Detailed research on treatment options

Here’s a long list of questions and research that I have compiled this weekend.  My goal is to have these questions answers in the next couple of weeks, so I can know what is the best course of treatment.  

Treatment options:

1.     Radical cystectomy: pros & cons

a.     Prognosis

b.     Is RC still the standard of care?  Or is the standard evolving?

c.      Prostate cancer research: too much unnecessary surgery; standard of care recently has changed.  Why is bladder cancer different?

d.     Therapeutic interventions targeting organ preservation in muscle-invasive bladder cancer: a review, Clin Transl Oncol. 2011 May;13(5):315-21. (“Nowadays in modern oncology there is a tendency towards therapies that target organ preservation. Organ preservation protocols have become standard in the treatment of laryngeal carcinoma, oesophageal cancer, breast carcinoma and soft tissue sarcomas. The three-combined therapy consisting of a transurethral resection of the bladder tumour followed by concomitant chemoradiotherapy has been shown to be an attractive alternative for bladder preservation in selected patients with muscle-invasive bladder cancer. In order to evaluate the organ preservation approaches in muscle-invasive bladder cancer we have conducted a comprehensive literature review. Data reported from the studies have shown that bladder preservation therapy with a trimodality approach is safe and effective. Moreover, such an approach provides patients with the opportunity to maintain an intact and functional bladder with a survival rate similar to that of radical cystectomy.”) www.ncbi.nlm.nih.gov/pubmed/21596659

 e.     Why remove bladder, prostate, and lymph nodes?

 f.      If T0 is confirmed via TURBT, then why RC?

 g.     Is it true that 50%+ of recurrence is in distant locations?  So RC has zero effect in those cases? 

h.     Why no double-blind clinical trials comparing RC to bladder preservation?  Are there any currently underway?

i.       Treatment Trends and Outcomes of Small-Cell Carcinoma of the Bladder, Int J Radiat Oncol Biol Phys. 2011 Oct 20.  (“A bladder-sparing approach involving transurethral resection of the bladder tumor (TURBT) combined with chemotherapy and radiation yielded no significant difference in overall survival compared with patients undergoing at least a cystectomy (of whom over 90% received radical cystectomy) with chemotherapy (p > 0.05). The analysis of treatment trends indicated that these two general strategies for cure combined to account for fewer than 20% of patients. . . . Relatively few patients with small-cell carcinoma of the bladder receive potentially curative therapies. Chemotherapy should be a major component of treatment. Cystectomy and bladder-sparing approaches represent two viable strategies and deserve further investigation to identify the patients who may benefit from organ preservation or not. In addition, the role of radiation in regional-stage disease should be investigated further, because it positively affects survival after TURBT.”)

 2.     Bladder preservation: pros & cons

 a.     Prognosis

b.     Do recent studies suggest prognosis is about the same? 

 c.      Chemoradiotherapy for muscle-invasive cancer: Methods, surveillance and results. An update from the committee of cancer from the French National Association of Urology. Prog Urol. 2012 Jan; 22(1):13-6. Epub 2011 Nov 9 (“Radical cystectomy is the treatment of choice for non-metastatic, muscle infiltrating bladder cancer. However, bladder-sparing approaches can be discussed in carefully selected patients. Bladder-preservation protocols aim to guaranty local control and survival with a functional bladder and a good quality of life. The ideal candidate for bladder-preservation therapy is a patient with a small tumor, stage T2, in whom a complete trans-urethral resection of the bladder tumor is achievable, who has no associated carcinoma in situ or hydronephrosis, and who is medically fit to receive chemotherapy. The 5- and 10-year survival rates for muscle-invasive tumors are approximately 50% and 35%, comparable to the results achievable with cystectomy. Approximately 80% of long-term survivors will preserve a native bladder, and approximately 75% of them will have a normal-functioning bladder.”) http://www.ncbi.nlm.nih.gov/pubmed/22196000

