The current relevance of salvage cystectomy broadening the definition

Although radiation therapy alone is rarely used today in the United States as definitive therapy for bladder cancer, it is still important to discuss salvage cystectomy for many reasons.

The first and foremost reason is the patient with advanced urothelial tumour who, after undergoing definitive chemotherapy, has persistent or recurrent disease within the bladder, despite the absence of distant metastatic disease. Since the difficulty of performing surgery after multiple courses of chemotherapy is in many patients very similar to the difficulty after radiation therapy, salvage cystectomy is also appropriate for these patients and these individuals now constitute a large pool of eligible patients. Looking at our report of salvage cystectomy in 1980, we performed an average of 6.2 salvage cystectomies a year between 1969 and 1979 for patients for whom definitive irradiation had failed.9 An unpublished review of our experience from 1979 to 1987 showed that we were still performing 6.1 salvage cystectomies per year, predominantly for treatment failure after radiation therapy. Looking at the years 1993 to 1998, however, we performed only 1.4 salvage cystectomies per year after definitive radiation therapy, including cystectomies on four patients who underwent planned combination therapy with irradiation and chemotherapy on so-called 'bladder preservation' protocols. During this same timespan, however, we also performed 7.2 salvage cystectomies a year for patients who had undergone definitive chemotherapy and had persistent or recurrent disease. In fact, if we were to expand the use of the term 'salvage cystectomy' to also include patients who had received non-definitive doses of irradiation for urothelial cancers, or definitive doses of irradiation for other cancers, or who had received systemic chemotherapy with or without irradiation, we performed a total of 97 salvage cystectomies between 1 July 1993 and 30 June 1998, which amounts to 19.4 per year (Table 2).

While it is true that the term 'salvage cystectomy' has classically meant salvage therapy after prior definitive therapy, if we consider it from the standpoint of technical difficulty (which is why this procedure has a bad reputation), then the difficulty after multiple courses of chemotherapy, or chemotherapy plus radiation therapy, or surgery plus chemotherapy or irradiation is sufficient to warrant including these patients. The procedure

Table 2: Treatments that might precede salvage cystectomy

Cancer of the bladder and/or urethra

Definitive irradiation Combined irradiation and chemotherapy Definitive or neo-adjuvant chemotherapy Miscellaneous (e.g. thermal or photodynamic therapy) Pelvic surgery plus irradiation (e.g. partial cystectomy)

Other cancers (e.g. prostate, uterine, cervix, rectal)

Definitive irradiation

Combined irradiation and chemotherapy

Definitive or neo-adjuvant chemotherapy

Pelvic surgery (e.g. radical retropubic prostatectomy, abdominal perineal resection)

is difficult largely because tissue planes have been obliterated, small vessels in the skin, the ureter and the bowel have been compromised, and there is no reserve to the blood supply. This pathophysiologic injury secondary to radiation therapy also occurs in many patients who have had chemotherapy, particularly multiple courses of chemotherapy, and expecially in those patients whose tumour was extravesical and who experienced a significant tumour response.

It is currently very popular to give chemotherapy to patients with locally advanced (and sometimes lesser stage) bladder cancer followed by planned cystectomy. Such neo-adjuvant therapy has been shown to reduce the tumour size and sometimes clinical stage of patients with bladder cancer, but there is no agreement about how many courses need to be given or whether surgical morbidity is increased in these patients. We recently completed a prospective randomized trial that offered either immediate cystectomy followed by five courses of post-operative, adjuvant chemotherapy or two courses of neo-adjuvant chemotherapy, followed by radical cystectomy and then the remaining three courses of adjuvant chemotherapy. Two-thirds of the patients had stage T3b or T4 disease. In an interim analysis of 95 of these patients, we noted that cystectomy after two courses of chemotherapy increased such surgical variables as operative time, estimated blood loss, and number of units transfused.18 We also noted that more patients had complications (28 compared with 19) and that the total number of complications was higher (36 compared with 20), as were the number of catastrophic complications (14 compared with eight). However, none of these differences was statistically significant. Despite the absence of statistically significant differences, however, it was the subjective impression of all surgeons who participated that cystectomy was more technically demanding in the patients who had completed two courses of chemotherapy before surgery, which was clinically important. Because of the relatively small number of patients, it is not possible to answer whether there was truly no difference in morbidity between the two approaches or whether our sample size was too small to detect a statistically significant difference.

Contemporary 'true' salvage cystectomies at the University of Texas md Anderson Cancer Center

We recently reviewed our cystectomy experience for the period between 1 July 1993 and 30 June 1998. During this time we performed 311 radical

Table 3: Prior therapy in 311 patients who underwent cystectomy between July 1993 and June 1998 at the University of Texas MD Anderson Cancer Center

214 patients had no prior therapy 97 patients had prior therapy 60 had chemotherapy

17 received >60 Gy irradiation (plus chemotherapy in 15) 19 received <50 Gy irradiation (plus chemotherapy in 8) 1 received photodynamic therapy cystectomies: 214 of these were performed in patients who had had no prior therapy, and 97 were performed following prior therapy (Table 3).

