ECCLU 2011 - M. De Santis - Palliative chemotherapy

Editor's Notes

• #5: For standard chemotherapy in urothelial cancer we have a high level of evidence by several randomized phase III trials. They showed that MVAC was better than CISCA and Cisplatin monotherapy; that Gem/Cis was about as effective as MVAC, but less toxic; that HD MVAC+GCSF provided no statistically significant improvement in OS over standard MVAC, but significantly more CR and a longer PFS. And finally MVAC was better than 5FU/ IFN/ Cisplatin and the newest doublet Cisplatin/Docetaxel (this advantage was more pronounced because of an imbalance of performance status in favor of MVAC). Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours C.N. Sternberg*, the EORTC Genito-Urinary Cancer Group A B S T R A C T EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat (ITT) analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% .The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HDM- VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC. 2005 Elsevier Ltd. All rights reserved. 1. Introduction In Europe, cancer of the bladder is the fourth most frequent cancer among men [1]. Systemic chemotherapy is the only modality that has been shown in phase III trials to improve survival in responding patients with advanced bladder cancer [2,3] The M-VAC (methotrexate, vinblatine, adriamycin and cisplatin) regimen, first reported in 1985 at Memorial Sloan Kettering Cancer Center (MSKCC), revealed that urothelial carcinoma was sensitive to chemotherapy [4]. Patients with measurable lesions were found to have a 72% response rate (RR) and 36% attained a complete response (CR) [5]. Longterm survival was achieved in patients who attained CR. Overall survival for the entire population was 13.1 months. 0959-8049/$Stratification was according to the treating institution and WHO performance status. The main endpoint of the phase III trial was overall survival. Secondary endpoints included progression- free survival, time to progression, response rate and toxicity. The objective of the trial was to detect a relative difference of 50% in median overall survival between the two arms from 12 months to 18 months (hazard ratio = 0.67). This corresponds to an absolute difference of 13% at the time of the median. With a two-sided logrank test at the 5% significance level and 80% power this objective required 192 events (deaths). All analyses were carried out according to the intent-totreat principle and statistical significance was claimed at the two-sided 0.05 level. Time to event comparisons were performed using the logrank test. Estimation of survival curves was by the Kaplan–Meier technique. Comparison of distribution of binary and non-ordered categorical variables was performed using the v2 test and that of continuous variables using the Wilcoxon Rank Sum test. Comparison of ordered categorical variables was performed using a v2 test for linear trend.
• #15: Only in the post-hoc analysis of the bladder primary patients of this study was the difference significant . Only in the post hoc analysis of the bladder primary patients in this study, this difference showed statist significance.
• #16: Based on evidence in breast cancer and hematologic malignancies, the concept of dose dense and sequential chemotherapy was also explored in urothelial cancer by the „Memorial“ group. The sequence of adriamycin, gemcitabine followed by ifosfamide, paclitaxel, cisplatin in patients fit for cisplatin showed high response rates, but considerable toxicity. In patients with a good performance status but impaired renal function, the sequence of adriamycin/gemcitabine followed by paclitaxel/carboplatin was feasible with a good drug delivery ratio. A phase III trial will have to show the real potential of this concept. Summary: AG-ITP: toxicity AG-TC: feasible, randomized trials needed. Galsky, Cancer 2007: Good dose density/ drug delivery; Patients received treatment with sequential doublets of doxorubicin 50 mg/m2 administered by intravenous (i.v.) infusion plus gemcitabine 2000 mg/m2 administered i.v. every other week 5 cycles followed by paclitaxel 65 mg/m2 i.v. plus carboplatin AUC 1.7 i.v. weekly 12 cycles. Milowsky, JCO 2009: The conclusion that more chemotherapy is not necessarily better chemotherapy has been borne out in the recently reported randomized trial in which GC was compared with paclitaxel, cisplatin, and gemcitabine; a higher overall response rate for paclitaxel, cisplatin, and gemcitabine did not translate into improved progression-free or overall survivals.26 In exploratory subgroup analyses, a benefit was seen for patients with bladder primaries who received triplet therapy, and the benefit of triplet therapy appeared to be limited to patients with zero or one risk factor. Thus, more intensive chemotherapy does not appear to be associated with an improvement in survival for the entire patient population; however, subgroups who do derive a benefit may exist.
