Survival Outcome and Prognostic Factors Post Inadvertent Hysterectomy in Carcinoma Cervix Treated With Salvage Chemo-Radiation

doi:10.21203/rs.3.rs-2992680/v1

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Survival Outcome and Prognostic Factors Post Inadvertent Hysterectomy in Carcinoma Cervix Treated With Salvage Chemo-Radiation

https://doi.org/10.21203/rs.3.rs-2992680/v1

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Journal Publication

published 11 Jul, 2023

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Introduction:

The standard of care for treating early invasive cervical cancer is radical hysterectomy or radiation alone while chemo-radiation is a definitive treatment for advanced disease. Occasionally, simple hysterectomy is performed in cancer cervix and these patients merit adjuvant treatment in view of high chances of loco-regional recurrences. Aim of the study was to analyze the survival outcome of these patients treated with salvage chemo-radiotherapy and also to determine the prognostic factors affecting survival.

Materials and methods

The medical records of all patients of cervical cancer post simple hysterectomy outside and who received salvage treatment in our department between 2014 and 2020 were retrieved. The data regarding clinical, treatment details and survival were analyzed.

Results

A total of 198 patients were included. Median follow up duration was 45.5 months. Gross disease and lymphadenopathy was seen in 60% and 28% patients, respectively. The 5-year progression free survival(PFS) and overall survival(OS) was 75% and 76%, respectively. Concurrent chemotherapy alone or in combination with induction chemotherapy using three drug regimens showed better survival compared to those treated by radiation alone. On multivariate analysis, factors found to be adversely affecting OS and PFS were lymph node (LN) size of more than 2cm, non squamous histology, overall treatment time(OTT) of more than 12 weeks and use of non three drug chemotherapy regimen.

Conclusion

Subtotal hysterectomy results in higher incidence of local recurrence of disease. Factors that impair the outcome in this sub-group of patients are gross lymphadenopathy, non-squamous histology and prolong OTT.

Cervical cancer

Inadvertent hysterectomy

Radiotherapy

Treatment outcome

Prognostic factors

Cervical cancer is the fourth most common malignancy also the fourth leading cause of cancer related death in women worldwide. It contributes to 6.5% of all the new cases and 7.7% of all the cancer related mortality in females globally (Sung et al. 2021). Treatment for early stage cervical cancer is either surgery or radical radiotherapy while in patients with advanced disease; radiotherapy with concurrent Cisplatin is the standard of care(Green et al. 2001; Bhatla et al. 2021). Post operative adjuvant treatment is recommended in presence of adverse prognostic factors(Sedlis et al. 1999; Peters et al. 2000a). This disease is more prevalent in rural settings with inadequate infrastructure for both diagnosis and treatment. Very commonly patients from these rural background land up with inappropriate surgery in the form of simple hysterectomy due to various reasons like lack of pre-operative complete evaluation, emergency hysterectomy, false-negative Pap test etc(Roman et al. 1993; Choi et al. 1997; Garg Sonali, Desai Ava, Patel Shilpa, Chauhan Anila 2004; Saibishkumar et al. 2005; Sharma et al. 2011; Liegise et al. 2022). Radical procedures i.e. radical parametrectomy, upper vaginectomy along with pelvic lymph node dissection should be carried out in such patients depending upon status of residual disease and feasibility of resection(Green and Morse 1960; Park et al. 2010). But these procedures are rarely performed due to technical difficulties encountered and lack of trained gynecological oncologist at low and middle income countries, where the disease is far more prevalent. The most frequently administered salvage treatment in clinical practice is concurrent chemo-radiation (CCRT). Presence of gross disease after inadvertent hysterectomy confers poor prognosis, however, less is known about other prognostic factors(Andras et al. 1973; Davy et al. 1978; Roman et al. 1993; Choi et al. 1997; Saibishkumar et al. 2005).

We planned a study to evaluate various non-surgical therapeutic options in patients of carcinoma cervix having undergone inadvertent hysterectomy. The aim of our retrospective study was to analyze the survival outcome of these patients and to determine the prognostic factors affecting survival.

