膀胱癌化疗

Safety and Efficacy of I tte- Interferon �-2b Therapy Blad in Patients With Prosthetic Devices He an Fro A a A B C N b prov Univ City FAX uiow with cals trum Ente 19 nry M. Rosevear, Andrew J. Lightfoot, Kenneth G. Nepple d Michael A. O’Donnell*,† m the Department of Urology, University of Iowa, Iowa City, Iowa bbreviations nd Acronyms HV� artificial heart valve CG� bacillus Calmette-Guérin IS� carcinoma in situ MIBC� nonmuscle invasive ladder cancer Submitted for publication March 8, 2010. Study received institutional review board ap- al. * Correspondence: Department of Urology, ersity of Iowa, 200 Hawkins Dr., 3 RCP, Iowa , Iowa 52242-1089 (telephone: 319-384-6981; : 319-356-3900; e-mail: michael-odonnell@ a.edu). † Financial interest and/or other relationship Abbott Laboratories, Alynlam Pharmaceuti- , Viventia, Anadys Pharmaceuticals, Spec- , Loras, Endo Pharmaceuticals and Medical rprises. Purpose: Patients with bladder cancer who have prosthetic devices, such as a cardiac pacemaker, artificial heart valve or orthopedic hardware, and who un- dergo intravesical bacillus Calmette-Guérin therapy are theoretically at higher risk for complications, including bacterial seeding of pacemaker wires or ortho- pedic hardware, and at further risk for infective endocarditis. We assessed the safety and efficacy of bacillus Calmette-Guérin plus interferon �-2b therapy in patients with nonmuscle invasive bladder cancer and a pacemaker, artificial heart valve or orthopedic hardware. Materials and Methods: We evaluated 1,045 patients with nonmuscle invasive bladder cancer enrolled in a multicenter American phase II trial of bacillus Calmette-Guérin plus interferon �-2b therapy, including 143 with a prosthetic device (pacemaker in 87, artificial heart valve in 13 and orthopedic hardware in 43). Weekly physician toxicity assessments and standard adverse effect reporting were done. Results: No patient had infective endocarditis or hardware infection. One patient with a pacemaker, 2 with orthopedic hardware and none with an artificial heart valve required treatment cessation for fever greater than 102.5F. All defervesced within 24 hours and had no long-term sequelae. Due to intolerable, nonlife threatening side effects 12 patients with a pacemaker, 2 with orthopedic hard- ware and 1 with an artificial heart valve stopped treatment. Of the remaining patients with a prosthesis 99 and 24 stopped treatment due to intolerable, nonlife threatening and serious side effects, respectively. Conclusions: Patients with a pacemaker, artificial heart valve or orthopedic hardware were no more likely than the general population to have infection or fever, or discontinue treatment due to side effects. These patients should not be excluded from intravesical bacillus Calmette-Guérin plus interferon �-2b therapy for nonmuscle invasive bladder cancer. Key Words: bladder, bladder neoplasms, BCG vaccine, interferons, prostheses and implants ACCORDING to the most recent American Urological Association guidelines BCG is the preferred adjuvant therapy for carcinoma in situ and high risk non- muscle invasive bladder cancer.1 Inter- feron-� combined with BCG has been investigated to improve the overall out- come, and allow BCG dose reduction during maintenance and even during induction in relapsing cases.2–4 BCG is a live attenuated strain of Mycobacterium bovis originally devel- 20 www.jurology.com 0022-5347/10/1845-1920/0 Vol. 184, 1920-1924, November 2010 THE JOURNAL OF UROLOGY® Printed in U.S.A. © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2010.06.149 ntravesical Bacillus Calme for Nonmuscle Invasive Guérin Plus der Cancer op ex for a tre pr Th cli th blo to pa co wi pl fil m BC ca th pa th m (A TI tie pa fu ex pe W in bin NM ha PA A inc ga tre BC Fe th ter su pa cyc a t th sta ac his ur cop pr th fir ren tio dia ex AH giv we irr tit ar de wh We sta de gra viv aft tes ing an fec do an RE Of (9 or (1 