Home
Donation
Contents
A CLL Primer
Current Articles
Topics Alert
Project Alpha
Your Charts
Feedback
Reference
Textbooks
Search Tools
About Us

 

 

Chemotherapy


Drug Dosages in Popular "Standard" Therapies

9/13/03

by Chaya Venkat

There is supposedly an old Chinese curse, "May you live in interesting times". Times of change are certainly interesting, and there is no question about it, a lot of things are changing in the way CLL patients are treated today. Some of the popular combinations of monoclonal antibodies and chemotherapy drugs are just emerging from clinical trials, and there has not been sufficient time to have fully formulated dosages and protocols. If you are about to start one of these therapies with your local oncologist, you might want to see how the dosages your guy recommends compare with some of the more well known national studies. First, some basics.

Calculating individual drug dosages:

It makes intuitive sense that a big six foot tall and heavy-set guy would need a larger amount of a given chemotherapy drug than a petite and slender woman. In order to make this distinction, drug dosages are given as standard numbers that have to be multiplied by a "size factor". The measure of a person's size is given by the surface area of his/her body, and this is called "Body surface area" or BSA. The BSA is calculated using the person's height and weight, and some special formulas.

This page from the BC Cancer Agency will tell you more than you have ever wanted to know about BSA (such as, how do you correct BSA for someone who has one leg amputated?): 
http://www.bccancer.bc.ca/HPI/DrugDatabase/Appendices/Appendix9.htm 

BSA Calculator: This unofficial site has a handy dandy calculator to do the BSA computations for you. As an additional bonus, it will calculate your dosage and inform you of your body mass index, lean body weight and "ideal body weight". "Ideal", of course, is a matter of opinion.
http://www.halls.md/body-surface-area/bsa.htm 

For easy bookmarking, you will find the above links in the Reference section of this site.

Example: Your chosen protocol calls for 375 mg/m2. That should be read as 375 milligrams of Rituxan per square meter. If you are 5' 10" tall, and you weigh 170 lbs, the BSA calculator above gives you a BSA of 1.95 square meters. That is the surface area of your entire body. To get the drug dosage customized for you, simply multiply the 375 milligrams by 1.95 square meters, and you come up with 731 milligrams of Rituxan.

Remember, the Rituxan will be administered in a saline solution. Does it matter whether the nurse used half a liter of saline solution or three quarters of a liter of saline solution? It does not, as long as the quantity of saline solution is within reasonable limits, and the amount of Rituxan dissolved in the saline solution is the right amount, 731 milligrams in the case of our example.

Rituxan monotherapy:

Some of the largest sections in this website deal with Rituxan as single agent therapy. You may wish to browse those sections. The link below gives a good overview of the many different Rituxan trials in CLL and NHL. The Table tries to capture some of the drug dosage specifics. In the two dose escalation studies at M. D. Anderson and Walter Reed Army Medical Center, I have tabulated the maximum dosages used. As you can see, the total amount of Rituxan given in each of these protocols is quite different. At this point in time, it appears that most of the non-clinical trial administrations of Rituxan for CLL patients is following the dosages used in either the Hainsworth (375 mg/m2, once a week for 4 weeks) or the Thomas protocol (375 mg/m2, once a week for 8 weeks). Both of the dose escalation studies were accompanied by more side effects, and while the response rate was better at these higher dosages, it was not sufficiently improved to justify the additional cost or increased adverse effects.

It is also worth noting that only the Thomas study used chemotherapy-na´ve patients, in earlier stage (Rai stages 0,1 or 2), and this study also got the highest overall response rate and highest percentage of complete responses.
http://www.iwmf.com/PanPacConf.htm 

Institution:

Sarah Cannon 
Cancer Center

M. D. Anderson 
Cancer Center

Walter Reed 
Army Medical Center

M. D. Anderson 
Cancer Center

Lead 
Expert(s):

Hainsworth, J

Keating M, O'Brien S.

