Urology

World J Urol (1985) 3:115-120

© Springer-Verlag1985

Adjuvant chemotherapy for locally advanced bladder cancer* John D. Cant ~, Maurizio Brausi 2 and Mark S. Soloway 1 i Department of Urology, University of Tennessee Center for the Health Sciences, Memphis, TN 38163, USA 2 Department of Urology, B. Ramazzini Hospital, Carpi, (MO) Italy

Summary. Although controversy over the relative efficacy of full-dose pelvic radiation and radical cystectomy, with or without pre-operative radiation, continues, none of these treatments directed only at the disease in the pelvis cures more than 50 percent of patients with locally advanced disease. An effective systemic therapy is needed. The most effective single agent in metastatic bladder cancer, Cis-platin, has not altered the cure rate when used as an adjuvant. Limited trials using Cis-platin based three and four drug combination chemotherapy regimens have yielded 50-70 percent overall response rates with 30 percent complete responses in metastatic disease. It seems appropriate to perform pilot studies using these more intensive programs as adjuvant chemotherapy for good performance status patients at high risk of progression, e.g. positive lymph nodes.

The management of locally advanced bladder cancer is unsatisfactory. Despite radical surgery and/or radiation therapy, tumors which invade the muscle wall of the bladder, whether superficial or deep, will compromise the patient's survival in approximately 50% of cases [35]. There has been some improvement in survival over the past two decades attributable to improvements in patient selection, surgical technique and pre- and postoperative care. Further progress is unlikely without the incorporation of effective systemic adjuvant therapy against occult metastases. Transitional cell carcinoma of the urinary tract has been found to be moderately responsive to chemotherapy and several agents alone or in combination are capable of producing objective responses in 20%-50% of patients with metastatic tumors. If chemotherapy is used as an adjuvant to surgery and/or radiotherapy, effectiveness is theoretically more likely since tumor burden is usually much lower and patient tolerance to chemotherapy often superior. We have reviewed recent studies in which chemotherapy has been used as an adjuvant with curative * Supported by PHS Grant CA15934 awarded by the National Cancer Institute and the Veterans Administration Medical Research Service

intent. Unfortunately, these are few in number and difficult to assess. Results to date have been almost universally discouraging. Standard definitive therapy

The effect of adjuvant therapy can only be assessed ifa baseline of acceptable local management of muscle invasive bladder cancer is established. Unfortunately, there is no consensus as to optimal therapy. In the 1950's and early 1960's, cystectomy and radical radiotherapy appeared closely matched with 5-year survivals of 9%31% and 19%-33%, respectively [6]. In the late 1960's and the 1970's, precystectomy radiotherapy was introduced and 5-year survivals of 33%-53% were recorded [35]. This improvement over previous cystectomy series was attributed to downstaging of the tumor by the preoperative radiotherapy, resulting in improved local control. Alternatively, some have argued that those tumors which are downstaged have a less aggressive biologic potential, and that this, rather than their radiosensitivity, is responsible for their better prognosis [4]. Similar survival rates with an acceptable incidence of pelvic recurrence have been reported in the 1980's with cystectomy alone [30]. Radical radiotherapy continues to have many advocates - particularly in Canada and Europe. Improvements in technique, e.g. the linear accelerator, have reduced morbidity while emphasis on salvage cystectomy in patients with residual tumor at the initial followup has reduced the number of patients who develop progressive disease after local failure [16, 2]. Despite the various types ofpotentiaily curative local treatments, a substantial percentage of patients will have regional and distant tumor from which they will succumb. Clearly, an effective systemic modality is needed. Chemotherapy for transitional cell carcinoma of the bladder

Yagoda [36] and Harker and Torti [10] have reviewed the chemotherapeutic agents with activity against transi-

