Carboplatin

[Scott]

I wanted to pass along some additional information about carboplatin as a treatment for stage I seminoma from Mark Kantrowitz, one of the most knowledgeable members of the TC-NET mailing list. The study in question is this one.

Many of the criticisms in that article also apply to previous studies of carboplatin, such as the larger study comparing carboplatin with radiation therapy published last year. I would add a few additional cautions:

1. Until any protocol passes through phase III clinical trials, it is unsuited for routine use in cancer treatment. Many treatments that supposedly showed great promise in their phase II trials had their advantages evaporate under the rigor of a well-designed phase III trial.
2. The study described by the article lacks statistical power. It is making a very basic error in assuming that because 314 patients is (barely) representative of the population of TC patients, it is sufficient for studying alternatives to surveillance. The sample size must be statistically significant relative to the population of TC patients who relapse while on surveillance, not the population of patients with TC. Since very few patients relapse while on surveillance, this means a much larger sample size, easily into the thousands of stage I seminoma patients.
3. Since carboplatin isn't 100% curative for stage I seminoma patients, the cross-sensitivity with cisplatin is a big concern. If you relapse while on watered-down chemotherapy, you may be reducing the effectiveness of BEP chemotherapy to cure the cancer. (Although the MRC/EORTC study's relapses were "cured" with BEP chemo, that study lacks sufficient longevity to report anything other than an initial response to BEP chemo, not 5 year rates. These are all very preliminary results.)

In addition, carboplatin has been shown, definitively, to not be effective at curing stage II seminoma (see, for example, Krege 2005: Single agent carboplatin for CS IIA/B testicular seminoma. A phase II study of the German Testicular Cancer Study Group (GTCSG), which showed only 81% complete response rate, with 13% of those later relapsing), so there is little reason to believe that it would be curative for earlier stage disease.

The MRC and EORTC study referenced by this article was far from conclusive in comparing RT with carboplatin. In that study the RT arm involved two different forms of RT, 30 Gy in 15 fractions and 20 Gy in 10 fractions. Also, only 13% of the RT patients received dogleg, with the rest just para-aortic. 7% of the RT patient relapses were only in the para-aortic nodes and 38% in the pelvic nodes. This was exceedingly strange, given that there almost never are relapses within the irradiated field. Also, the study was designed to show only signficant differences in relapse rates of 3% or more at 2 years (4% at 3 years) with 90% confidence, not the 95% confidence usually used in such studies. There was a significantly greater delay until the start of treatment in the RT arm than in the carboplatin arm. They failed to use scrotal shielding in most patients, leading to a high rate of secondary cancers in the RT arm. There is also suggestive evidence that they deliberately sent the higher risk patients to the RT arm and did not really randomize the patients (e.g., a much greater percentage of RT patients had primary tumor size > 4cm -- 73% vs 35% -- and the rate of second primary cancer was four times higher in the RT arm -- 1.96% vs 0.54%). They also included patients who were restaged prior to the start of treatment. Finally, if you look at just the 118 patients in the study who received dogleg RT, none relapsed, compared with a 4.8% relapse rate on carboplatin.

Carboplatin may have fewer side effects than cisplatin, but it still has some, and BEP chemotherapy is not being considered for stage I seminoma. Rather, the proper comparison is with RT (fewer side effects than carboplatin) and surveillance (no side effects). Emphasizing the lower side effects as compared with cisplatin smacks of a straw man argument.

The bottom line is carboplatin as an alternative to radiation therapy or surveillance remains an unproven therapy. Unless you are receiving it as part of a clinical trial and are made fully aware of the risks, you should opt for therapy that has been proven curative.

[Scott]

Side Effects

Since I had seen reports that carboplatin was "safer" than radiation therapy, I also asked about side effects and late effects of treatment with carboplatin.

