35 years, (p=0.021), class 2 hysterectomies (p=0.002) and class 3 (p=0.008) hysterectomies vs class 1 hysterectomies and the presence of lymph node metastases (p=0.032) Table 6B.

Variable included in the model

B

SE

Wald

OR (IC 95%)

P Value

Age group

1.076

0.465

5.348

2.933

0.021

Type of surgery performed

   

9.538

 

0.008

Class 3 Radical

Hysterectomy

0.667

0.628

1.128

1.948

0.288

Class 2 Radical hysterectomy

1.002

0.325

9.498

2.724

0.002

Lymph nodes metastasis

1.736

0.810

4.600

5.676

0.032

Table 6B: Multivariate analysis for Overall survival in 75 patients undergoing hysterectomies (Cox Regression).

Differences between groups in 75 patients undergoing hysterectomies were assessed using the Log-Rank Test Figures 3 and 4.



Pelvic exenterations

General characteristics of 30 patients undergoing pelvic exonerations are shown in Table7.

Variable

Mean (SD) or Percentage (n)

Age (years)

46.9 (11.3)

Age Groups (years)

 

35 years or minor

13.3 (4)

>35 years

86.7 (26)

Clinical Stage

 

 I

3.3 (1)

 IIA

6.7 (2)

 IIB

46.7 (14)

 IIIA

3.3 (1)

IIIB

36.7 (11)

IVA

3.3 (1)

Histologic type

 

Squamous carcinoma

76.7 (23)

Adenocarcinoma

23.3 (7)

Previous treatment

 

Radiotherapy plus Chemotherapy (RT + CT)

70.0 (21)

Tele therapy plus Chemotherapy (TLT+CT)

30.0 (9)

Type of surgery performed

 

Anterior Exoneration

46.7 (14)

Total Exoneration

43.3 (13)

Posterior Exoneration

10.0 (3)

Surgical specimen with nodes

 

No

70.0 (21)

Yes

30.0 (9)

Number of lymph nodes resected

1.5 (3.1)

Lymph node metastasis

 

No

96.7

Yes

3.3

Central tumor

 

No

36.7 (11)

Yes

63.3 (19)

Residual tumor in the surgical specimen

 

No

23.3 (7)

Yes

76.7 (23)

Parametria infiltration

 

No

53.3 (16)

Yes

46.7 (14)

Hydronephrosis

 

No

93.3 (28)

Yes

6.7 (2)

Bladder invasion

 

No

86.7 (26)

Yes

13.3 (4)

Invasion to the uterine body

 

No

96.7 (29)

Yes

3.3 (1)

Invasion of the rectum

 

No

83.3 (25)

Yes

16.7 (5)

Tumor persistence (months)

2.6 (1.1)

Postsurgical recurrence of the tumor (months)

12.2 (7.4)

Disease-free survival (months)

18.7 (18.0) Minimum: 2 Maximum: 79

Table 7: General characteristics of 30 patients undergoing pelvic exonerations.

Twenty-five of the 30 patients (83.3%) had a follow-up of 1 to 79 months without evidence of disease with a mean DFS of 18.7 months and OS of 20.2 months Figure 5.

In this series 7/25 (28.0%) patients had a disease-free follow-up of >25 months. The remainder ceased follow-up without evidence of disease during the course of the first 2 years.


Figure 5: Disease-free survival and Overall survival 25 pelvic exonerations (18.7 and 20.2 months respectively).

The univariate analysis for DFS showed variables with statistical significance for prognosis: absence of residual tumour in the surgical specimen (p=0.034) and the report of central tumour (p=0.024) and parametria infiltration (p=0.007). Table 8A In the Univariate analysis of OS, only parametria infiltration influenced prognosis (p=0.030) Table 8B.

Variable

N

Media

DE

P value

Residual tumor in the surgical specimen

     

0.034

No

5

33.8

27.7

 

Yes

20

14.9

13.2

 

Central tumor

     

0.029

No

11

6.3

10.7

 

Yes

19

20.9

19.2

 

Parametria infiltration

     

0.007

No

16

23.5

19.9

 

Yes

14

6.5

9.6

 

Yes

8

18

12.8

 

Table 8A: Univariate analysis of disease-free survival for different variables in 30 patients undergoing pelvic exonerations for cervical cancer.