116 tional cell carcinoma. Four drugs, cis-platin, adriamycin, methotrexate and vinblastine have been found to be most effective, with response rates of 15%-40% when used as single agents. The vast majority of responses are partial, i.e. greater than 50% reduction in the size of measurable tumor. The development of firm, objective response criteria has been aided by the increased availability of imaging techniques such as CT and ultrasound. Stabilization of disease as an indicator of response is fraught with error, since slow growth may represent the natural history of the tumor or the inability to accurately measure tumor growth at certain sites. When these stricter criteria of response have been adhered to, the response rates for such drugs as 5-fluorouracil and adriamycin have been substantially lowered compared to the initial glowing reports of limited trials performed in the early 1970's. The population with advanced bladder cancer includes a high proportion of elderly patients. Performance status scales have been used in an attempt to objectively determine the patient's general condition, and not surprisingly, better chemotherapy responses have ben noted in those patients with a better performance status. Cis-platin provides the greatest anti-tumor activity when used as a single agent (20%-40%) and has been incorporated in many of the most recent combination regimens. It is a heavy metal, non-cell cycle-specific drug which functions as an alkalating agent by inhibiting D N A by intrastrand cross linkage. In vitro and in vivo studies indicate a synergistic effect with radiotherapy [33]. Although recent phase I trials have explored very high doses of cis-platin with hypertonic saline, the standard dose is 70-100 mg/M 2 IV given at 3-week intervals. Nephrotoxicity, nausea and vomiting as well as ototoxicity are the major concerns and are greatly alleviated by intensive treatment regimens incorporating hydration, mannitol-induced diuresis, and antiemetics. The onset of response often occurs within 14 days with objective responses measurable at 4-6 weeks and persisting for an average of 6 months. Thus, if no response has occurred after the second course of treatment, continuation is unlikely to be of benefit. Methotrexate is an anti-metabolite which blocks intracellular tetrahydrofolic acid production and thus inhibits D N A and R N A production. It is cell cycle phase-specific. Yagoda's [36] review of the literature indicates a response rate of 29%, The usual dosage is in the range of 30-60 mg/M 2 given weekly. Very high doses requiring folinic acid rescue have been used but are not clearly superior. The drug can be given orally as well as intravenously and is generally well-tolerated, making it an attractive drug for adjuvant protocols. Toxicity includes myelosuppression, stomatitis, and GI-ulceration. The drug is excreted via the kidney and renal function must therefore be adequate. Yagoda [36] has noted increased toxicity in some patients with ileal conduits, presumably due to reabsorption from the urine. Drug

interactions may occur with salicylates, probenecid, certain antibiotics, and warfarin. Adriamycin is an anti-tumor antibiotic which affects all phases of the cell cycle and interferes with RNA and D N A transcription. The usual dose is 60-75 mg/M 2 IV every 3 weeks which is adjusted downward if there has been previous radiotherapy or chemotherapy. Singleagent response rates initially reported to be 35 % have fallen to the 5%-20% range with stricter response criteria. Average duration of response is 3-5 months. Cardiac toxicity is dose-limiting and may exclude older patients with a history of cardiac disease. Myelosuppression, nausea and vomiting, and alopecia are other toxic effects. Excretion is by the biliary tract so that hepatobiliary disease may require dose modification. The usefulness of adriamycin as a single agent would appear to be limited and its role in combination studies with cis-platin and 5FU is not clear. Vinblastine is a vinca alkaloid which inhibits meitotic spindles, causing arrest of mitosis in metaphase and is therefore a cell cycle phase-specific agent. Responses are similar to those seen with adriamycin and its role would also appear to be as a component in combination therapy rather than as a single agent. Other agents with limited activity which have been used in combination regimens include 5-Fluorouracil, cyclophosphamide, mitomycin C, and the podophyllotoxin derivatives of VP-16 and VM-26. Similar drug combinations used by different investigators have yielded a wide range of results. Most studies have not been controlled and have used small numbers of patients with advanced metastatic disease so that interpretation of results is difficult. Cis-platin as the most active single agent has formed the basis for many recent drug trials. In an attempt to increase the response rates and duration of responses over that cis-platin alone, combinations of drugs have been given. Recently the combination of cis-platin, methotrexate, adriamycin, and vinblastine has been used with a complete plus partial response rate of over 70 % [34]. A cooperative group used a similar regimen (omitting adriamycin), with an initial response rate of 57% [9]. Toxicity with this 3- or 4-drug combination is substantial. Drug-related deaths were observed by both investigators. This is the first combination chemotherapy regimen which provides response rates clearly superior to cis-platin used as a single agent.

