Adjuvant Radiotherapy After Cystectomy: A Good Idea?

Madrid, Spain (UroToday.com) Dr. Fontyne discussed the role of adjuvant radiotherapy after radical cystectomy. It is known that patients after radical cystectomy are still at considerable risk for local urothelial recurrence, of up to 40%.This risk is affected by the pathological T stage, N stage, whether neoadjuvant chemotherapy was given, and the patient’s gender.2  There are several risk stratifications for predicting local-regional recurrence rates after radical cystectomy. One example for such a risk stratification is the PENN risk stratification, demonstrated in Figure 1, showing that higher T stage, positive surgical margins, and a lower lymph node count are major risk factors for recurrence.3

UroToday 3rd Bladder Congress Molecular characterization of muscle invasive bladder cancer
Figure 1 – The PENN risk stratification for predicting local-regional recurrence after radical cystectomy:

The location of the positive surgical margin rate also has a clear impact on the rate of local failure and recurrence after radical cystectomy, as can be seen in figure 2. It is depicted that positive margins at the rectosigmoid region have a 5-year local recurrence rate of less than 2%, while a positive margin at the external/internal iliac region confers a 5-year local recurrence rate of almost 20%!3

UroToday 3rd Bladder Congress Five year local recurrence rate after radical cystectomy stratified by the location of positive surgical margins
Figure 2 – Five-year local recurrence rate after radical cystectomy stratified by the location of positive surgical margins:

Importantly, the way the local recurrence is identified also has a tremendous impact on the cancer-specific survival and overall survival of patients with local recurrence. It has been demonstrated that a recurrence diagnosed by routine follow-up vs. when it is diagnosed only when the patient is symptomatic, has a hazard ratio for cancer-specific and overall survival of 0.65 (p=0.013) and 0.66 (p=0,015), respectively. 4 This means the routine long-term follow-up of these patients is critical, enabling early diagnosis of local recurrence and improved disease-specific and overall survival rates.

Next, Dr. Fonteyne discussed the actual evidence that demonstrates the added benefit that postoperative radiotherapy adds to these patients. In some relatively old nonrandomized studies published in 1986, and 1992, a patient who received postoperative radiotherapy had a five-year disease specific survival of 44-49% compared to 25% in patients who only had radical cystectomy without adjuvant radiotherapy. 5,6 However, the authors of these studies reported unacceptable toxicity in those receiving radiotherapy. This unacceptable toxicity was common more than 20 years ago, but with the technology and modalities used today, the radiation oncologists can accurately direct the radiotherapy given to the desired areas only (Figure 3), and avoid much of the toxicity.

UroToday 3rd Bladder Congress Accurate radiotherapy avoiding the associated toxicity
Figure 3- Accurate radiotherapy, avoiding the associated toxicity:

A more recent study in 2014 also demonstrated a statistically significant advantage to postoperative radiotherapy-treated patients in disease-free survival, but not in overall survival. 7 In an even more recent study published in 2017, a total of 198 patients after radical cystectomy were randomly assigned to either adjuvant chemotherapy alone, adjuvant radiotherapy alone, or the combination of both.8 This study demonstrated an improved two-year local recurrence-free survival in the group treated with chemotherapy and radiotherapy (96%) compared to chemotherapy alone (69%), as demonstrated in figure 4. However, no statistically significant difference was demonstrated in the overall survival rate.

UroToday 3rd Bladder Congress The two year local recurrence free survival rate significantly improved for chemotherapy radiotherapy compared to chemotherapy alone
Figure 4 – The two-year local recurrence-free survival rate significantly improved for chemotherapy + radiotherapy compared to chemotherapy alone:

The European Association of Urology (EAU) clearly state that there are only limited, old data on adjuvant radiotherapy after radical cystectomy. Advances in targeting and reducing the damage to surrounding tissues may yield better results in the future. However, the EAU guidelines also state that: “In locally advanced bladder cancer (>=T3, N0/N1, M0) the local recurrence rate seems to decrease with postoperative radiotherapy. The National Comprehensive Cancer Network (NCCN) guidelines are much more supportive of adjuvant radiotherapy to these patients. These guidelines state that adjuvant radiotherapy should be considered in high-risk bladder cancer patients (T3-T4, positive nodes, positive surgical margins or high-grade disease), or if no neo-adjuvant chemotherapy was given (level 2A).

Dr. Fonteyne summarized her talk by stating that locoregional recurrence after radical cystectomy has been underestimated and that local control is correlated with survival parameters. According to some published evidence, adjuvant radiotherapy reduces the risk of local recurrence and improves disease-specific survival. This kind of adjuvant therapy should at least be considered in high-risk patients, according to the NCCN guidelines.

Presented by: Valerie Fonteyne, Ghent, Belgium

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the Global Conference on Bladder Cancer 2018 - September 20-21, 2018 Madrid, Spain 

References:
1. Eapen et al. Can Urol Assoc J 2016
2. Bandini et al. Eur Urol 2018
3. Baumann et al. Bladder Cancer 2017
4. Giannarini et al. Eur Urol 2010
5. Zaghloul et al. Radiother Oncol 1986
6. Zaghloul et al. Int J Radiat Oncol Biol Phys 1992
7. Bayoumi et al. Cancer management and research 2014
8. Zaghloul et al. JAMA Surgery 2017
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