Chloe Liang , Dr. Nimira S. Alimohamed
Age 16 | Calgary, Alberta
Youth Science Canada Online STEM Fair 2020: Regional Award, Youth Science Canada Online STEM Fair 2020: Youth Science Canada (YSC) Award
INTRODUCTION
BLADDER CANCER
In 2019, an estimated 11,800 Canadians were diagnosed with bladder cancer, making it the fifth most common malignancy in Canada (Canadian Cancer Statistics Advisory Committee, 2019). Classified into many histological types, the three most common are urothelial (transitional cell) carcinoma which comprises more than 90% of all bladder cancers in North America, squamous cell carcinomas which account for 5%, and adenocarcinomas which compose less than 2% (Kaufman et al., 2009). The staging of bladder cancer is determined via the tumour-node-metastases (TNM) staging system (Amin et al., 2017). Bladder cancer is most commonly diagnosed in patients aged 50 to 75 and is three times more common in men than women (Canadian Cancer Statistics Advisory Committee, 2019). Factors contributing to a higher risk of developing bladder cancer are genetic and molecular abnormalities, exposure to specific chemical and environmental elements, and chronic irritation. A major environmental exposure factor is smoking (Kaufman et al., 2009). 1/3 of patients with bladder cancer present with or develop metastatic cancer (Sternberg, 2006), which is typically incurable and has a prognosis of 12-15 months of survival.
CISPLATIN-BASED CHEMOTHERAPY
The preferred initial treatment (first-line treatment) for patients with metastatic urothelial cancer is cisplatin-based chemotherapy (Bellmunt et al., 2020). Many studies have shown that cisplatin tends to produce better response rates in patients when compared with other agents such as carboplatin (Ardizzoni et al., 2007; Hotta et al., 2004; Jiang et al., 2007; Valdivieso et al., 2017). The combination of cisplatin and gemcitabine (GC) is commonly used to treat Alberta patients in the first-line setting (Baggstrom et al., 2007; de Castria et al., 2013). An alternate treatment regimen for patients eligible for cisplatin is dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). However, this regimen is used less frequently due to its similar response rate and worse toxicity profile compared to GC (Kaufman et al., 2000; Moore et al., 1999; von der Maase et al., 1999, 2000). Although cisplatin-based chemotherapy is the preferred first-line treatment for metastatic urothelial cancer, it is associated with high rates of toxicity including nausea, vomiting, nephrotoxicity (toxicity within kidneys) and ototoxicity (toxicity within the ear) (de Castria et al., 2013; Santana-Davila et al., 2014). Therefore, a patient’s eligibility for cisplatin is determined by multiple factors including previously diagnosed comorbidities, age and performance status (measure of a patient’s well-being and the effect of disease on their daily activities) (De Santis, 2013; Oken et al., 1982). Based on consensus-agreed criteria, patients are not eligible to receive cisplatin if they meet at least one of the following: Eastern Cooperative Oncology Group Performance Score of 2 or Karnofsky Performance Status of 60-70%, creatine clearance 60mL/min (decreased renal function), Common Terminology Criteria for Adverse Events (CTCAE) v4 grade ≥ 2 audiometric hearing loss, v4 grade ≥ 2 peripheral neuropathy, or New York Heart Association (NYHA) class III heart failure (Bellmunt et al., 2020; Galsky et al., 2011a, 2011b). Although age is not directly correlated to a patient’s eligibility for cisplatin, older age is associated with decreased renal function (Raj et al., 2006). Thus, up to 50% of patients with metastatic urothelial cancer are ineligible to receive cisplatin-based treatment in the first-line setting (Bellmunt et al., 2020; Dash et al., 2006; Galsky et al., 2011b). Suggested first-line treatment for these patients includes carboplatin-based regimens such as a combination of gemcitabine and carboplatin, or non-platinum-based regimens such as paclitaxel or gemcitabine (Bellmunt et al., 2020).
