cisplatin

1 month 3 weeks ago #60371 by joea73
Replied by joea73 on topic cisplatin
Thanks for the confirmation and some background. I might have seen it but the clinical directory said it was only offered at the University of Utah, so I did not think it was being offered at Moffitt.

My background is in computer science and electrical engineering. I moved to sales and business development later in my career till I retired. I did a lot of business analysis. I was diagnosed with BCa 3 years ago. I have been running a local bladder cancer support group for 2.5 years, mostly learning from the participants. I did not even know even the anatomy of my own bladder till I was diagnosed with BCa. Just as other many patients, I have been learning mostly from Professor Google.

This is my perspective. It may sound like a sales pitch.

1. Your husband can withdraw from the program even in the middle of the program it becomes too hard.
2. Your husband had passed the inclusion criteria.
The immune system is working. The blood counts are normal.
The liver is functioning normally.
The kidneys are functioning normally.
3. Your husband had passed the exclusion criteria.
The oncologist does not consider that your husband has active co-morbidity which is severe enough to exclude him from the trial.
So, the oncologist thinks your husband can bear the treatment with the help of known drugs for side effects if required.

4. You mentioned that you have to drive 6 hours. I am concerned about how you manage the frequency of visiting the hospital while your husband is on the program.

4.1 I think every treatment, testing your husband receives is free. Immunotherapy drug costs $10K to $15K per treatment.

5. I am curious why they included transitional carcinoma (urothelial carcinoma), adenocarcinoma, squamous-cell and sarcomatoid carcinoma, but excluded other variants such as nested pattern, microcystic, micropapillary, lymphoepithelial-like, plasmacytoid and lymphoma-like, giant cell, trophoblastic differentiation, clear cell, lipid cell.

It may be because Opdivo (Nivolumab) has experience with adenocarcinoma, squamous-cell carcinoma, and sarcomatoid carcinoma for other cancer with some successful data, but not with other variants.
See below.

Nivolumab-Induced Impressive Response of Refractory Pulmonary Sarcomatoid Carcinoma with Brain Metastasis
www.karger.com/Article/FullText/492666

Nivolumab for Metastatic Cutaneous Squamous Cell Carcinoma
www.karger.com/Article/FullText/505478

Nivolumab Improves Survival for Some Patients with Advanced Stomach Cancer
www.cancer.gov/news-events/cancer-currents-blog/2020/stomach-cancer-immunotherapy-nivolumab

"Most (about 90% to 95%) cancers of the stomach are adenocarcinomas" American Cancer Society


Depression makes patients less proactive to the new treatment

You have mentioned that your husband is depressed. According to a study, those who are diagnosed with depression make less proactive to the new treatment. The concern is that a treatment decision by a patient is affected by the patient's mental condition. I have been aware for some time of the profession called psyco-oncology. Some large hospitals have an in-house psychologist who specifically deals with cancer patients and the family. I am wondering if your husband was depressed when he mentioned to his urologist that he did not want aggressive treatment.

Below is the study in 2000

We report on the degree of acceptance of adjuvant chemotherapy in patients with breast cancer who have concomitant depression. Only 20 (51.3%) of the study group accepted and received the proposed chemotherapy compared with 75 (92.2%) of the control group (p<0.0001). Treatment of depression might be essential for tailoring adjuvant treatments with chemotherapy.

pubmed.ncbi.nlm.nih.gov/11073026/


best

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1 month 4 weeks ago #60370 by ckfun
Replied by ckfun on topic cisplatin
Thank you again...Much appreciated.

The clinical trial in on clinicaltrials.gov NCT03171025
Adjuvant Nivolumab Following Chemo-Radiation in Localized MIBC

The clinical trial starts after the chemo-radiation to see if Opdivo is effective in adenocarcinoma originating in the bladder. My husband does not have cancer in any other major organs. He has had every test available.

MRIs, colonoscopy, PET scans CT scans etc.

The oncologist at Moffitt believes he should enter the trial. The local oncologist remembers my husband telling him he did not want any aggressive treatments. That is why he is not in favor of the chemo.

It is a tough decision, since he has other health issues.
He has to make up his mind by Wednesday since the radiation starts on Monday, Jan.4.

Thank you again.
What is your background?

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1 month 4 weeks 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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1 month 4 weeks 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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2 months 1 day 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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2 months 2 days 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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