Is Early Stenting Beneficial in Advanced Cervical Cancer : Prospective Study to Determine the Factors Predicting Successful DJ Stent Insertion in Malignant Ureteric Obstruction Secondary to Cervical Cancer

doi:10.21203/rs.3.rs-4663056/v1

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Is Early Stenting Beneficial in Advanced Cervical Cancer : Prospective Study to Determine the Factors Predicting Successful DJ Stent Insertion in Malignant Ureteric Obstruction Secondary to Cervical Cancer

https://doi.org/10.21203/rs.3.rs-4663056/v1

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AIM

To study the clinical, biochemical and radiological factors predicting successful DJ stent insertion in cases of advanced carcinoma cervix with obstructive uropathy in order to proactively stent patients with advanced cervical cancer at an earlier stage

METHODS

Prospective study where 109 patients of advanced Carcinoma cervix with obstructive uropathy were included. DJ stent insertion was considered successful if atleast one ureter was intubated. Clinical, laboratory and imaging parameters analysed with the primary outcome of successful DJS insertion using ROC curves. Sensitivity, specificity and accuracy calculated. FIsher's test and Chi square test used to calculate the value of significance. P < 0.05 considered significant.

RESULTS

11%, 31%, 35%, and 22% of subjects had grade1, grade2, grade 3, grade 4 HUN respectively. DJS was successful in 66 patients. The likelihood of DJS declined with increase in tumor's size (chi sq 17.3, p = 0.0051) and HUN grade (chi sq 13.68, p = 0.003). Plotting ROC curves showed that serum albumin < 2.9 mg/dl (sn − 44% and sp − 83.3%), serum creatinine of > 4.4 mg/dl (sn -75%, sp − 80.95%), and serum urea level of more than 47 mg/dl (sn − 62%, sp = 88%) and eGFR < 11.2ml/min/1.73m² reduced the success of DJ stent.

CONCLUSION

Probability of successful DJ stent depends on grade of HUN, size of the tumour, eGFR ,serum albumin, presence of bladder infiltration and history of radiotherapy. Efficacy of diversion by DJS and PCN insertion with respect to return of renal function were not significantly different.

Carcinoma cervix continues to be one of the leading causes of gynaecological malignancies worldwide. This is more applicable in the developing nations. There are about 14 million new cancer cases detected annually and accounts for about 8 million deaths per year. Cervical cancer has become a public health issue in developing countries, especially in India. India alone contributes to about one-quarter of the worldwide cervical cancer cases.^[1] the death rate of this disease among women aged 30 to 69 is alarmingly high accounting for 17% of all cancer deaths. 1 in 53 women are affected by cervical cancer as compared to about 1 in 100 in the developed countries.^[2]

The fact that roughly 70% of patients report in advanced stages is another management problem.^[3] Our organisation is a tertiary care facility specialised in nephrology and urology, that serves a population which is from poor socio-economic strata. As a result, many patients with advanced cervical cancer who present with obstructive uropathy are referred from oncological hospitals to our institute. The majority of these patients come from low-income, socially marginalised families with little educational experience. As a result, many default to seeking therapy until their symptoms are intolerable. The presenting symptoms are that of obstructive uropathy with electrolyte disturbances, metabolic acidosis and renal failure, electrolyte imbalance, respiratory distress, and potentially fatal renal compromise. Renal replacement therapy in the form of hemodialysis is given to the patients when indicated in order to stabilise these patients. A further difficulty is the fact that the majority of patients are malnourished and extremely anaemic.

The patient cohort includes newly detected carcinoma cervix with obstructive uropathy and also those developing malignant ureteral compression during the treatment process of the primary malignancy. i.e patients who have already received radiation or chemotherapy.

The operative management of carcinoma cervix with obstructive uropathy aims at providing some form of diversion in the form of insertion of a DJ stent or percutaneous nephrostomy (PCN). While inserting a DJ stent is comparatively ideal as the stent is indwelling which alleviates the need to carry a drainage bag, successful insertion of the DJ stent is challenging with high failure rates. This is mainly secondary to the tumour infiltrating the bladder and edema of the bladder mucosa which hinders visualising the ureteric orifice. Extrinsic compression proximal to the vesico-ureteric junction also sometimes prohibits insertion of the intrinsic stent.