m in (se or an stu en sta th 5 th me re po pa (4 wi th tre en BACILLUS CALMETTE-GUÉRIN IN PATIENTS WITH PROSTHETIC DEVICES 1921 ed in 1921 as a tuberculosis vaccine.5 While the act mechanism of action of BCG is unknown, ef- ts to use heat treated BCG have failed to produce similar therapeutic effect, presumably since heat ated BCG is not internalized by bladder cells, eventing initiation of the inflammatory cascade. us, the need to use a live bacterium creates a nical challenge since in a small percent of patients e serious complication of BCG infection in the odstream (BCG sepsis) may develop.6 BCG can disrupt urothelial cells with the ability gain access to the lymphatics and blood. Certain tient populations are at theoretically increased mplication risk. Immunocompromised patients th a history of chronic steroid use or organ trans- antation tolerate BCG treatment with toxicity pro- es similar to those of the general population but any clinicians are still reluctant to treat them with G.7,8 Patients at theoretically increased compli- tion risk due to intravesical BCG therapy are ose with a history of prosthetic surgery, including tients with a cardiac pacemaker, an AHV or or- opedic hardware. Manufacturers of the most com- only used strains of BCG, including Connaught ventis-Pasteur, Swiftwater, Pennsylvania) and CE®, recommend against using BCG in these pa- nts. The concern is a risk of bacterial seeding of cemaker wires or orthopedic hardware and the rther risk of infective endocarditis. Case reports ist describing pacemaker wire seeding and ortho- dic hardware infection after BCG treatment.9–12 e analyzed the experience in a national, multi- stitutional, phase II trial of treatment with com- ed BCG plus interferon �-2b in patients with IBC and a pacemaker, an AHV or orthopedic rdware to evaluate BCG safety and efficacy. TIENTS AND METHODS total of 1,106 patients with NMIBC (CIS, T1 or Ta1), luding those with primary and recurrent disease re- rdless of previous intravesical chemotherapy or BCG atment, were enrolled in a phase II study of combined G plus interferon �-2b therapy between May 1999 and bruary 2001.4 Briefly, all patients underwent transure- ral resection, followed by an intravesical BCG plus in- feron �-2b induction cycle tailored to prior BCG expo- re with dose reduction to a minimum of a third in tients previously treated with BCG. BCG maintenance les were automatically dose reduced, usually as a third, enth and a tenth during each maintenance cycle, but e interferon �-2b dose of 50 million U remained con- nt. TICE or Connaught strain was used at all centers cording to physician practice preference. Tumor recurrence was defined as visible tumor unless tologically confirmed to be benign, definitive positive ine cytology, positive biopsy even with negative cystos- y and any transitional cell carcinoma regardless of esenting site, including the upper tract, prostate, ure- du ha ra or metastasis. Time to recurrence was indexed to the st intravesical treatment date. Patients in whom recur- ce was not observed were treated as censored observa- ns on survival analysis. Patients with a history of a car- c pacemaker, an AHV or orthopedic hardware were not cluded by study protocol. Data on bovine vs mechanical Vs were not available. Prophylactic antibiotics were not en before intravesical BCG therapy according to protocol. Each patient completed a daily questionnaire for 1 ek after each BCG plus interferon �-2b cycle, describing itative symptoms such as frequency, urgency and cys- is, hematuria, flu-like symptoms, fevers, arthralgia or thritic symptoms and any other health related inci- nts. Before subsequent cycles patients were asked ether they had required hospitalization in the interim. ekly physician toxicity assessments were done and ndard serious adverse events were reported. Fever was fined as temperature greater than 102.5F since low de fever has been reported