cisplatin

4 months 2 weeks ago #60342 by ckfun
cisplatin was created by ckfun
Hello,
I have posted in the past regarding my husband's diagnosis of adenocarcinoma bladder which was muscle invasive.
He had a partial cystectomy in late August.
He is considering entering a clinical trial.
The first 7 weeks involve radiation and cisplatin. After the 7 weeks, Opdivo 1x a month for 12 months.
Would like to know the side effects that patients have had with the cisplatin.
Our local oncologist is not sure this trial is a good idea since the cisplatin has not been shown to be effective in adenocarcinomaof the bladder.
Any thoughts appreciated.
~caryl

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4 months 2 weeks ago #60344 by sara.anne
Replied by sara.anne on topic cisplatin
I think that I would have a long talk with the clinical trial people and ask your questions. Mine would include "Is this trial specifically for adenocarcinoma of the bladder or for bladder cancer patients in general?" and "Why do you think that this particular treatment might be of benefit to patients like me?"

Think the answers to these questions might help make up your minds.

Sara Anne

Diagnosis 2-08 Small papillary TCC; CIS
BCG; BCG maintenance
Vice-President, American Bladder Cancer Society
Forum Moderator

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4 months 2 weeks ago #60345 by joea73
Replied by joea73 on topic cisplatin
Side effects of cisplatin

I know a man who lost hair due to neoadjuvant chemo with cisplatin, but his hair came back. I know a female with metastatic bladder ca. She lost taste and some food tasted like metal. The taste came back later. I know another man who had cisplatin but he did not have visible side effects except nausea. Those are temporary side effects.
Another side effect, which can be long-term, is a change in hearing. NIH says cisplatin and other similar platinum-containing drugs can damage the cochlea, leaving 40%–80% of adults, and at least 50% of children, with significant permanent hearing loss, a condition that can greatly affect the quality of life. The cause is that cisplatin gets stuck inside the cochlea and can't come out. It is noted that usually unused cisplatin molecules are excreted through the kidney to the bladder within a few days.

www.cancer.gov/news-events/cancer-currents-blog/2018/cisplatin-hearing-loss#:~:text=But%20cisplatin%20and%20other%20similar,greatly%20affect%20quality%20of%20life.


Mechanism of how cisplatin helps kill cancer cells / healthy cells.

Cisplatin-Pt(NH3)2Cl2- is a very small molecule that consists of a platinum atom, two chlorine atoms, and two ammonia molecules. When it is administered intravenously, it is delivered to all of the body as part of blood. It is so small and it will penetrate into the nucleus of cancer cells & normal cells. Once inside the nucleus, the platinum atom becomes like a hook and lock DNA and prevent the DNA from replicating, thus stops the cell division and lead the cell to die. Cisplatin cannot distinguish whether the cancer cell is urothelial cancer cells or normal cells or adenocarcinoma cells, and where the platinum atom locks in the DNA can be anywhere. That is why cisplatin works for various cancers. So, technically speaking, it should work for urothelial cancer cells and adenocarcinoma cells. But clinically, some studies show cisplatin was not as effective for adenocarcinoma in the bladder as urothelial carcinoma, and I assume that is what the urologist is saying.

I see generally recommended treatment of any non-urothelial carcinoma is radical cystectomy. I have seen in other posts that two people who were diagnosed with squamous were recommended radical cystectomy and somewhat reluctantly because there were not approved treatment to preserve the bladder such as BCG. I was wondering then why no such treatment exist for squamous bladder cancer.

Anyway, for someone who does not want RC or has a high risk of having RC, there have not been many studies or clinical trials for non-urothelial carcinoma such as adenocarcinoma. Pharmaceutical companies tend to focus their investment in their drug development in most common cancer types first, i.e. urothelial carcinoma in case of bladder cancer. The problem is that the same drug cannot be used for non-urothelial carcinomas, i.e. Keytruda was first approved for advanced bladder cancer and metastasized bladder cancer treatment, the clinical trial was done for urothelial carcinoma patients only. Consequently, when it was approved by FDA, the use was limited to those urothelial carcinoma patients whose cisplatin treatment failed as the first-line treatment. It means Keytruda cannot be prescribed to patients with non-urothelial carcinoma, including adenocarcinoma. Maybe in the future, if they do the clinical trial specifically for non-urothelial carcinoma patients.

So, the only treatment adenocarcinoma patients can receive is chemotherapy and radiation if a patient decides bladder salvation treatment rather than radical cystectomy as far as I am aware. But, this is almost the same as trimodal bladder salvation therapy for urothelial carcinoma patients or those who are too high risk to have radical cystectomy.

The clinical trial which is mentioned "The first 7 weeks involve radiation and cisplatin. After the 7 weeks, Opdivo 1x a month for 12 months" is just about the same as treating the patient with chemotherapy + radiation + keytruda.
Immunotherapy is to block the like (friendly handshake) between PD-L1 on T-cells and PD-1 on cancer cells, so the T-Cells attack the cancer cells. Keytruda blocks PD-1 on cancer cells and so does Opdivo. So, it sounds like this clinical trial is a way to enable adenocarcinoma patients to get treated with immunotherapy in addition to chemotherapy and radiation therapy.

FDA has approved the use of Opdivo (nivolumab) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that has progressed during or after platinum-based chemotherapy. American Cancer Society says
"About 80% to 85% of lung cancers are NSCLC. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma". So, in an amateur view, if Opdivo works for adenocarcinoma in lung, it may work for adenocarcinoma in the bladder.