Variable

N

Media

DE

P Value

Histologic type

     

0.080

Squamous carcinoma

23

16.2

11.9

 

Adenocarcinoma

7

29.0

26.5

 

Parametria infiltration

     

0.030

No

16

25.37

19.490

 

Yes

14

12.21

9.839

 

Invasion of the rectum

     

0.061

No

25

21.80

17.371

 

Yes

5

6.40

2.191

 

Table 8B: Univariate analysis of Overall survival for different variables in 30 patients undergoing pelvic exoneration for cervical cancer.

In the multivariate analysis for DFS, no statistically significant differences were found. Table 9A In the multivariate analysis for OS, only the invasion of the rectum showed significant differences, (p=0.006) Table 9B.

Variable included in the model

B

SE

Wald

OR (IC 95%)

P value

Histologic type

0.009

0.544

0.000

1.009 (0.347- 2.93)

0.987

Central tumor

0.213

0.696

0.094

1.238 (0.316- 4.84)

0.759

Parametria infiltration

1.116

0.685

2.657

3.054 (0.798- 11.6)

0.103

Residual tumor in the surgical specimen

0.416

0.627

0.441

1.516 (0.444- 5.18)

0.507

Table 9A: Multivariate analysis for disease-free survival in 30 patients undergoing pelvic exenterations for cervical cancer (Cox Regression).

Variable included in the model

B

SE

Wald

OR (IC 95%)

P Value

Histologic type

-0.113

0.521

0.047

0.893 (0.322 - 2.47)

0.828

Parametric infiltration

0.717

0.455

2.486

2.048 (0.840 – 4.99)

0.115

Invasion of the rectum

1.752

0.643

7.422

5.769 (1.63 – 20.35)

0.006

Table 9B: Multivariate analysis for Overall survival in 30 patients undergoing pelvic exoneration for cervical cancer (Cox Regression).

Differences between groups were assessed using the Log-Rank Test Figure 6.


Figure 6: Disease-free survival and Overall survival 30 pelvic exenterations. (Log Rank Test).

Tumour recurrences

The number of recurrences was 13/105 (12.3%) during the period of 5 to 29 months after surgery with an average of 12.3 months. This corresponded to 9/75 (12.0%) hysterectomies and 4/30 (13.3%) exenterations. Ten out of 74 (13.5%) patients had a previous history of radiotherapy plus concomitant chemotherapy and 3/31(9.6%) had tele therapy plus chemotherapy. Five out of 105 patients (4.7%) with radical surgery with no residual tumour in the surgical specimens developed tumour recurrences. The includes 3/75 (4.0%) of the hysterectomies and 2/30 (6.6%)

exenterations. In 6/13 cases (46.1%), the recurrences were local or loco regional and distant in 7 (53.8%). In 3 cases (23.0%), the dissemination was regional and distant and the remaining 4 (30.7%) had several distant sites without loco regional activity. We performed additional therapeutic procedures in two patients, both stage IIB adenocarcinoma who received CCRT and class 3 hysterectomy. Case 1: the patient had been treated with incomplete CCRT, had residual tumour in the sample with the neoplasm recurring in the vaginal dome and required treatment with adjuvant ICBT at 30 Gy with a DFS of 36 months. Case 2: the patient had a local residual tumour and a metastatic lymph node and 7 months later had tumour recurrence in the vaginal dome and spleen requiring treatment with 4 cycles of paclitaxel plus vinorelbine and 5 cycles of gemcitabine with complete response demonstrating 24-month follow-up without tumour activity.

