Are Surgery and Chemotherapy Sufficient to Treat Locally Advanced Bladder Cancer?

Libni Eapen, MD

In the decades’ long debate around the feasibility, efficacy and desirability of attempting organ preservation versus extirpative cystectomy, there has been a relative paucity of attention directed towards the exact locoregional tumor eradication rate following surgery. Rather, this argument about surgery versus organ preservation has distracted the uro-oncology community from critically examining and addressing this important matter. Pelvic tumor recurrence following contemporary cystectomy has traditionally been considered a relatively infrequent event. Cagiannos and Morash¹ compiled 8 institutional series published between 1977 and 2006 reporting local recurrence rates ranging from 3.9% to 29%. These series may have underestimated the true risk of pelvic relapse for patients with locally advanced disease for a variety of reasons including: excluding failures when observed co-synchronously with distant metastases or when there was no biopsy confirmation, using simple numerator/denominator crude risk calculations rather than cumulative incidence rates that account for loss of follow-up and competing risks, or aggregating risk assessments across low and high-risk cohorts.

More recent assessments of pelvic failure risks have suggested the rates are higher than previously assumed. Herr et al,² reporting the surgical parameters in the neoadjuvant chemotherapy SWOG 8710 trial, demonstrated that despite requiring biopsy confirmation, the crude risk of developing local recurrence following cystectomy in pT3/4 disease was 32%. The 2011 update of the MRC neoadjuvant chemotherapy— cystectomy trial (International Collaboration of Trialists) reported a 48% and 49% rate of pelvic recurrence with and without neoadjuvant chemotherapy, respectively. In a 2011 Canadian survey of contemporary cystectomy, comparably high 48% to 50% cumulative incidence rates of pelvic failure were found.³ As neither neoadjuvant nor adjuvant chemotherapy reduce pelvic failure, locoregional control currently is pursued by optimizing nodal dissection. The well-characterized University of Southern California (USC) experience together with the Memorial Sloan Kettering Cancer Center (MSKCC) and SWOG 8710 reports emphasize the importance of thorough node dissections defined as a minimum of 10-12 nodes. In a 2012 reanalysis of the USC experience following adequate dissection and counting all pelvic failures except those that occur subsequent to the diagnosis of distant metastases, there is a 24% pelvic recurrence rate (Daneshmand, MD, oral communication). In 2014, Christodouleas⁴ reported the University of Pennsylvania and SWOG 8710 pelvic recurrence experience and identified low, intermediate, and high risk groups according to stage, extent of node dissection, and margin status. These risk groups experienced 8%, 20%, and 41% pelvic recurrence rates at 5 years, respectively.

In aggregate, to date, these clinical data emphasize the neglected problem of significant pelvic failure in pT3/4 patients following cystectomy. In the entire arena of locally advanced solid tumor management—except for bladder cancer—clinical experience and formal experimentation have established multimodality treatment involving varying combinations of surgery, radiotherapy, and systemic treatments to be pivotal in securing optimal cure rates and symptom control. The exhaustive list includes melanomatous and non-melanomatous skin cancer, sarcomas, CNS tumors, head and neck cancers, thyroid cancers, breast, lung, esophagus, gastric, pancreatic, rectal, anorectal, endometrial, cervix, vulvovaginal, and prostate cancers. It is possible that the nexus of under enumeration of pelvic relapse, contention that pelvic recurrence is trumped out of clinical relevance by distant metastases, and concern about the toxicity of integrating cystectomy with adjuvant radiotherapy has created a reluctance to study this approach in the uro-oncologic community, save for in Egypt.

Figure 1. Axial CT of a patient with prior radical cystectomy.

The image shows a proposed clinical target volume (red), planning target volume (blue) and 80% plus dose distribution for adjuvant radiation of bladder cancer.

Urologists are rightly addressing the importance of pelvic tumor control by emphasizing that, whilst in 2015 the standard cystectomy has to involve a meticulous node dissection, there may be further surgical pelvic tumor control gains to be had by a still more cephalad-extended nodal dissection. This is being formally examined in an ongoing SWOG phase 3 trial. This pelvic failure can be observed in isolation or co-synchronously with distant metastases. As such, it constitutes an absolute ceiling on the curability of bladder cancer by surgery and chemotherapy, and also can be a source of significant patient morbidity. One randomized and several retrospective series of postoperative radiotherapy in squamous and transitional bladder cancer suggest superior pelvic control and survival. In 1992, Zaghloul et al,⁵ published the results of a phase III trial of postoperative radiotherapy in mainly squamous cell bladder cancer showing reduced pelvic failure. In 1999, Cozzarini from Milan⁶ presented their retrospective review of postcystectomy radiotherapy. They compared partial/ total cystectomy alone versus with postoperative radiotherapy of 45-66Gy (median 50.4Gy). Adjuvant RT to doses 50.4 Gy or higher was associated with improved survival and improved pelvic control. There was an attendant 7% risk of bowel obstruction reported, emphasizing the importance of further careful study.

