Population-based validation of the National Comprehensive Cancer Network recommendations for baseline imaging for bladder cancer: a case for routine baseline bone scan?
Abstract
Aim: This study aims at evaluating the performance of some of the imaging recommendations of the National Comprehensive Cancer Network (NCCN) for initial evaluation of bladder cancer. Methods: Surveillance, epidemiology and end results program (2010–2015) was queried and patients with clinically (T1–T4) bladder cancer and complete information about clinical T/N (tumor/nodal) stage and metastatic sites were extracted. The following characteristics were evaluated in the current analysis: sensitivity, specificity, number needed to investigate (NNI), positive predictive value (PPV), negative predictive value and accuracy. Results: According to the current NCCN guidelines, PPV (for the recognition of lung metastases) is 4.7% and NNI to detect one case of lung metastasis is 21.2. Similarly, PPV (for the recognition of liver metastases) is 3.1% and NNI to detect one case of liver metastasis is 32.2. Using a different imaging threshold (i.e., routinely imaging all patients >T2N0), PPV (for the recognition of lung metastases) is 10.4% and NNI to detect one case of lung metastasis is 9.6. Similarly, PPV (for the recognition of liver metastases) is 7% and NNI to detect one case of liver metastasis is 14.2. The above two thresholds were also evaluated for routine bone scanning. PPV (for the detection of one case of bone metastasis) is 5.3% using the first threshold and 11.2% using the second threshold. Conclusion: Imaging per current NCCN guidelines results in few patients with undetected asymptomatic lung or liver metastases. A routine baseline bone scan should be additionally considered for some asymptomatic patients with muscle-invasive disease.
Initial assessment of newly diagnosed patients with urinary bladder carcinoma should encompass the assessment of patient-related factors, disease-related factors and potential treatment-related factors [1]. Important patient-related factors would include age and comorbidity status, while important disease-related factors would include disease biology and disease extent [2]. In order to properly assess disease extent, baseline staging investigations are important to identify possible sites of metastatic disease [3,4].
Current national comprehensive cancer network (NCCN) recommendations for initial staging of bladder cancer propose a simplified risk-based approach whereby chest and abdominal/pelvic imaging is recommended for all patients >T1N0 disease. Bone imaging is, however, only recommended among patients with symptoms suggestive of bone metastasis [5]. These recommendations were echoed by a number of other international societies interested in streamlining urologic oncology practice (like the European Association of Urology and European Society of Medical Oncology) [6–8].
Given the prevalence of bladder cancer, there are huge medical and cost consequences of these recommendations [9]. It is thus important to assess the performance characteristics of these recommendations in a population-based setting and this is the aim of the current study. Such an assessment will hopefully outline the potential weaknesses and strengths of this approach and might lead to an improvement of the current staging algorithm for those patients. The current study hypothesizes that routine baseline bone scan might be warranted in some asymptomatic patients with locoregionally advanced bladder cancer.
Methodology
Study cohort selection
Within the Surveillance, epidemiology and end results (SEER) database, bladder cancer cases (T1–T4) diagnosed from 2010–2015 were selected. Cases with Ta or Tis disease were not included in the current cohort. This time period was selected because detailed information about metastatic sites was not available before these years. The selection criteria also included complete data about clinical T/N stage and sites of metastases (bone, brain, liver or lung). Surgical pathology T/N stages were not considered in the current analysis. SEER-18 registry was used to extract these data [10], and SEER*Stat software (Version 8.3.5) was used to perform this extraction. In this manuscript, all assessments of clinical staging as well as sites of distant metastasis refer to the status at diagnosis (i.e., at baseline).
Assessment of the NCCN baseline imaging recommendations
A number of analyses were considered in this study. These relate to the assessment of the performance characteristics of current NCCN bladder cancer recommendations for the detection of lung and liver metastases (i.e., routinely imaging all patients >T1N0 disease). Moreover, another imaging threshold was examined that entailed imaging all patients >T2N0.
Additionally, assessment of hypothetical recommendations for bone imaging using either one of the above two thresholds was conducted (i.e., either imaging all patients >T1N0 or imaging all patients >T2N0).
