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Chemotherapy

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Drug Dosages in Popular "Standard" Therapies

Date: September 13, 2003

by Chaya Venkat

The Protocols Practised by Leading Institutions

Related Article:
Methods of Drug Delivery.

drip

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. Here are two helpful aids:

The BC Cancer Agency is an authoritative source of information on BSA and related topics. Their website will tell you more than you have ever wanted to know about BSA (such as, for example, how do you correct BSA for someone who has one leg amputated?): BSA Calculations 

BSA Calculator: This unofficial site (halls.md) 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.

For easy bookmarking, you will also 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:

One section in this website deals with Rituxan as single agent therapy. You may wish to browse that section. 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-naïve 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.

Rituxan Dosage in Monotherapy Protocols
References Provided in Table
Institution Sarah Cannon
Cancer Center
M. D. Anderson
Cancer Center
Walter Reed
Army Medical Ctr.
M. D. Anderson
Cancer Center
Lead Experts Hainsworth, J. Keating, M.
O'Brien, S.
Byrd, J. C. Thomas, D. A.
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
ASH abstract 
#1533, 2001
PMID 12721250 11226005 11304767 -
Type of Trial monotherapy;
maintenance 
monotherapy 
dose escalation
monotherapy 
dose escalation
frontline
monotherapy
Patients Previously treated Previously treated Previously treated Naïve, early stage
Dosage Week 1 375 mg/m
per week
375 mg/m
first week
475 mg/m2 first week 
(split, day 1 & day3)
375 mg/m2
Dosage Weeks 2-4 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
Cumulative Dose 1,500 mg/m2 7,125 mg/m2 3,850 mg/m2 3,000 mg/m2
Maintenance Repeat 
every six months
None None None
Premedications 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 (F). Fludarabine is the present day "gold standard" for CLL patients. It is one of three hematology drugs called purine analogues (and sometimes nucleoside analogues): the other two members of this triad are cladribine and pentostatin, more commonly used in other hematological malignancies. Yes, fludarabine is a standard chemotherapy drug for CLL, 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: 

Rituxan plus Chemotherapy Combinations;
Rituxan plus Fludarabine Therapy;
Fludarabine Monotherapy Is No Longer the Gold Standard;
RF Therapy: Not All Patients Have the Same Risks and Benefits;

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 listed above: Rituxan plus Fludarabine Therapy. This 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 in milligrams 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.

Ohio State RF Protocol
J. C. Byrd, Kanti Rai, et al., Blood, 1 January 2003.
Full-text article from Blood
Protocol Structure Agents Day 1 Day 2 Day 3 Day 4 Day 5 Total
Cycle 1
(month 1)
Rituxan (mg/m2) 375     375   750
Fludarabine (mg/m2) 25 25 25 25 25 125
               
Cycles 2-6
(28 days apart)
Rituxan (mg/m2) 375         375
Fludarabine (mg/m2) 25 25 25 25 25 125
               
Protocol Totals Rituxan (mg/m2)           2,625
Fludarabine (mg/m2)           750
               
Premedications allopurinol (mg) 300 Orally, first 14 days
acetaminophen (mg) 650 Orally, prior to each Rituxan infusion
diphenhydamine (mg) 50 IV, prior to each Rituxan infusion

Rituxan plus Fludarabine plus Cyclophosphamide:

This combination is rapidly becoming the one to beat. RFC (or FRC, or if you prefer, the third popular combination of the three letters, FCR. For some reason, the C never comes before the F!) combines the targeting capability of Rituxan with the cell kill capabilities of fludarabine and cyclophosphamide. (You will note that we are using the generic names for fludarabine and cyclophosphamide, which are not capitalized, while for Rituxan, we use the trade name rather than the generic name, rituximab. This is the general practice. You could, if you insist, use the trade names for the chemotherapy agents too, Fludara and Cytoxan, but for some reason that is rarely done.) 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 (polymerase chain reaction) 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 deep responses 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.

M. D. Anderson RFC Protocol
Michael J. Keating; Various sources.
Protocol Structure Agents Day 1 Day 2 Day 3 Day 4 Day 5 Total
Cycle 1
(month 1)
Rituxan (mg/m2) 375         375
Fludarabine (mg/m2) 25 25 25     75
Cyclophosphamide (mg/m2) 250 250 250     750
               
Cycles 2-6
(28 days apart)
Rituxan (mg/m2) 500         500
Fludarabine (mg/m2) 25 25 25     75
  Cyclophosphamide (mg/m2) 250 250 250     750
               
Protocol Totals Rituxan (mg/m2) 2,875
Fludarabine (mg/m2) 450
  Cyclophosphamide (mg/m2) 4,500
               
Additional Information: MDACC RFC Protocol
Michael J. Keating. Various Sources.
Characteristics Data
Number 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%
Nodulare Partial Response 17%
Partial Response 15%

Comparison with More Recent Protocols (June 2007)

FCR "Lite" and HuMax-CD20 + FC

You can see a comparison of the dosing scheme for the above FCR Classic protocol with those in more recent clinical trials in the announcement for Genmab's phase II chemoimmunotherapy clinical trial for HuMax-CD20: FCR Classic vs. FCR Lite vs. HuMaxFC.

 

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