• #17: There are clear limits of conventional chemotherapy. Let me cite J. Bellmunt who put it in a nutshell : We „squeezed it out“. So far no improvement in survival was achieved beyond 13-15 months and 10-15% long-term disease free survival with newer triplets, 4-drug-regimen, dose-dense - sequential chemotherapy.
• #18: We will be more and more confronted with comorbidity in our patients because age and comorbid conditions are clearly connected and the frequency of invasive cancers is expected to rise mainly in pts aged 65 and above. Projected change in frequency of invasive cancers in the United States by age and sex. Nonmelanoma skin cancers were excluded from projections. Data adapted.7
• #20: With increasing age, the number of comorbid illnesses increases. In a study of 7,600 patients older than 55 years with cancer, those age 55 to 64 had an average of 2.9 comorbid conditions compared with patients age ≥ 75, who had an average of 4.2 comorbid conditions. 59 has important prognostic implications. An observational cohort study including 17,712 patients receiving care for multiple cancer types suggested that the severity of comorbidities affected overall survival (OS) in a dose-dependent fashion, independent of cancer stage. 4 When formulating a treatment plan, oncologists juxtapose the risk from the malignancy against that of comorbid illness on life expectancy. The effect of treatment in decreasing this risk is also weighed. Utilizing this framework, indolent cancers may be managed more conservatively in the setting of a substantial comorbid disease that is more likely to have an impact on life expectancy. In contrast, more aggressive malignancies warrant cancer therapy if they are more likely to affect life expectancy than the comorbid illness. In practice, it appears that weighing risks of does take place, albeit in the absence of firm guidelines. The presence and extent of appears to impact surgical decision making in oncology, such as the use of axillary dissection, radical prostatectomy, and resection for breast, prostate, and lung cancer, respectively. 60 – 62 Similarly, appears to affect utilization of chemotherapy across multiple malignancies. 63 – 65 It is possible that the latter trend reflects studies suggesting greater chemotherapy-related toxicity among patients with , 66 , 67 although conflicting data does exist. 68 Specific comorbidities may have a unique bearing on prognosis and treatment outcome. In a series of 5,077 patients treated with neoadjuvant hormone therapy followed by radiation for localized prostate cancer, use of hormone therapy was associated with a higher risk of all-cause mortality in the presence of coronary artery disease, congestive heart failure (CHF), or prior myocardial infarction (26.3% v 11.2%; P = .04). 69 In contrast, no increased risk of mortality was observed in men without or with only one coronary artery disease risk factor. Other studies have investigated the role of diabetes in the progression of malignancy. Subset analyses of Intergroup-0089 (INT-0089), a randomized trial comparing four fluorouracil-based adjuvant therapy regimens in patients with stage II and III colon cancer, supported several smaller studies that identified a higher rate of overall mortality in patients with colon cancer who also had diabetes. 70 – 72 Molecular rationale for this phenomenon may be linked to elevated serum levels of insulin, which accelerates proliferation of colorectal cell lines. 73 Providing clinical validation for this theory, a study of surgically resected patients with colorectal cancer reported that higher levels of C peptide and low levels of insulin-like growth factor binding protein-1 were associated with increased mortality. 74 Similar findings have been noted in patients with breast cancer, where elevated fasting insulin levels have been associated with an increased risk of distant recurrence and mortality in early-stage disease. 75 These studies have led to the development of clinical trials evaluating whether modulating the insulin axis would affect cancer outcomes. A provocative study assessing patients from the M. D. Anderson Cancer Registry identified a higher rate of pathologic complete response with neoadjuvant chemotherapy among diabetic patients taking metformin as compared with nondiabetic patients. 