Best wishes

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4 months 2 weeks ago #60353 by ckfun
Replied by ckfun on topic cisplatin
Thank you very much for your thorough response.
Much appreciated.
Yes, I am convinced this trial is his only shot for a longer life. But what about quality?
At the age of 76, the side effects could be the deal breaker..
The clinical trial is not exclusively for adenocarcinoma bladder. It also includes squamous and 2 other bladder tumor types. My husband is someone that Moffitt really wants in the trial. He might be their only adenocarcinoma since it is so rare.
Thank you again..
He has a tough decision to make on December 30....

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4 months 1 week ago #60368 by joea73
Replied by joea73 on topic cisplatin
Thank you for clarifying about the clinical trial. I have spent a few days reading your past postings and tried to understand BCa with adenocarcinoma better. I have a clarification and some questions.

76 yrs old is not old for BCa. It is about the average age of being diagnosed with bladder cancer. Of 80,000 newly diagnosed BCa patients every year in the US, 5% are metastatic and 20% are muscle-invasive. As most metastatic and muscle-invasive BCa patients go through systemic chemotherapy including neoadjuvant/adjuvant chemotherapy for RC, so I estimate about 10,000 new patients who are the same or older than your husband will go through systemic chemotherapy every year.

You have listed the hospital proposed three options for the treatment.

1. Surveillance at every three months by CT.
2. Chemotherapy + Radiation
3. The clinical trial: Cisplatin + Radiation + immunotherapy (Opdivo)

1. Surveillance by CT scan
What will be the treatment if cancer returns?

There are a few studies that investigated the relationship between the number of positive lymph nodes and recurrence-free survival after radical cystectomy. Note that the studies were for urothelial carcinoma and some patients had adjuvant chemotherapy.

USC studied 1,600 patients who had RC. 181 patients had 1 or 2 positive lymph nodes. Estimated 5 and 10-year recurrence-free survival was 43.8% and 40.9% respectively for the 181 patients. Adjuvant chemotherapy was associated with a lower risk.

University of Ulsan College of Medicine, Korea analyzed data on 525 patients who had a radical cystectomy in their hospital. 54 had 1 positive lymph node and 23 had 2 positive lymph nodes. Five-year recurrence-free and disease-specific survival rates were 36.9% and 52.2% in patients with 1 positive lymph node. Five-year recurrence-free and disease-specific survival rates were 16.3% and 21.7% in patients with 2 positive lymph nodes.

2. Chemotherapy + Radiation
Since the doctor is saying cisplatin does not work well for adenocarcinoma, which chemo drug is the doctor recommending to use?

The presentation by Dr. Andrea B Apolo of the National Cancer Institute in Nov 2019 told that there has been chemotherapy borrowed from the treatment for colon cancers, but the samples were too small to determine the efficacy of those chemotherapies.

Also, because adenocarcinoma in the bladder is rare, the doctor should consider endoscopy and colonoscopy to exclude that it came from the stomach or colon. I understand the PET scan did not show cancer in other organs, so I do not know if endoscopy and colonoscopy are required. Incidentally, I have done endoscopy and colonoscopy several times in the past. I was put in pseudo sleep and did not feel anything. I had my wife drive me home as I was not supposed to drive 24 hours.




3. The clinical trial: Cisplatin + Radiation + immunotherapy ( Nivolumab: trade name Opdivo)

I could not find the clinical trial Chemotherapy + Radiation + Nivolumab in the directory of clinical trials. What I have found is the clinical trial in which MOFFITT is involved in the clinical trial NCT04610671- "Study of CG0070 Combined with Nivolumab in Cisplatin Ineligible Patients with MIBC".

Inclusion criteria say

MIBC (T2-T4a), N0-N1, pure or mixed histology urothelial carcinoma. I think the pathology would have shown also urothelial carcinomas.

Also, participants must be ineligible for cisplatin-based chemotherapy due to any of the following. Ineligibility includes "Refusing to undergo cisplatin chemotherapy. So, your husband does not have to have chemotherapy for this trial.

Incidentally, CG0070 is called oncolytic adenovirus. Adenovirus is like a virus of common cold without harmful virus genes. They use gene-editing technology to take out genes that make us sick. Oncolytic adenovirus contains anti-cancer agents in the adenovirus. CG0070 will penetrate into bladder cancer cells and it releases anti-cancer agent and kill the cancer cells. Google says CG0070 was developed y Cell Genesys in San Francisco in early 2005 and the paper was published in 2006. Incidentally, the technology of adenovirus has been used by Oxford–AstraZeneca for their covid-19 vaccine. In this case, adenovirus which contains DNA of S protein of covid-19 virus goes into the nucleus of muscle cells and other cells after the injection to our arm, and messenger RNAs of S protein are made in the cell and the S protein go outside of the cell and our immune system makes anti-body for S protein of Covid-19. Anyway, oncolytic adenovirus technology is field-proven.

The description of the clinical trial says that CG0070 will be administered intravesically similar to BCG treatment.
Opdivo will be administered intravenously.

You may want to confirm with MOFFITT about the clinical trial. If this is the clinical trial they are proposing,
your husband does not go through cisplatin chemotherapy, which you are concerned about possibly affecting the quality of control.

The link to the clinical trial. Clinical trial at MOFFITT
clinicaltrials.gov/ct2/show/NCT04610671?term=Nivolumab&cond=Bladder+Cancer&draw=3&rank=14


Best

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4 months 1 week ago #60369 by joea73
Replied by joea73 on topic cisplatin
The brief summary of the clinical trial says "Investigators will evaluate the safety and efficacy of combination neoadjuvant therapy using intravesical CG0070 and IV Nivolumab in cisplatin-ineligible patients with Muscle Invasive Bladder Cancer (MIBC)". So, the trial maybe applies to only the patients who could not tolerate cisplatin or refuse it for neoadjuvant chemotherapy before radical cystectomy.

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