Because the pelvicalyceal system is frequently dilated, technically, PCN insertion is simpler in this situation. Nevertheless, there are numerous risks associated with PCN insertion. Firstly, most of these patients are bedridden. The PCN tubes exit the patients from their backs which cause distress and pain to the patients, especially while being nursed in supine position. Studies have also reported Percutaneous nephrostomy causing complications like bleeding, septicemia, tube blockage and accidently tube dislodgement. It has been reported that the rates of PCN dislodgement ranges from 18–63%. The most common complication of PCN was reported to be bleeding. ^[4]

There are no definitive guidelines on the preferred method of urinary diversion. Most authors agreed that decisions should be individualised.^[5] The studies pertaining to obstructive uropathy secondary to carcinoma cervix are scanty. Unfortunately this disease is a poor women’s disease with poor prognosis despite urinary diversion. Although there are a few studies which investigate and compare the role of DJ stenting and external diversion in malignant ureteral obstruction ,studies on its applicability in carcinoma cervix are limited.Studies have shown that, a more distal obstruction and higher degree of HUN are associated with a greater likelihood of stent failure in patients with extrinsic malignant obstruction.^[6] This applies to the topic of interest as obstruction of ureter due to carcinoma cervix is of distal origin.

Given the circumstances, we postulated that there might be a few straightforward variables, which are frequently assessed as part of the preoperative work up, that could serve as markers for successful DJ insertion in patients with ureteral obstruction due to cervical cancer. We have not included any characteristics in the study that would have required the patients to undergo additional testing because of financial constraints.Additionally, assessed the efficacy of DJ stent and PCN in recovering renal function.

After obtaining institutional research review board clearance under the protocol number - INU/RRC/04/2023-24, we conducted a prospective observational study for a period of 1 year ,from November 2022 to November 2023. To achieve a confidence level of 95% with 5% margin of error,a sample size of 108 patients were assessed. Women of all age who presented with obstructive uropathy with biopsy confirmed cervical cancer were included.

We included both newly detected cervical cancer which were chemo or radio naive and Patients receiving treatment for the primary disease in the form of chemotherapy or radiotherapy, as well as patients of recurrent cervical cancer with obstructive uropathy. All patients had to be mentally capable of understanding the instructions and giving valid consent to participate in the study.

Exclusion criteria in the study included patients with Anatomical Kidney abnormalities, Concomitant stone disease,previous history of CKD and those who were Lost of follow-up.

DJ stenting was considered to be successful if it was inserted in at least one of the kidneys. The following clinical data was obtained - Cervical cancer staging, based on the International Federation of Gynecology and Obstetrics (FIGO) classification, History of chemotherapy, radiotherapy, and surgery

Utilizing NCCT KUB imaging, pre-operative data was gathered with respect to the degree of hydronephrosis, diameter of the carcinoma, and the existence of bladder infiltration. Blood urea nitrogen (BUN) levels, creatinine, and albumin were measured as laboratory variables..

Research subjects were divided into two groups: First group consisted of patients who had a successful DJ stenting while the Second group included patients who had a failed DJ stenting and underwent percutaneous nephrostomy insertion.

Categorical data were analysed using Fisher's exact test and Chi-square test, while numerical data were analysed using independent t-tests. Logistic regression analysis for both univariate and multivariate variables were carried out to determine the factors that aided the success of the DJ stents’ insertion.

ROC were plotted to calculate the cut off of various variables, for which the sensitivity, specificity and accuracy were further calculated to serve as a predictor of successful DJ stenting. P < 0.05 to be considered significant.

Mean age of study population was 50.86 years, median age being 49 years. The most frequent age group was 40–50 years(47%). We found that Advanced age, defined as age > 60 years had no significance on the failure of DJS (p = 0.4).

The most common presenting symptom was pain abdomen which was present in 31% of the patients. Bleeding per vagina was the second most common symptom, being the chief complaint in 21% of the patients.

15% of the cohort had Vomiting or anorexia, 14% had swelling of lower limbs, 16% presented with oliguria or anuria. Surprisingly 3% of the patients had no symptoms despite being in obstructive uropathy and were detected incidentally on imaging at the oncological center.Out of the 108 patients, 66 patients had successful insertion of DJS while 42 patients had failure of DJS insertion and had to be treated with Percutaneous nephrostomy.

