|Ahead of print
Outcomes of locally advanced cervical cancer presenting with obstructive uropathy: An institutional audit
Rohan Salunkhe1, Supriya Chopra2, Suyash Kulkarni3, Nitin Shetty3, Reena Engineer1, Umesh Mahantshetty1, Jaya Ghosh4, Sudeep Gupta4, Shyam Kishore Shrivastava1
1 Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Interventional Radiology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Advanced Centre for Treatment Research and Education in Cancer, Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Submission||30-Oct-2018|
|Date of Decision||09-Apr-2019|
|Date of Acceptance||16-Apr-2019|
|Date of Web Publication||05-Aug-2020|
Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Homi Bhabha National Institute, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: There is paucity of outcome data of patients with cervical cancer presenting with malignant obstructive uropathy. The present retrospective study describes outcomes of patients with cervical cancer who presented with obstructive uropathy at the time of diagnosis and underwent urinary diversion with percutaneous nephrostomy (PCN) before/during treatment.
Methods: Patients who underwent PCN from January 2010 to June 2015 were included. Intent of treatment (radical or palliative) was decided within multidisciplinary team depending on disease stage, Karnofsky performance status (KPS), and degree of renal derangement. Treatment and outcome details were retrieved from electronic records. Time to normalization of creatinine, feasibility of delivering planned treatment, and overall survival (OS) were determined. Impact of various prognostic factors on outcomes was determined using univariate or multivariate analysis.
Results: After PCN and double-J stenting, 50% were eligible for (chemo) radiation. All radically treated patients (26/52) received brachytherapy. The median EQD2 to point A was 78 Gy (72–84 Gy). The median OS was 10 (0.5–60) months. Patients who completed chemoradiation had median OS of 31 months. Those receiving radical radiation and palliative radiation had median OS of 11 and 6 months, respectively. On univariate analysis, smaller tumor size (p = 0.03), high KPS (P = 0.04), and radical intent of treatment (P = 0.05) predicted for OS.
Conclusion: 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.
Keywords: Cervical cancer, FIGO stage IIIB, outcomes, urinary diversion, urinary obstruction
|How to cite this URL:|
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 [Epub ahead of print] [cited 2020 Oct 1]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=291416
| » Introduction|| |
Cervical cancer is the fourth most common cancer in women worldwide with estimated 570,000 new cases in the year 2018. While high-income countries have been able to decrease incidence and mortality of advanced cancers due to early detection, a majority of patients diagnosed in developing world are still in a locally advanced stage. In an institutional audit from India, approximately 40% of the patients present as stage III (33%) and stage IV (6%). While most of the patients may be candidates for radical chemoradiation, small proportion of patients present with obstructive uropathy, therefore precluding radical chemoradiation. Although it may be intuitive to perform diversion procedures in an attempt to normalize renal function and facilitate delivery of radical (chemo) radiation, it is unclear whether such diversion procedures ensure delivery of full course radical (chemo) radiation and improve overall oncological outcomes. The present audit was undertaken to report oncological outcomes of patients who presented with malignant obstruction due to locally advanced disease and underwent percutaneous nephrostomy (PCN) and double J (DJ) stenting before or during treatment.
| » Materials and Methods|| |
Institutional ethics approval was obtained to audit case records of patients who underwent urinary diversion using PCN before or during treatment for cervical cancer from 1st January 2010 to 1st June 2015. The primary objective was to report (a) response in renal parameters to the procedure and subsequent feasibility of delivering radical chemoradiation after PCN and (b) to report overall survival (OS).
The electronic medical records and databases of radiation oncology and intervention radiology department were reviewed. Medical records of all patients undergoing PCN at our institution were evaluated, and these consisted of patients undergoing PCN before or after local treatment. Of these, only patients who underwent PCN for stage III–IVA disease or those with postsurgical recurrence and who underwent stenting due to deranged serum creatinine >1.5 mg/dL at the time of treatment were included. Those undergoing PCN/stenting for postsurgical complication or during follow-up or at diagnosis of postradiation local recurrence were excluded from the present analysis.
As an institutional policy, the intent of treatment and need for PCN were decided in a joint multidisciplinary clinic considering the stage of disease, performance status of the patient, and degree of renal derangement. All patients received antibiotics for 5 days after the procedure and underwent DJ stenting. Hence, retrospectively these patients were categorized into three therapeutic groups wherein decisions for therapeutic plan were made by multidisciplinary team based on patients' performance status, creatinine recovery, and disease burden.
Patients with normal creatinine after PCN and good Karnofsky performance score
This group of patients received radical chemoradiation and brachytherapy. Patients in this cohort were often planned for external radiation of 46–50 Gy followed by brachytherapy to a total dose of 75–80 equivalent doses in 2 Gy (EQD2) to point A. The treatment aim also included delivery of concurrent weekly cisplatin (40 mg/m2).