IMMUNOTHERAPY
Immunotherapy has recently been investigated for the treatment of various malignancies, including urothelial cancer. Types of immunotherapy include monoclonal antibodies, checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus therapy, cytokines, and adjuvant immunotherapies (Stanculeanu et al., 2016). However, metastatic urothelial cancer is typically treated with checkpoint inhibitors. These checkpoint inhibitors target specific proteins found on T cells (CTLA-4, PD-1) and prevent them from attaching to their respective ligands in order to keep the T cells active in aiding the process of killing cancer cells (Kanesvaran et al., 2018). Immunotherapy agents for metastatic urothelial cancer under investigation include PD-L1/PD-1 (programmed death-ligand 1/programmed death 1) antibodies such as pembrolizumab, atezolizumab, avelumab, durvalumab and nivolumab and the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors including ipilimumab and tremelimumab (O’Donnell et al., 2017). In the second-line setting, once a patient has progressed from their first-line treatment, pembrolizumab has demonstrated a significantly longer overall survival as well as lower toxicity levels when compared to alternative chemotherapy regimens (Bellmunt et al., 2017; Kanesvaran et al., 2018). This approach is now the standard of care in the second-line setting in Canada. In the first-line setting, pembrolizumab has been approved by Health Canada for patients with PD-L1 positive tumours, that are also cisplatin-ineligible or chemotherapy-ineligible (pCODR Expert Review Committee (pERC), 2019). However, this approach is not currently funded nor readily available.
Although clinical trial data demonstrates improved outcomes using immunotherapy in the second-line treatment setting for advanced bladder cancer (Bellmunt et al., 2017; Kanesvaran et al., 2018), there is limited data on the effectiveness in the real-world setting. The examination of real-world outcomes is necessary to understand the effectiveness of immunotherapy within Alberta patients as there may be significant differences between the real-world patient population and the clinical trial population. Therefore, this study aims to determine the efficacy of immunotherapy as a treatment for Alberta patients with metastatic urothelial cancer by comparing real-world outcomes of patients treated today to historical outcomes of patients treated before the development of immunotherapy. These results will assist in furthering the development of treatment for metastatic urothelial cancer, which is currently incurable, and potentially identify a regimen that maximizes a patient’s quality of life.
MATERIALS AND METHODS
A retrospective analysis was performed on all patients diagnosed with metastatic urothelial cancer and treated with immunotherapy between 2016 and 2019 in Alberta. From this retrospective review, 55 patients were identified, 18 of whom were female, and 37 were male. Common immunotherapy regimens included pembrolizumab and atezolizumab. Common chemotherapy regimens included cisplatin and gemcitabine, carboplatin and gemcitabine, and paclitaxel. These patients were treated at one of five cancer centers in Alberta (Calgary, Red Deer, Edmonton, Lethbridge, Medicine Hat). Both trial-ineligible patients and clinical trials patients were included in the study. Trial-ineligible patients would have received standard treatment regimens for immunotherapy and chemotherapy, while clinical trial patients would have received nonstandard immunotherapy and chemotherapy regimens. Some clinical trial regimens included in this study are the IMvigor trial (study of atezolizumab) (Tewari, 2019), SAUL trial (study of atezolizumab) (Hoffmann-La Roche, 2016), and BL12 clinical trial (paclitaxel chemotherapy) (Canadian Cancer Trials Group, 2014). All patients were 18 years or older.
DATA COLLECTION AND STATISTICS
Patient data was collected using ARIA MO, an Albertan cancer database. Information collected included patient characteristics (age, date of diagnosis, staging), treatment factors (regimens, treatment start and end dates) and outcome data (progression, response to treatment, date of late follow-up). Using the data of when patients began and ended treatment, time to treatment failure (TTF) was calculated. Similarly, using the date of diagnosis and the last follow-up date, overall survival (OS) was calculated. Graphing and analysis were done in Microsoft Excel (2019). This study received the Health Research Ethics Board Approval (University of Calgary).