as a common side effect. We used the Kaplan-Meier method to construct sur- al curves and estimate cancer-free survival 3 years er the initiation of intravesical therapy. The log rank t for trend was used to test for recurrence rate order- across age categories. We applied Cox univariate d multivariate regression models to estimate the ef- t of age on time to cancer recurrence. All tests were ne with p �0.05 considered significant using SAS® d GraphPad® Prism®. SULTS the original 1,106 clinical trial patients 1,045 5%) provided information on pacemakers, AHVs or thopedic hardware. Of the 1,045 patients 143 3.7%) had a prosthetic device, including a pace- aker in 87, an AHV in 13 and orthopedic hardware 43, including an artificial joint or Harrington rod e table). Patients with an AHV, a pacemaker and thopedic hardware tended to be older (ages 76, 75 d 73 years, respectively, vs 68 in the remaining dy population) but this was not significantly differ- t. Previous analysis of this study suggested that ge (T1 vs Ta), tumor size (less than 1 vs greater an 5 cm), tumor multifocality (greater than 5 vs 2 to vs solitary) and prior BCG (greater than 2 vs less an 1) were significant predictors of successful treat- nt.4 However, study groups were similar in these spects to the overall study population. BCG dosing varied based on patient previous ex- sure to BCG. Of the patients 49 of 87 (56%) with a cemaker, 7 of 13 (54%) with an AHV, 19 of 43 4%) with orthopedic hardware and 554 of 902 thout hardware (61%) received full dose BCG erapy. The remainder received reduced dose BCG atment at a third or a tenth dose. These differ- ces were not significantly different. Figure 1 shows the Kaplan-Meier curve for the rable disease-free rate. The AHV and the non- rdware cohorts tended to have higher recurrence- fre th (42 no tie wi fol m af wi pa to tie ph (8 in 43 ce wi tie ca cia wi tio fev (2. di th (2 di fec or sim DI Pa ha ar op co ra wh 26 de in se BC ar tio m tre an ar op ye pla tiv be dia sin Stu Me % % T A C % L I H No. L 1 G % No. tu L 5 % S 2 G % * p † M BACILLUS CALMETTE-GUÉRIN IN PATIENTS WITH PROSTHETIC DEVICES1922 e survival (57% and 55% disease-free at 3 years) an the pacemaker and orthopedic hardware groups % and 37%, respectively) but this difference was t statistically significant. Regarding treatment safety and toxicity, no pa- nt in any cohort had endocarditis, or pacemaker re, joint or hardware infection during 3 years of lowup. One of the 87 patients (1%) with a pace- aker required cessation of treatment due to fever ter treatment 6, which resolved within 24 hours th no sequelae. Another 12 patients (14%) with a cemaker requested treatment cessation due to in- lerable, nonlife threatening side effects. No pa- nt with an AHV had treatment stopped by the ysician due to significant side effects while 1 of 13 %) stopped treatment at patient request due to tolerable, nonlife threatening side effects. Two of patients (5%) with orthopedic hardware required ssation of treatment due to fever, which defervesced thin 24 hours with no sequelae. An additional pa- nt (2%) with orthopedic hardware showed signifi- nt irritative voiding symptoms, for which the physi- n discontinued treatment. Another 2 patients (5%) th orthopedic hardware requested treatment cessa- n due to nonsignificant side effects but neither had er. Overall in the prosthetic group 3 of 143 patients 1%) had fever greater than 102.5F and 15 (10.5%) dy cohort demographic data Parameter* Nonprosthetic AHV Pacemaker Orthopedic Hardware an age (median) 68 (70) 76 (77) 75 (76) 73 (75) Male/female† 75/25 77/23 75/25 67/33 Stage:† a only 48 38 41 53 ny T1 27 31 34 23 IS (any/isolated) 36 31 36 20 Grade:† ow 17 23 16 21 ntermediate 28 15 25 26 igh 42 31 44 51 size (cm): ess than 1 32 38 37 33 –5 43 46 40 47 reater than 5 7 15 10 11 Prior chemotherapy† 23 23 23 20 transurethral bladder mor resection: ess than 5 84 85 80 79 or