 d.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Bladder preservation may be accomplished in appropriately selected patients with muscle-invasive UCB without compromising outcomes using a trimodality approach with maximal transurethral resection (TUR) followed by concurrent chemotherapy and radiation therapy. Optimal application of this approach requires close coordination among the urologist, medical oncologist, and radiation oncologist. Appropriate candidates have T2-4a and clinically node-negative disease, primary tumors amenable to complete or near complete TUR, no hydronephrosis and adequate renal function to tolerate cisplatin. Salvage cystectomy is required for persistent or recurrent disease at repeat cystoscopy, either during or after chemoradiotherapy (CRT), and is typically necessary in approximately one-third of patients [39]. The largest single-institution series from the University of Erlangen (415 patients) showed that early tumor stage and a complete TUR are the most important factors predicting CR and survival [40]. Chemotherapy alone is not an appropriate treatment for muscle-invasive UCB being treated for cure. . . . In appropriately selected patients, bladder preservation with TUR, chemotherapy, and radiation are feasible and produces high rates of CR with acceptable disease control and OS with intact bladders. Concurrent cisplatin-based radiation has the most supporting data, but newer agents are being evaluated. The value of induction chemotherapy has not been established, and the value of postradiation adjuvant therapy, while conceptually attractive, lacks sufficient data for definitive conclusions. Careful, continued surveillance with cystoscopy both during and after CRT is mandatory.”) www.ncbi.nlm.nih.gov/pmc/articles/PMC3217602/

 e.     Long-Term Outcomes of Selective Bladder Preservation by Combined-Modality Therapy for Invasive Bladder Cancer: The MGH Experience, Eur Urol. 2011 Nov 12. www.ncbi.nlm.nih.gov/pubmed/22101114

BACKGROUND:

Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown.

OBJECTIVE:

Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. 

DESIGN, SETTING, AND PARTICIPANTS:

We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2-4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr.

INTERVENTIONS:

Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC-60 for less than CR and 42 for recurrent invasive tumors.

MEASUREMENTS:

Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method.

RESULTS AND LIMITATIONS:

Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3-4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3-4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p<0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity.

CONCLUSIONS:

CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.

 

f.      Primary cT2 bladder cancer: a good candidate for radiotherapy combined with cisplatin for bladder preservation, Jpn J Clin Oncol. 2011 Jul;41(7):902-7. Epub 2011 May 25. http://www.ncbi.nlm.nih.gov/pubmed/21616918

BACKGROUND:

Bladder preservation therapy (BPT) has been attempted for patients with localized muscle-invasive bladder cancer. However, the indication for BPT has not yet been established. To identify patients who are good candidates for BPT, we evaluated our long-term experience with chemoradiation therapy (CRT) for bladder preservation.

METHODS:

Between 1994 and 2009, 82 patients with bladder cancer (clinical stage T2-N0M0) without concurrent upper urinary tract urothelial cancer were treated with CRT. Before CRT, the patients had a biopsy or resection of the tumor by transurethral resection (TUR). The response to CRT was evaluated by TUR, urine cytology and computed tomography.

RESULTS:

Thirty-two cases (39.0%) had a pathological complete response (pCR) that was defined as no microscopic residual tumor in the bladder. After TUR, 69 cases (84.0%) achieved local control of the cancer, which was considered as a clinical complete response (cCR). There was no significant association between achievement of pCR and examined parameters. The long-term results of CRT were evaluated in cCR cases. The median follow-up was 42.8 months (range, 4.1-155.1). The 5-year overall survival rate was 77.7% and 5-year progression-free survival rate was 64.5%. Clinical T stage and type of tumor (primary or recurrence) were predictive factors for overall survival as well as progression-free survival. In addition, primary cT2 cases had significantly better prognosis than cT3-4 and recurrent cases in overall survival and progression-free survival (P= 0.008 and P= 0.046, respectively).