Patients with creatinine above normal after PCN and intermediate Karnofsky performance score
This group received radiotherapy (RT) alone due to anticipated toxicity or difficulty in delivering concurrent chemotherapy. These patients were considered for biologically equieffective hypofractionated RT schedule (like 40 Gy/16 fractions). This was followed by brachytherapy based on response and performance status of the patient. The aim in this cohort was to deliver upto 70 Gy EQD2 to point A.
Patients with persistently abnormal creatinine and poor performance status
This group of patients received palliative RT. Once-monthly fractionation of 10 Gy was followed in these patients for a total of up to three fractions based on patients' treatment response. In addition, they were upfront referred to palliative care unit.
Treatment records were reviewed to record the demographic details of the patients (such as age, stage, histology, serum creatinine at presentation and after stenting, duration of hospital stay, postprocedure complications). Compliance and response to planned radiation and chemotherapy were recorded by chart review. Details regarding local, nodal, and distant relapse and any posttreatment complications and death were recorded.
SPSS version 21.0 was used for all statistical analysis. While demographic details were reported as categorized data, compliance and complications were reported as actual percentages. Paired t-test was used to find difference between pre- and postprocedure creatinine. OS was calculated as death from any cause. All calculations were from the date of diagnosis. Log-rank test was used to investigate the impact of known prognostic factors on OS, and Cox proportional hazard was used to find out independent impact of various factors on OS.
| » Results|| |
Overall, 125 women underwent diversion procedure within the specified duration. Of these, 73 patients were excluded from analysis as PCN was done after local treatment either for postradiation recurrence or treatment related complications. Only 52 patients who underwent diversion due to advanced disease at presentation and resultant malignant obstructive uropathy were included. The summary of study patients is depicted in [Table 1]. The median age of the study cohort was 55 years (32–85 years). Of these, 60% had stage IIIB and 20% had stage IVA at presentation, while others presented with postsurgical pelvic recurrence. A majority (82%) of the patients had mild to moderate hydroureteronephrosis (HUN) on imaging. The median serum creatinine before diversion was 6.2 mg/dL [interquartile range (IQR) 2.8–8.1 mg/dL]. Overall, 83% patients had reversal to normal serum creatinine. The median time to nadir creatinine was 11 days (IQR 7–20 days) and the median duration of hospitalization was 12 days (IQR 10–16 days). The median postprocedure creatinine after 7 days was 1.65 mg/dL (1.3–2.5 mg/dL) (P < 0.001).
After PCN and DJ stenting, 50% of patients were treated with potentially radical intent (26/52) (group A) and another 50% received palliative treatment (groups B and C) [Figure 1]. No patients received neoadjuvant chemotherapy. Radical chemoradiation was possible for 12 of 52 patients (23%). Of those receiving concurrent chemotherapy, only 10 of 12 (83%) could complete four or more cycles of concurrent chemotherapy. Two patients received two or more cycles of concurrent chemotherapy. Other 14 of 52 (27%) patients underwent radical radiation alone, mostly due to persistent deranged creatinine clearance or poor performance status [Table 2]. All radically treated patients (26/52) received brachytherapy. The median EQD2 to point A was 78 Gy (IQR 72–84 Gy).
|Figure 1: Kaplan Meier plot showing overall survival of patients with patients those who could be treated with radical intent (depicted in green) versus those who were treated with palliative intent (depicted in red)|
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Among patients receiving palliative radiation, dose of 30–40 Gy/10–16 fractions was used in 7 of 26 (27%) patients (group B). Two patients (out of seven) who were started on palliative radiation had excellent local response and also went ahead to receive brachytherapy. Monthly palliative RT was used in 19 of 26 (73%) patients (group C). The choice of palliative fractionation was often decided by treating physician based on the bulk of disease, performance status of the patient, and ability to come for fractionated treatment.
At the time of analysis, 46 (88.4%) patients were dead or had disease relapse. While three patients were disease-free at a median follow-up of 15 months, another three patients were disease-free >4 years since treatment. The median survival of the entire cohort of 52 patients was 10 months (range 0.5–60 months) [Figure 2]. Patients who completed radical treatment along with planned concurrent chemotherapy had median OS of 31 months [95% confidence interval (CI) 20–42 months]. The group treated with definitive radiation alone had median OS of 11 months [95% CI 3–25 months]. The group treated with palliative radiation alone had statistically significant poor outcomes (P < 0.05). The median OS was 6 months (95% CI 3.7–8.3 months).