Greater 14 15 20 19 Multifocal:† olitary 34 23 26 35 –5 38 38 38 23 reater than 5 18 23 17 17 Primary/recurrent† 28/68 23/54 28/70 19/77 �0.05. ay not total 100% since some parameters were not specified in some patients. scontinued treatment due to minor side effects. Of e remaining 902 patients with no prosthesis 20 .2%) had fever and 99 (11.0%) requested treatment Fig (p scontinuation due to nonlife threatening side ef- ts. Overall patients with a pacemaker, an AHV or thopedic hardware had an overall toxicity profile ilar to that of the remaining cohort (fig. 2). SCUSSION tients with bladder CIS or high risk NMIBC who ve a pacemaker, an AHV or orthopedic hardware e a clinical dilemma for practicing urologists since timal therapy includes intravesical BCG, which is ntraindicated in the drug package insert. A real but re complication of BCG therapy is BCG bacteremia, ich was reported by Lamm to develop in 0.4% of 02 treated patients.6 Populations with a prosthetic vice would theoretically be at risk for the infection of dwelling artificial prosthetic material. Case reports exist describing pacemaker wire eding and orthopedic hardware infection after G treatment.9–12 In a report of loose total hip throplasty revision done 10 years after implanta- n watery pus was found that grew BCG 10 onths after the start of induction intravesical atment that also included maintenance.11 Segal d Krauss reported a case of BCG infected total hip throplasty with an iliopsoas abscess that devel- ed more than 10 years after implantation and 4 ars after intravesical treatment.10 Hip arthro- sty osteomyelitis, vertebral osteomyelitis and reac- e polyarthritis after intravesical BCG have also en reported in rare cases.10,13 BCG infection of car- c valves or leads are even less commonly reported ce our literature review only revealed 1 reported ure 1. Kaplan-Meier analysis of durable disease-free rate �0.05). ca wi ha wa ca re th Re th gu so for in co Gu cle tio ica an pl m 20 ge th ro pl th Fig . C, pa 1 t BACILLUS CALMETTE-GUÉRIN IN PATIENTS WITH PROSTHETIC DEVICES 1923 se of defibrillator BCG infection.9 BCG infection th mycotic aortic aneurysms and an aortic graft ve been reported but not in relation to an AHV.14–16 Based on the anecdotally reported risk of hard- re or pacemaker wire infection, or infective endo- rditis and the lack of safety data the previous commendation was to withhold BCG therapy in is patient population and err on the side of caution. cently the AmericanHeart Association Taskforce on e Prevention of Infective Endocarditis changed its idelines, stating that “administration of antibiotics lely to prevent endocarditis is not recommended patients who undergo a genitourinary or gastro- testinal tract procedure,” citing no evidence-based nclusive link to an increased endocarditis risk.17 idelines for prior orthopedic hardware are less ar since the 2008 American Urological Associa- n guidelines recommend antibiotics before urolog- l procedures only if there is a risk of bacteremia d a risk factor in the patient, including joint re- acement within 2 years, prior joint infection, im- unocompromise, diabetes or malignancy.18 In 09 the American Academy of Orthopaedic Sur- ons expanded recommendations to “recommend at clinicians consider antibiotic prophylaxis (cip- ure 2. Cohort toxicity profiles. A, AHVs. B, orthopedic hardware o 6, respectively, of weekly treatment cycle. floxacin dose 1 hour prior) for all total joint re- acement patients before any invasive procedure at may cause bacteremia,” especially in those with ha lat te k factors, while excluding nonsynovial hard- re.19 Our retrospective review suggests that BCG plus terferon �-2b therapy does not increase the risk of stemic or local side effects in patients with a pace- ker, an AHV or orthopedic hardware compared to at in the general population without hardware. The k of bacteremia due to catheterization and intraves- l