Table 1

Presenting symptoms with its incidence
SYMPTOMS	PERCENTAGE OF PATIENTS
Bleed PV	21%
Vomitting /anorexia	15%
Swelling of limbs	14%
Pain abdomen	31%
Oliguria/anuria asymptomatic	16% 3%

With respect to the grade of HUN , all the patient's who had grade 1 HUN had successful DJS insertion. For grade 2 HUN , 23 patients had successful DJS and 11 could not be stented. Where as for grade 3 HUN 34 patients could not be stented while 15 patients could be stented. Out of the 24 patient who had grade 4 HUN , 8 could be stented while 16 couldn't not be stented. Grade of HUN had a significant impact on the success of DJS.(chi-square = 13.6483, p .003425). We also found that stage of the disease had a direct correlation with the grade of HUN. (R = 0.3652, p =.000095). On analysis the success of DJS with respect to the stage of the disease we found that , the stage of the disease was not a statistically significant determinant of DJS insertion.(p = 0.5132).

Table 2

Clinical parameters predicting the success of DJS insertion
Sl no	Clinical parameter		DJS successful	DJS unsuccessful	P value
1	HUN
		Grade			0.0034
		1	12	0
		2	23	11
		3	34	15
		4	8	16
2	Stage of HUN				0.512
3	Size of tumour	< 4cm	26	10	0.00159
		> 4cm	40	32
4	Bladder infiltration	Present	16	32	0.16
		Absent	50	10
5	History of radio therapy	Present	23	26	0.008
		Absent	41	16

ROC curve was plotted for the size of the tumour to determine if there was significant cut off value. ROC revealed a cut off of 4 cm, beyond which the likelihood of DJS reduced. (chi square = 17.4344, p .001591). However, specificity and sensitivity to use this as a predictor of successful insertion of DJS was low.

The effect of bladder infiltration on success of DJ stenting was analysed. Out of the 66 patients who had successful DJ insertion, 50 patients had no bladder infiltration whereas 16 patients had bladder infiltration. Out of the 44 patients who had a failed DJS insertion, 32 patients had bladder infiltration and 10 did not have bladder infiltration. However this was not statistically significant.(p = 0.06).

Table 3

Biochemical parameters predicting the success of DJS insertion
Sl no	Biochemical parameter		DJS successful	DJS unsuccessful	P value
1	Serum creatinine	Cut off = 4.4 mg/dl
		< 4.4 mg/dl	50	8	0.002
		> 4.4 mg/dl	16	34
2	Blood urea	Cut off = 66mg/dl			0.0001
		< 66 mg/dl	41	5
		> 66 mg/dl	25	37
3	Albumin	Cut off = 2.9 mg/dl			0.0019
		< 2.9 mg/dl	19	11
		> 2.9 mg/dl	23	55
4	eGFR	Cut off = 11.29 ml/min/1.73ml²			0.001
		< 11.29	47	5
		> 11.29	10	46

We then analysed biochemical parameters for the predictor of DJS insertion. Serum creatinine was performed in all the patients. On plotting the ROC curve, we arrived at a cut off value of 4.4 mg/dl. Creatinine < 4.4 mg/ dl had 80% success rate of DJS insertion with sensitivity of 75%, specificity = 80% ( P = 0.002). On calculating a similar cut off for blood urea, ROC revealed a cut off Value of 66 mg/dl (Fisher exact test statistic value is < 0.00001. The result is significant at p < .05 ). This could be predicted with a Sensitivity of 62% and Specificity of 82%. eGFR was calculated using MDRD formula. ROC provided a cut off value of 11.29ml/min/1.73ml²,with a significant p value (0.001) and sensitivity of 82.46%, specificity of 90.20% and accuracy of 86.11%.

Serum albumin was a significant predictor of successful insertion of DJS. On plotting the ROC curve a value of less than 2.9 mg/ dl had a negative impact on successful insertion of DJ stents with a fair specificity of 89%. However the sensitivity was low, 49%.

