Improvement in Systemic Chemotherapy Options for Advanced Cases of Bilharzial Bladder Cancer

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1 Med. J. Cairo Univ., Vol. 77, No. 3, June: 37-43, Improvement in Systemic Chemotherapy Options for Advanced Cases of Bilharzial Bladder Cancer YASSER A. SALLAM, M.D.*; ZIKRI K. ZIKRI, M.D.; MAMDOUH EL-SHERBINY, M.D.** and AYMAN A. GABER, M.D.* The Department of Medical Oncology, National Cancer Institute*, Cairo* and Beni Suef** Universities. Abstract Bilharzial bladder cancer is a major health problem in Egypt, as well as some African and Asian countries it represents a distinct clinicopathologic disease. In order to investigate efficacy of chemotherapy in cases with advanced bilharizial bladder cancer as well as different clinicopathologic factors, that may impact response to chemotherapy, we conducted a phase III study, upon 58 patients, over the period from April 1999 to Dec The 58 patients had pathologically proven bladder carcinoma on top of previous bilharzial cystitis presenting with either metastatic, inoperable, or recurrent disease. The 55 patient s evalvuable for response, 26 patients were randomized to receive single agent epidoxorubicin, claimed to be most active single agent in cases of bilharzial bladder cancer and the remaining 29 patients received the combination of epidoxorubicin with vincristine alternating with etoposide and ifosfamide. The clinicopathologic characteristics of the two groups were comparable, except for the higher frequency of grade 3 tumors in the combination chemotherapy group. Those who received single agent chemotherapy, had a response in only 4 cases response rate (15.38%) with only 2 cases achieving complete remission, those receiving combination chemotherapy had a response in 11 patients (response rate of 37.9%) with only 2 patients achieving complete responses. In terms of disease control rate (CR+PR+SD) epirubicin had a control rate of 46.15%, with a mean TDP of 8 months and mean OS of 9 months, versus 62% for those receiving combination treatment with a mean TDP of 7 months and a mean O.S. of 9.4 months. The 5 year actuarial PFS rate for patients who have achieved PR and CR in both treatment groups (15 patients) was 20.5%, SE = 5.8. Combination treatment group had a higher PFS of 36.2%, in contrast to 15.4% in the group receiving epidoxorubicin treatment, a difference that proved to be statistically significant ( p=0.04). Patients randomized to receive combination treatment had a higher 5 year overall survival rate of 37.9%, versus 25.5% in patient receiving epidoxocubicin treatment, however, this difference was not statistically significant (p=0.4). Seventy six percent of patients receiving combination treatment expressed both MDR and p53 versus 33% and 50% respectively for those receiving single agent epidoxorubicin, yet such occurrence had no statistically significant correlation with response, but MDR affected OS and PFS for responding cases. Toxicity from treatment was in the form of vomiting, mucositis, diarrhea, leucopenia, anemia and were all comparable between both groups except for alopecia which was more prominent in those receiving single agent epidoxorubicin Among different clinicopathologic variables only the pathologic cell type seemed to affect response. Key Words: Bladder cancer Bilharziasis Chemotherapy. Introduction BILHARZIAL bladder carcinoma is the most common cancer, particularly in Egyptian males, accounting for 14-30% of all malignant diseases presenting to, NCI, Cairo University [1]. Classically carcinoma in bilharzial bladder is most commonly of squamous cell type. Decline in prevalence of bilharziasis in Egypt during past decade was associated with significant changes in the pathology of bladder carcinoma, with decline in frequency of squamous carcinoma and increase in transitional carcinoma. Radical cystectomy with urinary diversion is the only curative modality so far identified with long term survival rate in the range of 27% to 39% [2]. Twenty five percent of patients presenting with bladder cancer are inoperable. In addition; the reported overall rate of local recurrence following radical cystectomy ranges from 40%-50% most of them occur during the first year following surgery [3]. In contrast to reports claiming rare incidence of distant metastasis from bilharzial bladder cancer due to extensive fibrosis blocking lymphatic channels, yet its incidence was estimated to be as high as 23%, needing systemic chemotherapy as their main treatment [4]. So the Aim of this work is to 37