Discussion

The role that complementary surgery in patients with local advanced cervical cancer previously treated with CCRT is considered controversial due to surgical morbidity, mortality and oncologic results at 5 years compared to conventional treatment scheme with CCRT alone [11,12,14,21]. Working in an institution without optimal resources for the diagnosis and conventional treatment of advanced CC and the fact that the patients are admitted with advanced neoplasms, lack social security and live far from Mexico City, makes it very difficult to keep them under surveillance. Therefore, our Service decided to implement the treatment plan shown here for patients who received incomplete CCRT [8] or in patients who did receive it but who ended up with a confirmed or suspected residual tumour and/or in patients with local advanced cervical cancer whose response to CCRT is poor [17-19]. Performing surgery a few weeks after the end of conventional treatment offers the advantage of avoiding radiation-induced fibrosis in the pelvic tissues, which will hinder surgical dissection due to inflammation and adhesion formation resulting in an increased risk of morbidity [11]. Of the 105 surgeries performed for curative purposes, 59 (56.1%) had residual tumour with the majority beginning in complementary class 1 hysterectomies (13/17, 72.4%) who did not receive brachytherapy. Sixteen (15.2%) experienced postoperative complications, 13 belonging to the group of 83 patients previously treated with complete CCRT (15.6%) vs. 1 of 22 (4.5%) of those in the incomplete CCRT group. (p = 0.2912) The number of complications included 7/75 (9.3%) in hysterectomies with complete CCRT and 9/30 (30.0%) in exenterations of which 8/21(38.0) had complete CCRT and 1/9 (11.1%) incomplete. The lower number of complications observed in this series in patients without brachytherapy is attributed to the fact that the increased dose of radiation received in the pelvis favors the inflammation and fibrosis processes described, with a higher risk of morbidity during surgical dissection [11]. Major complications in patients treated with salvage surgeries due to persistent or recurrent CC after radiation consists of serious events that must be resolved judiciously. Serious adverse events have been reported in 16-27% of patients treated with hysterectomies after radiotherapy, the majority being class 3 hysterectomies [9,14,22]. In the series by Mazeron et al [22] with 54 cases, the figure was 25.9%; the report by Mabuchi S et al [9] with 31 patients 27%; and in Fanfani et al [14] with 73 patients, the figure was 16.4%. For PE, the numbers of serious adverse events are higher and generally reach 60% or more [20]. In the present series, 9/30 (30.0%) exenterations had major complications, 6 of them with complete CCRT and 1 with incomplete CCRT. The analysis of the 105 patients with common variables and surgeries for curative purposes showed a median OS of 24 months. For DFS and OS, univariate analysis and multivariate analysis of OS showed significant differences in favour of age < 35 years (p=0.031, p=0.051 and p=0.007) adenocarcinoma vs squamous carcinoma (p=0.023 and p=0.019) and for the absence of lymph vascular infiltration (p=0.003 and p=0.001). The multivariate analysis for DFS and OS only showed significant differences for the absence vs presence of lymph vascular invasion. (p=0.001 and p<0.0001). For age, we selected the analysis of the groups 35 years old and under and 36 years old and greater because a previous publication on prognostic factors for pelvic exenteration for cervical cancer demonstrated that patients aged 35 years and younger had a better prognosis [20]. The differences in prognosis observed in the univariate analyses in favour of adenocarcinoma in which conventional therapy does not offer the desired results [17-19] suggests that the treatment modality employed by the authors could be useful in the treatment of advanced lesions of this histologic variety, although it will be necessary to have more data accumulated. Lymph vascular infiltration negatively influenced the prognosis of the 105 patients in the multivariate analyses for DFS and OS (p=0.001 and p=0.003) and has been previously reported [23,24]. For hysterectomies, the OS was 32.4 months and 38 (56.7%) patients were free of disease 25 months and greater during follow-up. The following variables were found with statistical significance in univariate analysis: age equal to or less than 35 years (p=0.004 and p=0.007) and class 3 hysterectomies (p=0.003 and p=0.003). For the multivariate analysis, statistical significance was found for age equal to or less than 35 years (p=0.004 and p=0.021) and class 3 hysterectomies (p<0.001 and p=0.003) suggesting the need for more radical surgical treatment of these patients when hysterectomies are indicated. Mabuchi et al reported [9] 30 radical hysterectomies due to persistent or recurrent CC with the 3-year survival rate being 53%. Fanfani et al [14] compared the results obtained for stage III CC in 77 patients treated with CCRT vs. 73 to whom radical hysterectomy was added to the management without ICBT. The 3-year DFS range was 62.9% for the first group and 68.3% for the second (p = 0.0686). Houvenaeghel et al [13] reported the results in 35 patients in stages IB-IVA treated with CCRT plus surgery with 26 radical hysterectomies (21 with Para aortic lymphadenectomy) and 8 pelvic exonerations. In 17 patients (48.5%), there was a complete response with a reported 10-year DFS of 66.4% of the cases in the presence of lymph node metastases (p=0.032). Also noteworthy is the absence in this series of differences for DFS (p=0.080) and OS (p=0.112) when comparing the results obtained with the use of CCRT vs tele therapy plus chemotherapy. The latter scheme was accompanied by less surgical morbidity (1/22, 4.5%, vs 13/83, 15.6%) which suggests its safe to use in patients who are unable to complete their treatment regimen [8,14]. The results obtained with pelvic exonerations showed failure of surgical treatment in 5/30 (16.6%) patients. DFS and OS for the 25 patients were 18.7 and 20.2 months respectively. The univariate analysis for DFS showed variables with statistical significance for prognosis being the absence of residual tumour in the surgical specimen (p=0.034), the report of central tumour (p=0.024) and parametrial infiltration (p=0.007). For multivariate analysis, parametrial infiltration (p=0.008 and p=0.012), for DFS central tumour (p=0.008) and rectal invasion for OS (p=0.006) were statistically significant. These results are consistent with those reported in the literature. [25,26]. regarding the benefit of adjuvant hysterectomy after concurrent chemo radiation for locally‑advanced cervical cancer is controversial; the met analysis recently published by Weijia Lu et al [27]. Indicated that the recurrence rate may be higher in patients undergoing CCRT without hysterectomy. In this series, 13/105 (12.3%) patients had recurrences and in 7 (53.8%) cases the recurrences were distant, 4 of them without loco regional tumour activity. Eleven patients died with tumour activity and 2 (15.3%) patients diagnosed with adenocarcinoma obtained control of their disease for 36 and 24 months, one with local recurrence through ICBT application that she had not previously received and the other with the combination of chemotherapy agents. The observation that 53.8% of recurrences in this series were distant suggests consideration of chemotherapy for patients with lesions at risk for recurrence with reported parametrical, bladder and/or rectal invasion, lymph vascular infiltration and lymph node metastases.