Data collection & statistical calculations
The following data were collected from each case within the study cohort: age, race, gender, histology, grade, subsite within the bladder, clinical stage, treatments offered (including surgery, radiotherapy and/or chemotherapy), bone, brain, liver and lung metastases. Descriptive analyses were then performed to illustrate the frequencies and proportions of different baseline characteristics. Performance characteristics for different imaging thresholds among different metastatic sites were then evaluated. These performance characteristics included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number needed to investigate (NNI) and accuracy. SPSS statistics 20.0 (IBM, NY, USA) was used to perform all the calculations (Table 1).
| Parameter | N (%) |
|---|---|
| Race White Black Others Unknown | 33,849 (87.8%) 2648 (6.9%) 1794 (4.7%) 270 (0.6%) |
| Sex Females Males | 9159 (23.8%) 29,402 (76.2%) |
| Age <40 years 40–69 years ≥70 years | 156 (0.4%) 13,492 (35%) 24,913 (64.6%) |
| Subsite Trigone Dome Lateral wall Anterior wall Posterior wall Bladder neck Ureteric orifice Urachus Overlapping lesion Bladder, NOS | 2242 (5.8%) 1642 (4.3%) 6957 (18%) 1036 (2.7%) 3364 (8.7%) 1386 (3.6%) 880 (2.3%) 32 (0.1%) 4857 (12.6%) 16,147 (41.9%) |
| ISUP grade Low grade High grade Unknown | 3558 (9.2%) 29,569 (76.7%) 5434 (14.1%) |
| Histology Urothelial carcinoma Nonurothelial carcinoma | 35,684 (92.6%) 2877 (7.4%) |
| Clinical stage T1N0 T2N0 >T2N0 | 23,652 (61.3%) 10,888 (28.2%) 4021 (10.4%) |
| Radical surgery No Yes Unknown | 36,863 (95.6%) 1650 (4.3%) 48 (0.1%) |
| Chemotherapy Yes No/unknown | 12,087 (31.3%) 26,474 (68.7%) |
| Radiotherapy Yes No/unknown | 4166 (10.8%) 34,395 (89.2%) |
| Bone metastases Yes No | 941 (2.4%) 37,620 (97.6%) |
| Brain metastases Yes No | 67 (0.2%) 38,494 (99.8%) |
| Liver metastases Yes No | 562 (1.5%) 37,999 (95.8%) |
| Lung metastases Yes No | 856 (2.2%) 37,705 (97.8%) |
ISUP: International society of urologic pathology; N: Number; T/N: Tumor/nodal.
Results
Patient characteristics
After excluding patients with insufficient data sites of distant metastases and clinical T/N stage, a total of 38,561 patients were included in the study. Urothelial carcinoma represented the majority of cases (92.6%) and age group ≥70 years represented the majority of cases (64.6%). The white race represented 87.8% and males represented 76.2% of the study population. Most patients have high-grade disease according to International society of urologic pathology (ISUP) grading system (76.7%). Details of clinical stages, as well as subsites, were summarized in Table 2. In this cohort of patients, bone metastases were reported in 2.4% of patients, liver metastases in 1.5% of patients, lung metastases in 2.2% of patients and brain metastases in 0.2% of patients.
| Reference: Lung metastases as shown on chest imaging | NNI (1/PPV) 21.2 | ||
|---|---|---|---|
| Lung metastases (856 patients) | No lung metastases (37,705 patients) | ||
| Chest imaging recommended (14,909 patients) | TP N = 704 patients | FP N = 14,205 patients | PPV = TP/(TP+FP) 4.7% |
| Chest imaging not recommended (23,652 patients) | FN N = 152 patients | TN N = 23,500 patients | NPV = TN/(TN+FN) 99.4% |
| Sensitivity = TP/TP+FN 82.2% | Specificity = TN/FP+TN 62.3% | Accuracy (TN+TP/All) 62.7% | |
| Reference: Liver metastases as shown on abdominal imaging | NNI (1/PPV) 32.2 | ||
| Liver metastases (562 patients) | No liver metastases (37,999 patients) | ||
| Abdominal imaging recommended (14,909 patients) | TP N = 458 patients | FP N = 14,451 patients | PPV = TP/(TP+FP) 3.1% |
| Abdominal imaging not recommended (23,652 patients) | FN N = 104 patients | TN N = 23,548 patients | NPV = TN/(TN+FN) 99.6% |
| Sensitivity = TP/TP+FN 81.5% | Specificity = TN/FP+TN 62% | Accuracy (TN+TP/All) 62.2% | |
FN: False negative; FP: False positive; NNI: Number needed to investigate; NPV: Negative predictive value; PPV: Positive predictive value; TN: True negative; TP: True positive.
Assessment of NCCN baseline imaging recommendations for chest & abdominal imaging
Among included patients in this analysis, 23,652 patients (61.3%) have a T1N0 disease (thus, chest and abdominal imaging should not be recommended as per the NCCN recommendations), while 14,909 (38.7%) have a more advanced disease (i.e., routine imaging would be recommended).