CONCLUSION:

Cases with a primary cT2 tumor could be good candidates for BPT with radiation combined with cisplatin.

g.     Significantly fewer side effects?

h.     Current management of muscle-invasive bladder cancer, Clin Transl Oncol. 2011 Dec;13(12):855-61 (“Management of muscle-invasive bladder cancer (MIBC) has changed little in the last twenty years. The gold standard treatment is still cystectomy, but it has a significant negative impact on quality of life. Bladder-preservation strategies can be used in some cases but patient selection for this approach remains unclear. New chemotherapy and biologic agents in combination with surgery or radiotherapy could improve results and these possibilities are currently under investigation.”) http://www.ncbi.nlm.nih.gov/pubmed/22126728

 

i.       Selective organ preservation in muscle-invasive bladder cancer: Review of the literature, Surg Oncol. 2011 Nov 14.  (“The standard of care for transitional-cell carcinoma of the bladder with invasion to the muscularis propria is radical cystectomy with bilateral pelvic lymph node dissection. However, currently there is a tendency for organ preservation in selected cases of muscle-invasive bladder cancer. Trimodality treatment, including transurethral resection of the bladder tumor (TURBT), radiation therapy and chemotherapy, has been shown to produce 5-year and 10-year overall survival rates comparable to those of radical cystectomy. The current 5-year overall survival rates range from 50 to 67% with trimodality treatment, and approximately 75% of the surviving patients maintains their bladder. After trimodality treatment complete response is obtained in more than 70% of patients with muscle-invasive bladder cancer. Clinical criteria helpful in determining patients for bladder preservation include such variables as small tumor size (<2cm), early tumor stage (T2-T3 disease), a visibly and microscopically complete TURBT, absence of ureteral obstruction, no evidence of pelvic lymph node metastases, and absence of carcinoma in situ (Tis). The close collaboration of urologists, radiation oncologists and medical oncologists is of paramount importance in succeeding in bladder preservation.”) www.ncbi.nlm.nih.gov/pubmed/22088598

 j.       Why not seek to keep bladder, than do salvage RC if needed?

 3.     Partial cystectomy: pros & cons

a.     Prognosis

b.     Why generally not favored?

 4.     Pre-adjuvant therapy

 a.     Must RC decision be made first?

 b.     What does pre-adjuvant therapy typically include?

 c.      Chemo (see below) 

 d.     Pre-adjuvant radiation

                                               i.     Pros & cons

                                              ii.     Does it preclude neobladder option?

                                             iii.     Image-guided radiation therapy for muscle-invasive bladder cancer, Nat Rev Urol. 2011 Nov 8;9(1):23-9. doi: 10.1038/nrurol.2011.173. “(Organ preservation protocols that incorporate chemoradiotherapy have shown good efficacy in bladder cancer. Owing to changes in rectal filling, urinary inflow and subsequent bladder volume with bladder wall deformations, irradiation must take into account interfractional and intrafractional internal target motion. Growing evidence suggests that image guidance during irradiation is essential in order to appropriately treat bladder cancer in this way. We performed a literature search on the imaging techniques and margins used for radiation therapy planning in the context of whole-bladder and partial-bladder irradiation. The most common image-guided radiation therapy (IGRT) method was based on cone-beam CT using anisotropic margins. The role of cine-MRI for the prediction of intraindividual bladder changes, in association with cone-beam CT or ultrasonography, is promising. Drinking protocols, diet and laxatives were used in most cases to minimize large variations in bladder size and shape. IGRT is crucial for avoiding tumor undercoverage and undue toxicity during radiation therapy for bladder cancer. IGRT-based adaptive radiation therapy can be performed using cone-beam CT or ultrasonography: modeling of bladder changes with cine-MRI or other imaging techniques might also be useful for facilitating adaptive radiation therapy with personalized margins.”) www.ncbi.nlm.nih.gov/pubmed/22064641

 e.     BCG

                                               i.     Does it ever make sense to use BCG with MIBC? 

                                              ii.     Why not BCG, then chemo?

                                            iii.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Given the experience in nonmuscle-invasive UCB with BCG and interferon, there has been interest in the application of immunotherapy to more advanced bladder cancer as well. Ongoing trials are evaluating a human chorionic gonadotropin-β vaccine (Celldex Therapeutics, CDX1307-03, NCT01094496), and the anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab (NCT00462930), both in the neoadjuvant setting.”) www.ncbi.nlm.nih.gov/pmc/articles/PMC3217602

 f.      Interferon

 5.     Chemo: how to decide which type?

 a.     Molecular markers?  How to assess, measure, and design treatment?