After the PCN procedure, 50% of patients had grade III/IV dyselectrolytemia during their hospital stay of which hyponatremia was the most common electrolyte abnormality. Acute grade I–II gastrointestinal and genitourinary toxicities were observed in 20 of 26 patients receiving radical treatment. Grade III gastrointestinal and genitourinary toxicities were observed in 7.7% and 15.4% of patients with no grade IV toxicity. Late toxicity was not adequately recorded and represents one of the fallacies of a retrospective audit.
Univariate and multivariate analyses
The results of univariate and multivariate analyses are depicted in [Table 3]. In summary, baseline Karnofsky performance status (KPS), baseline creatinine >3 mg/dL, tumor size >5 cm, and intent of treatment predicted for OS [Figure 3] and [Figure 4]. Age at treatment, FIGO stage, radical or salvage treatment, and pelvic or paraaortic nodal disease did not predict for OS. On multivariate analysis, tumor size (P = 0.03), KPS (P = 0.04), and intent of treatment (P = 0.05) predicted for OS.
|Table 3: Univariate and multivariate analyses of factors impacting treatment outcomes|
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|Figure 3: Kaplan–Meier plot showing overall survival of all patients in the study|
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|Figure 4: Impact of factors on overall survival. (a) Kaplan Meier plot showing OS for patients with pre-percutaneous nephrostomy creatinine ≤3 mg/dL (depicted in green) versus those with creatinine >3 mg/dL (depicted in red). (b) KM plot of patients showing OS with Karnofsky performance status (KPS) ≥70 (depicted in green) versus those with KPS <70 (depicted in red). (c) KM plot showing OS of patients with age <60 years (depicted in green) versus age ≥60 years (depicted in red). (d) KM plot showing OS of patients with tumor size ≤5 cm (depicted in green) versus patients with tumor size >5 cm (depicted in red)|
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| » Discussion|| |
In developing countries, due to limited resources for early screening and diagnosis, patients often present with advanced stage disease, which is associated with a poor prognosis and high mortality rate. While a majority of patients present with stage IB2–IIIB, a small proportion of patients may present with features of obstructive uropathy and resultant HUN secondary to compression of distal ureter. Although these patients are categorized as FIGO stage IIIB, their prognosis is often worse than that of patients with stage IIIB who have no features of obstructive uropathy. For this cohort of patients, dilemma remains for the clinician whether to be aggressive in decompressing the upper urinary tract to offer radical chemoradiation or to treat patients with palliative intent. Although there is a paucity of evidence about managing this cohort of patients, the therapeutic decision is often governed by the extent of disease on clinical examination, performance status of the patient, presence of extrapelvic disease, severity of obstructive uropathy (determined by serum creatinine values), and potential ability of patients to tolerate chemoradiation. If the decision is made to decompress the urinary tract, then it is most often performed percutaneously rather than retrograde fashion as cystoscopic procedures may be associated with higher failure rates. As reported in other series, the antegrade approach of performing a PCN followed by stenting was found to be safe and was used in all the patients in this study, and normalization of deranged renal function was seen 7–8 days after PCN. DJ stent conversion rate was 100% which is in agreement with previously published reports wherein the success rate for antegrade stenting was 83% for obstruction due to diverse etiology including other pelvic malignancies. While we observed 50% rate of dyselectrolytemia that is expected in patients with obstructive uropathy and renal function derangement.
Chemoradiotherapy currently represents standard of care for treatment of locally advanced cervix cancer, including stage IIIB wherein use of concurrent chemotherapy is associated with improved 5-year OS. In this study, only 12 patients (23%) could receive radical chemo-radiation (CTRT), and the 3-year OS for this group was 24.4%. All stage IIIB patients by virtue of HUN had a median survival of 10 months [Figure 5]. This is substantially inferior to reported outcomes of locally advanced stage IIIB where chemoradiation is associated with 5-year OS of 50%–54% suggesting that obstructive uropathy in stage IIIB may be an independent adverse prognostic factor. In our cohort of patients who received radical intent treatment with RT alone, the median survival was 11 months. In patients who received palliative radiation, the survival was 6 months. This survival is comparable to those deemed for upfront palliative radiation in our institution. Lau et al. reported outcomes of patients presenting with obstructive uropathy and reported outcomes similar to our series. While the median survival in patients with primary and recurrent cancers with obstructive uropathy who proceeded to receive treatment was 27 and 20 weeks, respectively, it was 6.5 weeks in those with recurrent cancers and no further treatment. Lau et al. also suggested caution before deciding on diversion procedure due to poor outcomes of the patients; another series from Christie Hospital reported similar dismal outcomes.