49 patients had a history of radiotherapy, out of which stenting was possible in 23 patients. 57 patients had no history of radio therapy, 41 patients of which had successful DJ stent insertion. History of Radiotherapy, significantly affected DJS insertion negatively (chi square = 6.8, p = 0.008).

On multivariate analysis using all the factors mentioned above, we found that presence of bladder infiltration and serum urea were significant factors that could predict the successful insertion of DJS insertion.

Table 4

Table depicting Multivariate analysis of various clinical and biochemical parameters
Intercept	P-value
AGE	0.82504
STAGE OF CA CERVIX	0.169073
DIAMETER OF TUMOUR	0.533067
HUN SFU	0.180764
BLADDER INFILTRATION	0.000413
BLOOD UREA	0.000372
SERUM CREATININE	0.898879
SERUM ALBUMIN	0.122612
HISTORY OF RADIO THERAPY	0.390193

We evaluated the efficiency of both the procedures for the return of renal functions. Mean drop of creatinine on Post operative day 3 was 1.7 mg /dl for DJS group

3.7 mg/dl for PCN group. However the difference was not statistically significant (p > 0.05).Mean drop of creatinine were similar for both the groups at 1 month of follow up, with no statistical significance.

Table 5

Table depicting complications and associated morbidities
Complication and associated morbidities	Number of patients
Pulled out PCN	5
Ca breast	1
Sepsis, perirenal hematoma, thrombocytopenia leading to Death	1
Pleural effusion	2
Ca rectum	1
VVF	3
Pleural effusion and MI	1
Death due to sepsis	2
Adrenal hematoma /mets	1

In our follow up, 5 patients had Pulled out PCN within the first month. 2 patients had pleural effusion, 68% % of the PCN group had bleeding which settled on post operative day 1. 35.6% had PCN tube blockage by clots which had to be flushed with saline.1 patients in our patient cohort had a diagnosis of Ca breast in the follow up period. 3 patients died within our follow up period. One patient developed Sepsis, perirenal hematoma, thrombocytopenia which eventually led to her demise, whereas 2 patients had septicemia which led to their death.

This prospective study investigates the feasibility and predictors of successful DJ stent insertion as a urinary diversion method in patients with advanced cervical cancer and obstructive uropathy. Cervical cancer, being a prevalent issue in developing countries, poses a challenge in its management, especially when patients present in advanced stages with associated obstructive uropathy.

We identified several factors influencing the success of DJ stent insertion, offering valuable insights for clinical decision-making. The grade of hydronephrosis (HUN) emerged as a significant predictor, indicating that as the severity of hydronephrosis increases, the likelihood of successful DJ stent insertion decreases. This underscores the importance of early intervention before the progression of obstructive uropathy.

Tumour size was also found to impact the success of DJ stenting. The study revealed a significant reduction in the probability of successful insertion beyond a tumour size of 4 cm. This information can guide clinicians in assessing the feasibility of DJ stenting based on tumour dimensions.

Serum urea, serum creatinine and hence eGFR, along with serum albumin levels were identified as biochemical markers influencing successful DJ stent insertion. Elevated serum urea and creatinine levels were associated with a decreased likelihood of success, emphasising the importance of preoperative renal function assessment. Additionally, low serum albumin levels correlated with a reduced success rate, highlighting the impact of nutritional status on the procedure's outcome.

Bladder infiltration and a history of radiotherapy were also identified as significant predictors. Patients with bladder infiltration had a lower success rate, potentially due to the anatomical challenges posed by tumour invasion into the bladder. Furthermore, a history of radiotherapy negatively influenced DJ stent insertion success, underscoring the need for careful consideration in such cases.

The study's findings have significant clinical implications, particularly in guiding clinicians in the selection of urinary diversion methods for patients with advanced cervical cancer and obstructive uropathy. Identifying predictive factors allows for a more informed and individualised approach to treatment.

According to a study by Kadek Budi Santosa et al. ^[7] on the predictor of successful DJ stent insertion in advanced cervical cancer, low-grade hydronephrosis, normal albumin levels, lower Federation of Gynecology and Obstetrics (FIGO) staging, and no prior radiation therapy history were factors that contributed to the success of DJS insertion. Similar results have also been obtained from our investigation.