76 These and other supporting data have led to the development of a phase III intergroup trial (National Cancer Institute of Canada MA.32) examining the effect of metformin as adjuvant therapy for breast cancer. 77 The evolving understanding of the relationship between breast cancer and diabetes, ultimately leading to a potential therapeutic intervention, underscores the importance of understanding the link between and cancer. It is increasingly recognized that may also have a substantial impact on treatment tolerance. In the setting of advanced lung cancer, a randomized trial comparing vinorelbine alone or in combination with gemcitabine demonstrated a higher rate of treatment discontinuation among patients with a Charlson index (CCI) score of higher than 2. 78 Supporting this finding, data from a series of patients with breast cancer receiving dose-dense adjuvant chemotherapy identified an association between (defined as a CCI ≥ 1) and grade 3/4 toxicity. 79 Certain comorbidities may have an impact on tolerance for specific therapies as well. For instance, early observations with paclitaxel therapy suggested an increased risk for severe neuropathy in patients with a concomitant diagnosis of diabetes. 80 Similarly, the risk of cardiac toxicity with the HER2-directed monoclonal antibody trastuzumab is higher in patients with pre-existing hypertension. 81 , 82 Of note, an effort should be made to distinguish from treatment-related toxicity, as these may have different prognostic implications. As one example, the vascular endothelial growth factor targeting antibody bevacizumab has been noted to cause hypertension in clinical application across malignancies. 83 – 85 Subset analyses from pivotal trials of bevacizumab in lung and breast cancer have associated the development of hypertension with extended OS. 86 , 87 These results have led some investigators to question whether hypertension should be considered a dose-limiting toxicity. 88 59. Yancik R: Cancer burden in the aged: An epidemiologic and demographic overview. Cancer 80:1273-1283, 1997 60. Konety BR, Cowan JE, Carroll PR: Patterns of primary and secondary therapy for prostate cancer in elderly men: Analysis of data from CaPSURE. J Urol 179:1797-1803, 2008 61. Smith TJ, Penberthy L, Desch CE, et al: Differences in initial treatment patterns and outcomes of lung cancer in the elderly. Lung Cancer 13:235-252, 1995 of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885-892, 2001 63. Keating NL, Landrum MB, Klabunde CN, et al: Adjuvant chemotherapy for stage III colon cancer: Do physicians agree about the importance of patient age and comorbidity? J Clin Oncol 26:2532-2537, 2008 64. Hurria A, Wong FL, Villaluna D, et al: Role of age and health in treatment recommendations for older adults with breast cancer: The perspective of oncologists and primary care providers. J Clin Oncol 26:5386-5392, 2008 65. Blanco JAG, Toste IS, Alvarez RF, et al: Age, comorbidity, treatment decision and prognosis in lung cancer. Age Ageing 37:715-718, 2008 66. Aparicio T, Desrame J, Lecomte T, et al: Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly. Br J Cancer 89:1439-1444 67. Asmis TR, Ding K, Seymour L, et al: Age and comorbidity as independent prognostic factors in the treatment of non-small-cell lung cancer: A review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol 26:54-59, 2008 68. Moscetti L, Nelli F, Padalino D, et al: Gemcitabine and cisplatin in the treatment of elderly patients with advanced non-small cell lung cancer: Impact of comorbidities on safety and efficacy outcome. J Chemother 17:685-692, 2005 69. Nanda A, Chen M-H, Braccioforte MH, et al: Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 302:866-873, 2009 70. Meyerhardt JA, Catalano PJ, Haller DG, et al: Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 21:433-440, 2003 71. Payne JE, Meyer HJ: The influence of other diseases upon the outcome of colorectal cancer patients. Aust N Z J Surg 65:398-402, 1995 72. Yancik R, Wesley MN, Ries LAG, et al: Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients. Cancer 82:2123-2134, 1998 73. Tran TT, Medline A, Bruce WR: Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 5:1013-1015, 1996 74. Wolpin BM, Meyerhardt JA, Chan AT, et al: Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol 27:176-185, 2009 75. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002 76. Jiralerspong S, Palla SL, Giordano SH, et al: Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297-3302, 2009 77. Goodwin PJ, Ligibel JA, Stambolic V: Metformin in breast cancer: Time for action. J Clin Oncol 27:3271-3273, 2009 78. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18:2529-2536, 2000 79. Zauderer M, Patil S, Hurria A: Feasibility and toxicity of dose-dense adjuvant chemotherapy in older women with breast cancer. Breast Cancer Res Treat 117:205-210, 2008 80. Rowinsky EK, Eisenhauer EA, Chaudhry V, et al: Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol 20:1-15, 1993 81. Perez EA, Suman VJ, Davidson NE, et al: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26:1231-1238, 2008 82. Suter TM, Procter M, van Veldhuisen DJ, et al: Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25:3859- 3865, 2007 83. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 84. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007 85. Sandler A, Gray R, Perry MC, et al: Paclitaxelcarboplatin alone or with bevacizumab for non-smallcell lung cancer. N Engl J Med 355:2542-2550, 2006 86. Dahlberg SE, Sandler AB, Brahmer JR, et al: Clinical course of advanced non-small cell lung cancer (NSCLC) patients (pts) experiencing hypertension (HTN) during treatment (TX) with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) on E4599. J Clin Oncol 27:417s, 2009 (abstr 8042) 87. Schneider BP, Wang M, Radovich M, et al: Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672-4678, 2008 88. Jain RK, Duda DG, Sorensen AG: Emerging Paradigms and Potential Biomarkers of Response and Resistance in Antiangiogenic Therapy of Cancer. Alexandria, VA, American Society of Clinical Oncology, 2009, pp 716-721
• #21: Whether cisplatin can be replaced safely by carboplatin in cisplatin-eligible patients, as we use to do in several other tumors (such as metastastic lung cancer or ovarian cancer), was addressed in one randomized phase III trial that was closed early due to slow accrual. Therefore we have no answer to that question with a high level of evidence. 3 randomized phase II studies showed lower CR and survival rates for the carboplatin combinations. In these studies older combinations like MVAC and MVECa, MVAC and Carbo MV and the newer doublets cis/gem vs carbo/ gem were used. and several smaller phase II studies with carboplatin/paclitaxel were disappointing with only about 9 months survival and RR below 50%. Carboplatin is an analog of cisplatin that appears to have a similar mechanism of actiong and spectrum of antineoplastic activity as cisplatin, and that may also have a more favorable toxicity profile. Carboplatin has been tested in the treatment of TCC fairly extensively. As a single agent, responses in 0-28% of patients have been reported.” A 45% response proportion has been reported for carboplatin in combination with methotrexate. When standard doses of carboplatin have been used in combination with methotrexate and vinblastine, 42-53% of patients will exhibit a response.”-I3 Waxman et al. added mitoxantrone Carboplatin for Transitional Cell GancerlSmall et al. 1779 to a carboplatin-based regimen, treating patients with methotrexate, 50 mg/mz; vinblastine, 3 mg/m'; mitoxantrone, 10 mg/m2, and a considerably lower carboplatin dose than that used in this trial (200 mg/m2) on Day 1, and methotrexate, 50 mg/m2 on Day 15 of a 28-day cycle. Although 64 patients were evaluable for response, only 27 patients were being treated for metastatic disease. An overall response proportion of 45% was rep~rted.'"
• #27: Figure 1: Patients with only one reason for being unfit for cisplatin have a better OS than patients with both reasons (GFR<60 and WHO-PS2). The statistical difference between the 3 curves is significant. Figure 2: The post hoc analysis of OS by the Bajorin risk groups showed that, as the number of Bajorin risk factors increases, the OS decreases (highly significant). The data suggest that the Bajorin risk group is valid in this patient population. (The very small numbers in each risk group by treatment arm rule out a definitive conclusion in the treatment groups).
• #33: 05/17/11 13:56
• #39: MDS: If time runs short, this slide might be omitted
• #43: This is comparing gemcitabine/carboplatin (GC) and M-CAVI in cisplatin ineligible patients.