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Perioperative Chemotherapy in Cisplatin “Unfit” Patients

Madrid, Spain (UroToday.com) Dr. Maria De Santis gave a talk on the large subset of cisplatin “unfit” patients. Of all patients with muscle-invasive bladder cancer (MIBC) only ~50% will be alive five years after diagnosis. Relapse mostly occurs with distant metastasis – but the disease is always a systemic one. Cisplatin-based chemotherapy and immunotherapy are active and have shown to improve survival. Cystectomy is the preferred definitive treatment in many parts of the world. Neoadjuvant chemotherapy is indicated in patients with clinical stage T2-T4 N0 M0. Induction chemotherapy is indicated in positive node disease but with localized MIBC.

In an ideal world, every patient receives perioperative chemotherapy, and optimal surgery with an extensive lymph node dissection is performed. Neoadjuvant chemotherapy has been proven to add a significant survival benefit in many studies. 1 There are several options for the neoadjuvant setting. The first and oldest option is the methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) option, developed in the 1980s 2; before the advent of antiemetics and growth factors. MVAC was later upgraded to a high dose (HD), dose-dense (DD) 3 or accelerated dose (AMVAC) 4. The newer option is Gemcitabine and cisplatin (GC), which has similar efficacy to MVAC but with improved toxicity profile in the metastatic setting 5. Later, GC was upgraded to GC split dose6 The various neoadjuvant MVAC schedules have caused downstaging to pT0 in 34-38% of cases.

The European Association of Urology (EAU) and the European Society for Medical Oncology (ESMO) guidelines state that neoadjuvant chemotherapy should be offered to patients with T2-T4a N0M0 bladder cancer, and cisplatin-based combination chemotherapy should always be the regimen that is used (grade A evidence). Adjuvant cisplatin-based combination chemotherapy should be offered to patients with pathological T3/4 and N+ disease if no neoadjuvant chemotherapy has been given. However, the guidelines also state that in patients who are ineligible for cisplatin-based chemotherapy, neoadjuvant chemotherapy is not recommended. The American Society of Clinical Oncology (ASCO) guidelines add a qualifying statement, in which they support neoadjuvant chemotherapy in cisplatin-ineligible patients if the goal is to downstage surgically unresectable tumors. Unfortunately, the proportion of patients who are unfit for cisplatin chemotherapy is quite high, at around 40-50%.

For positive node patients with any T stage, it has been shown that chemotherapy and radical cystectomy confer higher survival rates than adjuvant chemotherapy after radical cystectomy, or radical cystectomy alone, or chemotherapy alone, as seen in figure 1.7 induction chemotherapy after radical cystectomy in this unique subset of patients confers an added 39% pathological complete response (downstaging), and 53% risk reduction of death.8

UroToday WCE2018 Comparison of different treatment strategies in Clinical node positive disease
Figure 1- Comparison of different treatment strategies in Clinical node-positive disease:

In 2011 criteria to define cisplatin “unfit” patients were formed. (9) These include:

  • - WHO or ECOG performance status 2 or Kranofsky of 60-70%
  • - Creatinine clearance <60 ml/min
  • - Common Terminology Criteria for Adverse Events (CTCAE) v4 grade >=2 audiometric hearing loss
  • - CTCAE v4 grade >=2 peripheral neuropathy
  • - New York Heart Association Functional Classification (NYHA) class III heart failure
In a study assessing what oncologists would do in patients with renal insufficiency who are scheduled to receive neoadjuvant chemotherapy, 50% of the oncologists would consider splitting the cisplatin dose, or substituting cisplatin with carboplatin, or go straight to radical cystectomy. (10). Most oncologists would consider not giving neoadjuvant chemotherapy in ECOG 2 or above, at a glomerular filtration rate (GFR) of less than 50 ml/min and would not consider age as a factor at all. (10) If the patient is clinical stage T2-T4 N0M0 but is unfit for cisplatin, we need to do everything possible to make him fit. That includes insertion of a nephrostomy tube or ureteral stent, and hydration to improve renal function. Another option is to give cisplatin at a reduced dose (split dose), or give carboplatin instead, or some other combination.

