It is very difficult to say which method is better as chemotherapy drugs were different, heating methods were different and patients selections were not exactly the same. Nevertheless, The approach which University of Arizona used seem to give better efficacy - 55% vs 33% (Duke) recurrence free after 2 years. I was particularly surprised to see that 55% recurrence free after 2 years for patients BCG did not work is much higher than 25% of recently approved MERCK Keytruda for BCG unresponsive patients.
I have listed a few notable differences in their approaches between Duke University and University of Iowa.
The list is from comparing two published papers. I have listed listed the links to the two papers.
Chemotherapy drug used
Duke : Mitomycin C
Univercity of Arizona : Gemistabine and Docetaxcel
University of Arizona
1. Keep warming bladder by inserting a Foley balloon catheter and fill it with 43–45°C warm water.
2. 200 mg Gemcitabine in 10 mL of warm water is instilled. The patient rotate while the water in the Foley
balloon is exchanged every 20 minutes with warm water.
3. After one hour, the Gemcitabine is emptied and 20 mg of Docetaxel in 10 mL of warm water is instilled,
and the catheter is removed. The patients are instructed to retain the fluid in their bladder for 120
Frequency of the treatment
Duke University For induction, 6 weekly-instillations, followed by monthly for 4 months.
University of Arizona For induction, 6 weekly-instillations, followed by 3 weekly-instillations af 3,6 and 9 mth.
1. 10 (67%) subjects experienced recurrent bladder cancer, with a median time to recurrence of 15.4
months, but none of these recurrences progressed to muscle invasive.
2. Of the 10 subjects that recurred with bladder cancer, six (60%) underwent radical cystectomy at a
median time of 20.1 months from study enrollment. Pathological stage at cystectomy was pTis in five
subjects, pT1 in one subject, and pelvic nodes were negative in all patients (median node count = 15)
University of Arizona 60 patients
1. 60 patients received treatment with a median follow-up of 14.9 months.
55% at 2 years recurrence free.
2. Of the 60 subjects, 3 underwent cystectomy. Of the 60 subjects, 3 has progression.
I also have read that cancer cells with high PD-L1 expression tend to respond to immunotherapy. But I also find that it is not quite simple.
I often get confused PD-1 and PD-L1. My understanding is PD-1 is a protein on the surface of immune T-Cell and PD-L1 is a protein on the surface of the cancer cell. If PD-1 and PD-L1 shake their hands, our immune T-Cells will not attack the cancer cell. One type, i.e. Pembrolizumab (trade name is Keytruda by MERCK) of immunotherapy drugs is to put a glove on PD-1 on T-Cell. The other type, i.e. Atezolizumab (trade name is Tecentriq by Roche) is to put a glove on PD-L1 on the cancer cell. Either way, it prevents from PD-1 and PD-L1 from shaking their hands and that make free T-Cells to attack the cancer cell. NCI explains those two drugs more technically.
Pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells. The ligands for PD-1 include programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells. (National Cancer Institute).
Atezolizumab binds to PD-L1, blocking its binding to and activation of its receptor programmed death 1 (PD-1) expressed on activated T-cells, which may enhance the T-cell-mediated immune response to neoplasms and reverse T-cell inactivation. (National Cancer Institute).
In terms of PD-L1 expression, they use Combined Positive Score (CPS). When MERCK was doing a clinical trial for Keytruda, they used a specific assay (stain) over tumor cells from a biopsy. The assay makes cells PD-L1 protein change color. A specially trained pathologist counts the number and cells which changed color and applies the formula CPS = # PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by Total # stained and unstained tumor cells x 100. In the case of bladder cancer, the specimen is considered to have PD-L1 expression if CPS greater than or equal to 10. In 2017, FDA approved Keytruda for advanced or metastatic urothelial carcinoma for patients whom Cisplatin chemotherapy did not work. FDA approval of Keytruda was based upon
clinical trial NCT02335424, Phase II trial of Keytruda which showed patients with PD-L1 expression 10% or more met the objective goal. Because Keytruda is expensive - about $10.000 per dose of 200mg and it requires a dose every 3 weeks it costs $150,000 per year or $300,000 per two years - and there are some side effects, for a patient to qualify Keytruda for advanced and metastatic urothelial carcinoma the patient's PD-L1 expression needs to be 10% or greater. I think this raises some ethical questions. What if PD-L1 expression is 8%? What if the patient is not covered by insurance.
I have attached JPG file, which shows examples of PD-L1 expression. Brown colored cells are stained cells by the special assay ( manufactured by Agilent) .
Left side is PD-L1 less than 10% or CPS <10 and right side is PD-L1 greater than or equal 10 or CPS>=10.