A~uv~t ~emo~e~py In spite of response rates of 30%-50% in metastatic disease, the clinical impact of chemotherapy has been limited by the relatively short duration of responses. However, there is hope that with an initial small tumor burden the benefit will be increased. Chemotherapy combined with radiotherapy or cystectomy has therefore been advocated since, theoretically, micrometastases would be more susceptible to the drugs. Since more than

117 Table 1. Adjuvant chemotherapy regimens for invasive bladder cancer

Author

Drug

Comment

Oliver [22] London and Oxford Coop. Group [20] Raghavan [24]

MTX + FA a MTX

Pilot study; well-tolerated Randomized controls; in progress

Cis-platin

Well-tolerated; encouraging response rate

Chemo during RT

Jakse [15] N B C C G A P8 [28] Clyne [3] Herr [11]

Cis-platin + VM-26 Cis-platin A D M + 5-FU Cis-platin

Well-tolerated; small numbers Encouraging Survival not improved One dose; possibly higher downstaging

Chemo after RT

YUCRG [26]

A D M + 5-FU

Survival not improved; well-tolerated

Chemo after RT + C

N B C C G A P7 [5] Hall [8]

Cis-platin A D M + BL + MTX + 5-FU

No survival benefit; poorly tolerated Toxic; ineffective

Chemo after C

Skinner [29] Socquet [31]

Cis-platin based comb. MTX Hd b + FA

Survival not improved Well-tolerated; no controls; many partial cystectomy

C h e m o before RT/C

a FA = Folinic acid rescue b H d = High doses

50% of bladder cancer patients subjected to radical therapy for cure eventually die of metastatic disease, the concept is attractive. Local control of tumor might also be enhanced by downstaging with effective chemotherapy if the drugs are given prior to cystectomy or by radiosensitization when given in conjunction with radical or preoperative radiotherapy. There are several theoretical considerations regarding adjuvant chemotherapy. Optimal treatment with currently available drugs probably requires maximally tolerated doses. Multiple drugs may be necessary to eliminate cells which are resistant to any given agent and an effective multi-agent chemotherapy program may not require treatment in excess of 4-6 months. There have only been a few adjuvant chemotherapy trials and none show convincing evidence of benefit. In these studies a variety of surgical and radiotherapeutic methods have been used to deal with the primary tumor. Staging and patient selection also varies widely. Prospective randomized controls are therefore essential, but have been incorporated in less than half a dozen trials. Patient numbers have been small and recruitment has been difficult in the face of uncertain benefit and very definite risks to patients already undergoing taxing therapy. The majority of reported studies have been small, uncontrolled, pilot or preliminary investigations incorporating a variety of drugs alone or in combinations before, during, and after definitive therapy. The intent of many of these studies has been to assess drug dosages, toxicity, and patient tolerance prior to larger trials.

Adjuvant chemotherapy given after definitive treatment The timing of administration of adjuvant chemotherapy may be critical in terms of ultimate anti-tumor activity,

but this aspect has been less clear than its effect on toxicity and patient tolerance. Cis-platin, as the agent with the highest reponse rates, has formed the basis for many recent protocols. The National Bladder Cancer Clinical Collaborative Group Protocol 7 (Table 1) randomized 43 patients to receive 8 courses of cis-platin, 70 mg/M 2 IV every 3 weeks for 8 courses following 4000 rads of preoperative radiotherapy and cystectomy compared to a control group not given the cisplatin [5]. This study was discontinued because of poor patient compliance, with only 9 of 43 patients willing or able to complete all 8 courses of cis-platin. In addition, many patients initially considered for this study were never entered or withdrew, introducing the problem of selectivity. Of the 43 patients who received adjuvant cis-platin, 17 relapsed, while 21 of 40 who did not receive adjuvant platinum but may have received chemotherapy later - relapsed (P>0.05). The median disease-free interval was 27 months and 22 months, respectively. Soloway [12] reviewed 15 patients receiving adjuvant cis-platin following cystectomy at the University of Tennessee. Of 8 patients with negative lymph nodes, 3 are living from 1831 months. Seven patients with one or more lymph nodes involved with tumor are all dead, with the longest survivor 30 months following surgery. In this small group of patients, the addition of cis-platin did not appear to have any major impact. Skinner [29] gave a variety ofcis-platin based combinations determined in part by in vitro chemosensitivity testing after radical cystectomy without pre-operative radiotherapy. This was a prospective randomized trial in which 18 patients received adjuvant chemotherapy postoperatively while 14 patients served as controls. Toxicity and patient tolerance were acceptable but no improvement in survival was noted.