While the NRG has this year opened the randomized phase 2 trial discussed below, colleagues in England, France, and India are well advanced in designing their own prospective trials examining postoperative radiotherapy. In NRG GU001, the hypothesis to be tested is that postoperative intensity-modulated radiation therapy (IMRT) will reduce any pelvic tumor recurrence (occurring either in isolation or together with distant metastases) with acceptable toxicity in patients with pT3/ T4 urothelial bladder cancer following cystectomy. This trial is important, as it will be the first prospective randomized trial in Europe and North America to address the significant problem of pelvic failure. The IMRT regimen utilized will mirror the radiotherapy delivered postoperatively in uterine cancers in RTOG trials. This contemporary radiotherapy minimizes both gastrointestinal and pelvic marrow toxicity. The latter is particularly relevant in patients who may have received neoadjuvant or adjuvant chemotherapy and in those patients who might need chemotherapy for the palliation of metastatic disease. Using IMRT we can expect to achieve this improved pelvic control with certainly no more, and likely less toxicity than reported from the Egyptian and European experiences.⁷

The Cairo group has published in April 2013 the results of their pre- versus post-op randomized phase III radiotherapy trial demonstrating very low rates of gastrointestinal and surgical serious toxicity with 50Gy/25 fractions with non-IMRT radiotherapy. To avoid the potential for radiation to damage a reconstructed urinary reservoir, patients with “neobladders” will be ineligible in the NRG study. Stringent collection of all serious bowel toxicity encountered will be buttressed by well-defined stopping rules to ensure that we identify any clinically significant increase in bowel toxicity that requires surgical correction. To reconcile the concept of studying radiotherapy in only those patients who have had the ideal operation (minimum of ten removed nodes and negative margins) when the ideal is commonly not achieved, we will study all radical cystectomy pT3/T4 patients and stratify according to intermediate and high-risk failure grouping. In a similar vein, we will utilize a pragmatic approach to the issue of adjuvant and neoadjuvant chemotherapy. Clinical guidelines call for the use of neoadjuvant chemotherapy but only 8% of patients get neoadjuvant chemotherapy in North America. In addition, in many centers, there is a strong conviction that patients should be considered for post-operation adjuvant chemotherapy while in others, many patients may not receive any peri-operative chemotherapy. The heterogeneity in the use of peri-operative chemotherapy challenges any adjuvant radiation therapy trial design. Specifically, randomization before chemotherapy will likely result in a proportion of patients not getting the assigned adjuvant radiotherapy because of chemotherapy toxicity, overall treatment fatigue, and early manifestation of some of the 30% of pelvic recurrences that occur within 6 months of cystectomy.

Thus, we will register trial eligible patients 4-6 weeks post cystectomy and randomize regarding adjuvant radiotherapy at that time for patients not getting chemotherapy, but delay that randomization until after chemotherapy in patients so treated. However, the pelvic relapse data will be collected in all registered patients. This approach that deals with issues of the surgical quality and chemotherapy grounding the study in the reality of contemporary North American management of locally advanced bladder cancer allows us to ask in a generalizable way whether adjuvant radiotherapy can usefully help the pelvic recurrence problem. In summary, the challenge of pelvic failure following contemporary cystectomy has been engaged and the clinical trials to pursue the amelioration of this problem have commenced.

Author affiliations:

Department of Radiation Oncology, Ottawa Hospital (LE), Ottawa, ON, Canada; Department of Radiation Oncology, Hospital of the University of Pennsylvania (JC), Philadelphia, PA; Department of Radiation Oncology, Massachusetts General Hospital (JE), Boston, MA. Corresponding author: Libni Eapen, MD; The Ottawa Hospital; Regional Cancer Centre; 501 Smyth Road; Box 902; Ottawa; Ontario; K1H 8L6. E-mail: LEapen@toh.on.ca.

References

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