2 38 Improvement in Systemic Chemotherapy Options for Advanced Cases investigate efficacy of chemotherapy in cases with advanced bilharizial bladder cancer as well as different clinicopathologic factors, that may impact response to chemotherapy, in randomized phase III trial to compare between the most active single agent and combination treatment. Patients and Methods This randomized prospective study was conducted at the NCI, Cairo University, during the period between April 1999 and December It included 58 patients, with histologically proven, measurable, advanced, recurrent or metastatic urinary bladder carcinoma, with positive evidence of bilharzial infestation and cystitis. Inclusion criteria were; Age ranged from years, good Performance status (<70% karnofsky scale), Adequate hematological, kidney and liver function, with no evidence of impending or overt heart failure, with left ventricular ejection function <60%. No prior radio or chemotherapy. All Patients were accessible for treatment and follow-up, after signing informed consent. All eligible patients were subjected to the following: Full history and complete general examination, bimanual pelvic examination and lab work up that included complete blood picture, hepatic and renal profiles, as well as radiologic evaluation including, Chest X-ray, transrectal ultrasonography, or abdominal and pelvic C.T., Cystoscopic examination and biopsy. Eligible patients were randomized into 2 groups: Group A: Receiving single agent chemotherapy treatment, this group included 26 patients who received epidoxorubicin as a single agent treatment at a dose of 120mg/m 2 every 21 days, IV and Group B: Included 29 patients who received combination chemotherapy regimen consisting of: Epidoxorubicin 120mg/m 2 IV, DI and Vincristine 1.4mg/m 2 IV push DI and D8, Alternating with: Etoposide 100mg/m 2 IV infusion Dl-5 and Ifosfamide 1800mg/m 2 IV infusion Dl-5. Sodium 2- mercaptoethane sulphonate (Mesna) administered at 40% of ifosfamide dose at 0,4,8 hours after ifosfamide infusion as uroprotector. After Premedication with ondansetron (8mg), hydrocortisone (100mg), given routinely to all the patients receiving either line of therapy. All patients receiving combination regimen were hospitalized. Courses were repeated every 3 weeks. Each course, complete blood picture in addition to kidney and liver function tests were evaluated and dose was adjusted accordingly. Toxicity evaluation was carefully looked for and reported according to ECOG criteria. Patients were given at least 2 cycles and then reevaluated for response (WHO response criteria). If the patient had disease progression treatment was stopped. Otherwise, if the patient was responding or had stable disease, 2 more cycles were given, then the patient was reevaluated. If the disease was stable at that time, treatment was stopped, but if is still responding, treatment was continued up to 6 cycles of chemotherapy. Analytic tests used included unpaired t test (two sided) for comparing 2 treatment groups. p values <0.05 were considered significant. Results Patient s characteristics: The following Table summarizes the clinicopathologic characteristics of the patients in the two groups. No statistically significant differences could be depicted between the two groups; except for tumor grade difference. In our study, patients who received single agent chemotherapy had a mean received dose intensity of 90.5% while the combination group of patients had a mean received dose intensity of 75.8%. No significant difference was observed between the mean received dose intensity of both group ( p= 0.297). Response evaluation: Detailed presentation and response evaluation of patients included in this study are shown in Table (2). Group A had a response in only 4 cases (response rate 15.38) with two cases having complete remission, after receiving 6 and 8 cycles. So, the mean duration of response of all responding cases this group was months. So, disease control rate for group A (CR + PR + SD) was 12 out of 26 (45.15%), with a mean TDP of 8 months. Group B, Eleven patients (37%) have achieved a remission, 2 cases (6.89%) of them had complete response and the remaining 9 patients (31 %) had partial response. So this group had RR of 37.9% with a mean duration of response of months. Seven patients in group B had their disease stabilized. So, in terms of disease control (CR + PR + ND), its rate was (18/29) or 62%, with a mean TDP of 7 months. Detailed response evaluation of the 2 groups of patients that have received single agent or combination chemotherapy is shown in Fig. (1).

