|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2150-2154 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.043 Adjuvant Chemotherapy With Paclitaxel and Carboplatin in Patients With Advanced Carcinoma of the Upper Urinary Tract: A Study by the Hellenic Cooperative Oncology GroupFrom the Departments of Clinical Therapeutics, and Department of Urology, University of Athens, School of Medicine; Medical Oncology Department, AHEPA Hospital, University of Thessaloniki, School of Medicine; 3 Hygia Hospital, Athens, Greece Address reprint requests to Aristotle Bamias, MD, 31 Komninon St, Haidari 124 62, Athens, Greece; e-mail: abamias{at}med.uoa.gr
PURPOSE: Radical surgery represents the treatment of choice for carcinoma of the upper urinary tract. Nevertheless, approximately 50% of patients with stage T  3 or lymph node involvement die from their disease, mainly as a result of the development of distant metastases. Therefore, there is a need for effective adjuvant systemic treatment. We prospectively studied a cohort of patients who underwent surgery for high-risk carcinoma of the upper urinary tract to assess the feasibility of the combination of paclitaxel and carboplatin as adjuvant treatment.
PATIENTS AND METHODS: Thirty-six patients with tumor stage RESULTS: Median follow-up was 40.6 months. Chemotherapy was well tolerated with 32 patients (89%) receiving full carboplatin and paclitaxel doses without delays. The most frequent grade 3/4 toxicity was neutropenia (39%), which was complicated with fever in only one case (3%). Nonhematologic grade 3 or 4 toxicities were reported in only one case. Five-year survival was 52% (95% CI, 35% to 69%), while 5-year disease-free survival was 40.2% (95% CI, 15.8% to 64.6%). Local failure rate was 30%, as opposed to 17% of patients who developed distant metastases. No patients with grade 2 tumors relapsed during follow-up, as opposed to 60% of patients with grade 3 tumors. CONCLUSION: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and may reduce the risk of distant metastases in high-risk upper urinary tract carcinoma.
Carcinoma of the upper urinary tract (renal pelvis and ureter) is rare, accounting for approximately 5% of the tumors of the urinary tract.1 Surgery represents the treatment of choice in patients without distant metastases. Nevertheless, recurrence of the disease will occur in 50%, which underlines the need for adjuvant therapies. Tumor stage (T) and grade are the most important prognostic factors, as reported in most series with greater than 50 cases2–5; prognosis significantly worsens for patients with T3 and/or grade 3 tumors. The most frequent cause of treatment failure is the development of lymph node or distant metastases,2,3 which implies that an effective adjuvant therapy should have a systemic effect. The efficacy of chemotherapy in advanced upper urinary tract carcinoma has been mostly investigated in studies, including patients with bladder cancer, who formed the majority of the population enrolled. Nevertheless, it seems that, at least for transitional cell carcinoma, chemotherapy is equally active in upper urinary tract as in bladder cancer.5,6 The combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) has been used in most studies, because it has long been considered the standard treatment for metastatic urothelial cancer. Nevertheless, there are no data regarding adjuvant chemotherapy in upper urinary tract carcinoma, since the rarity of these tumors precludes the performance of prospective studies. Newer agents, including the taxanes paclitaxel and docetaxel, have shown promising single-agent efficacy in advanced urothelial cancer.7,8 On the other hand, carboplatin has shown promising single agent activity in urothelial carcinoma9 and could be substituted for cisplatin in order to avoid the nonhematologic toxicity and to produce easier-to-administer combinations. The lack of nephrotoxicity is particularly relevant in this patient population who may have age or disease-related renal function impairment. The combination of paclitaxel and carboplatin has shown promising efficacy and favorable toxicity profile in two phase II studies.10,11 Since there are no data on the use of this regimen as adjuvant treatment in upper urinary tract cancer, we performed a prospective study of this combination as post-surgery chemotherapy in patients with high risk for relapse. We used paclitaxel at 175 mg/m2, since neutropenic fever was frequently reported10 with a paclitaxel dose of 225 mg/m2.
Patients Patients with histologically proven carcinoma of the renal pelvis or ureter were entered into this prospective combination chemotherapy study. The patients should have undergone radical surgery with removal of all macroscopic disease. Patients should be at high risk for relapse, ie, pT3N0 (invasion of the periureteric or peripelvic fat or renal parenchyma), T4N0 (invasion of adjacent organs or through the kidney into perinephric fat), or any pT with involved regional lymph nodes. Patients should not have evidence of distant metastases. Other exclusion criteria included uncontrolled cardiac arrythmias and cardiac or respiratory failure. Baseline evaluation included complete blood counts, renal and liver function tests, chest x-ray (followed by computed tomography [CT] scan of the thorax if there was suspicion of metastases), CT scan of the abdomen and pelvis, and bone scan if clinically indicated. The protocol of the study was approved by the Scientific Committee of the Hellenic Cooperative Oncology Group and the institutional review board of each participating center. Patients gave their informed consent before their enrollment.
