What do we do next?
In today’s world there exist many reasonable options for cancer therapy, ranging from surgery to chemotherapy to radiation. While it may sometimes hold true that variety is the spice of life, for a patient encountering bladder cancer for the first time – forced to investigate a world which had never even previously existed to them – these options can quickly become more overwhelming than reassuring. Therefore, today’s blog entry aims to address one of the most prevalent questions facing patients considering surgery: the role of neoadjuvant chemotherapy (or chemotherapy prior to surgery).
Historically, in patients eligible for surgery, the use of chemotherapy was considered only after surgery had been performed. The rationale for this is no less intuitive than it seems – if you can remove a cancer, you remove it…now! And while this dogma still frequently holds true, surgical and medical oncologists have learned over the past several years that sometimes it is best to delay surgery for a short period to allow for treatment with chemotherapy first. Such treatment occurring prior to surgery is called “neo-adjuvant” therapy, while the more traditional “adjuvant” therapy refers to additional treatment after surgery.
In recent years, large collaborative associations both in the United States and abroad have recommended the use of neo-adjuvant chemotherapy (NAC) in treatment of muscle-invasive bladder cancer. You may find yourself asking, though, why would a patient need chemotherapy before surgery if the cancer can be removed with surgery anyway? On what grounds were these recommendations based? What are the pros and cons of using neoadjuvant chemotherapy? Finally, and perhaps most importantly, are these recommendations right for me? In this month’s Journal of Urology, Dr. Hugh Lavery and colleagues closely examined the best-available data on the topic and set out to answer these and other questions surrounding the use of NAC in the setting of muscle-invasive bladder cancer.[1]
Why would a patient need chemotherapy before surgery if the cancer can be removed with surgery alone?
As Dr. Lavery and colleagues describe, the overall cure rate for bladder cancer after radical surgery (i.e. surgery to remove a cancerous organ along with its blood supply and adjacent tissues, such as lymph nodes) is substantially lower than that of other cancers we treat. The reasons for this are not entirely clear, and it has led urologists to investigate what else can be done to increase the number of patients who are cured of bladder cancer with treatment. One patient group that helps to understand the need for multiple treatment approaches, or “multimodal therapy,” is that which underwent radical cystectomy (i.e. removal of the bladder) but were then found to have no evidence of cancer remaining in the bladder at all (i.e. pathological T-stage zero, or pT0 for short). This can be achieved if either 1) the entire tumor was removed during local excision of the mass, or 2) the cancer in the bladder was treated completely using NAC.From following patients with pT0 disease, we have learned that even when there is no cancer left in a bladder that was removed, not all of these patients are cured in the long term. This tells us that in some cases, a number of cancer cells too few to be seen on imaging had left the bladder and traveled elsewhere in the body. While we believe surgery provides the best chance of curing any cancer in and around the bladder, it is no match for cells that have traveled elsewhere. Thus, we look to systemic (i.e. entire body) treatments such as chemotherapy to assist in eradicating cancer from the body completely.
On what grounds are recommendations supporting NAC based?
Just like a contested case in court, the jury must ultimately look back to the evidence for guidance. In the case of NAC, the evidence stems from four large randomized-controlled trials (RCTs) which compare patients who received NAC to those who did not.[2-6] Although understanding the attributes of different studies could make up its own blog entry, graduate-level course, or even research career, we will just say here that a randomized-controlled trial is widely considered the best possible design for clinical trials. So what did these trials reveal? A small (5-10% absolute and 16-33% relative improvement in survival) – but significant – overall survival benefit in patients who received NAC prior to surgery.As could be expected, there was significantly better survival among patients who achieved pT0 status, whether they underwent NAC or not. The main advantage was that more patients who received NAC were found to be pT0 than those who went straight to surgery (and it is hypothesized that the increased number of pT0 patients accounts for the survival benefits observed). Of course, even well-performed trials are not perfect, and Dr. Lavery and colleagues describe the limitations of the studies in detail. Acknowledging this, the trials seem to confirm two critical pieces of information: 1) patients with no visible tumor in the bladder at the time of surgery have better survival, and 2) use of NAC gives patients a better chance of being tumor-free at surgery. While these trials are not perfect, they provide the best available insight as to the effects of NAC in the setting of surgery.
What are the pros and cons of NAC?
Like most treatments, chemotherapy offers potential benefit at the risk of unwanted side effects. The hope is of course that NAC, in combination with surgery, will cure the body of cancer completely. As described above, we have fairly strong evidence that these treatments can achieve that in some patients. Unfortunately, many cancers treated with chemotherapy will not respond, and in these cases, patients are subjected to the side effects of treatment without gaining significant benefit. Identifying which tumors will and will not respond to chemotherapy is an area of active research, but as of yet we cannot predict this, and therefore we cannot restrict NAC to only those patients who will benefit from it. In addition to the toxic side effects of chemotherapy, another drawback of NAC is that it inevitably delays surgery, usually for between 3 and 6 months. While it is generally presumed that chemotherapy protects against the spread of cancer during this time, there are no studies which have looked specifically at this question. It is therefore impossible to rule out the potential for cancer to spread outside the bladder during the delay prior to surgery.Are these recommendations right for me?
As described above, the potential benefit of chemotherapy will have to be weighed against its side effects, which can range from life-threatening (e.g. blood disorders) to unpleasant (e.g. nausea). A discussion with your physician should consider both your body’s ability to tolerate such side effects and your desire to do so in exchange for an uncertain benefit. In the future, we hope that additional research can allow us to identify which patients will benefit from chemotherapy – and, better yet, lead to the development of more effective, less toxic therapies. Until that time, deciding whether NAC is the right choice for each individual remains a difficult decision, but one that patients can aim to answer with the support of their friends, family, and healthcare team. |
| Jeffrey Tosoian, MD |
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| Nilay Gandhi, MD |
[1] Hugh J. Lavery, Kristian D. Stensland, Guenter Niegisch, Peter Albers, Michael J. Droller, Pathological T0 Following Radical Cystectomy with or without Neoadjuvant Chemotherapy: A Useful Surrogate, The Journal of Urology, Volume 191, Issue 4, April 2014, Pages 898-906, ISSN 0022-5347, http://dx.doi.org/10.1016/j.juro.2013.10.142.
[2] Advanced Bladder Cancer (ABC) Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol, 48 (2005), p. 202
[3] H.B. Grossman, R.B. Natale, C.M. Tangen et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med, 349 (2003), p. 859
[4] A. Sherif, E. Rintala, O. Mestad et al. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer—Nordic Cystectomy Trial 2 Scand J Urol Nephrol, 36 (2002), p. 419
[5] E. Rintala, E. Hannisdahl, S.D. Fosså et al. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol, 27 (1993), p. 355
[6] International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol, 29 (2011), p. 2171