|Figure 5: Kaplan–Meier plot showing overall survival of stage IIIB patients only|
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As most trials using concurrent chemoradiation or testing new strategies often exclude patients with HUN and obstructive uropathy, the outcomes of patients with stage IIIB with HUN and obstructive uropathy are not very clear. In our study, despite using urinary decompression and radical treatment in at least 50% of patients, the outcomes remain inferior to that of stage IIIB presenting without HUN and malignant obstruction. On analyzing prognostic factors for OS in this cohort, performance status, size of tumor at presentation (greatest dimension >5 cm), and intent of treatment determined outcomes. Also, on univariate analysis, serum creatinine <3 mg/dL predicted for better outcomes (38% vs 9%, P = 0.03). Although not significant on multivariate analysis, this could be used as one of the objective criteria in predicting outcomes of this cohort and selecting patients for urinary decompression and further radical treatment. Lutaif et al. reported the utility of using baseline renal cortical thickness <13 mm to predict for nonrecovery of renal function, and hence potential for inferior outcomes. Therefore, in addition to prognostic factors identified on multivariate analysis, renal cortical thickness and serum creatinine may be used to identify patients who may have better outcome and be selected for urinary decompression and further potentially radical treatment.
As the observed outcomes of patients with obstructive uropathy are inferior to that of patients with stage IIIB and akin to patients deemed for palliative care, we believe that presence of obstructive uropathy should be redesignated as a separate substage (in the current FIGO staging, as the current FIGO stage allocation does not predict dismal outcomes and survival of this cohort). While prospective data may be desirable to bring forth this change, a large prospective series or a trial is unlikely to become available as such patients are often excluded from analysis in prospective trials, and outcome data specific to this small but sizeable group of patients are lacking.
| » Conclusion|| |
Malignant urinary obstructive uropathy in patients with cervical cancer is associated with dismal outcome with median survival less than a year despite diversion procedures and further treatment. While patients with good performance status, small tumor size, and serum creatinine <3 mg/dL may be selected for diversion procedures and potential radical treatment, upfront palliative radiation without diversion may be considered for the rest of the cohort.
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Conflicts of interest
There are no conflicts of interest.
| » References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A Cancer Journal for Clinicians 2018;68:394-424.
Dickinson JA, Stankiewicz A, Popadiuk C, Pogany L, Onysko J, Miller AB. Reduced cervical cancer incidence and mortality in Canada: National data from 1932 to 2006. BMC Public Health 2012;12:992.
Chopra S, Gupta M, Mathew A, Mahantshetty U, Engineer R, Lavanya G. Locally advanced cervical cancer: A study of 5-year outcomes. Indian J Cancer 2018;55:45-9.
] [Full text]
Mishra K, Desai A, Patel S, Mankad M, Dave K. Role of percutaneous nephrostomy in advanced cervical carcinoma with obstructive uropathy: A case series. J Palliat Care2009;15:37-40.
Hopkins MP, Morley GW. Prognostic factors in advanced stage squamous cell cancer of the cervix. Cancer 1993;72:2389-93.
Chitale SV, Scott-Barrett S, Ho ETS, Burgess NA. The management of ureteric obstruction secondary to malignant pelvic disease. Clin Radiol 2002;57:1118-21.
Sharma SD, Persad RA, Haq A, Appleton DS, Doyle PT, Bullock KN, et al
. A review of antegrade stenting in the management of the obstructed kidney. Br J Urol 1996;78:511-5.
Lukka H, Hirte H, Fyles A, Thomas G, Elit L, Johnston M, et al
. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer-a meta-analysis. Clin Oncol 2002;14:203-12.
Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al
. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;1:22-5.
ShrivastavaS, Mahantshetty U, Engineer R, Chopra S, Hawaldar R, Hande V,et al
. Gynecologic Disease Management Group. Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix a randomized clinical trial. JAMA Oncol 2018;4:506-13.
Mishra SK, Laskar S, Muckaden MA, Mohindra P, Shrivastava SK, Dinshaw KA. Monthly palliative pelvic radiotherapy in advanced carcinoma of uterine cervix. J Cancer Res Ther 2005;1:208-12.
LauMW, Temperley DE, Mehta S, Johnson RJ, Bernard RJ, Clarke NW. Urinary tract obstruction and nephrostomy drainage in pelvic malignant disease. Br J Urol 76:565-9.
Chan S, Robinson ACR, Johnson RJ. Percutaneous nephrostomy: Its value in obstructive uropathy complicating carcinoma of cervix uterus. Clin Oncol1990;2:156-8.
Lutaif NA, Yu L, Abdulkader RCRM. Factors influencing the non-recovery of renal function after the relief of urinary tract obstruction in women with cancer of cervix. Ren Fail 2003;25:215-23.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]