Forty-two patients underwent 'true' salvage cystectomy, as originally understood, meaning cystectomy following previous definitive therapy for urothelial carcinoma (Table 4). This included 35 patients who underwent previous definitive chemotherapy for T3-4 or N1-2 disease, one of whom had a T3 recurrence after previously receiving 65 Gy of radiation for a bladder cancer. Seven patients received at least 60 Gy of radiation, four of whom had received simultaneous chemotherapy as part of 'bladder preservation' protocols, one who also received thermotherapy, and one who received irradiation alone. One patient was treated with multiple courses of photodynamic therapy and had a very small contracted bladder with tumour recurrence.

It should not be surprising that at least some of the contemporary operations considered to be salvage cystectomies by the original definition would be performed on patients who have been enrolled in protocols for

Table 4: Contemporary 'true' salvage cystectomy at MD Anderson Cancer Center after definitive therapy for urothelial cancers

34 patients had received chemotherapy for T3-4 or N1-2 7 patients had received >60 Gy irradiation

4 received chemotherapy (planned 'bladder sparing') 1 received chemotherapy for T3 recurrence after 65 Gy 1 received thermotherapy 1 received irradiation alone 1 patient had received photodynamic therapy bladder preservation. Shipley et al. reported in 1998 on 123 patients entered in a phase III trial of bladder preservation and treated with combined radiation therapy and chemotherapy.19 The patients received 39.6 Gy of radiation plus concurrent cisplatin; some of these patients had received two cycles of methotrexate, cisplatin and vinblastine before initiating radiation therapy plus cisplatin. Patients were reassessed for response after 39.6 Gy of radiation plus two courses of concurrent cisplatin, and 25 of the 123 patients were noted at this restaging to be incomplete responders; these 25 underwent radical cystectomy. Among the responding patients who received an additional 25.2 Gy and a third dose of concurrent cisplatin, 12 patients later underwent salvage cystectomies. In our current series, four patients who underwent contemporary salvage cystectomy had previous unsuccessful bladder preservation with radiation therapy and concurrent chemotherapy.

Of our 35 patients who received doses of chemotherapy considered to be definitive, five had stage T3 tumours, two of which were small-cell carcinoma; one patient, previously described, had already undergone definitive irradiation unsuccessfully. Twenty-three patients had stage T4 tumours, in one of whom treatment failed after a bladder preservation protocol. Four patients had N1 disease and three patients had N2 disease, but these patients had an apparent complete response in the lymph nodes and underwent cystectomy as consolidative therapy for their bladder cancer. Four patients had three courses of chemotherapy, 12 had four courses, 12 had five courses, and seven had six courses. Although a strict linear relationship was not observed, it does appear that the technical difficulty of radical cystectomy increases with the number of prior courses of chemotherapy.

It is possible, of course, that the patients who had received more courses of chemotherapy may have had more advanced disease, which would account for the increased difficulty. We have observed that patients with extravesical tumour who respond well to chemotherapy tend to have more of a desmoplastic reaction outside the bladder, which makes the surgery slightly more difficult because of obliteration of tissue planes. Nonetheless, the morbidity rate is quite acceptable. We had one operative death among the 42 patients undergoing true salvage cystectomy. A 67-year-old man with grade III transitional cell carcinoma in muscularis propria in June 1996 received 60 Gy of radiation with concurrent chemotherapy with cisplatin and 5-fluorouracil (5-FU) plus two more courses ofchemotherapy following completion of the radiation therapy. In January 1997, he had recurrent muscle-invasive transitional cell carcinoma and underwent radical cystoprostatectomy with an Indiana continent cutaneous diversion. The surgeon noted that the bladder and pelvic structures were 'very stuck' in dense fibrous tissue, but he was able to successfully complete the surgery without undue operative morbidity. On the third post-operative day, the patient had a pulmonary embolus, followed ultimately by renal failure and sepsis, and he died 25 days after surgery.

Otherwise, when we consider the other most feared complications of salvage cystectomy, namely rectal injury and ureteral-ileal leak, our results in these 42 patients who underwent surgery between 1993 and 1998 were not dissimilar from results for 114 salvage cystectomies performed between 1969 and 1987 at the MD Anderson Cancer Center. Although there were no operative deaths among those 114 patients, three patients had rectal injuries that required colostomy and two patients had ureteral-ileal leaks. In the present series, there were two rectal injuries, one of which was treated with primary closure alone and one with primary closure plus colostomy, and no ureteral-ileal leaks.