The patients of carcinoma cervix having undergone simple hysterectomy who attended Radiotherapy Out Patient department (RT-OPD) during the period of 2014-2020 were identified. After approval by institute ethical committee (Reference no.-Dean2021/EC/3163), the medical records of all these patients were retrieved and information regarding demographic profile, clinical details, treatment and survival were extracted. Patients who did not attend OPD after treatment completion were contacted telephonically regarding their disease status. Patients were deemed lost to follow up if all the attempts to contact failed.

(a) Initial assessment- All the patients attending RT-OPD were subjected to detailed clinical examination including comprehensive gynecological assessment to document initial disease extent. Routine blood investigation included Complete blood count, Renal function test, Liver function test, Viral markers, Radiological investigations included Chest X-ray, computed tomography scan (CTscan) or Magnetic Resonance Imaging (MRI) of abdomino-pelvic region.

(b) Radiotherapy (RT) – All the patients received adjuvant radiation in the form of External Beam Radiotherapy (EBRT)followed by brachytherapy. The doses of EBRT ranged from 45-50.4Gy in 1.8-2Gy per fraction over 5 weeks. It was delivered on Telecobalt unit or 6 MV accelerator with 2-field or 4-field Box Technique. After the completion of EBRT, intravaginal brachytherapy was delivered by low dose rate (LDR) using Cesium-137 or by high dose rate (HDR) using Iridium-192. Diameter and length of vaginal cylinders to deliver radiation was selected according to patient vaginal anatomy and initial disease extent. Total LDR dose was 15Gy in one fraction and HDR total dose was 9- 16Gy in 1-2 fractions delivered one week apart.

(c) Chemotherapy (CT) -Induction and/or concurrent chemotherapy was administered to all the patients. Adjuvant chemotherapy was given as salvage treatment in cases of recurrence. Cisplatin was most commonly used agent in CCRT, given weekly at a dose of 50mg/m²along with radiation. Carboplatin was used in case creatinine clearance was less than 50 ml/min at a dose of AUC5. Induction CT comprised of Taxane and Platinum based regimen or combination of three drugs consisting of taxanes, carboplatin and 5-fluorouracil.

(d) Statistical Analysis-Statistical analysis was done using SPSS software version 20.0.Overall survival (OS) was defined as the duration from date of registration in our department to death due to any cause. Progression free survival (PFS) was defined from the date of registration to disease progression or disease recurrence both local and distant sites. Descriptive statistics was used to analyze continuous variables and were expressed as mean, median with corresponding standard deviation .Categorical variables were expressed as number and percentages and were analyzed using Chi square test. Univariate analysis was performed to assess important prognostic factors affecting OS and PFS. Survival analysis was done using Kaplan Meier method and groups were compared using log rank test. p value was considered significant if it was less than 0.05 at two tailed test. Multivariate analysis was done using Cox proportional hazard method to identify prognostic factors affecting the survival.

A total of 198 patients were included in this retrospective study. Table 1 illustrates baseline characteristics of the cohort and the treatment outcome. Median age was 50years (range: 28–73). Squamous cell carcinoma (SCC) of the cervix was the most common histopathological type seen in 95% of patients. At the time of presentation, 60% patient had gross residual disease at the vault, of which 72 patients presented with bulky disease defined as > 4cm. Fifty five patients(28%) had positive regional and/or para-aortic lymphadenopathy at presentation. Scar metastasis was seen in 9 patients, in which one had inguinal lymphadenopathy and another had omental deposits at the time of referral.