Using NCCN guidelines, 152 patients (0.3%) with lung metastases would have been missed, and 104 patients (0.2%) with liver metastases would have been missed. Meanwhile, 14,205 patients (36.8%) would have chest imaging in the absence of lung metastases, and 14,451 patients (37.4%) would have abdominal imaging in the absence of liver metastases.
This means a PPV (for the recognition of lung metastases) of 4.7% and NNI to detect one case of lung metastasis of 21.2. Similarly, this results in a PPV (for the recognition of liver metastases) of 3.1% and NNI of 32.2 to detect one case of liver metastasis. Additional performance characteristics including sensitivity, specificity, NPV and accuracy were detailed in Table 2.
Assessment of modified baseline imaging threshold for chest & abdominal imaging
A proposed alternative imaging threshold would exclude patients with T1N0/T2N0 from a routine chest and abdominal imaging. Among included patients in this analysis, 34,540 patients (89.5%) have T1N0/T2N0 disease (thus, chest and abdominal imaging should not be recommended as per the alternative threshold), while 4021 (10.5%) have a more advanced disease (i.e., routine imaging would be recommended).
Using this alternative threshold, 437 patients (1.1%) with lung metastases would have been missed, and 282 patients (0.7%) with liver metastases would have been missed. Meanwhile, 3602 patients (9.3%) would have chest imaging in the absence of lung metastases, and 3741 patients (9.7%) would have abdominal imaging in the absence of liver metastases.
This means a PPV (for the recognition of lung metastases) of 10.4% and NNI to detect one case of lung metastasis of 9.6. Similarly, this results in a PPV (for the recognition of liver metastases) of 7% and NNI of 14.2 to detect one case of liver metastasis. Additional performance characteristics including sensitivity, specificity, NPV and accuracy were detailed in Table 3.
| Reference: Lung metastases as shown on chest imaging | NNI (1/PPV) 9.6 | ||
|---|---|---|---|
| Lung metastases (856 patients) | No lung metastases (37,705 patients) | ||
| Chest imaging recommended (4021 patients) | TP N = 419 patients | FP N = 3602 patients | PPV = TP/(TP+FP) 10.4% |
| Chest imaging not recommended (34,540 patients) | FN N = 437 patients | TN N = 34,103 patients | NPV = TN/(TN+FN) 98.7% |
| Sensitivity = TP/TP+FN 48.9% | Specificity = TN/FP+TN 90.4% | Accuracy (TN+TP/All) 89.5% | |
| Reference: Liver metastases as shown on abdominal imaging | NNI (1/PPV) 14.2 | ||
| Liver metastases (562 patients) | No liver metastases (37,999 patients) | ||
| Abdominal imaging recommended (4021 patients) | TP N = 280 patients | FP N = 3741 patients | PPV = TP/(TP+FP) 7% |
| Abdominal imaging not recommended (34,540 patients) | FN N = 282 patients | TN N = 34,258 patients | NPV = TN/(TN+FN) 99.2% |
| Sensitivity = TP/TP+FN 49.8% | Specificity = TN/FP+TN 90.2% | Accuracy (TN+TP/All) 89.5% | |
FN: False negative; FP: False positive; NNI: Number needed to investigate; NPV: Negative predictive value; PPV: Positive predictive value; TN: True negative; TP: True positive.
Assessment of hypothetical baseline imaging thresholds for routine bone imaging
Current NCCN guidelines recommend bone scan only if there are suggestive clinical findings. Based on the observation that bone metastases were reported in this cohort at a frequency higher than liver and lung metastases, it was reasonable to explore the performance characteristics of two hypothetical imaging thresholds for a routine bone scan. These two imaging thresholds include either doing a routine bone scan for all cases, except T1N0 patients or routine bone scan for all cases, except T1N0/T2N0.
Using the first threshold (all patients except T1N0), PPV (for the detection of one case of bone metastasis) is 5.3% and NNI to detect one case of bone metastasis is 18.8. Likewise and using the second threshold, PPV (for the detection of one case of bone metastasis) is 11.2% with NNI to detect one case of bone metastasis of 8.9. Other performance characteristics of both thresholds (including sensitivity, specificity, NPV and accuracy) are detailed in Table 4.