I can't speak to the issue of late effects, because trials involving carboplatin have not gone on long enough to yield reliable statistics concering late effects. This is, of course, a big concern. In particular, there is insufficient history with carboplatin to judge the impact on cardiovascular events and the incidence rate for second cancers. An advantage of RT is reduced likelihood of cardiovascular events. (Overall incidence of second cancers is very slightly reduced with RT, but not enough to be worth mentioning. The main difference is in the types of cancers, with the RT second cancers being more likely to be abdominal. The Lancet study comparing carboplatin with RT did show four times as many contralateral TC with RT, but that probably has nothing to do with the effectiveness of the therapy and more to do with (1) a bias toward higher risk patients in the RT arm and (2) a surprising lack of scrotal shielding for most of the RT arm patients.)

The rest of this message concerns short-term side effects of carboplatin.

The major (more common) side effects of carboplatin include
thombocytopenia
neutropenia
leukopenia
anemia & fatigue
nausea & vomiting
pain
asthenia
alopecia
mucositis

Minor (as in less common) side effects include:
infections
bleeding
transfusions
peripheral neuropathy
ototoxicity
elevated serum creatinine
elevated blood urea
elevated bilirubin
elevated SGOT
elevated ALP
loss of electrolytes (sodium, potassium, calcium, magnesium)
cardiovascular effects
respiratory effects
allergic reaction

Generally, the side effects with carboplatin are less severe and somewhat less frequent than with cisplatin, but they are still present. The major side effects are all treatable.

Small studies suggest that the likelihood of kidney damage, hearing loss, and neurologic problems when carboplatin is substituted for cisplatin in treating TC is very much reduced. The studies go so far as to say that there is no risk of these side effects, but I've seen similar studies involving ovarian cancer where the risk is still present, albeit much reduced, so I suspect the "no risk" results may be due more to the small size of the studies than anything else. Also, the ovarian cancer studies demonstrated dose dependency in the risks of these side effects, and some of the studies suggesting no risk to carboplatin were at low doses.

The side effects with RT tend to be limited to the irradiated field. These are generally less severe than with cisplatin, mostly fatigue, nausea, vomiting, diarrhea, skin reactions. Long-term side effects also tend to be limited to the irradiated field, which deliberately excludes the heart.

Assuming you use scrotal shielding, RT is also much less likely to lead to temporary or permanent sterility.

The large-scale phase II comparison of carboplatin with RT published in Lancet did note less fatigue among the carboplatin group. But I find it surprising that they did not report on the more objectively measurable side effects, like low WBC and RBC counts. (Also, note that the comparison is relative to the start of treatment, not end of treatment, which yields an inherent bias against RT since the treatment is of longer duration. Even so, when the results were compared separately for 20 Gy and 30 Gy, carboplatin was much closer to the former.) There is, of course, insufficient longevity data to compare the two on long-term side effects, which is the key concern.

[Krokar]

I must add some comment while I didn't want until now to mix discussions from forum Tc-NET and this forum.
Mark Kantrowich is from my point of view a perfect mathematician but he will nevere be a perfect oncologist and he can speak just for himself.

His biggest problem is, that he is always speaking just from his perspective and he is not taking any other opinion in consideration. He is an odd fellow with "I'm always right" perspective.
I must says this because many members also on this forum stoped to debate on Tc-NET just because he is disproving other's arguments with some data wich has in many cases nothing to do with TC and be honest, not everybody can spent so much time to disprove his arguments again back.
Specially his way of comparing USA and European research, where mybe accidentally arguments and research from EORTC (European cancer research and Treatment of Cancer) and Medical Research Council (MRC) from UK are always wrong and uncapable of making statistical methods... Does really nobody in Europe know anything about statistical methods and they are poisoning us with something they dont know ?

Also there is no evidence in no research that Carbopaltin is not effective at stage I Seminoma. To withdraw something is much eazier than to prove against. Until some research center will not do this Carboplatin will stay like a third option for stage I Seminoma at leaset somewhere. While Kantrowich talk about more side effects with Carboplatin against Radiation , I can just say : "Be serious man".

So please Scott, be so kind and let the users view the whole story and read all his posts and mybe they can make their own picture. Like I sad, if he is good mathematician does not prove he can judge for all persons on the world what is right and what is wrong and be smartest then research centers.