Table 1

Patient, tumor and treatment characteristics and the outcome
Parameters	n (%)
Age (years) Median (Range) ≤ 50 > 50	50 (28–73) 88 110
Local Disease at presentation Yes No	119 (60) 79 (40)
Lymph nodal (LN) status at presentation Negative Positive Pelvic LN Para-aortic LN Pelvic + para-aortic	143 (72) 50 (25) 1 (0.5) 4 (2)
Primary tumor size at presentation (n = 119) ≤ 2cm 2.1-4cm > 4cm	2 45 72
LN size at presentation (n = 54) ≤ 2cm 2.1-4cm ≥ 4cm	34 (17) 45 (23) 72 (36)
Distant spread at presentation Yes No	9 (4.5) 189 (95.5)
Site of distant spread at presentation (n = 9) Scar metastasis Scar and inguinal Scar and omental	7 (3.5) 1 (0.5) 1 (0.5)
Histological type SCC Adenocarcinoma Clear cell carcinoma	188 (95%) 7 (3.5) 3 (1.5)
Grade 1 2 3 Unknown	39 (20) 46 (23) 20 (10) 93 (47)
Lymphovascular space invasion (LVI) Positive Negative Unknown	25 (12) 21 (11) 152 (77)
Margin status Positive Negative Unknown	20 (10) 26 (13) 152 (77)
Parametrial status Positive Negative Unknown	3 (1) 31 (16) 164 (83)
Pathological Lymph node involvement Positive Negative Unknown	14 (7) 23 (12) 161 (81)
Treatment group CT-RT CT-CCRT CCRT alone	78 (40) 56 (28) 64 (32)
Pre RT Chemotherapy regimen Taxane + platinum compound Taxane + platinum compound + 5FU None	76(38) 58 (30) 64 (32)
EBRT machine and technique Cobalt 60 ( Conventional RT) Linear accelerator (3D conformal RT)	179 (90) 19 (10)
Dose of EBRT 46Gy/23# 45Gy/25# 50Gy/25# 50.4Gy/28#	157 (79) 32 (16) 2 (1) 7 (4)
Type of brachytherapy LDR HDR	74 (37) 124(63)
Total Dose of brachytherapy 15Gy/1# 9.6Gy/1# 14Gy/2# 16Gy/2#	74 (37) 43 (22) 24 (12) 57 (29)
RT duration (weeks) Median (Range) ≤ 8 9–10 ≥ 10	7 (5–19) 157 (79) 28 (14) 13 (7)
Overall treatment time (weeks) ≤ 8 9–12 ≥ 12	64 (32) 22 (11) 112 (57)
Recurrence Yes No	45 (23) 153 (77)
Recurrence pattern Local Distant Loco-regional Local + distant Locoregional + distant None	9 (4.5) 19 (10) 5 (2.5) 7 (3.5) 5 (2.5) 153 (77)
Site of distant metastasis (n = 31) Liver Scar Liver and scar Lung Bone Omental SCF	10 5 3 3 4 4 2
Last follow up status of patient Alive Dead Lost on follow up	128 (65) 42 (21) 28 (14)
Progression free survival (PFS) 5 year PFS Mean (Range) months	75% 51 (3-113)
Overall survival (OS) 5 year OS Mean (Range) months	76% 52 (3-113)

Table 2

Intergroup comparison according to the type of the treatment received
Characteristics	CT-RT group (n = 78)	CT-CCRT (n = 56)	CCRT (n = 64)	P value
Age (years) ≤ 50 > 50	51 27	34 22	34 30	0.330
Local Disease at presentation Yes No	55 23	42 14	24 42	0.000
Lymph nodal status at presentation Negative Positive	52 26	35 21	56 8	0.020
Tumor size at presentation ≤ 2cm 2.1-4cm > 4cm No disease	1 19 35 23	0 14 28 14	1 12 9 42	0.000
Lymph nodal size at presentation ≤ 2cm 2.1-4cm ≥ 4cm	14 9 2	14 7 0	6 2 0	0.564
Histopathology SCC Adenocarcinoma Clear cell carcinoma	68 7 3	55 1 0	62 2 3	0.057
Differentiation Well differentiated Moderately differentiated Poorly differentiated Unknown	11 16 9 42	15 9 0 32	13 21 11 19	0.541
Overall treatment time ≤ 8 weeks 9–12 weeks > 12 weeks	2 6 70	6 9 41	56 7 1	0.000
RT duration ≤ 8 weeks 8-10weeks > 10 weeks	60 13 5	41 8 7	56 7 1	0.130
Site of disease recurrence Local Distant Loco-regional Local + distant Locoregional + distant	2 9 3 3 4	4 5 1 3 1	3 5 1 1 0	0.660