3 Yasser A. Sallam, et al. 39 Survival results: The 5 year actuarial PFS rate for patients in combination treatment group was in the range of 36.2%, in contrast to 15.4% in the group receiving epidoxorubicin treatment, a difference that proved to be statistically significant (p=0.04) the following (Fig. 2). Overall survival: The 5 year actuarial overall survival rate of patients randomized to receive combination treatment had a higher 5 year overall survival rate of 37.9% versus 25.5% in patient receiving epidoxo- rubicin treatment, however, this difference was not statistically significant (p=0.4). The response rate of the 26 cases randomized to receive epidoxorubicin was correlated to the different variables included in the study, namely the patient's age, sex, pathologic cell type of tumor, tumor grade, disease status, P53 and MDR expression. No statistically significant difference was found for all those variables between responders and non-responding cases except for the pathologic subtype, where cases having transitional cell carcinoma achieved a higher response rate compared to those having squamous cell carcinoma. Table (1): Clinicopathologic characteristics of patients in both groups of the study. Parameter Combination group Single agent group Total p Value Number of patients Sex: Male Female Male: female ratio 3,83:1 5,5:1 4,5:1 Age: Mean 52, 9 y 50, 8 y 51, 85 y Range y Pathologic subtypes: Squamous cell carcinoma Transitional cell carcinoma Adenocarcinoma Undifferentiated carcinoma Pathologic Grade: Gr 1 and Gr Tumor at presentation: Bladder mass only Bladder mass with metastasis Lung Liver Bone Liver and lung 1 1 Lung and nodal Metastatic disease after removal of primary bladder tumor: Lung Lung and liver Lung, liver and nodal Lung, liver and skin Lung, bone and supramal Skin Skin and liver Nodal metastasis Local recurrence after removal of bladder tumor Local recurrence and metastasis (bone-liver-lung-nodal-bone) 3 2 5

4 40 Improvement in Systemic Chemotherapy Options for Advanced Cases Table (2): Comparison between responding and resistant patients among the two different modalities of treatment. Response Single agent Treatment modality Combination No. % No. % SD + ID PR + CR p value 0.04* also by Both MDR & p53 (p=.03). PFS: was affected by Treatment type, (p=.04), MDR expression, (p=.046). TDP: was affected by, Pathologic cell type (p=.0016), Both MDR & p53, (p=.02) Table (3): Correlating the response with the different variables in epidoxorubicin single agent group. 60 Variable Disease Remission Total p-value Pathologic type: SCC TCC Total Grade: Total % Single agent Combination Total group Diseases OR Age: < > Total Sex: Male Female Total Disease site: Bl+Rec Mets Total p53: +Ve Ve Total MDR: +VE VE Total % Single agent Combination Total group OR CR Fig. (1): Comparison between the two treatment groups in OR rates. On the other hand, none of these clinicopathologic variables correlated significantly, with the ability to achieve a remission in cases receiving combination chemotherapy regimen. Again, when combining both groups together, none of these variables affected response rate significantly. Survival rate: The most important factors that significantly affected treatment outcome were as follows: Overall response was affected by: Treatment modality with (p=.04), as well as by MDR expression, (p=.046). Group A response: was only affected by Pathologic cell type, (p=.031). Survival results, was affected by Pathologic cell type, p=.006, MDR expression, (p=.049) and Cumastive proportion surviving p values = 0.04* Complete Censored Fa Cc Time/month Fig. (2): Comparison between the two treatment groups in 5- year actuarial PFS rate.