I must say all this because forums should be debating clubs where specialy like here on medicine we amateurs can share our experiances and ideas and I don't want that it is some dictatorship of one opinion, whic is at the end not even on the strong foundation.

Regards,
Alex

[Lunge]

For all readers in Europe I want to write this:

Overall incidence of second cancers is very slightly reduced with RT

RAISED not reduced!

Since carboplatin isn't 100% curative for stage I seminoma

neither is RT.


- There are two opinions differing from each other. Be sure to check both sides before believing in one.
- Read carefully all patient reports about side effects of RT compared with Carboplatin and you will see the difference.
- Search for relapses or second cancers of patients treated with Carboplatin and see the truth (Yes, I know that there can be no conclusion on long term side effects, since it is relatively new)
- Search, for comparison, the same about RT treatment.
- Read about carboplatin treatment in european forums (GERMAN: Krebs-Kompass )
- Wait-and-See is not sideeffect-less. Count in the psychic pressure.

[Scott]

I agree with you; it's important to see all sides of the story.

[Scott]

Doug Bank adds:

I think Mark meant to say that the incidence of second cancers is slightly INCREASED with radiotherapy, and that is the main reason that they are trying to come up with an alternative (and carboplatin is a lot cheaper, too). The really big problem is that radiotherapy is extremely effective and well known. Any alternative has to do better. Since seminomas are known to recur many many years after the original cancer, you have to monitor any new treatment protocol for at least 10 years to even have a hope of understanding its long term effects.

As far as second testicular cancers go, Mark and I find the numbers in the study very strange. As Mark pointed out, there were many more second testicular cancers in the arm receiving radiation. Yet, on this list in the past 6 months we have seen two people who received carboplatin get a second testicular cancer. This means to me that the study was not designed well or the results were a fluke.

I wont go so far as to say that carboplatin is a bad idea, but I do not understand why the single agent single cycle regimen was thought up in the first place and I have yet to see a convincing study showing why it being recommended so much more than surveillance. My last comment is that if I were getting carboplatin, I would not assume I was cured and I would be very sure to get followup scans and checkups.

I won't cross-post more on this topic at this time. I realize it is controversial, but I think it's important to discuss.

[Scott]

I would also encourage Krokar, Lunge, and others to keep adding their perspectives. We all learn from hearing from each other.

[Krokar]

This comment from Doug Bank is in the same concept like from Mark Kantrowich. Let's discuss that accuracy they would like to point it always :

Doug Bank adds:
Quote:
I think Mark meant to say that the incidence of second cancers is slightly INCREASED with radiotherapy, and that is the main reason that they are trying to come up with an alternative (and carboplatin is a lot cheaper, too). The really big problem is that radiotherapy is extremely effective and well known. Any alternative has to do better. Since seminomas are known to recur many many years after the original cancer, you have to monitor any new treatment protocol for at least 10 years to even have a hope of understanding its long term effects.

As far as second testicular cancers go, Mark and I find the numbers in the study very strange. As Mark pointed out, there were many more second testicular cancers in the arm receiving radiation. Yet, on this list in the past 6 months we have seen two people who received carboplatin get a second testicular cancer. This means to me that the study was not designed well or the results were a fluke.

1. Did anybody said on this list that this two people who received Carboplatin for them treatement were participant in that clinical trial ?
2. As far as I remember at least one of them had TC on the other testicle and we are talking about about cure rate.

What makes me bother is that they are using all arsenal of "evidence" but they don't exactly define them.And now Doug is an expert who can sugest that results are fluke.Hes opinion is mixing with statistical facts and in this case his opinion is important, facts are a fluke.

I wont go so far as to say that carboplatin is a bad idea, but I do not understand why the single agent single cycle regimen was thought up in the first place and I have yet to see a convincing study showing why it being recommended so much more than surveillance. My last comment is that if I were getting carboplatin, I would not assume I was cured and I would be very sure to get followup scans and checkups.

No study is good enough for him and Mark.