| Reference: Bone metastases as shown on bone scan | NNI (1/PPV) 18.8 | ||
|---|---|---|---|
| Bone metastases (941 patients) | No bone metastases (37,620 patients) | ||
| Bone imaging recommended (14,909 patients) | TP N = 796 patients | FP N = 14,113 patients | PPV = TP/(TP+FP) 5.3% |
| Bone imaging not recommended (23,652 patients) | FN N = 145 patients | TN N = 23,507 patients | NPV = TN/(TN+FN) 99.4% |
| Sensitivity = TP/TP+FN 84.6% | Specificity = TN/FP+TN 62.5% | Accuracy (TN+TP/All) 63% | |
| Reference: Bone metastases as shown on bone scan | NNI (1/PPV) 8.9 | ||
| Bone metastases (941 patients) | No bone metastases (37,620 patients) | ||
| Bone imaging recommended (4021 patients) | TP N = 450 patients | FP N = 3571 patients | PPV = TP/(TP+FP) 11.2% |
| Bone imaging not recommended (34,540 patients) | FN N = 491 patients | TN N = 34,049 patients | NPV = TN/(TN+FN) 98.6% |
| Sensitivity = TP/TP+FN 47.8% | Specificity = TN/FP+TN 90.5% | Accuracy (TN+TP/All) 89.5% | |
FN: False negative; FP: False positive; NNI: Number needed to investigate; NPV: Negative predictive value; PPV: Positive predictive value; TN: True negative; TP: True positive.
Discussion
Overall, the current analysis suggests that the current NCCN baseline imaging recommendations for bladder cancer provide a reasonable paradigm to the initial evaluation of bladder cancer patients. In a population-based setting, adherence to these guidelines would lead to few patients with undetected asymptomatic lung or liver metastases. These findings are reassuring to the oncologists and urologists managing bladder cancer. On the other hand, the current analysis shows that routine bone scan might be considered among patients with muscle-invasive disease (especially those with ≥T3 and/or node-positive disease).
Current NCCN guidelines also do not support routine brain imaging in the initial staging of asymptomatic patients. Given the overall low incidence of brain metastases in the current population-based cohort, this recommendation seems reasonable and should not be altered.
Accurate assessment of the true extent of disease is a fundamental step in the evaluation of newly diagnosed bladder carcinoma cases. A balanced approach to the initial staging of bladder cancer is important in order to ensure that cases with metastatic disease are not offered unnecessary and overly morbid radical surgeries, and meanwhile to ensure that cases with early-stage disease are not overwhelmed with unnecessary over investigations.
A number of weaknesses have to be noted in the current analysis. Foremost, the current study is based on cases diagnosed and treated within the USA. Thus, the generalizability of the results of the current analysis to other jurisdictions needs to be done with caution. Second, there is no detailed information about the type and extent of investigations that helped to decide local stage of the disease in each patient as well as whether he/she does or does not have a distant metastatic disease. However, it is expected that the vast majority of patients diagnosed and treated within community/academic centers in the USA would have been adequately staged and assessed prior to starting treatment. Third, the SEER database does not include information on symptoms. Patients with bone metastases who are technically (according to the NCCN guidelines) not candidates for staging imaging studies may have symptoms, which would mandate imaging studies.
These weaknesses should be viewed in the context of the strengths of the current study. Most importantly, the utilization of such a large dataset which is derived from the SEER database with its well-known rigorous quality assurance process is a major point of strength. Another relevant strength is the ability of the SEER database to provide adequate information about the type of initial staging approach of each patient (i.e., clinical or pathological or pathological after neoadjuvant treatment). This is in contrast to the majority of other institutional or population-based datasets, which report only surgical pathology staging. Reliance on clinical staging in the current analysis would allow the proper simulation to real-life clinical situations where bladder cancer patients present initially with cystoscopic and pelvic imaging findings and cases are then discussed in the multidisciplinary team to evaluate future staging and treatment options.
It has to be noted also that although the main reason behind the chest and abdominal imaging is to identify lung and liver metastases (respectively), other distant sites of metastases might be identified through the chest and abdominal imaging (including distant lymph nodes and adrenal metastases). Moreover, abdominal imaging for urothelial carcinoma of the bladder might serve as a screening investigation for possible second primary urothelial carcinoma as well as concurrent urological or vascular abnormalities. Unfortunately, it is not possible to quantify accurately the number of cases with adrenal or distant abdominal/thoracic lymph nodes within the current SEER dataset. Thus, it is not possible to assess the added benefit of these imaging investigations in terms of recognizing these additional sites of metastases. It has to also be noted that because of the common risk factors between lung and bladder cancer, routine chest imaging in those cases might work as a screening test for potential second primary lung cancer.
An important question that remains unanswered within the current study is whether we should accept the current threshold proposed by the NCCN guidelines (i.e., imaging all patients >T1N0)? This is particularly relevant given the improvement in specificity and PPV with excluding T2N0 from routine investigations (at the expense of worsening sensitivity).
While improving performance characteristics of the current staging approach of bladder cancer is a legitimate end point, other important end points need also to be considered.