The last topic discussed was the role of immune checkpoint inhibitors in the setting of cisplatin unfit patients. Table 1 describes what current immune checkpoint inhibitors are approved by the European Medical Agency (EMA) and the US Food and Drug Administration (FDA). Table 2 demonstrates the comparison of various 1st line treatment regimens for cisplatin “unfit” patients. It is shown that immune checkpoint inhibitors achieve a response rate of 23-28%, while carboplatin + gemcitabine reaches a response rate of 38%. However, the median overall survival is longer with the immune checkpoint inhibitors (12.8-15.9 months vs. 9.3 months).

UroToday WCE2018 Checkpoint inhibitors for urothelial carcinoma patients
Table 1 – Checkpoint inhibitors for urothelial carcinoma patients:

UroToday WCE2018 Comparison of various first line treatments for cisplatin unfit patients
Table 2 – Comparison of various first-line treatments for cisplatin “unfit” patients:

Lastly, Dr. De Santis discussed the possible role of immune checkpoint inhibitors in the neoadjuvant setting before radical cystectomy. Two studies that were presented in the ASCO meeting in Chicago in 2018 analyzed the effect of Pembrolizumab and Atezolizumab given as neoadjuvant therapy before radical cystectomy in pT2-T4N0 patients. These studies were the PURE-01 trial (NCT 02736266)11 and the ABACUS trial (NCT 02662309) 12. The phase two PURE-01 study is the preoperative Pembrolizumab before radical cystectomy for muscle-invasive bladder cancer patients: interim clinical and biomarker finding. The ABACUS study assessed the safety and efficacy of neoadjuvant Atezolizumab. In the PURE-01 study, the results demonstrated a 40% pathological complete response rate, with downstaging occurring in 51% of patients. Grade 3 or 4 complications occurred in 5.4% of patients. In the single-arm phase two ABACUS trial, the pathological complete response rate was 23%.

In the conclusion of her talk, Dr. De Santis tried to summarize all the information conveyed and stated that perioperative chemotherapy in clinical T2-T4a is still the standard of care and improves survival. In positive node disease, induction chemotherapy followed by radical cystectomy is better than any other therapy. Whenever and if possible, physicians should make patients for cisplatin. However, in cisplatin-ineligible patients, carboplatin combinations and other treatment options can be used. There are currently only preliminary results showing that immunotherapy has promising downstaging potential. Further studies are underway, including combinations of immunotherapy.


Presented by: Maria De Santis, Berlin, Germany

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the Global Conference on Bladder Cancer 2018 - September 20-21, 2018 Madrid, Spain 

References: 
  1. Advanced Bladder Cancer (ABC) meta-analysis collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005 Aug; 48 (2): 202-205
  2. Sternberg et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989 Dec; 64: 2448-2468
  3. Sternberg et al. 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. Eur J. Cancer. 2006 Jan; 42: 50-54
  4. Plimack et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 June; 32(18):1895-901.
  5. Von der Masse et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000; 18: 3068-3077
  6. Hussain et al. A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer Br J Cancer 2004; 91:844-849
  7. Galsky MD et al. Comparative Effectiveness of Treatment Strategies for Bladder Cancer With Clinical Evidence of Regional Lymph Node Involvement. J Clin Oncol. 2016; 34:2627-2635
  8. Hermans et al. Perioperative treatment and radical cystectomy for bladder cancer – a population based trend analysis of 10,338 patients in the Netherlands. Eur J Cancer. 2016 Feb;54:18-26
  9. Galsky et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011 June; 29:2432-2438
  10. Apolo et al. Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States. Urologic Oncology. 2014 Jul; 32(5):637-44
  11. Necchi A et al. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 4507-4507.
  12. Powels T et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 4506-4506.