Adjuvant treatment comprised of three different sequences of CT and RT. Induction CT followed by RT alone was given in 40% of patients, induction CT followed by CCRT in 28% and CCRT only given in 32% of patients. Patients who had clinically no evidence of local disease or lymphadenopathy at the time of presentation were preferably treated by CCRT (Table 1). Among the three groups of type of treatment received, as shown in Table 3, a trend towards improved 5 year OS and PFS was seen in CCRT arm (OS: 79 months, PFS: 76 months) followed by CT-CCRT group (OS: 74 months, PFS: 73 months) and CT-RT group (OS: 71 months, PFS: 70 months).

Table 3

Univariate and multivariate analysis to determine factors affecting overall survival and progression free survival
Prognostic factors	Univariate analysis		Multivariate analysis			Univariate analysis		Multivariate analysis
	5 year OS					5 year PFS
	(%)	p value	HR	95% CI	p value	(%)	p value	HR	95% CI	p value
Age (years) ≤ 40 > 40	64 80	0.105				63 76	0.087
Local Disease at presentation Yes No	72 76	0.241				72 74	0.229
LN status at presentation Negative Positive	58 82	0.011	1.00 2.14	1.12–3.56	0.589	63 81	0.02	1.00 1.54	1.10–2.89	0.457
Tumor size at presentation ≤ 6cm > 6cm	78 47	0.013	1.00 2.34	1.23–3.44	0.761	75 54	0.042	1.00 1.77	1.15–3.04	0.422
LN size at presentation ≤ 2cm > 2cm	83 28	0.000	1.00 8.07	2.86–12.77	0.000	81 26	0.000	1.00 9.56	3.33–17.54	0.000
Histopathology SCC Others	85 50	0.037	1.00 3.51	1.44–8.61	0.019	85 50	0.015	1.00 2.84	1.17–6.93	0.100
Differentiation Grade 1 Grade 2 Grade 3	85 79 77	0.512				74 78 57	0.174
Treatment group CT-RT CT-CCRT CCRT alone	71 74 79	0.819				70 73 76	0.754
PreRT CT regimen 2drug^# 3 drug^* None	62 83 78	0.046	0.14 0.28 1.00	. 0.027-.746 0.058–1.41	0.012 0.124	60 81 78	0.005	0.13 0.31 1.00	0.026-0.70 0.06–1.51	0.008
OTT ≤ 12 weeks > 12 weeks	86 69	0.036	1.00 6.83	1.30-13.33	0.029	81 68	0.047	1.00 7.20	1.47–15.53	0.020
RT duration ≤ 8 weeks 8-10weeks > 10 weeks	76 74 68	0.689				76 72 60	0.572
Brachytherapy type LDR HDR	77 71	0.984				77 70	0.422
OS: Overall Survival, PFS: Progression free survival, RT: Radiotherapy, CT: Chemotherapy, LN: Lymph Node, OTT: Overall Treatment Time, SCC: Squamous Cell Carcinoma, HR: Hazard Ratio
^#Taxane, platinum compound
^*Taxane, Platinum compound, 5 Fluorouracil

Median dose received in EBRT was 46Gy (range45-50.4Gy) and median duration was 7 weeks (Range: 5–19). CCRT was received by 60% patients while remaining received RT alone after induction chemotherapy. One hundred fifty seven (72%) patients completed RT within eight weeks. The median follow up duration was 45.5 months (Range: 3-112). Recurrence of disease either local or distant was seen in 45 patients (Table 1). The 5-year progression free survival (PFS) and overall survival (OS) for the study population was 75% and 76% respectively (Fig. 1a and 1b). At the time of analysis, 65% of patients were alive. Patients who had gross disease of more than 6cm at the time of presentation had inferior outcome compared to those with smaller tumor or no disease. Figure 2a and 2b shows OS and PFS difference according to size of tumor at local site.