Although it was relatively easy to assess survival for patients who received salvage cystectomy for tumour recurrence after previous definitive radiation therapy, it is difficult to make such an assessment for patients who have been treated with definitive chemotherapy because many, if not most patients receiving definitive chemotherapy do so for advanced disease and have known or suspected metastatic disease. Thus, this is a very heterogeneous group, and survival ultimately depends more on the response to chemotherapy than on the surgery. Two patients in our series help illustrate this. One patient was a 53-year-old man diagnosed with grade III transitional cell carcinoma of the bladder in February 1993. His clinical stage was T4 because the tumour mass was fixed to the pelvic sidewall. He received three courses of 5-FU, a-interferon and cisplatin, which caused his tumour mass to shrink approximately 50%. He then received two courses of methotrexate, vinblastine, doxorubicin and cisplatin, which caused his tumour mass to shrink even further. Finally, following three courses of paclitaxel, methotrexate and cisplatin, his tumour mass, which still measured 4 x 5 x 5cm, became mobile. It now extended to the pelvic sidewall, but was no longer fixed to it. He underwent a radical cystectomy and ileal conduit urinary diversion in February 1994 for what turned out to be pT3b NO M0 disease. At last follow-up in June 1999, 63 months after his cystectomy, he was clinically free of disease.

The second patient was a 64-year-old man who was found to have an inflammatory-looking lesion in the bladder during cystoscopy for evaluation of a ureteral calculus. Biopsy revealed anaplastic signet-ring adenocarcinoma. Bimanual examination found a fixed tumour mass and a rectal 'shelf that was positive on biopsy. The patient received two courses of paclitaxel, methotrexate and cisplatin with no response. He was then given two courses of gemcitabine, ifosfamide and cisplatin, and the tumour mass, which had previously been fixed to the pelvic wall, became mobile. He underwent a third course of gemcitabine, ifosfamide and cisplatin, followed by radical cystectomy in October 1997. There was complete obliteration of all tissue planes by a dense desmoplastic tumour response. Multiple biopsies in the pelvis and on the pelvic sidewall were negative for cancer. A cystectomy was finally performed and revealed poorly differentiated cancer still present in the bladder; one deep surgical margin was positive. The patient received several additional courses of gemcitabine, ifosfamide and cisplatin post-operatively, but experienced recurrent disease in the pelvis eight months later and died 14 months after his radical cystectomy.

Thus it appears that the response to chemotherapy determines the ultimate result. Whether more extensive surgery might improve survival rates for patients who fail in pelvic or retroperitoneal lymph nodes is the subject of a protocol currently underway at MD Anderson Cancer Center. This protocol seeks to determine whether surgical consolidation after response to chemotherapy in patients with positive lymph nodes without other evidence of metastatic disease will improve the survival rate. All urologic oncologists have seen patients who have disease relapse in the pelvic and retroperitoneal lymph nodes after maximum response to chemotherapy. This protocol tests whether aggressive dissection of pelvic or retroperitoneal lymph nodes, or both, may resect occult cancer in some patients and decrease regional relapse. Under this protocol, patients with bladder cancer who have positive retroperitoneal lymph nodes and a clinical complete response to chemotherapy are offered radical cystectomy plus complete pelvic and retroperitoneal lymph-node dissection to the level of the renal vessels. The problem we seek to solve is illustrated by the case of a 68-year-old man who underwent cystectomy in

Figure 1: Intraoperative photograph after complete retroperitoneal lymph-node dissection in a patient who had undergone prior radical cystectomy and ileal conduit and multiple courses of chemotherapy.

Figure 1: Intraoperative photograph after complete retroperitoneal lymph-node dissection in a patient who had undergone prior radical cystectomy and ileal conduit and multiple courses of chemotherapy.

Retroperitoneal Node Dissection

May 1995 for pT3 N1 bladder cancer. He received four courses of cisplatin, methotrexate and vinblastine as adjuvant therapy, but had disease relapse in the retroperitoneum in December 1995. He then received three courses of paclitaxel, methotrexate and cisplatin alternating with 5-FU, a-interferon, cisplatin and methotrexate with a clinical complete response, although he again had relapse in October 1996. He then received two courses of gemcitabine and cisplatin, again achieving a clinical complete response, and underwent retroperitoneal lymph-node dissection in January 1997, as shown in Figure 1. Twelve of 18 lymph nodes were positive, and the patient received post-operative chemotherapy. In November 1997 he had disease relapse outside of the surgical field, and despite multiple chemotherapy regimens, he experienced rapid progression, including liver metastases, in late 1998 and died. It should be stressed that such an aggressive surgical approach, even in a salvage setting, is best performed only when there is a protocol to evaluate such an approach.

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  • gerardina
    What does salavage radical cystectomy mean?
    5 years ago
  • margarette
    What does salvage radical cystectomy mean?
    2 years ago

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