118 Socquet [31] gave high-dose methotrexate with folinic acid rescue following partial or complete cystectomy. There was minimal toxicity and excellent survival figures with 31 of 33 patients alive at 1.5 years. No controis were used and the fact that 25 patients required only partial cystectomy would indicate a selection bias. The largest randomized study is from the Yorkshire Urological Group [26] in which 110 evaluable patients were assigned in equal numbers to either radiotherapy alone or radiotherapy followed within 3 months by 5FU (500 mg/M 2) and adriamycin (50 mg/M2). Cardiac toxicity and poor patient tolerance because of nausea and vomiting were a problem in a pilot study. By reducing chemotherapy to a maximum of 4 courses, toxicity was low and the drugs were well-tolerated with no patient refusing treatment. Unfortunately, no survival benefit was noted at the 2-year follow-up. Questions remain as to whether higher doses of these drugs given prior to radiotherapy might have been more effective. Clyne [3], in a small preliminary trial utilizing an identical drug regimen but given prior to radiotherapy, also noted minimal morbidity but no survival advantage.

Adjuvant chemotherapy given before or during radiotherapy Many chemotherapeutic agents may act as radiosensitizers. Their interactions with radiation therapy are complex and poorly understood. They may include sensitization of hypoxic cells or other effects rendering the cell more susceptible to radiation damage as well as inhibiting the repair of radiation damage [21]. Cis-platin plus radiotherapy in transplanted and primary tumors in mice was shown to be more effective than cis-platin or radiotherapy alone [33]. The precise timing of drug administration and radiation may be critical. One study has indicated that the response was maximal when cis-platin was administered immediately following radiotherapy [19]. Very little clinical information is available to indicate the ideal sequence and timing. Toxicity may also be affected by this synergism, particularly in relation to the suppression of rapidly proliferating cells in the GI tract and the bone marrow. Soloway [32] used cis-platin plus radiation therapy in 8 patients with advanced bladder cancer, in 5 of whom the tumor was locally recurrent or metastatic. Treatment was well-tolerated and the survival for patients with recurent or metastatic tumor averaged 24 months compared to 4 months which Babaian [1] had reported for untreated metastatic tumors. Jakse [15] used a similar cis-platin-radiation regimen with the addition of VM-26 maintenance chemotherapy in 8 patients with locally advanced disease who were not candidates for cystectomy. Six of the patients had complete responses with a mean follow-up of 7.7 months. Based on these encouraging preliminary studies, the

N B C C G A initiated Protocol 8 in 1980 [28]. This was an uncontrolled pilot study to evaluate the toxicities associated with concurrent administration ofcis-platin and small-field pelvic radiation therapy for patients with localized muscle invasion, but who are, not suitable for cystectomy. Patients received cis-platin, 70 mg/M 2 IV, 1 day prior to the initiation of external beam radiotherapy (6480 rads) and continued every 3 weeks for a total of 8 courses. A high complete response rate (76%) was observed in patients with visible tumor prior to therapy. Toxicity was acceptable. It is too early to determine the effect on survival. Patient tolerance with cisplatin was once again a long-term problem since the median number of courses of chemotherapy was 4. Herr [11] reported a series of 31 patients who received a single dose of cis-platin, 70 mg/M 2, during a 1week course of 2000 rads pre-cystectomy radiation therapy. In this format, the cis-platin was well-tolerated with no unusual toxicity. Disease survival at 2 years for all patients was 55%, which was felt to be superior to a comparable group of 39 patients who, although not randomized controls, were treated during the same time interval with low-dose preoperative radiotherapy and cystectomy. Downstaging occurred in 36% of the patients with resectable tumor, but did not confer any additional survival advantage over patients who dit not have downstaging at the time of cystectomy. Raghaven [24] performed a pilot study using cisplatin, 100 mg/M 2, at 3 weekly intervals for 2 cycles before a variety of definitive therapies and reported a 60% partial response rate and excellent patient tolerance. Unfortunately, most of the patients were treated subsequently without cystectomy and information on pathologic downstaging is not available. Based upon the results of this pilot study, a larger series with a singletreatment regimen is to be initiated by the Australian Bladder Cancer Group. Oliver [22] gave high-dose methotrexate with folinic acid rescue prior to radiotherapy to 19 patients. Survival was not improved over that of historical controls. A large randomized prospective study has been initiated by the London Oxford Cooperative Urological Cancer Group [20] utilizing methotrexate followed by 4400 rads prior to cystectomy for patients with T3 tumors less than 65 years of age. Patients over 65 years old are to receive definitive radiotherapy with 6400 rads. Pending the results of this and other trials, the role of methotrexate is uncertain. Major toxicities may occasionally be attributable to the combination of chemotherapy and radiation therapy. Schaeffer [27] used adriamycin before and after radiation therapy in patients with persistent local regional disease after cystectomy. Of 8 patients, 7 suffered small bowel obstruction, 5 of whom required surgical bypass procedures. Hall [8] noted small bowel necrosis which, in conjunction with pulmonary fibrosis, led to the death of 2 of his 10 adjuvant patients. These patients had been given a combination of adriamycin, bleomycin, 5FU, and