Chemotherapy If ANC on day 7 was less than 0.5 x 109/L, G-CSF was administered for 5 days and thereafter prophylactically on days 6 to 18 of the following courses. Apart from the addition of G-CSF, no other dose modifications were applied for neutropenia with the exception of prolonged (> 7 days with ANC < 0.5 x 109/L) neutropenia or febrile neutropenia in G-CSF supported patients. In these cases a 25% dose reduction for both drugs was performed. The following dose modifications were applied according to the nadir value of platelets: if platelets were between 25 and 49 x 109/L, a 25% dose reduction (all drugs) was made; a 50% dose reduction was applied for platelet counts below 25 x 109/L.
Follow-Up
Statistical Considerations
Patients Between January 1997 and August 2001, 36 consecutive patients were enrolled onto the study. Baseline characteristics are shown in Table 1. All patients underwent nephroureterectomy with removal of the bladder cuff. Most tumors were located in the renal pelvis (83%). Most patients had T3 stage (72%), while lymph node involvement was found in five cases (14%). In 14 cases (39%) no lymph node sampling was performed. The majority of cases showed transitional cell histology (86%), while mixed histology (transitional and squamous or adenocarcinoma, n = 6), undifferentiated carcinoma (n = 1) and carcinosarcoma (n = 1) accounted for the rest of cases.
Chemotherapy The median number of cycles was four (range, 1 to 4 cycles). One patient did not complete the four chemotherapy courses because he refused further treatment after the second cycle. Treatment was well tolerated. Thirty-two patients (89%) received full carboplatin and paclitaxel doses without delays. The most frequent grade 3/4 toxicity was neutropenia, except for alopecia, which was universal. There were 14 cases (39%) of grade 3/4 neutropenia, which was complicated with fever in only one patient (3%). There was only one case of thrombocytopenia (grade 2). Nonhematologic grade 3 or 4 toxicities were reported in only one case of renal toxicity. The most frequent nonhematologic toxicity was neurotoxicity, which was reported in 11 patients (30%). Allergic reactions were reported in three patients (8%), but they were not serious and did not require treatment discontinuation or dose reductions. There were no treatment related deaths.
Survival and Disease-Free Survival
Upper urinary tract carcinoma is rare and, therefore, data regarding the efficacy and tolerability of chemotherapy as adjuvant treatment after surgery is extremely limited. To our knowledge this is the largest prospective series addressing this question. Chemotherapy seems to be active in the upper urinary tract, as shown in patients with inoperable or recurrent disease, although these tumors have been studied together with the more frequent bladder cancer.13–16 The role of chemotherapy as adjuvant treatment following surgery has not been defined in upper urinary tract carcinoma, since randomized studies including such patients are practically impossible to conduct because of the rarity of these tumors. Information regarding the role of chemotherapy as adjuvant treatment is mostly available from randomized studies including patients with bladder cancer.17–21 These studies suffer from serious limitations of lack of statistical power, variability of inclusion criteria and chemotherapy used22 and, therefore, the role of adjuvant chemotherapy hopefully will be defined by current randomized studies.23 Nevertheless, existing data suggest a possible benefit from MVAC, or similar regimens in patients with extravesical tumor extension or regional lymph node involvement,22 and this treatment has been used outside the context of clinical trials.24 The toxicity of the long considered as standard MVAC has been a serious drawback of this regimen and has steamed research towards novel agents and combinations. The administration of MVAC or other cisplatin-based regimens as adjuvant treatment for patients with upper urinary tract carcinoma may be of particular concern because these patients undergo nephrectomy. The non-nephrotoxic combination of carboplatin and paclitaxel has shown promising activity and favorable toxicity profile compared to MVAC.10,11 Our study showed that four cycles of this combination are well tolerated in this cohort of patients. There was only one case of neutropenic fever (3%), which compares favorably with the results of MVAC or MVAC-like combinations, although the toxicity of this regimen has been lower when used in the adjuvant or neoadjuvant setting. In addition, there was only one case of grade 3 nonhematologic toxicity, while there was no grade 3 or 4 stomatitis, which has been consistently reported for