These include the economic costs associated with routinely investigating all patients with a muscle-invasive disease, the rare – but possible – dangers from excessive radiation exposure and contrast administration from contrast-enhanced imaging as well as the psychological burden entailed within each new investigation/procedure that the patient is exposed to [11]. Another important point to be considered might be related to the impact of metastatic disease finding on therapeutic decision making in bladder cancer. Discovery of one site of metastatic disease would most probably lead to exclusion of radical cystectomy as a potential therapeutic option. This also has important cost and quality considerations both to individual patients as well as the whole healthcare system.
Another important aspect of the current NCCN approach for bladder cancer imaging might be related to the suboptimal performance of current pelvic imaging technologies to identify local/nodal extent of bladder cancer. This is another area of improvement in the future that needs to be considered.
In conclusion, imaging per current NCCN guidelines results in few patients with undetected asymptomatic lung or liver metastases. On the other hand, routine bone scan should be additionally considered for asymptomatic patients with muscle-invasive disease (particularly those with >T2N0 disease).
This study aims at evaluating the performance characteristics of some of the imaging scans recommended by the National comprehensive cancer network (NCCN) guidelines for initial evaluation of bladder cancer.
Surveillance, epidemiology and end results program (2010–2015) was queried and patients with clinically (T1–T4) bladder cancer and complete information about clinical T/N stage and metastatic sites were extracted.
The following characteristics of performance evaluated in the current analysis included sensitivity, specificity, number needed to investigate (NNI), positive predictive value (PPV), negative predictive value and accuracy.
According to the current NCCN guidelines, PPV (for the recognition of lung metastases) is 4.7% and NNI to detect one case of lung metastasis is 21.2.
Similarly, PPV (for the recognition of liver metastases) is 3.1% and NNI to detect one case of liver metastasis is 32.2.
Using a different imaging threshold (i.e., routinely imaging all patients >T2N0), PPV (for the recognition of lung metastases) is 10.4% and NNI to detect one case of lung metastasis is 9.6.
Similarly, PPV (for the recognition of liver metastases) is 7% and NNI to detect one case of liver metastasis is 14.2. The above two thresholds were also evaluated for routine bone scanning.
PPV (for the detection of one case of bone metastasis) is 5.3% using the first threshold and 11.2% using the second threshold.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
This article does not contain any studies with human participants or animals performed by the author.
Informed consent: As this study is based on a publicly available database without identifying patient information, informed consent was not needed.
References
Papers of special note have been highlighted as: • of interest
1.
Griffiths TR. Current perspectives in bladder cancer management. Int. J. Clin. Pract. 67(5), 435–448 (2013).
2.
Gray PJ, Fedewa SA, Shipley WU et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National cancer data base. Eur. Urol. 63(5), 823–829 (2013).
3.
Vikram R, Sandler CM, Ng CS. Imaging and staging of transitional cell carcinoma: part 1, lower urinary tract. Am. J. Roentgenol. 192(6), 1481–1487 (2009).
4.
Abdel-Rahman O. Validation of the eighth AJCC new substages for bladder cancer among different staging contexts. Clin. Genitourin. Cancer 15(6), e1095–e1106 (2017).
• Illustrates the impact of the new American joint committee on cancer staging system for bladder cancer.
5.
Spiess PE, Agarwal N, Bangs R et al. Bladder cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 15(10), 1240–1267 (2017).
• Reviews National comprehensive cancer network guidelines for bladder cancer.
6.
Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Horwich A. Bladder cancer: ESMO practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25(Suppl. 3), iii40–iii48 (2014).
7.
Witjes JA, Comperat E, Cowan NC et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur. Urol. 65(4), 778–792 (2014).
8.
Mossanen M, Chang SL, Kimm S, Sonpavde GP, Kibel AS. Current staging strategies for muscle-invasive bladder cancer and upper tract urothelial cell carcinoma. Urol. Clin. North Am. 45(2), 143–154 (2018).
9.
Kaplan AL, Litwin MS, Chamie K. The future of bladder cancer care in the USA. Nat. Rev. Urol. 11(1), 59–62 (2014).
10.
NIH. About the SEER program (2016). http://seer.cancer.gov/about.
11.
Fabritius G, Brix G, Nekolla E et al. Cumulative radiation exposure from imaging procedures and associated lifetime cancer risk for patients with lymphoma. Sci. Rep. 6, 35181 (2016).
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© 2019 Future Medicine Ltd.
History
Received: 18 October 2018
Accepted: 26 November 2018
Published online: 9 January 2019
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Population-based validation of the National Comprehensive Cancer Network recommendations for baseline imaging for bladder cancer: a case for routine baseline bone scan?. (2019) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2018-0113
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