Conclusions

In this series, 83 patients received complete CCRT treatment with 13 (15.6%) having MC vs 1 of 22 (4.5%) treated with incomplete CCRT. The Kaplan Meier curves showed DFS and OS in the 105 hysterectomies and pelvic exenterations with a median follow up of 20 months and 24.0 months respectively. For complementary or salvage hysterectomies, the mean OS was 32.4 months. For pelvic exonerations, OS was 20.2 months. The analysis of the 105 cases treated with radical surgery demonstrated by univariate analysis statistical significance in favour of age < 35 years and the absence of lymph vascular infiltration. The multivariate analysis for DFS and OS only showed significant differences for the absence vs presence of lymph vascular invasion. In hysterectomies, the multivariate analysis for OS showed the following variables with statistical significance: age equal to or less than 35 years, class 3 hysterectomies and the presence of lymph node metastases. In pelvic exonerations, the univariate analysis for DFS showed variables with statistical significance for prognosis being the absence of residual tumour in the surgical specimen, the report of central tumour and parametrial infiltration. The results obtained in this series with adjuvant or rescue surgeries suggest that it could be used in patients with advanced adenocarcinoma in which the conventional treatment offers less favourable results than those obtained with squamous carcinoma. In this series, 53.8% of tumour recurrences were detected at distant sites with or without tumour in the pelvis, which suggests the benefits of using adjuvant chemotherapy in patients at risk for recurrence.

Conflict of interest: The authors declare that there was no conflict of interest in the preparation of this article.

Funding: The authors declare that there was no financing for the preparation of this article.

Author Contributions: BR, MM and SI developed the database and manuscript development. SA supported translation of the manuscript. BY performed radiotherapy treatment planning. MF performed statistical analysis. OJ performed several of the surgical procedures. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

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