5 Yasser A. Sallam, et al. 41 Cumastive proportion surviving p values = 0.4 Complete Censored Co Ferma Time/month Fig. (3): The 5 year actuarial overall survival rate of patients with combination versus single agent treatment. Discussion Carcinoma in bilharzial bladder is the commonest malignant tumor in Egyptian males, accounting for 14-30% of all malignant diseases, presenting to NCI of Cairo University [1]. Classically carcinoma in bilharzial bladder is most commonly of squamous cell type. Decline in prevalence of bilharziasis in Egypt during the past decade was associated with significant changes in the pathology of bladder carcinoma, with decline in relative frequency of squamous carcinoma and increase in transitional carcinoma [2]. Radical cystectomy with urinary diversion is the only curative modality so far identified, with long term survival rates of about 35% [2]. Twenty five percent of patients presenting with bladder cancer, are inoperable [3]. In addition, the reported overall rate of local recurrence following radical cystectomy ranges from 40%-50%. Most of them occur during the first year following-surgery [2]. In contrast to reports claiming rare incidence of distant metastasis from bilharzial bladder carcinoma, due to extensive fibrosis blocking lymphatic channels, compared to non-bilharzial carcinoma, yet its incidence was estimated to be as high as 23%, in bilharzial bladder cancer patients. The risk factors for developing distant metastasis are positive nodal involvement (54%), stage P4a disease (33%) and high grade tumors (38%) [4]. Although the western type of bladder transitional carcinoma is a chemosenstive malignancy however only a small proportion (=10%) of patients with advanced disease succeed to have long term survival following chemotherapy. A number of single chemotherapeutic agents with different mechanisms of action are active against bladder tumors, producing as overall response rate of 12%- 31%, with duration of response on the order of 3-4 months. Complete responses are rare, usually less than 10%. The most active single agents include paclitaxel, methotrexate doxorubicin, cisplatin, cyclophosphamide, ifosfamide, pemetrexed and gemcitabine [5]. A series of phase II study was conducted at Cairo NCI, starting in 1976, in which various chemotherapeutic agents were screened in groups of patients, with inoperable metastatic or recurrent bilharzial bladder cancer, who had not previously received chemotherapy. The drug epidoxorubicin, showed the highest objective response rate of 60% in 18 patients. Other active drugs included vincristine, ifostamide and etoposide, with a response rate of 41%, 40% and 36%, respectively [6]. Unfortunately, in spite of quite good response rates, very few durable remissions were observed, This outcome has improved, however, with the development of 3 and 4 drug combination regimens, which resulted in durable complete responses. Khaled et al. (1996) used a combination of epidoxorubicin plus vincristine alternating with ifosfamide and etoposide in patients with locally advanced and metastatic disease, giving a response rate of 41% with a median duration of response of 5 months. Such variability in response rate, called for conduction of a randomized phase III trial to compare between the most active single agent and combination treatment [7]. In our study, 58 patients with bilharzial bladder carcinoma, having locally advanced, metastatic, or recurrent disease with no previous chemo or radiotherapy, were randomized to receive either single agent or combination treatment. Three patients have been excluded being inevaluable for response. The remaining 55 patients were randomized into two groups: 26 patients were randomized to receive single agent epidoxorubicin and the remaining 29 patients were randomized to receive a combination treatment of ifosfamide plus etoposide alternating with epidoxorubicin plus vicristine. In this group patients age ranged from years. Despite the fact that most of the previous studies of bilharzial bladder cancer had squamous cell carcinoma as the most frequent pathology followed by transitional cell carcinoma, yet these studies consistently proved an in increase in the frequency of transitional cell carcinoma from 21% to 40% as reported by Zaghloul et al., 1996; Khaled et al., 1996 and Ghoneim et al., 1997 [2,4,7]. Pathologic subtype of bladder cancer apparently affected response to treatment, as for the whole group patients who had 13.6% for cases who had squamous cell carcinoma. Also, in the higher response rate of 28.6% compared to 13.6% for those who had received single agent epidoxorubicin. The