treatment is presumed to be quite low but it was t specifically studied in our patient population. In 2007 Agrawal et al reported a randomized trial ggesting that BCG dose reduction decreases the nical toxicity of treatment without affecting effi- cy.20 This observation allows continued treatment th BCG dose reduction in patients who have mild nical side effects. The statistical similarity of our tient cohorts supports full dose BCG treatment as st line therapy in those with a prosthetic device th dose reduction according to standard regimen. Intravesical therapy in this population is not thout risk. BCG is a live bacterium and the risks herent to this treatment are well reported, includ- g the ability to gain access to the lymphatics and od. Rather, our study shows that clinical risks in tients with a pacemaker, an AHV or orthopedic cemakers. D, nonprosthetic cases. TR-I1 to TR-I6, treatments ris wa in sy ma th ris ica no su cli ca wi cli pa fir wi wi in in blo pa rdware are no greater than in the general popu- ion. We acknowledge that the implications of bac- remia in patients with a prosthetic device are cle shou to loo clu r tr re cal ac ma iza s (1 ca pedi wh m a tra ncer kn ll p bla e re th nt i po diti wa he k fit thi tiv ple low spe sig acy BC pat pa ha su thes pl o ou sent se u BC nts sses foll rowt to de sho CG d to s. plus acem rs a on. y in nt e of inf ins ion RE 1. for the management of nonmuscle invasive blad- 2. 3. 4. 5. 6. 7. bacillus Calmette-Guerin for the treatment of ncer in r n 2003; II and Kl on of an esical th nfect Dis S: Infect al bacill y 2007; ers P: A mycobac nt with ncer. J efauvea f BCG th ’Keefe litis inv lar baci in Infect an E, M and ve bacillu oentgen therapy for bladder cancer. South Med J 1995; BACILLUS CALMETTE-GUÉRIN IN PATIENTS WITH PROSTHETIC DEVICES1924 der cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178: 2314. Belldegrun AS, Franklin JR, O’Donnell MA et al: Superficial bladder cancer: the role of interferon- alpha. J Urol 1998; 159: 1793. Weiss GR, O’Donnell MA, Loughlin K et al: Phase 1 study of the intravesical administration of re- combinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother 2003; 26: 343. Joudi FN, Smith BJ and O’Donnell MA: Final results from a national multicenter phase II trial of combi- nation bacillus Calmette-Guerin plus interferon al- pha-2B for reducing recurrence of superficial blad- der cancer. Urol Oncol 2006; 24: 344. Morales A, Eidinger D and Bruce AW: Intracavi- tary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976; 116: 180. Lamm DL: Efficacy and safety of bacille Calmette- Guerin immunotherapy in superficial bladder can- cer. Clin Infect Dis, suppl., 2000; 31: S86. Yossepowitch O, Eggener SE, Bochner BH et al: Safety and efficacy of intravesical bacillus Calmette-Guerin instillations in steroid treated superficial bladder ca tients. Transplantatio 9. Stone DR, Estes NA I bacterium bovis infecti lator following intrav Calmette-Guerin. Clin I 10. Segal A and Krauss E plasty after intravesic therapy. J Arthroplast 11. Reigstad O and Siew ment infected with intravesicular treatme Guerin for bladder ca 2008; 90: 225. 12. Clavel G, Grados F, L ticular side effects o Spine 2006; 73: 24. 13. Guerra CE, Betts RF, O terium bovis osteomye plasty after intravesicu for bladder cancer. Cl 14. Rozenblit A, Wasserm fected aortic aneurysm tis after intravesical therapy. AJR Am J R and immunocompromised patients. J Urol 2006; 176: 482. 15. Hellinger WC, Oldenburg W Vascular and other serious inf enal transplant pa- 76: 1514. empner MS: Myco- implantable defibril- erapy with bacille 1993; 16: 825. ed total hip arthro- us Calmette-Guerin 22: 759. total hip replace- terium bovis after Bacille-Calmette- Bone Joint Surg Br u P et al: Osteoar- erapy. Joint Bone RJ et al: Mycobac- olving a hip arthro- lle Calmette-Guerin Dis 1998; 27: 639. arin ML et al: In- rtebral osteomyeli- s Calmette-Guerin ol 1996;