The survival rate of patients with cervical cancer who undergo nephrostomy is dependent on having an ECOG performance level of greater than 1, diabetes mellitus, and ascites, according to a seminal cohort study conducted by Perri et al., (2019) ^[8]. The research also suggested that in these patients, urine diversion could not be helpful. This highlights even more how important it is to diagnose and treat patients with carcinoma cervix early on.

Additionally, a study conducted in south India by Selvaluxmy Ganesarajah et al. on The Prognostic Significance of Hydronephrosis and Role of Ureteric Stenting in Cervical Cancer Patients Treated with Radical Radiation Therapy revealed that before beginning oncological treatment, patients with serum creatinine levels > 1·1 mg/dL or bilateral hydronephrosis should seek relief from obstructive uropathy. ^[9]

A study by Rohan et.al on Outcomes of locally advanced cervical cancer presenting with obstructive uropathy: An institutional audit found that : Patients presenting with obstructive uropathy have median OS less than a year despite urinary diversion. Select cohort with good performance status, small tumor size, and serum creatinine of ≤ 3 mg/dL may be selected for diversion procedures and potential radical treatment ^[10].

A similar study by Bambang Sasongko Noegroho et. al on the Factors Affecting Survival Outcome After Percutaneous Nephrostomy as Palliative Urinary Diversion in Obstructive Uropathy due to Advance Cervical Cancer Patients, concluded that The survival after nephrostomy in advanced cervical cancer patients is largely affected by age, metastasis, and performance status. The choices of doing nephrostomy in those patients should be considering those factors to maximize the benefit over the risk of complications. ^[11]

Our study had a few notable limitations. Relatively small sample size was a noteworthy limitation. Use of serum creatinine and blood urea as a cut off although proved to be significant in our study its practical use to predict the successful is still debatable. Our study failed to include a few associated clinical parameters such as presence of ascites, pleural effusion, presence of lymph nodes to name a few. Patient reported quality of life following DJS or PCN is an important factors which wasn't considered. Relatively short follow up is another limitation. We did have date No data on patients of advanced carcinoma cervix without obstructive uropathy, which could have provided a control group. As ours is a regional urological centre, only cases with upper tract involvement are referred.

Prospective MDT studies with control groups are required to identify patients having high risk of obstructive uropathy using these parameters, and to evaluate the benefits of prophylactic DJS in patients of advanced carcinoma cervix with high risks of obstructive uropathy

Probability of DJS insertion decreased as the grade of HUN increased, and as the size of the tumour increased. Serum urea level of more of 66 mg/ dl, serum creatinine of > 4.4 mg/ dl ,serum albumin < 2.9 mg / dl decrease the likelihood of successful DJS.Presence of bladder infiltration and history of radiotherapy also determine the successful insertion on DJS.

CKD – Chronic kidney diesease

DJS – Double ‘J’ stent

eGFR – estimated glomerular filtration rate

HUN – hydroureteronephrosis

KUB – Kidney , ureter , bladder

NCCT – non contrast computed tomography

RT – radio therapy

ETHICAL APPROVAL AND CONSENT TO PARTICIPATE – Approved (INU/RRC/04/2023-24)

Consent for publications – obtained from the institution, research review board and all authors

Availability of Data and material – Raw data and material shall be provided if required

Competing interest – none

Funding – no funds were obtained for the conduct of the study and publication

Authors contributions

1. VH ASHWATH VENKATARAMANA¹

i. conception and design

ii. Data acquisition

iii. Data analysis and interpretation

iv. Drafting and manuscript

v. Statistical analysis

2. SANJAY RP²

i. Conception and design

ii. Data analysis and interpretation

iii. Drafting manuscript

iv. Critical revision of manuscript for scientific content

v. Supervision

3. KESHAVAMURTHY R³

i. Conception and design

ii. Data analysis and interpretation

iii. Critical revision of manuscript for scientific content

iv. Statistical analysis

v. Supervision

vi. Correction of manuscript and proof reading

ACKNOWLEDGMENT

The authors would like to express our sincere gratitude to the patients who participated in the study, who spent additional time and provided valuable information and data to assess the utility of both the scores.

We would like to thank the Research review committee and Prof Dr Nagabushan, Head of RRC for approving and permitting us to conduct the study.