RESULTS
A total of 55 patients received immunotherapy in Alberta, 18 of whom were female, and 37 were male. The median age of patients was 68 years, ranging from 38 years to 81 years. Most patients were former or current smokers (n=39, 71%).
Treatment Regimens and Outcomes
Of the 55 patients, 20 patients received atezolizumab, 30 received pembrolizumab, and 5 patients received both atezolizumab and pembrolizumab. As shown in Table 1, all 55 patients were treated with first-line treatment, and 11% (n=6) of these patients received immunotherapy in the first-line setting (Figure 1). The remaining 44 patients received chemotherapy as first-line treatment. The most common chemotherapy regimens include cisplatin and gemcitabine, carboplatin and gemcitabine, and paclitaxel. The calculated time to treatment failure in the first-line setting was 7.4 months. A total of 50 patients moved onto second-line treatment, with 66% (n=33) of these patients receiving immunotherapy in this line (Figure 1). This treatment line had a time to treatment failure of 3.2 months. Furthermore, 19 patients received third-line treatment, with 68% (n=13) receiving immunotherapy (Figure 1). The observed time to treatment failure in the third-line setting was 2.6 months. Only around 7% (n=4) of patients advanced to receive fourth-line treatment, with 3/4 of these patients receiving immunotherapy (n=3, 75%). The overall median survival for all patients who received immunotherapy was 20.2 months.
Figure 1: Proportion of Alberta Metastatic Urothelial Cancer Patients Treated with Immunotherapy in the First, Second, Third and Fourth Lines of Treatment for Alberta
Table 1: Summary of Treatment, Time to Treatment Failure and Overall Survival of Alberta Metastatic Urothelial Cancer Patients (2016-2019)
Figures 2 and 3 illustrate the individual patient’s overall survival, with each bar representative of one patient. The median overall survival was 20.2 months, with a patient survival ranging from 4.7 months to 114.3 months. Figure 2 demonstrates each patient’s overall survival (in months), with each colour indicating the total lines of treatment that the patient received. Many patients with a more prolonged overall survival had three to four lines of treatment, although the longest surviving patient received only two lines of treatment. Patients receiving one to two lines of treatment typically had lower overall survival. Similar to Figure 2, Figure 3 illustrates the patients’ overall survival with respect to the line of treatment where they received immunotherapy. Most patients were treated with immunotherapy in the second line. The median OS within each treatment line setting is demonstrated in figure 4. As shown, patients treated with immunotherapy in the second-line setting had the lowest median OS, while patients treated with immunotherapy in the fourth-line setting had the highest median OS.
Figure 2: Individual Overall Survival (Months) of Alberta Metastiatic Urothelial Cancer Patients with Respect to Total Lines of Treatment Received
Figure 3: Individual Overall Survival (Months) of Alberta Metastatic Urothelial Cancer Patients with Respect to the Line that the Patient Received Immunotherapy
Figure 4: Median Overall Survival (Months) of Patients within the Treatment Line Setting Where They Received Immunotherapy
DISCUSSION AND CONCLUSIONS
In this era of immunotherapy, the median overall survival (OS) in Alberta for patients with metastatic urothelial carcinoma has improved significantly. Compared to previous studies, the median OS of patients has increased from 9 months to 20 months (Yip et al., 2018). This illustrates the effectiveness of immunotherapy in treating advanced bladder cancer. These results are supported by a recent study that indicated a significantly improved median OS for bladder cancer patients treated with pembrolizumab in the second-line setting compared to chemotherapy (10.3 months vs. 7.4 months) (Bellmunt et al., 2017). The results of this study also indicate that the median OS of patients receiving immunotherapy within the fourth-line setting was the greatest among all treatment setting lines (38 months). Surprisingly, although immunotherapy is the standard second-line treatment within Canada (pCODR Expert Review Committee (pERC), 2019), patients treated with immunotherapy in the second-line setting had the lowest median OS. Despite this, however, the OS in the second line still showed a significant improvement from 8 months historically to 15 months (Yip et al., 2018). The discrepancy may be primarily due to the different sample sizes of the treatment lines, with 33 patients having received immunotherapy in the second-line setting, and only 3 patients receiving immunotherapy in the fourth line. Moreover, the individual patient OS results demonstrate how the setting line of when the patients received immunotherapy does not directly correlate with the length of their survival, as both the patient with the most prolonged OS and the patient with the shortest OS received immunotherapy in the second-line setting. There is also minimal study on the relationship between setting lines and the effectiveness of immunotherapy. Thus, further investigation would have to be realized to determine whether the treatment setting of when immunotherapy was received impacts the patient’s outcomes.