6 42 Improvement in Systemic Chemotherapy Options for Advanced Cases tumors of patients who received combination treatment were mostly of grade 3, (15/29) or 51.7%. Those who received single agent treatment were mostly of grade 1-2 (14/26) or 52.8%. Patients who presented with metastatic bladder cancer had a higher response rate amounting to 30.4% compared to patients with locally advanced bladder masses, who had a response in only 14%, in the whole group, as well as in the combination group who had 24% response rate for metastatic cases versus 0% for locally advanced cases, a finding most probably related to bilharzial peritumoral fibrosis. Results with the use of single agent epidoxorubicin have been unexpectedly inferior to those previously reported, since epidoxorubicin produced as overall response rate of 15.38% (4/26, 2 of them in durable CRs) with (CR + PR + SD) of 46% (12/26). In the previously published phase II study, epidoxorubicin produced partial and short lasting responses in the majority of responding cases and CR was infrequent [6]. On the other hand, the combination treatment produced an overall response rate of 11/29 (37.9%), with a mean duration of response of months which is similar to that reported in the phased II study published by Khaled et al. (1996) [7]. P53 mutations are common events in bilharzial bladder cancer and are associated with higher tumor stage and grade [8]. Nuclear accumulation of p53 in superficial and in invasive bladder cancer correlates with poor outcome and reduced survival [9]. Also MDR (P-gp) is one of the mechanisms by which the cells acquire resistance to some chemotherapeutic agents, acting as an efflux pump transporting drugs out of cells. MDR was found to be highly expressed in specimens from patients with bladder cancer particularly those under chemotherapy [10]. P53 which correlates with poor outcome and reduced survival, was expressed in 76% of cases receiving combination treatment versus 50% for those receiving single agent epidoxorubicin. Also MDR was expressed in 76.44% in patients who have received combination treatment versus 33% for those who received single agent chemotherapy. Most patients in our study, used ondasetron plus dexamethazone and despite that, experienced grade 2-3 vomiting especially with combination treatment in (42%) of patients. Twenty seven percent of patients receiving single agent epidoxorubicin suffered from grade 1-2 leucopenia, versus 24% patients receiving combination treatment. Such difference was statistically insignificant (p=0.346). Other promising combinations include gemcitabine and cisplatin in, a phase II study was performed in NCI, Cairo University over 37 patients with previously untreated advanced bilharzial bladder cancer. Although the overall response rate in this study (54%), yet; this is the first study to report on the achievement of a CR rate of 24% (8/33 patients) in advanced bilharzial bladder cancer, currently this combination is standard treatment of such cases [11]. Another combination of cisplatin and gemcitabine given as prolonged infusion was then tried in a phase II study of 57 untreated patients with stage III/IV disease, of 54 evaluable patients, 5 (9%) achieved CR and 27 (50%) PR, for an overall response rate of 59%. The median survival time was 11.5 months. Both hematologic and non-hematologic toxicities were minimal and tolerable [12] Protracted six hours infusion proved more cost-effective regimen over the conventional one hour infusion regimen, without any significant difference in overall response, or toxicity profile [13]. Summary and Conclusion: Combination chemotherapy of epidoxorubicin with vincristine alternating with etoposide and ifosfamide for treatment of bilharzial bladder cancer proved to be more successful in treatment, with a higher response rate than that of the single agent epidoxorubicin treatment, without any increase in incidence of side effects. Yet, the response rates barely exceeded 37.9% which is a lower rate than that recorded for chemotherapy of non bilharzial bladder cancer. This may be explained by many factors including innate chemo resistance of biharzial bladder cancer or possibly due to the need to introduction and trial of new chemotherapeutic agents in treatment of bilharzial bladder cancer like gemcitabine, taxanes, gallium nitrates. etc. Also it was noted that MDR expression by bilharzial bladder cancer cells, is a good prognostic index, being correlated with rapid progression of disease and poor survival. Introduction of other biologic markers of disease might be of help in guiding the treatment line, and possible outcomes e.g. PAX-5, BCL-2, WAF1, MDM2, EGFRs. Expression of p53 had no clear impact on response to treatment, survival rate or progression of disease. References 1- NCI, Cairo University, Cancer Registry, GHONEIM M.A., EL MEKRESH M.M., EL BAZ M.A., et al.: "Radical cystectomy for carcinoma of the bladder: Critical evaluation of the results in 1026 cases". J. Urol., 158: pp , 1997.

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