I would liek to copy this from http://www.cancer.gov/clinicaltrials...testicular0604 :
“These are encouraging results,” said Wyndham Wilson, M.D., of the National Cancer Institute’s Center for Cancer Research. “They suggest that carboplatin may be safer than radiation” in terms of the risk of second cancers. With further follow-up, the difference between the trial’s two arms may become even greater, he added, “in that the risk of second cancer from radiation increases with time, out to 25 years and beyond.”

And this is what I'm 100% agree with. We know that radiation is sucesfull and also dangerous on long term. We know that Carboplatin is sucessfull but we don't know about long term effects, we assume there will not be many of them because we have experiance with familiar cisplatin.

So for the end some controversial for me :

I understand that Carboplatin is inferior comparing to Cisplatin when we compare them directly at high level disease. But we use them in a different cases so :

Argument against Carboplatin is "why it would work with micrometastasis if it is not so good with advance disease" ?
I would ask one question back : Why radiation is in use with lymph nodes under 2cm with Seminoma ? Why we need chemo (BEP or EP) for bigger size if radiation is so successfull ?
Mybe not most well-chosen example but answer is that mybe we don't need so much radiation or so much chemo to be successfull with micro disease like we need it for high developed disease.
And there is no evidence or no trial made till now which will say that there is difference between micro and advance Seminoma, except trials for I stage which would like to point that there can be a case for Carboplatin.

And now we can turn this weel of fortune around and start to speak about examples at colon cancer, cross resistance, bribable doctors in EU or at least some cases, mistakes in statistical methods of EORTC (European cancer research and Treatment of Cancer) or Medical Research Council (MRC) and fluke with statistic... but

Is there any trial to suggest that Carbolpatin for I stage Seminoma can not be compared against RT at least till Phase II ? I don't find it. Because of that I would stay at point where Carboplatin is promising method and not some unproven thigs where nobody knows how it works.

Thank you Scott for your understanding but I don't wont that you copy now my thoughts back to Tc-NET and then back here and so on, because I quit debating on that forum and would like that my words stay here. Thanx.

[Scott]

One more bit of information that Mark posted today:

This does not mean, however, that oncologists won't find a less toxic form of chemotherapy that can substitute for RT with equivalent effectiveness. The third generation platinum drugs, such as oxaliplatin, show a lot of promise. One key difference between oxaliplatin and carboplatin is that oxaliplatin shows very little cross-resistance with cisplatin, while carboplatin shows a lot. This means that if a patient relapses while on oxaliplatin, it is unlikely to make the cancer resistant to BEP chemotherapy. (Or, conversely, if a patient fails BEP chemotherapy, combination chemotherapy involving oxaliplatin has a chance of succeeding.) But testing of oxaliplatin is still in the early phases, so we know even less about its effectiveness than we do about carboplatin.

[LoneNutTheorist]

Ahhhh.

I love a little controversy.

I know the regs here all know this, but none of this stuff (radiation, carboplatin) is anything that any sane person should go near if they don't have cancer! All of these things are bad for you because all kill our cells.

Reading these posts over the past year I've learned that ANYTHING can contribute to cancer risk (i.e. physical trauma -- which I believe played a role in mine -- can increase the risk of mutation!)

Just because carboplatin isn't radioactive doesn't mean that there's no cancer risk. I'm not saying that there is one, but if all non-radioactive substances were safe, people would still be smoking in doctors' offices. And tobacco is a "natural" substance to boot!

Basically, we already have cancer, so it could be argued that we are at greater risk than the general public.

Here's my view:

Radiation = bad for you, but curative in many cases
carboplatin = bad for you, but curative in many cases

Neither one of these is a magic pill. These treatments are comprised of dangerous matter and/or energy that damage all kinds of cells (just that the non-cancerous ones can recover from the damage).

The only "safe" option is surveillance, but that up-front safety comes with a price of higher recurrence rates.

So when it comes to treating TC, it really is a case of choosing your poison.

[Krokar]

One more bit of information that Mark posted today:

Another completely Mark's definition. This cross resistance he get from ovarian cancer where doses are completely different. There is no evidence or proof that with that one or two cycles at TC anybody will be cross resistand.
Because of this way of arguments I can not take him seriosly.

[Scott]

Krokar, I don't know whether there is proof, but there is certainly some suspicion, as suggested here and elsewhere.