On univariate analysis (Table 3), factors found to significantly affect OS and PFS were positive lymphadenopathy at presentation, gross residual disease at vault of more than 6cm in size, gross lymphadenopathy of size more than 2cm, histopathological type, type of induction chemotherapy received and overall treatment time. On multivariate analysis, factors found to be adversely affecting OS and PFS were LN size of more than 2cm (Fig. 2c and 2d), OTT of more than 12 weeks and non three drugs CT regimen (Fig. 3a and 3b). Non-squamous histology was found to be adversely affected the OS and not the PFS (Table 3).

This is one of the limited studies that included a larger population of post hysterectomy carcinoma cervix patients to evaluate long term outcome and factors affecting the survival. To the best of our knowledge, this is the only study that addresses efficacy of different adjuvant treatment options in patients who were treated by upfront sub-optimal surgery.

Simple hysterectomy is considered as an inadequate treatment option in invasive cervical carcinoma with FIGO stage beyond IA. Literatures from across the world suggest that approximately 5–15% of patients at the tertiary referral centres presents with inadvertent hysterectomy(Münstedt et al. 2004; Saibishkumar et al. 2005; Park et al. 2010; Sharma et al. 2011). As reported by a German study ,the incidence of inadvertent hysterectomy in early stage cervical cancer may be as high as 15%(Münstedt et al. 2004). Improper diagnosis and suboptimal surgery further lead to incomplete histopathological report, creating a challenge for the treating oncologist to categorise such patients under high or low risk groups. Similar challenge was faced in the present study also. Overall, the risk of recurrence in such patients has been reported as high as 34.6–60% in the absence of any adjuvant treatment(HW Jones 1943; Park et al. 2010). Hence these patients do merit aggressive adjuvant treatment as soon as feasible for better outcome.

Adjuvant radiotherapy with or without CT as a salvage treatment also provide an excellent 5-year survival rate of 71–90% and local control rate of 80–90% (Perkins et al. 1984; Hopkins et al. 1990; Roman et al. 1993; Hsu et al. 2004). Postoperative RT provides better loco- regional control in high risk early stage cervical cancer patients(Sedlis et al. 1999; Peters et al. 2000b). However, these studies included patients who underwent radical hysterectomy. Our study included patients post inadvertent hysterectomy treated with three different strategies comprising of RT and CT. Although no significant difference in OS or PFS was observed in patients treated in three groups, there was an imbalance in patient characteristics wherein patients with gross residual disease and having lymph nodes were preferentially treated with few courses of CT prior to RT. This finding paves the way to further explore the effectiveness of chemotherapy prior to CCRT in subset of patients having advanced disease in a prospective study setting.

Concurrent Chemotherapy has been a backbone and an integral component in treatment of cervical cancer (Peters et al. 2000a; Green et al. 2001). We analysed that RT alone confers unfavourable outcome even if induction chemotherapy is delivered. Out of the three treatment types, CCRT showed improved PFS, although not significant probably because of lesser number of patients in each group. Furthermore, in the era of sub-optimal RT techniques, salvage surgery showed an advantage over RT in these patients. With the adaptation of more conformal EBRT and advancement in brachytherapy dosimetry, it is theoretically now possible to achieve comparable local control with lesser toxicity. Incorporation of advanced RT techniques like IMRT, VMAT along with utilization of interstitial brachytherapy, may further increase the chances of local control in case of gross residual disease because of the possible dose escalation. Although, this need to be explored and validated by a well-designed prospective study.

Gross residual disease in post hysterectomy patients also carries a poor prognosis(Roman et al. 1993). However, in our study, there was no significant difference observed in patients who had gross disease compared to those without disease (5 year OS: 72 and 76 months respectively, p = 0.241). This can be explained due to the fact that 82% of these patients received induction chemotherapy prior to definitive chemo-radiation. This strategy decreases the gap between surgery and adjuvant treatment while intensifying the treatment overall. Such intensive treatment could have led to improved survival in patients having advanced disease. A significant improvement of 21 months in 5-year OS and PFS was observed with three drug regimen. In case of intact cervical cancer patients, combination of paclitaxel and cisplatin in stage IVB improves progression free survival as reported by Moore et al in their phase III study(Moore et al. 2004).

