Interesting new study on Taxol/carboplatinum

• By gpawelski
• Posted October 6, 2009 at 9:02 am
• Report post

Thanks for pointing out this article momanderson. It was truly ironic.

I've always felt the way my wife was treated for her cancer back in 1972 was the reason she survived so long (twenty-four years before a recurrence). In my paper "Cancer Medicine's Dark Corners," written years ago, I've pointed out that "by giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors."

Her postoperative chemotherapy regimen was among the slowest acting and least toxic of the alkylating agents (pill-dose). Depression of the immune system was slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells.

The lower-dose regimen may have attacked the blood vessels that fed the tumor (although not known at the time). Her type of treatment sounded very similar to the Angiogenesis and Low Dose Chemotherapy treatment that is finding increasing acceptance in some cancer centers today.

She also may have had some of her own anti-angiogenesis predisposition. In fact, it has been shown that low-dose chemotherapy induces an anti-angiogenic effect (sometimes referred to as 'metronomic' chemotherapy), the protocol mechanism that Judah Folkman discovered.

Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis.

But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

I'm glad more researchers are finding out more about the way it happens and what players are involved so more cancer patients can benefit from these kind of treatment protocols.

• Reply

• By koh847
• Posted October 6, 2009 at 9:42 am
• Report post

Hi Mom Anderson....If I am reading this right...it is like what I had. I had Carbo every 3 weeks and taxol every week for the 18 weeks of treatment. A little confused about the toxicity because each week the taxol was a lower dose, as the article states. Maybe toxicity is just because it is overall more of the drug due to it being every week? I did not have any taxol side effects.

Thanks for posting this...we all need to keep our eyes out for changes in treatment.

:)Kim

• Reply

• By Shearaw
• Posted October 6, 2009 at 12:05 pm
• Report post

Thanks for posting this. I have a friend who was treated for stage II breast cancer with a bi-weekly dose dense schedule. She is doing fine 3 years out. I don't know how reduced the dosing was, as she had many of the side effects we do.

• Reply

• By Shamrock2009
• Posted October 6, 2009 at 1:43 pm
• Report post

koh847,
Each week the dose was lower? I do not see that in the article.

• Reply

• By Shamrock2009
• Posted October 6, 2009 at 2:27 pm
• Report post

I found another dose dense study to compare with the Japanese study. It seems that the Japanese study (first-line therapy) of weekly dose dense 80 mg/m2 vs the Sweden/Finland study (women with who had a prior platinum-based therapy) of weekly dose dense 76 mg/m2 had a higher toxicity profile but showed better efficacy. Could the difference in efficacy be because the Japanese study was given for first-line treatment rather than recurrence as in the Swedish/ Finland study??

The Sweden and Finland dose dense study:

ADMINISTERING TAXOL ON A WEEKLY BASIS SHOWN SAFE AND EFFECTIVE IN THE TREATMENT OF OVARIAN CANCER

* Novel TAXOL Administration Schedule Provides New Hope for Women with Advanced Ovarian Cancer

New Orleans, USA - Research from Sweden & Finland, presented at the 36th annual meeting of the American Society of Clinical Oncology (ASCO), shows that administering TAXOL (paclitaxel) in smaller weekly doses is as effective as giving a larger dose every three weeks. In addition the new weekly schedule has the advantage of substantially reducing both haematological and non-haematological side-effects.

"This is an important study because it shows you can minimise side-effects by using a weekly regimen," said Dr Per Rosenberg of the University Hospital of Linkoping, Sweden. "But it is also important because it suggests we could increase the dose of TAXOL given weekly without increasing toxicity."

TAXOL in combination with a platinum drug is now the gold standard therapy for women with ovarian cancer. This was recently confirmed in the prescribing guidance issued earlier this month by the UK Government's National Institute for Clinical Excellence (NICE). However, physicians are still looking for new ways of delivering the drug that minimise toxicity while preserving anti-tumour activity.

In the study conducted by the Swedish and Finnish ovarian cancer co-operative, grade 3 or 4 neutropenia occurred in 45 per cent of women treated with the standard three-weekly regimen, but in only 18 per cent of women who received TAXOL on a weekly basis. Twenty-nine per cent of women on three-weekly TAXOL had grade 3 neuropathy, but this complication affected only 11 per cent of women on the weekly schedule. Alopecia was also much reduced by weekly administration, affecting 79 per cent of women who received the drug on a three weekly basis as opposed to 46 per cent on the weekly TAXOL regimen.

Even though the weekly TAXOL regimen dramatically reduced the number of women experiencing side-effects, the switch to weekly treatment did not compromise efficacy. The proportion of women responding to treatment was 37% with TAXOL administration every three weeks and 35 per cent with weekly TAXOL. The overall median survival was comparable: 14.7 months among women randomised to receive the drug every three weeks, and 13.6 months in the weekly group.

More than 200 women were randomised to either weekly or three-weekly therapy. The weekly dose was calculated to give the same dose-intensity as the conventional three-weekly schedule - ie, 67 mg/m2 per week. All the women involved in the study had advanced ovarian cancer and had already received at least one course of platinum-containing chemotherapy.

Distributed by PR Newswire on behalf of BMS

Source:http: //www.prnewswire.co.uk/cgi/news/release?id=17960

Japanese Dose Dense study:

Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.
Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K; for the Japanese Gynecologic Oncology Group.

Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

BACKGROUND: Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer. METHODS: Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS: 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups. INTERPRETATION: Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. FUNDING: Bristol-Myers Squib

Source:
http://www.ncbi.nlm.nih.gov/pubmed/19767092?ordinalpos=1&itool=EntrezSystem 2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDoc Sum

• Reply

• By momanderson920
• Posted October 6, 2009 at 2:50 pm
• Report post

Thanks, Shamrock. The fact that the Japanese study had downside of worse side effects is troubling. This other study looks more promising.

• Reply

• By koh847
• Posted October 6, 2009 at 2:59 pm
• Report post

Hi Shamrock...no, I am not sure if each week the dose was lower on the Japanese study. It was not clear to me. It sounded like it only lasted 3 weeks total...?? Do you understand it?

I know my dose was the same lower dose for each of the 18 weeks. Suppose to be a benefit there. Who knows.
:)Kim

• Reply

• By momanderson920
• Posted October 6, 2009 at 3:00 pm
• Report post

Here is an excellent lecture explaining the various types of therapy being utilized many in clinical trials to fight ovarian cancer. She does a great job in explaining how they work.
http://fora.tv/2007/10/20/Novel_Therapies_for_Ovarian_Cancer#fullprogram

• Reply

• By koh847
• Posted October 6, 2009 at 3:02 pm
• Report post

Shamrock...and others...I just found my bills and it looks like I received 30mg of taxol each week and 50 mg of carbo every 3rd week.
Kim

• Reply

• By momanderson920
• Posted October 6, 2009 at 3:10 pm
• Report post

Thanks for sharing this Kim. I plan on mentioning this to my oncologist at my next appt. if I go back on chemo at some point.

• Reply

• By koh847
• Posted October 6, 2009 at 3:32 pm
• Report post

Now I am wondering if I had enough Taxol....30 mg/wk is only 90 over the 3 weeks and the standard doseage is suppose to be 175 every 3 weeks. Maybe I am reading this wrong...but if I am not I received only just over 1/2 the regular dosage when you add it up. Just one more thing to worry about....

• Reply

• By momanderson920
• Posted October 6, 2009 at 3:37 pm
• Report post

Kim, I would not worry. If your CA125 went down to normal levels and a CT was negative, it probably destroyed all that was there. My oncologist says that it is like sand and no matter what they give, there are almost always some cells left over unless you had a contained situation and were Stage I or II.

• Reply

• By koh847
• Posted October 6, 2009 at 4:17 pm
• Report post

Hi...I was stage 2, and wonder what the standard doses of carbo and taxol are suppose to be....
Anyone know?
Kim

• Reply

• By Shamrock2009
• Posted October 6, 2009 at 5:46 pm
• Report post

Kim,
Doses are calculated by your body surface area (BSA).
This link is to a site where you can calculate your BSA. You then times mg/m2 of the drug to get the dose they give you.
Me for example my BSA is 1.72
my Taxol every 3 weeks was 175 mg/m2
so 1.72 x 175 = 300 mg every 3 weeks.

http://www.halls.md/body-surface-area/bsa.htm

• Reply

• By Shamrock2009
• Posted October 6, 2009 at 5:54 pm
• Report post

PS
Carboplatin is not calulzated the same way it is based on an AUC dose usually by the Calvert Formula.
They calculate this by age and your creatinine blood test

• Reply

• By koh847
• Posted October 6, 2009 at 6:19 pm
• Report post

Thanks Shamrock...looks like I received 150mg (5 injections of 30mg) every week according to bill. My husband is a physician and explained what you explained above to me when he got home. So it looks like over a 3 week period I received 450 which is sort of high compared to your 300. My bmi is 1.87 which works out to 327. I received the 150 each week for the total of 450, so it is still higher than the 327, not sure why. I was just soooo upset today when I looked and saw 30mg each week. (I missed the 5 under quantity). Have to stop looking at all this stuff.
Thanks, Kim

• Reply

• By momanderson920
• Posted October 6, 2009 at 10:27 pm
• Report post

I had a lower dose for both drugs for my first dose since my creatinine level was over 1.5 (I think was 1.8) and my CA125 still went down considerably. Then when my CA125 went down to 1.3, they put me on a regular dose for my age and weight...not sure what it was. All I know is that my CA125 went down to 8 and my PET scan was clear....in my mind that is what matters.

• Reply

• By CATSMEOW
• Posted October 7, 2009 at 5:12 am
• Report post

Iam doing low dose carbo/gemzar every other week, even though I have NED.I had the first dose last week and feel just fine.Have not had the ca done yet, will get at the end of week.When I went in for my chemo and exam the dr. wanted to try the low dose at a more frequent level.He said it would be less of a suppression for me.So far I feel fine.The combo is working at bringing the ca down and no more visible tumors.I am glad I have a dr. like him.Always thinking about whats to be done next even before it happens.Keep Positive

• Reply

• By Mom82
• Posted October 7, 2009 at 9:34 am
• Report post

Interesting, but I don't understand why this approach has more side effects at lower doses than the conventional one? Can you explain that?

• Reply

• By gpawelski
• Posted October 7, 2009 at 10:54 am
• Report post

Mom82

As Dr. Bookman wrote, although it's possible that the dose intensity was responsible for the survival improvements, the more frequent, lower-dose treatment schedule is the most plausible explanation. Similar results might be achieved with a lower dose, with improved tolerability. Like metronomic chemotherapy, the lower-dose therapy may hamper the formation of blood vessels that feed tumors (an anti-angiogenic effect).

Cancers sufferers may be taking doses of treatments that are possibly well in excess of what they need. One such example is a study reported by a medical oncologist, Dr. Ian Haines, in the Journal of Clinical Oncology that a dose of Avastin tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram. In other words, it may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.

• Reply

Add to the discussion