MVAC. Neurotoxicity was encountered in 11 cases (30%), which is in concert with previous reports using the same combination.10,11 Notably, there was no grade 3 neurotoxicity, probably because only four courses of chemotherapy were administered. Our study was designed to test the feasibility of the combination of paclitaxel and carboplatin as adjuvant treatment in patients with high-risk of relapse following surgery for upper urinary tract carcinoma. Therefore, no firm conclusions regarding the efficacy of this treatment can be drawn from this study. This is a limitation related to the rarity of these tumors and conclusions have to be drawn from indirect comparisons and mainly retrospective analyses. Data from studies including a meaningful number of patients who were treated with surgery alone have shown 5-year survival of 41% to 80% for T3 stage and 0% to 21% for T4 stage (Table 2). In addition, 5-year survival for grade 2 and 3 tumors has been reported at 46% to 89% and 0% to 70%, respectively (Table 2). Our results showed similar survival for T3 tumors, but better survival for T4 and grade 2 tumors. Although these results indicate a possible benefit for the latter groups of patients, they should be viewed with caution because of the small number of patients included in our study. Furthermore, the results of previous retrospective analyses are difficult to compare with ours, as well as with each other, because there are differences in the length of follow-up, histopathologic grading, and type of surgery, while adjuvant treatment had been occasionally administered to some patients. The efficacy of the combination of paclitaxel/carboplatin (or other non-nephrotoxic combinations) compared to that of MVAC or the novel gemcitabine/cisplatin, which has emerged as a less toxic, equally effective regimen,31 remains unanswered. This question has become more relevant after the results of a recent meta-analysis and a published randomized study, both of which showed that cisplatin-based combination chemotherapy and MVAC may offer a survival benefit when used as neoadjuvant treatment in invasive bladder cancer.32,33 Interestingly, the toxicity of MVAC in the randomized study was lower than that expected from data in advanced disease. A finding supporting the speculation that adjuvant chemotherapy may be beneficial for some patients is the striking difference between local and distant failures compared with those reported in the literature for patients not receiving adjuvant treatment (Table 3). The number of local failures was double that of distant metastases, while the opposite has been almost universally reported previously.3–5 These results may indicate a degree of protection against the development of distant metastases by adjuvant chemotherapy.
Adjuvant chemotherapy did not seem to have an impact on the local failure rate in our study. Adjuvant radiotherapy has been studied in this context but its role remains unanswered.5 Nevertheless, it has been suggested that it might lower local failure rate, albeit without any impact on survival.4,34–37 Therefore, a combination of radiotherapy and chemotherapy may be a more effective adjuvant treatment than each modality alone.
In conclusion, adjuvant paclitaxel/carboplatin is well tolerated in patients with stage
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Bloom NA, Vidone RA, Lytton B: Primary carcinoma of the ureter: A report of 102 new cases. J Urol 103:590–598, 1970[Medline] 2. Guinan P, Vogelzang NJ, Randazzo R, et al: Renal pelvic cancer: A review of 611 patients treated in Illinois 1975–1985. Cancer Incidence and End Results Committee. Urology 40:393–399, 1992[CrossRef][Medline] 3. Hall C, Womack S, Sagalowsky AI, et al: Prognostic factors, recurrence, and survival in transitional cell carcinoma of the urinary tract: A 30-year experience in 252 patients. Urology 52:594–601, 1998[CrossRef][Medline] 4. Cozad SC, Smalley SR, Austenfeld M, et al: Transitional cell carcinoma of the renal pelvis or ureter: Patterns of failure. Urology 46:796–800, 1995[CrossRef][Medline] 5. Kirkali Z, Tuzel E: Transitional cell carcinoma of the ureter and renal pelvis. Crit Rev Oncol Hematol 47:155–169, 2003[Medline] 6. Lerner SE, Blute ML, Richardson RL, et al: Platinum based chemotherapy for advanced transitional cell carcinoma of the upper urinary tract. Mayo Clin Proc 71:945–950, 1996[Abstract]
7. Roth BJ, Dreicer R, Einhorn LH, et al: Significant activity of Paclitaxel in advanced transitional-cell carcinoma of the urothelium: A phase II trial of the Eastern Coopertaive Oncology Group. J Clin Oncol 12:2264–2270, 1994