The results of this study also show that the time to treatment failure (TTF) in the first-line setting had a slight improvement from 6.9 months historically to 7.4 months (Yip et al., 2018). This reflects an improved span of progression-free disease within the first-line setting, demonstrating how patients can better tolerate treatment with the immunotherapy drugs currently available. However, the TTF within the second-line setting shows no significant change, with previous studies in Alberta pointing to a period of 4.1 months (Yip et al., 2018), while this investigation demonstrates 3.2 months. The slight difference in TTF may be due to the difference in sample size, with 79 patients receiving second-line treatment in previous studies (Yip et al., 2018), and 50 patients receiving second-line treatment in this study. However, this difference can be overlooked as it is not statistically significant. Our results also indicate a decrease in TTF as the setting lines increase. A possible explanation for this pattern could be that patients became less responsive to treatment as they progressed to more lines of treatment since they would have already received multiple types of treatment regimens. Furthermore, there was a significant increase of patients who receive more lines of treatment, with only 30% of patients in previous studies moving onto second-line treatment (Yip et al., 2018), to 91% of patients receiving second-line treatment with the advent of immunotherapy drugs. This increase reflects an improvement in the ability of patients to tolerate more treatment with immunotherapy.
The results of this investigation support the hypothesis that patients treated with immunotherapy have improved outcomes compared to patients treated in the pre-immunotherapy era. This study indicates the effectiveness of immunotherapy in a real-world setting by including both clinical trial and clinical trial-ineligible patients, which is crucial to representing the entire population of bladder cancer patients. Since immunotherapy is still a new treatment, most studies have only observed clinical trial patients (Balar et al., 2017; Bellmunt et al., 2017; Crist et al., 2019; Nishiyama et al., 2020). However, the results of a sample population of only clinical trial patients do not accurately reflect the results that would be seen in a real-world setting, as clinical trial patients are typically in better health than regular patients. Therefore, this study can accurately determine the effectiveness of immunotherapy within advanced bladder cancer by including both clinical trial and clinical trial-ineligible patients. This information would be necessary for deciding new treatment regimens for patients that are chemotherapy-ineligible.
Although this study adequately determines that patients treated in the immunotherapy era have improved outcomes compared to patients treated in the pre-immunotherapy era, these results can account for the drugs pembrolizumab and atezolizumab. Additionally, immunotherapy is still being tested and developed today. Therefore, further investigation could be accomplished to compare other approved immunotherapy drugs such as nivolumab and durvalumab (Ghatalia et al., 2018), to evaluate which drug results in the best outcomes.
ACKNOWLEDGMENTS
Thank you to Dr. Nimira S. Alimohamed at the Tom Baker Cancer Centre, Department of Oncology for her full support and guidance throughout this project. Also, a special thanks to Dr. Beatriz Garcia-Diaz and Ms. Bogusia Gierus for their encouragement, valuable review, and support for this study.
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About the author
Chloe Liang
As an enthusiastic grade 12 student, Chloe enjoys learning about the biological sciences. While exploring her academic interests she has participating in science fair, as well as joined multiple school clubs such as Science Olympics and Genes Club. Outside of school, she is a passionate artist who expresses herself though her vibrant and meaningful works of art. Her interests also extend to sports where she plays an active role as a player on the school badminton team. As she continues her studies, Chloe hopes to pursue further research within the biochemical field.