119 methotrexate following preoperative radiotherapy and cystectomy. There is experimental evidence in mice that the combination ofadriamycin and radiation leads to an increased incidence of small bowel necrosis and proliferation or fibrosis, stenosis, and obstruction [23]. Further clinical evidence of this synergistic toxicity is also available. Ransom [25] reported that when adriamycin was added to treatment regimens for childhood rhabdomyosarcoma including triple chemotherapy, radiotherapy and surgical resection, delayed gastrointestinal complications led to debilitation or death in 6 of 12 evaluable patients. Caution should therefore be used in the use of radiosensitizers such as adriamycin and cis-platin. Further work will need to be done to determine the dosages and sequence of administration to obtain maximal benefit from their synergism while controlling toxicity.

Intra-arteriai chemotherapy and hyperthermia Efforts to reduce the systemic toxicity of chemotherapeutic agents while maintaining high tissue levels have stimulated several preliminary studies using intraarterial adjuvant chemotherapy. Kamidono [17], using intra-arterial adriamycin as well as hemodialysis to recover the drug from the general circulation, failed to show any reduction in toxicity. Kanoh [18] reported partial responses in seven out of eight patients in whom adriamycin was infused selectively into the inferior gluteal branch of the internal iliac artery. Local skin necrosis was the dose-limiting toxicity. Follow-up is short and the clinical significance of this adjuvant modality in combination with surgery or radiotherapy is unclear. Experimental studies on murine transitional cell carcinoma have indicated synergism between local hyperthermia and chemotherapeutic agents, in particular cisplatin, adriamycin, and cyclophosphamide [7]. Tumor vessels lack the ability to adapt to higher temperatures, presumably because of the inability to vasodilate. There is evidence that increased temperatures result in changes in the cell membranes which may facilitate the permeability of chemotherapeutic agents. Jacobs [13, 14] combined intra-arterial single-agent adriamycin or cis-platin with intravesical hyperthermia prior to cystectomy in the hopes of benefiting from the synergistic activity. The results to date are inconclusive.

Conclusion Adjuvant chemotherapy regimens of proven benefit have not yet been identified. Recent reports of high response rates with platinum-based 3- and 4-drug combination chemotherapy regimens seem quite promising, however, the duration of responses has not been documented to date. In addition, toxicity is significant and

may not be acceptable in the adjuvant setting. They may be more suited for use as initial therapy prior to surgery and/or radiation. New drugs with more specific action against transitional cell carcinoma or less toxic analogs of present drugs, e.g. platinum, allowing higher doses are needed. Improved techniques of local perfusion may help to reduce systemic toxicity. The sequence and timing of drug administration is important in determining toxicity and patient tolerance, but the effect on response rates and survival is less clear. Patients will tolerate only so much adjuvant chemotherapy as is evidenced in the cis-platin studies in which more than four courses of treatment were not tolerable to most patients. Ideally, intensive chemotherapy would appear to be best given prior to defmitive local treatment. As well as being better tolerated, this would have the theoretical advantage of potential downstaging of the primary tumor prior to surgery or radiosensitization in the case of definitive radiation therapy. The combined toxicities of radiation and chemotherapy are worrisome. Myelosuppression appears to be well-tolerated because of the small field of radiation, however, the increased susceptibility to small bowel complications has not been generally recognized. In spite of these obstacles, it is clear that only with the development of effective adjuvant systematic therapies will we see significantly increased survivals in invasive bladder cancer.

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