8. McCaffrey JA, Hilton S, Mazumdar M, et al: Phase II trial of Docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 15:1853–1857, 1997 9. Mottet-Auselo N, Bons-Rosset F, Costa P, et al: Carboplatin and urothelial tumors. Oncology 50:28–36, 1993 (suppl 2)
10. Vaughn DJ, Malkowicz SB, Zoltick B, et al: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: An active and tolerable outpatients regimen. J Clin Oncol 16:255–260, 1998 11. Redman BG, Smith DC, Flaherty L, et al: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 16:1844–1848, 1998[Abstract] 12. Kaplan EL, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 13. Sternberg C, Yakoda A, Scher HI, et al: M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 139:461–469, 1988[Medline] 14. Loehler PJ, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma. J Clin Oncol 10:1066–1073, 1992[Abstract]
15. Dimopoulos MA, Bakoyiannis C, Georgoulias V, et al: Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: A multicenter phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 10:1385–1388, 1999
16. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of treatment. J Clin Oncol 17:3173–3181, 1999 17. Skinner DG, Daniels JR, Russell CA, et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 145:459–467, 1991[Medline] 18. Stockle M, Meyenburg W, Wellek S, et al: Advanced bladder cancer (stages pTeb, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 cycles of adjuvant chemotherapy. J Urol 148:302–306, 1992[Medline] 19. Studer UE, Bacchi M, Biederman C, et al: Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: Results of a prospective randomized trial. J Urol 152:81–84, 1994[Medline] 20. Freiha F, Reese J, Torti FM: A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 155:495–499, 1996[CrossRef][Medline] 21. Bono AV, Benvenuti C, Reali L, et al: Adjuvant chemotherapy in locally advanced bladder cancer: Final analysis of a controlled multicentre study. Acta Urol Ital 11:5–8, 1997
22. Dimopoulos MA, Moulopoulos LA: Role of adjuvant chemotherapy in the treatment of invasive carcinoma of the urinary bladder. J Clin Oncol 16:1601–1612, 1998 23. de Wit R: Overview of bladder cancer trials in the European Organization for Research and Treatment. Cancer 97:2120–2126, 2003[CrossRef][Medline] 24. Sharma P, Bajorin D: Controversies in neoadjuvant and adjuvant chemotherapy for muscle-invasive urothelial cancer and clinical research initiatives in locally advanced disease. In: 2003 ASCO Educational Book, Alexandria, VA, American Society of Clinical Oncology, pp: 478–487 25. Morioka M, Jo Y, Furukawa Y, et al: Prognostic factors for survival and bladder recurrence in transitional cell carcinoma of the upper urinary tract. Int J Urol 8:366–373, 2001[CrossRef][Medline] 26. Mufti GR, Gove JRW, Badenoch DF, et al: Transitional cell carcinoma of the renal pelvis and ureter. Br J Urol 63:135–140, 1989[CrossRef][Medline] 27. Masuda M, Tanao Y, Iki M, et al: Apoptosis in transitional cell carcinoma of the renal pelvis and ureter: Association with proliferative activity, bcl-2 expression and prognosis. J Urol 158:750–753, 1997[CrossRef][Medline] 28. Rey A, Lara PC, Redondo E, et al: Overexpression of p53 in transitional cell carcinoma of the renal pelvis and ureter. Cancer 79:2178–2185, 1997[CrossRef][Medline] 29. Racioppi M, D'Adessi A, Alcini A, et al: Clinical review of 100 consecutive surgically treated patients with upper urinary tract transitional tumors. Br J Urol 80:707–711, 1997[CrossRef][Medline] 30. Corrado F, Ferri C, Mannini D, et al: Transitional cell carcinoma of the upper urinary tract: Evaluation of prognostic factors by histopathology and flow cytometric analysis. J Urol 145:1159–1163, 1991[Medline]
31. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077, 2000 32. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 361:1927–1934, 2003[CrossRef][Medline]
33. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866, 2003 34. Maulard-Durdux C, Dufour B, Hennequin C, et al: Postoperative radiation therapy in 26 patients with invasive transitional cell carcinoma of the upper urinary tract: No impact on survival? J Urol 155:115–117, 1996[CrossRef][Medline] 35. Hall C, Womack JS, Roehrborn CG, et al: Advanced transitional cell carcinoma of the upper urinary tract: Patterns of failure, survival and impact of postoperative adjuvant radiotherapy. J Urol 160:703–706, 1998[CrossRef][Medline] 36. Babaian RJ, Johnson DE, Chan RC: Combination nephrouterectomy and postoperative radiotherapy for infiltrative ureteral carcinoma. Int J Radiat Oncol Biol Phys 6:1229, 1980[Medline] 37. Brookland RK, Richter MP: The postoperative irradiation of transitional cell carcinoma of the renal pelvis and ureter. J Urol 133:952, 1985[Medline] Submitted September 9, 2003; accepted March 10, 2004.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