Bobdey S, Sathwara J, Jain A, Balasubramaniam G. Burden of cervical cancer and role of screening in India. Indian J Med Paediatr Oncol. 2016 Oct-Dec;37(4):278–285. doi: 10.4103/0971-5851.195751. PMID: 28144096; PMCID: PMC5234166.
Institute for Health Metrics and Evaluation. The Challenge Ahead: Progress in Breast and Cervical Cancer. Institute of Health Metrics and Evaluation. 2011. [Last accessed on 2016 Jan
Dinshaw KA, Rao DN, Ganesh B. Tata Memorial Hospital Cancer Registry Annual Report. Mumbai, India: 1999
New, F.J.; Deverill, S.J.; Somani, B.K. Outcomes Related to Percutaneous Nephrostomies (PCN) in Malignancy-Associated Ureteric Obstruction: A Systematic Review of the Literature. J. Clin. Med. 2021, 10, 2354. https://doi.org/10.3390/jcm10112354
J.H. Ku, S.W. Lee, H.G. Jeon, H.H. Kim, S.J.Percutaneous nephrostomy versus indwelling ureteral stents in the management of extrinsic ureteral obstruction in advanced malignancies: are there differences
OFER YOSSEPOWITCH, DAVID A. LIFSHITZ, YORAM DEKEL, MICHAEL GROSS, DANI M. KEIDAR, MARGALIT NEUMAN, PINHAS M. LIVNE, JACK BANIEL, PREDICTING THE SUCCESS OF RETROGRADE STENTING FOR MANAGING URETERAL OBSTRUCTION, The Journal of Urology, Volume 166, Issue 5, 2001, Pages 1746–1749, ISSN 0022-5347
Santosa KB, Prawira MM, Pramana IBP, Tirtayasa PMW, Yudiana W, Duarsa GWK, Oka AAG. Predictor of Successful DJ Stent Insertion in Advanced Cervical Cancer. Open Access Maced J Med Sci [Internet]. 2020 Sep. 25 [cited 2023 Aug. 1];8(B):882–6
Noegroho BS, Kurniawan AP, Wijayanti Z, Mustafa A. Factors Affecting Survival Outcome After Percutaneous Nephrostomy as Palliative Urinary Diversion in Obstructive Uropathy due to Advance Cervical Cancer Patients. Asian Pac J Cancer Prev. 2021;22(4):1211–1216. doi: 10.31557/APJCP.2021.22.4.1211. PMID: 33906314; PMCID: PMC8325148.
Ganesarajah, Selvaluxmy, Vasanth Christopher Jayapaul, Ram Madhavan and Vengada Krishnan. “The Prognostic Significance of Hydronephrosis and Role of Ureteric Stenting in Cervical Cancer Patients Treated with Radical Radiation Therapy, Real World Outcomes from a Regional Can akshay fadnis cer Centre, South India.” Asian Pacific Journal of Cancer Care (2022)
Salunkhe R, Chopra S, Kulkarni S, Shetty N, Engineer R, Mahantshetty U, Ghosh J, Gupta S, Shrivastava SK. Outcomes of locally advanced cervical cancer presenting with obstructive uropathy: An institutional audit. Indian J Cancer. 2020 Oct-Dec;57(4):416–422. doi: 10.4103/ijc.IJC_704_18. PMID: 33078748.
Noegroho BS, Kurniawan AP, Wijayanti Z, Mustafa A. Factors Affecting Survival Outcome After Percutaneous Nephrostomy as Palliative Urinary Diversion in Obstructive Uropathy due to Advance Cervical Cancer Patients. Asian Pac J Cancer Prev. 2021;22(4):1211–1216. doi: 10.31557/APJCP.2021.22.4.1211

No competing interests reported.

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Is Early Stenting Beneficial in Advanced Cervical Cancer : Prospective Study to Determine the Factors Predicting Successful DJ Stent Insertion in Malignant Ureteric Obstruction Secondary to Cervical Cancer

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Abstract

AIM

METHODS

RESULTS

CONCLUSION

Figures

INTRODUCTION

METHODOLOGY

RESULTS

DISCUSSION

CONCLUSION

Abbreviations

Declarations

References

Additional Declarations

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