Byrd JC

Thomas DA

Reference:

J Clin Oncol. 2003 May 1;21(9):1746-51

Semin Oncol. 2000 
Dec;27(6 Suppl 12):86-90

J Clin Oncol. 2001 
Apr 15;19(8):2153-64

 

PMID

12721250

11226005

11304767

ASH abstract 
#1533, 2001

 

 

 

 

 

Type of Trial

monotherapy;
maintenance 

monotherapy 
dose escalation

monotherapy 
dose escalation

frontline
monotherapy

Patients

Previously treated

Previously treated

Previously treated

Na´ve, early stage

Rituxan 
Dosage

375 mg/m2 
per week

375 mg/m2 
first week

475 mg/m2 first week 
(split, day 1 & day3)

375 mg/m2

 

 

2,250 mg/m2 
next three weeks 
(Maximum)

1,125 mg/m2 
next 3 weeks 
(Maximum)

 

 

 

 

(375 mg/m2, 
three times a week)

 

Number of 
weeks

4

4

4

8

Total 
Dosage

1,500 mg/m2

7,125 mg/m2

3,850 mg/m2

3,000 mg/m2

 

 

 

 

 

Maintenance:

Repeat 
every six months

None

None

None

Pre-
medications:

Allopurinol, 
300 mg, 
first 14 days

 

 

 

 

Tylenol, 650 mg, 
prior to 
Rituxan infusion

 

 

 

 

Benadryl, 50 mg, 
prior to 
Rituxan infusion

 

 

 

Rituxan Plus Fludarabine:

RF might be a good option for patients who may not be good candidates for Rituxan only monotherapy. There are good reasons for combining Rituxan with Fludarabine. Fludarabine is the present day "gold standard" for CLL patients. It is one of three drugs called purine analogues, the other two members of this triad are Cladribine and Pentostatin. Yes, Fludarabine is a standard chemotherapy drug, and it does have some risks of myelosuppression. But there is some terrific synergy between the anti-CD20 monoclonal Rituxan and the purine analogue Fludarabine. You can learn more about this combination in several other essays on this website: 
Response in Rituxan Plus Fludarabine Therapy
RF Therapy Clinical Trial
Rituxan plus Low Dose Oral Fludarabine
Rituxan plus Low Dose Fludarabine - II

One of the pivotal studies looking at the efficacy of Rituxan plus Fludarabine in CLL patients was done at Ohio State, with Drs. Byrd and Rai as the lead investigators. The protocol used in their study is now called the "Ohio State Protocol", and it is by far the most often used protocol for this particular combination. You can read all of the details of this study, including the comparison of sequential versus concurrent administration of the two drugs, statistics of the responses obtained, and the type and severity of the side effects observed by going to the journal article, or you can read our summary of it in CLL Topics listed above: RF Therapy Clinical Trial. The CLL Topics article also has a link to the original paper in Blood.

Below is a chart of the drug dosages used in this study. Remember, all the dosages are given in the standard milligrams per meter square (mg/m2) format, you will have to multiply the numbers by your own BSA to get the right dosages for you. The protocol calls for six cycles, each lasting one week, and the cycles are four weeks apart, to give your body a chance to recover between cycles. The first cycle dosage of Rituxan is double that of the next five cycles.

 

Institution:

"Ohio State Protocol"

Lead Expert(s):

John C. Byrd

Kanti Rai

 

 

 

 

 

Reference:

Blood, 1 January 2003. Volume 101, Number 1 

URL:

 http://www.bloodjournal.org/cgi/content/full/101/1/6 

 

Day of the week

Day 1

Day 2

Day 3

Day 4

Day 5

Total

First cycle

Rituxan

375

 

 

375

 

750

(Month 1)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Second cycle

Rituxan

375

 

 

 

 

375

(28 days after 1st cycle)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Third cycle

Rituxan

375

 

 

 

 

375

(28 days after 2nd cycle)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Fourth cycle

Rituxan

375

 

 

 

 

375

(28 days after 3rd cycle)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Fifth cycle

Rituxan

375

 

 

 

 

375

(28 days after 4th cycle)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Sixth cycle

Rituxan

375

 

 

 

 

375

(28 days after 5th cycle)

Fludarabine

25

25

25

25

25

125

 

 

 

 

 

 

 

 

Protocol Totals:

Rituxan

 

 

 

 

 

2625

 

Fludarabine

 

 

 

 

 

750

 

 

 

 

 

 

 

 

Pre-medications:

 

Allopurinol

300 mg

First 14 days 

Acetaminophen

650 mg

prior to all Rituxan doses 

Diphenhydramine

50 mg

IV, prior to all Rituxan doses

 

     

Rituxan plus Fludarabine plus Cyclophosphamide:

This combination is rapidly becoming the one to beat. RFC (or FRC, or any other combination of the three letters!) combines the targeting capability of Rituxan with the cell kill capabilities of Fludarabine and Cyclophosphamide. For the first time, complete responses (CR) are seen to be as high as 60%. Even more impressive, twelve out of 17 patients with CRs who were tested by the latest PCR technology were seen to be PCR negative. Extrapolating to the full set of patients, that suggests roughly 40% of the patients who underwent this RFC trial at M. D. Anderson had disease levels that were basically undetectable. It is too soon to tell the exact magnitude of the survival advantage of a PCR negative remission, but there seems little doubt that a deep response of this type translates into longer remissions, perhaps a "cure" for a certain percentage of patients. You may read more about it in a recent article elsewhere in CLL Topics: What Does It Mean to Be PCR Negative? .