The important point in that last post is that the search for effective and less toxic treatment continues.

[LoneNutTheorist]

We all want to feel good about our chosen treatment plan, but the fact is that all of them either include increased risk up front (surveillance) or poisonous/dangerous chemicals or radiation.

This argument is an important one, but there's no definitive answer. I don't know a lot, but I know that much.

It's a lot like religion. We all want to have faith in our treatment plan. Aggregate data for each method indicates that all 3 options offer substantial benefits when use in the correct situations.

It's like asking for carboplatin or radiation, "how many stage I people would never have a recurrence even without these two options?" A good solid number, but still too risky for some of us, so we weigh our options and decide the risk that we are willing to live with for peace of mind.

I think the issue with the low doses of radiation and chemo is that we want as little of the bad stuff as possible, but we want all of the benefits. We are all built differently. Our cells all react differently. Until a doctor can punch our own genetic/chemical makeup into a computer and come up with a custom-tailored plan, we're all going to be getting more than we need just to cover the variance in our individual responses to these treatments.

[Krokar]

I will finish with this discussion here because this copy/paste thing from that forum takes value of this one.
I have no problems with guys on this forum, I love to discuss different opinions with you Scott, LonenutTheorist... while we are all in the range of discussion. And with that cross resistance you are right Scott, I agree with you. There is a possiblity for it like there is a possibility that you will get second cancer because radiation. But I will not say that radiation should be forbiden. I think it is great treatement, but there is just research outside to find something better.Somewhere also they don't have enough equipement for radiation and additional methods can save lifes. If Carboplatin will perfect at Phase III time will tell and I agree also with this. I also like thinking from LonenutTheorist

But I hate when discussion become a dictate of one opinion against research centers, clinics and all other opinions. I don't know how somebody can take right to decide for all others when he is not even from the right occupation and tell that doctors of thousand patiants "are committing malpractice". Saying that doctors takes bribe, and results are fluke is not on the level of civilized conversation and when such persons are editors on forums with so sirious questions like "how to survive" I don't want to discuss anymore in this way.

So in general we all know that there is no 100% sure treatement and that everybody is trying to decide (and should decide) together with his doctors and that we all are looking to the same scope - how to stay alive. We can have doubts and thinkings but not conclusions like we are God.

I hope this forum will stay like it is now.

Regards and Good luck to all

Krokar, I don't know whether there is proof, but there is certainly some suspicion, as suggested here and elsewhere.

The important point in that last post is that the search for effective and less toxic treatment continues.

[LoneNutTheorist]

Good points.

I think that for many people, just the fact that there are options offers a lot of reasurance. We lose a lot of control during treatment. Even if it just makes it feel as though we have more control than we do, that can be a good thing.

There's definitely a psychological front in the war against this disease.

I will finish with this discussion here because this copy/paste thing from that forum takes value of this one.
I have no problems with guys on this forum, I love to discuss different opinions with you Scott, LonenutTheorist... while we are all in the range of discussion. And with that cross resistance you are right Scott, I agree with you. There is a possiblity for it like there is a possibility that you will get second cancer because radiation. But I will not say that radiation should be forbiden. I think it is great treatement, but there is just research outside to find something better.Somewhere also they don't have enough equipement for radiation and additional methods can save lifes. If Carboplatin will perfect at Phase III time will tell and I agree also with this. I also like thinking from LonenutTheorist

But I hate when discussion become a dictate of one opinion against research centers, clinics and all other opinions. I don't know how somebody can take right to decide for all others when he is not even from the right occupation and tell that doctors of thousand patiants "are committing malpractice". Saying that doctors takes bribe, and results are fluke is not on the level of civilized conversation and when such persons are editors on forums with so sirious questions like "how to survive" I don't want to discuss anymore in this way.

So in general we all know that there is no 100% sure treatement and that everybody is trying to decide (and should decide) together with his doctors and that we all are looking to the same scope - how to stay alive. We can have doubts and thinkings but not conclusions like we are God.

I hope this forum will stay like it is now.

Regards and Good luck to all