Originally published as JCO Early Release 10.1200/JCO.2006.07.1290 on July 24 2006

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Are Nomograms Better Than Currently Available Stage Groupings for Bladder Cancer?

Cora N. Sternberg

Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy

Bladder cancer is a highly aggressive neoplasm. It is the fourth most frequent solid tumor among men and the seventh most frequent solid tumor among women, with more than 350,000 new cases diagnosed annually worldwide.¹ Radical cystectomy with orthotopic bladder substitution is the preferred treatment for invasive transitional cell carcinoma. With the advent of orthotopic bladder substitution after cystectomy, the majority of fit patients are no longer burdened with external ileal conduits or cutaneous ureterostomies. Progress in operating techniques and postoperative care has also contributed to improvements in survival. However, after cystectomy, 5-year survival in major series ranges from 35% to 50%, but may also be as high as 65% when a high proportion of good prognosis pT2 patients are included.^2-5 High-risk patients with pT3-pT4 and/or pN+, M0 bladder cancer have a worse prognosis, and 5-year survival ranges between 25% to 35%. Histologic grade and TNM staging have been the most universally used methodologies to predict the risk of recurrence after cystectomy.

The article by Bochner et al⁶ in this issue of the Journal of Clinical Oncology reports a postoperative nomogram based on information from 9,064 patients after radical cystectomy for both superficial and invasive bladder cancer. The authors have constructed a database from some of the best international centers of excellence, and their nomogram represents the results of a long endeavor to collect and verify data from 12 collaborating institutions. Their aim was to develop a nomogram to predict the risk of recurrence at 5 years after cystectomy in patients with bladder cancer. The ultimate goal of such a tool is to aid clinicians in predicting the probability of progression after radical cystectomy and to identifying patients at high risk who may benefit from adjuvant chemotherapy after cystectomy. Although the authors make no therapeutic recommendations, this type of nomogram is potentially of tremendous importance because it has been extremely difficult to accrue patients to adequately sized randomized adjuvant chemotherapy trials.

Models for determining the risk of recurrence and the need for adjuvant chemotherapy in colorectal and breast cancer are extremely useful, user friendly, and readily available online.⁷ More recently, prognostic models and nomograms have been developed to determine patients at high risk with renal cell carcinoma^8-10 and prostate cancer.^11-13

The authors have sought to develop a similar nomogram to the one that has become increasingly used in the management of patients with prostate cancer.¹¹ The current nomogram uses a simple 100-point scale. To verify their results, the investigators have systematically reconstructed the nomogram after removing information from each individual institution and then testing it on the omitted institution’s data. This is beautiful work; however, it is not perfect.

The data were indeed collected from some of the most important international urologic centers of excellence. It has been shown that that the quality of surgery is an extremely important prognostic factor. In a study by Herr et al,¹⁴ which analyzed the Southwest Oncology Group neoadjuvant chemotherapy study, the quality of surgery was more important than whether or not patients actually received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy. The surgical variables associated with longer postcystectomy survival were negative margins and whether or not at least 10 lymph nodes were removed.

In the present analysis, there were difficulties in properly assessing lymph node status due to nonstandardized surgery and lymph node dissection among the various centers. Some institutions provided information on the total number of lymph nodes removed, but it is not mentioned how many patients were in that subset. A considerable amount of documentation on the lymph nodes presumably was missing. The nomogram was simplified out of necessity after a series of models were proposed because not enough detailed information on nodal status was uniformly available. As a compromise, nodal status is recorded as being either positive or negative. This is a potential problem because several investigators have shown that the number of lymph nodes removed at cystectomy is an extremely important prognostic factor.^15,16 The researchers acknowledge this limitation and hope to refine the current model using prospective data collection with more detailed nodal evaluation.

In an attempt to identify potential candidates for adjuvant chemotherapy, patients who received either neoadjuvant or adjuvant systemic chemotherapy were not included in the model. This is a critical point because patient selection may play an important role in the results. Better patients may have been selected for inclusion in the nomogram, whereas those at high risk who received perioperative chemotherapy were excluded. Given that the authors of this article hope to use the data to predict survival and determine who should receive adjuvant therapy, this may be a significant defect in the model.

It is also not clear why the median follow-up is only 30 months from such important centers of excellence, and why there was no attempt at central pathology review on at least a selected sample of patients. Because of the dramatic differences in reporting, a binary system of low versus high grade was applied, which does not allow for finer details of tumor grade. From such centers, it is also somewhat ambiguous why the pathology was unclassified in 690 of 9,064 (8%).

In addition, the institution that contributed the most patients to the model is Mansura University (Mansura, Egypt), where 1,115 of 2,136 (52%) of the patients had squamous cell carcinoma. Although this is the second most common cause of bladder malignancy after transitional cell carcinoma, it accounts for only 2% to 5% of the patients in Western countries.¹⁷ Bilharziasis is the leading cause of squamous cell carcinoma. The prognosis is poor, but it has a low incidence of distant metastases; most patients succumb to locoregional failure within 3 years. Chemotherapy is not usually recommended for these patients and it is extremely likely that the biology of the disease differs from that of transitional cell carcinoma.

Most importantly, the authors should have stressed that the nomogram was derived and is applicable to centers of excellence for bladder surgery. They claim that it can be broadly applied to centers worldwide. This conclusion must be viewed with extreme caution and certainly requires additional reflection.

Making predictions is a fundamental part of practicing medicine. It is particularly crucial when considering adjuvant treatment after cystectomy. Therefore, the authors must be complimented for a diligent effort toward resolution of an important problem and in assembling what constitutes perhaps the largest radical cystectomy database from centers of excellence. Accrual to randomized adjuvant chemotherapy trials has been extremely difficult. Results from small published trials have been misleading.¹⁸ In addition, attempts at meta-analyses of completed trials have not been definitive.¹⁹ In the absence of well-controlled randomized adjuvant chemotherapy trials, or clear data on molecular profiling in predicting patients at high risk, this approach is extremely innovative and promising. The tailored assessment provided by a well-constructed nomogram is an important step toward providing clarity to individual patients and their physicians in evaluating options after cystectomy. Whether or not this type of nomogram can be improved further and then universally applied is still to be determined. In any event, the authors should be applauded for their efforts.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on July 24, 2006.

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