                                               i.     HER2/neu overexpression

                                              ii.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Her2/neu is variably expressed on urothelial carcinomas and has been evaluated as a possible therapeutic target. One study screened 109 patients with advanced UCB and found that Her2-positive patients (52%) had more metastatic sites and higher rates of visceral disease than Her2-negative patients [85]. Forty-four patients were treated with trastuzumab, paclitaxel, carboplatin, and gemcitabine with an overall response rate of 70% with 57% confirmed responses. Median survival was 14.1 months. Toxicities included 93% grade 3-4 myelosuppression, 14% grade 3 sensory neuropathy, 22.7% grade 1–3 of cardiotoxicity (4.5% grade 3), and 3 therapy-related deaths.”) www.ncbi.nlm.nih.gov/pmc/articles/PMC3217602

                                             iii.     Targeted therapy for locally advanced and/or metastatic bladder cancer, Prog Urol. 2008 Jul;18(7):407-17. Epub 2008 Jun 26. (“Due to their molecular heterogeneity, optimal targeted therapy of bladder cancers will require the combined use of several molecules. Modulation of signalling pathways by these new molecules can restore chemosensitivity to cytotoxic drugs, which can then be associated with targeted therapy.”) http://www.ncbi.nlm.nih.gov/pubmed/18602599

                                             iv.     HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder, British Journal of Cancer (2003) 89, 1305–1309, 30 September 2003 (“Anti-HER2/neu therapy might be of use in the treatment of TCC.”) http://www.nature.com/bjc/journal/v89/n7/full/6601245a.html

                                              v.     Prognostic impact of HER2/neu protein in urothelial bladder cancer. Survival analysis of 80 cases and an overview of almost 20 years' research, J BUON. 2009 Jul-Sep;14(3):457-62. (“Conclusion: HER2 overexpression represents a prognostic factor for adverse disease outcome.”) http://www.ncbi.nlm.nih.gov/pubmed/19810139

 b.     Epidermal growth factor receptor (EGFR) expression http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217602/table/tab2 (“Table 2 summarizes the ongoing clinical trials with targeted agents in urothelial carcinoma. Epidermal growth factor receptor (EGFR) expression has been demonstrated on 50% of bladder tumors [86], and trials are ongoing with cetuximab. Vascular endothelial growth factor (VEGF) receptors are another potential target. Trials are evaluating the use of bevacizumab both in the metastatic and neoadjuvant setting as well as other anti-VEGF agents. However, a recent phase II experience with sunitinib in advanced UCB was disappointing, with only 4 responses in 77 patients [87].”)

 c.      Vascular endothelial growth factor (VEGF) receptors http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217602/table/tab2

 d.     Polysomy 17

 e.     Steve Jobs’ had his pancreatic cancer sequenced, which assisted his treatment.  Can same be done here?

 6.     Chemo delivery options

 a.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“UCB is considered a chemotherapy-sensitive disease with response rates in fit patients approaching 50%. Systemic chemotherapy remains the standard of care for patients with metastatic UCB. The principle challenge in this context is the high frequency of impaired performance status, renal dysfunction, and other comorbidities.”)

 b.     Intravesical

                                               i.     What type of drugs?

 c.      Systemic

                                               i.     IV

                                              ii.     oral 

 d.     Why not both intravesical and systemic?

 e.     Possible new option: balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation. Neoadjuvant and adjuvant chemotherapy for locally advanced bladder carcinoma: Development of novel bladder preservation approach, Osaka Medical College regimen.   Int J Urol. 2012 Jan;19(1):26-38. doi: 10.1111/j.1442-2042.2011.02856.x. Epub 2011 Nov 13 (“Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of "combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects ("Osaka Medical College regimen" referred to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21-814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review.”) www.ncbi.nlm.nih.gov/pubmed/22077821