It is unfortunate that the full details of this pivotal study are yet to be published in peer-reviewed journals. At this stage we have to make do with abstracts from conference presentations. Below is the ASH 2001 presentation abstract that provides some information. The tables below compile the drug dosages, observed toxicity, and the response statistics.

Abstract:

Rituxan in Combination with Fludarabine and Cyclophosphamide in CLL (Abstract #2214)

Researchers at the University of Texas M.D. Anderson Cancer Center, led by Dr. Michael Keating, presented preliminary data from an investigational Phase II trial designed to evaluate the combination of Fludarabine, cyclophosphamide and Rituxan in previously-untreated patients with advanced CLL.

In the study, 68 patients have been enrolled and are receiving fludarabine (25 mg/m2), cyclophosphamide (250 mg/m2) and Rituxan (375 mg/m2 for first cycle; 500 mg/m2 all subsequent doses). Treatment was given over three days and repeated every four weeks for six courses with Rituxan administered on day one of each three-day cycle.

To date, 56 patients are evaluable for response, 35 of these patients have completed all six courses and 21 patients, who are still undergoing treatment, have completed three courses of therapy. The overall response rate was 94 percent (57 percent complete response rate) in the patients receiving six courses of therapy and 81 percent (14 percent complete response rate) in the patients receiving three courses of therapy.

"Historically, we have been able to achieve complete remission rates of 35 percent when we treat our patients with CLL with fludarabine alone or 43 percent with fludarabine/cyclophosphamide combination therapy," said Dr. Keating. "The initial data from this study suggests that the addition of Rituximab to fludarabine and cyclophosphamide leads to a complete remission rate that is clinically significantly higher than we have been able to achieve with chemotherapy alone. In many patients, we are currently unable to find any CLL cells using the PCR (polymerase chain reaction) technique which can identify between one and 100,000 cells."

The addition of Rituxan to fludarabine/cyclophosphamide chemotherapy did not appear to cause a clinically significant increase in adverse events to those seen with fludarabine/ cyclophosphamide alone. Neutropenia was the most commonly reported adverse event, which led to a dose reduction of fludarabine/cyclophosphamide in 21 percent of patients. Additional adverse events seen with fludarabine/cyclophosphamide were nausea (21 percent), vomiting (7 percent) and infections (13 percent). Additionally, patients experienced Grade I/II (61 percent) and Grade III/IV (14 percent) infusion-related events during the first infusion of Rituxan. Infusion-related events in the subsequent courses of Rituxan were uncommon.

 

Institution:

M. D. Anderson Cancer Center

Lead Expert(s):

Keating, MJ

 

 

 

 

 

 

Reference:

http://www.intouchlive.com/journals/oncnews/n0102supp1s.htm

 

 

 

 

 

 

 

 

 

Day of the week

Day 1

Day 2

Day 3

Day 4

Day 5

   Total

First cycle

Rituxan

375

 

 

 

 

375

 

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Second cycle

Rituxan

500

 

 

 

 

500

(4 weeks later)

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Third cycle

Rituxan

500

 

 

 

 

500

(4 weeks later)

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Fourth cycle

Rituxan

500

 

 

 

 

500

(4 weeks later)

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Fifth cycle

Rituxan

500

 

 

 

 

500

(4 weeks later)

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Sixth cycle

Rituxan

500

 

 

 

 

500

(4 weeks later)

Fludarabine

25

25

25

 

 

75

 

Cyclophosphamide

250

250

250

 

 

750

Protocol Totals:

Rituxan

 

 

 

 

 

 2,875

 

Fludarabine

 

 

 

 

 

 450

 

Cyclophosphamide

 

 

 

 

 

 4,500

               

 

Additional Information: MDACC RFC Protocol

# of Patients

53

Patient type:

Untreated

Median age:

54 (30-85)

Stage:

41% in Rai Stage 3-4

Toxicity:

 

       Grades 1-2

61%

       Grades 3-4

14%

 

 

Response:

 

       Overall Response:

92%

       Complete Response:

60%

       Nodular Partial response

17%

       Partial Response:

15%


K  Chemotherapy

 Print

H  Home

G  Contents

:  Current Articles