An important finding in our study was significantly inferior OS and PFS in patients having residual disease of more than 6cm. The 5-year OS was 78 months in patients with local disease of less than 6cm compared to 47 months who had disease of 6cm or more (p = 0.013). Bulky disease has been historically defined as more than 4cm in cervical cancer patients and has been incorporated in staging. In case of intact organ, the disease beyond this size extends from cervical canal to the uterus superiorly and parametrium laterally. However, post hysterectomy, disease extends more along the vaginal wall and caudally protruding into the vaginal cavity. Probably this could be the reason that 4cm size criteria did not showed to affect the survival as the disease was confined to the vaginal cavity. Beyond this size, the lesion invades the nearby organs and deteriorates the outcome. Yan J et al reported pattern of growth in post operated cervical cancer patients and found that 66% of patients had endovaginal growth while 24% had paravaginal extension and in rest, invasion to nearly structures were seen. In their study also 4cm size criteria failed to affect overall survival on multivariate analysis(Yan 2022).

The effect of overall treatment time in fast growing malignancies cannot be ignored. Several publications have documented that local control worsen with prolongation of treatment time(Fyles et al. 1992; Girinsky et al. 1993; Perez et al. 1995). One theory for this impact is that radiotherapy accelerates the repopulation of tumour clonogens, which increases the chance of local relapse in patients who receive longer courses of treatment(Withers et al. 1988).Cervical cancer has a temporal effect that causes about 1% loss of control for every day of delay in treatment completion(Fyles et al. 1992). Radiobiologically, tumor doubling time starts with initiation of therapy, being it chemotherapy or radiation therapy. This is well evident in our study also, that treatment time of more than 12 weeks deteriorated the outcome. This finding re-emphasises to complete the whole treatment within stipulated time including all induction CT.

Involvement of lymph node in carcinoma cervix is a well established prognostic factor and is now incorporated in latest FIGO staging(Bhatla et al. 2021). We found that gross nodal size of more than 2cm resulted in inferior OS and PFS (p < 0.001). 5- year OS and PFS were 28 months and 26 months respectively, in patients with nodal size of more than 2cm compared to 83 and 81 months respectively, in those who had nodal size of 2cm or less. Koh et al. also depicted inferior DFS but not OS in these patients with positive lymph nodes(Koh et al. 2013). However, none of the studies have addressed the size of lymph nodes that affects the outcome. Tumor histology also emerged as one of the prognostic factors, which is in agreement with the report of Hopkins et al., conversely, this is contrary to few other studies (Andras et al. 1973; Davy et al. 1978; Hopkins et al. 1990; Roman et al. 1993).

The major limitation of this study is its retrospective design with inherent patient selection bias. Due to incomplete records, the details of high risk features like LVI, margin status, parametrial involvement and pathological LN involvement were not available in majority of patients. The difference in the toxicity profile also could not be analysed due to missing information.

The significance of our study can be explained in many ways. Firstly, it included a larger cohort of patients of suboptimal surgery salvaged with chemo-radiation with a long-term follow up results. Secondly, our study shows that these patients can still be effectively treated with post operative chemo- radiation. It paves the way for future prospective study with incorporation of induction CT for subset of patients having bulky disease at vault and/or lymph nodes. Furthermore, in the era of conformal radiation the outcome of patients of advanced disease can be improvised with dose escalation.

Inadvertent hysterectomy for locally advanced cervical cancer in India is quite commonly performed; however, these patients can be effectively treated with acceptable outcomes by postoperative chemo-radiation. Poor outcome was seen in patients with presenting with bulky disease, gross lymphadenopathy, non-squamous histology and prolong OTT. CCRT is the standard of care; nevertheless, multi-agent induction chemotherapy can be explored in subgroup of patients having gross disease. It is essential to prevent suboptimal surgery in people with invasive cervical cancer for the potentially best outcome.

Conflict of interest: none

Financial support: none

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No competing interests reported.

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Survival Outcome and Prognostic Factors Post Inadvertent Hysterectomy in Carcinoma Cervix Treated With Salvage Chemo-Radiation

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Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1