 7.     Drug choices: how to decide, pros & cons

 a.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Gemcitabine and cisplatin is the current standard of care for first-line treatment in fit patients with metastatic disease. Optimal second-line therapy remains undefined, and targeted agents are under investigation. Clinical trial participation should be encouraged in patients with urothelial carcinoma of the bladder to help improve treatment regimens and outcomes.”) http://www.ncbi.nlm.nih.gov/pubmed/22125450

 b.     MVAC

                                               i.     Methotrexate

                                              ii.     Vinblastine

                                            iii.     Doxorubine

                                            iv.     Cisplatin

                                              v.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Historically, the standard first-line therapy for fit patients in the combination chemotherapy era has been MVAC. MVAC has been compared to both cisplatin alone and a combination of cisplatin, cyclophosphamide, and doxorubicin (CISCA) with superior response rates and OS [53, 54], with median survival of 12.5 months [53]. However, MVAC is associated with significant toxicity including myelosuppression, neutropenic fever and sepsis, mucositis, nausea, vomiting, and a 3-4% toxic death rate [53, 55]. These side effects and the complex schedule often limit its use.”) http://www.ncbi.nlm.nih.gov/pubmed/22125450

 c.      GemCis

                                               i.     Gemcitabene

                                              ii.     Cisplatin

                                            iii.     Update on chemotherapy in the treatment of urothelial carcinoma, ScientificWorldJournal. 2011;11:1981-94. Epub 2011 Oct 26. (“Due to significant toxicities with MVAC, other regimens have been investigated in the first-line metastatic setting. A phase III trial of 220 patients demonstrated that MVAC was more effective than docetaxel and cisplatin with improved response rates, time to progression, and median survival [57]. After encouraging phase II data [58–60], gemcitabine and cisplatin (GC) were compared to MVAC in a randomized phase III trial with 405 patients [61]. While the study was not powered to show equivalency, overall response rate, time to progression, and median survival were similar for both regimens, with less grade 3-4 neutropenia, neutropenic fever, sepsis, mucositis and alopecia in the GC arm. The toxic death rate was 3% with MVAC and 1% with GC. Long-term followup after 5 years demonstrated continued similar survival between the two arms [62]. Based on these results, GC is now considered the standard-of-care first-line therapy for fit patients with metastatic bladder cancer. . . Based on the data from the metastatic setting where gemcitabine and cisplatin (GC) has replaced MVAC as preferred treatment due to similar response rates and reduced toxicity, GC has been studied in the neoadjuvant setting in small, nonrandomized trials. Herchenhorn et al. reported a single institution study with 3 cycles of neoadjuvant GC in 22 patients with T2-T4 disease and found a combined partial and complete radiographic response in 70% of patients [23]. Pathologic CR was found in 26.7% (4/15) of the patients who went onto surgery. Treatment was well tolerated with no deaths attributed to chemotherapy. With 26 month followup, the estimated median OS was 36 months. In a retrospective review from the Memorial Sloan-Kettering Cancer Center, 42 patients were treated with 4 cycles of neoadjuvant GC, with downstaging to pT0 in 26% of patients and to no residual muscle-invasive disease (<pT2) in 36% [24]. All the patients achieving <pT2 remained disease-free at the median followup of 30 months. However, despite widespread adoption, neoadjuvant GC has not been validated in prospective, randomized studies.”) http://www.ncbi.nlm.nih.gov/pubmed/22125450

 d.     GemCis+Paclitaxel.  “Attempts to improve upon this regimen have included adding a third drug to GC. The SOGUG found the combination of paclitaxel, gemcitabine, and cisplatin (PGC) to be feasible with an overall response rate of 77.6% (with 28% CRs) in 61 patients [63]. To more fully evaluate this tactic, the EORTC 30987/Intergroup Study randomized 627 patients to either PGC or GC with a primary endpoint of OS [64]. The first report in abstract form demonstrated an improved response rate with PGC (57% versus 46%) but only a trend in favor of OS (15.7 versus 12.8 month, P = 0.10). Of note, the study was powered to detect a 4-month difference in survival. There was more thrombocytopenia on the GC arm, while PGC was associated with increased leukopenia, neutropenia, and febrile neutropenia.”  Id.

 e.     CMV