dosage schedule of cisplatin in treatment of Basaloid squamous cell carcinoma - 1261725

Hi Mark. I dont think it matters for what reason you're getting cisplatin when you want to know its effects on preexisting tinnitus but I'll ask dr Weiss our head and neck spec to comment.
I hope you do well.
Janine

In lung cancer (which I realize is not head/neck cancer), cisplatin has been given in many different ways and is comparably effective pretty much any way you divide it up. It's most common to give it as a big slug once every 3-4 weeks, but it's definitely more likely to cause kidney damage and nausea/vomiting given all at once rather than divided. I routinely divide cisplatin over 2 days, either giving it on consecutive days on a once every 3 week regimen, or 2 weeks in a row if paired with other drugs given on a weekly basis. It's also reasonable to give divided week to week to week, and results are really comparable. However, none of the lower dose/more frequent options is as well studied as a big slug once every 3-4 weeks.

I don't really treat much head/neck cancer these days or study the field as closely, but I'd say that the same principles probably apply, though there's just far less research in head/neck cancer than in lung cancer, a more common cancer, and the vast majority of studies have used a big slug of cisplatin every 3 weeks. I think if a company were marketing cisplatin today, they would be working a lot harder to find ways to give it in a way that is a better balance of efficacy and tolerability, but since cisplatin is a dirt cheap drug developed 30-40 years ago, nobody's spending money to test for better ways to give it. I have long hoped we'd see some work done giving cisplatin given broken up into smaller doses more frequently in head/neck cancer, since I strongly suspect it's as likely to prove just as good and better tolerated.

I'll ask Dr. Weiss if he has more to add, since he has much more of a focus on head/neck cancer.

Good luck.

-Dr. West

The question that you ask has been on my mind the past few years, and even more so in the last few days, so your timing is interesting. Cisplatin at a dose of 100mg/m2 every three weeks is, by far, the best-proven chemotherapy to be used together with radiation for head/neck cancer. As you note, it has some big problems with side effects, including permanent ones. In the long term, cisplatin can damage the kidneys, hearing, and nerves; the risk is higher in people with diabetes. In the short term, it causes nausea and vomiting worse than any other chemotherapy drug that I use. In my practice, I do not use it for patients with the problems that you describe unless they tell me that their values are the extreme of valuing cure over avoidance of long term side effects.

There are alternatives to high dose cisplatin, but none have been as well proven to work and none have ever been compared head to head against cisplatin every three weeks. Perhaps the most commonly used alternatively is cisplatin at a dose of 30 mg/m2 every week. This regimen is certainly gentler. The list of risks and side effects is the same, but their frequency and severity is less. Is this because of the weekly schedule? Maybe. Alternatively, it may be a result of giving less total medicine (since radiation typically lasts 7 weeks, 30mg/m2 x 7 = 210, which is less than the typical 100mg/m2 x 3 or 300mg/m2 dosing). Does it work as well? There are a few small nonrandomized studies that suggest that it’s better than radiation alone. How does it compare to the standard every three-week cisplatin schedule? The existing data are completely inadequate to answer the question with any confidence. Doses of weekly cisplatin at 20mg/m2 and 40mg/m2 are also used. At 40mg/m2, the side effects profile starts creeping towards that of the standard schedule, but it has the advantage that you can “bail out” sooner if you get in trouble, instead of being stuck with 100mg/m2 of drug in you at a time…tbc

again, I data is inadequate to say how well it works compared to 100mg/m2 every three weeks. 20mg/m2 shouldn’t be used—the data that exist are concerning that it doesn’t work—why tolerate any side effects without efficacy against the cancer?

In my opinion, the best-studied alternative is cetuximab. You may have heard of this drug in the tabloids—it’s the one that Martha Stewart got in trouble for. Cetuximab is not chemo—it doesn’t work by poisoning rapidly dividing cells and it doesn’t cause classic chemo side effects, like nausea and fatigue. Rather, it’s an antibody to a receptor important in head/neck cancer called EGFR. Cetuximab has only one study comparing it to radiation. It was a well-conducted phase III trial and it was positive. However, you mentioned that your cancer was HPV positive. There is extraordinary controversy regarding whether cetuximab works better, worse, or the same for HPV+ cancer. The clinical trials and basic science here conflict a bit; the more science you understand, the less sense the entire story makes. I’d be happy to dive into more detail on this subject if you’re interested. In my practice, I do consider cetuximab.

There are other alternatives that are rarely used, but probably deserved more research than they got. There are hydrea/5FU combinations that have been extensively field-tested at UChicago. The experience was positive in terms of cure, but concerning in terms of early side effects. For a fit, motivated patient who is motivated for cure, but concerned about cisplatin, these regimens are reasonable, but there are few doctors who are comfortable with them. There’s also a cisplatin/taxol weekly regimen that gets the cisplatin dose down to 20mg/m2 weekly, with some help from taxol; its data is limited, but positive.

Finally, there are MANY trials going on nationally for people with HPV+ cancer that seek to de-intensity treatment, based on the existing data for higher cure rates with HPV+. For example…tbc

our trial at UNC gives a week less of radiation (6 weeks, or 60gy) along with weekly cisplatin at 30mg/m2. The good news with HPV is that no matter what you choose, you’re more likely to be cured than someone without HPV driving their cancer.

Very sorry not to see your followup question. Just contacted Dr. Weiss for input.
Much luck,
Janine

I'd say that this is the kind of thing we do very routinely, for one cancer or another. I certainly routinely adjust the dose gradually down as needed with cisplatin and often other drugs as needed in the setting of various cancers. I haven't used that exact dose in the setting of head/neck cancer, and my sense is that Dr. Weiss was speaking more based on general observations than an exact, direct experience mimicking what you're asking about. I may be wrong -- we can see what he says.

-Dr. West

I think that you're meaning to ask more about the relative toxicity of the two dose schedules (40mg/m2 per week x 7 doses vs. 100mg/m2 x 3 doses) than about dose reduction. Unfortunately, no good data really address the question that you're asking. I don't routinely use the 40mg/m2 dose so my comments cannot be more specific than a general impresson from the small number of published reports and listening to my colleagues. All kinds of dose schedules have been used with cisplatin in head/neck cancer. Some give dose weekly. Others break up the dose over several days, then give this either weekly or monthly. None, other than the high dose (100mg/m2 every 3 weeks) has ever been proven in a phase III study so it's hard to know if they're all the same, or if any one schedule is best. The questions that you're asking are good ones, but no one has a definite answer because the right studies haven't been done. To be honest, such studies may never be done -- we have new promising stuff that has too much promise to do studies of one cisplatin regimen vs. another.