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?):
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.
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.
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.
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:
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.
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.
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.