Topics Alert

Comparing Clinical Trials

Date: March 31, 2024

How many of you check out "Consumer Reports" and the like, before buying your new car? It makes sense to you check out the reviews and ratings before you pay hard earned cash, last thing you want is to be stuck with a lemon that looks sexy and has been hyped up in the TV ads, but does not deliver on the road or at the gas pump.

A new car is a big investment, but nothing compared to the investment you make when you are faced with therapy decisions. Your very life may hang in the balance. I thought I would bring to your attention the latest statistics on a some of the most popular chemotherapies and combination therapies.

The table below is abstracted from an article in the 2024 ASH Education book, from Dr. Keating's section of the article, titled "Do we have the tools to cure CLL?". It is available free of charge, all you have to do is click on the link below the table.

Do We Have the Tools to Cure CLL? by Michael J. Keating

I have highlighted the two present contenders for the top spot. The "FR" (fludarabine+ Rituxan, concurrent administration) combo from Ohio State, and the "FRC" (fludarabine + Rituxan + cyclophosphamide) combo from M. D. Anderson. As you can see, these two combo therapies are pretty much neck to neck in the statistics as reported in the seminal ASH paper. The Ohio State FR combo has slightly lower percent of CRs (Complete Responses), and the the Anderson FRC has slightly higher ORs (Overall Responses) as well.

I wish the choices are just this simple, straight comparison of apples with apples. Unfortunately, they are not, it falls more into the realm of apples versus kiwi fruit. The Ohio State "FR" protocol has been published as a detailed paper in Blood, the industry standard and leading peer reviewed journal of hematology. Patient profiles, selection criteria, details of the drug dosages, sequence of administration and other protocol details, blow by blow description of the toxicities, side effects, the whole ball of wax is reported in the FR article (PubMed abstract is given below, if you want to locate the full text article write to me and I will help you locate it). The statistics and the methodology of the FR clinical trial have been subject to the scrutiny of peer review. Even humble patients advocates like me can take a good look at the details, walk around and kick the tires as it were. You may agree or disagree with the statistical procedures, or the methodology (frankly, I think this is a very well conducted and thoroughly documented clinical trial), but at the very least the details are no secret, they are there for every one to see and judge.

Not so the FRC trial from Anderson. The table in the ASH article cites an impressive number of patients who have gone through this combo therapy, 202 of them as of the writing of the ASH article. Everything in Texas and Anderson is larger and bigger, even the clinical trial enrollments! I have no doubt the enrollment numbers have gone much higher than 202 by now. So, why is it that there is still no full length publication of this pivotal trial in a top rated and peer reviewed journal? All I have seen so far are meeting presentations and abstracts. Where are the details on patient profiles, selection criteria, detailed breakdown of toxicity and side effects, all the gory details? Were the patient profiles in the FR and the FRC trials comparable, patients in reasonably similar risk groups, same level of tumor load, age, Rai stage and so on? Were the toxicities and infections comparable in the two studies? How are we to judge and compare, without access to these details? I can understand that the protocol may get modified as researchers learn more, that is only right and proper. But how does that prevent the publication of the details of this very substantial effort up to this point? Hundreds of patient volunteers have participated in the the FRC clinical trial, surely the rest of us would like to know the details of how their efforts paid off?

Editorial

Information comes in many flavors. There is the stuff you hear at your barber shop or at the supermarket checkout. Then the "buzz" on the internet chat rooms, where several people chiming in with their anecdotal stories can create an atmosphere of excitement and consensus. Then there are the seminars and conferences, where researchers as well as drug industry folks can share new information. The ink is barely dry on some of the abstracts before the big pharmaceutical companies make their press releases, with an eye to the stock price. To my mind, none of these sources of information can claim to have done the full job of presenting scientifically impartial, detailed and, in the final analysis, useful and actionable information. Scientists and researchers form an honor society that has strict rules of conduct. One of the ways in which standards are enforced is by means of peer review of articles submitted for publication in top rated journals. Once in a rare while we hear of retractions, corrections of published articles. This is an indication of the self-policing and honor code of the research community working the way it is supposed to. But how do we get that oversight process going, if the papers are not submitted for publication, information 'leaks' out in slow dribbles of anecdotal information, meeting abstracts and press releases? Since all three drugs (fludarabine, cyclophosphamide and Rituxan) are commercial drugs, there cannot be "patent pending" and "business confidential" type of issues. Neither the research community nor the patient community is well served by these protracted delays in publishing full details of important clinical trials.

Be well,

Chaya
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Abstract

Blood. 2024 Jan 1;101(1):6-14. Epub 2024 Jul 05.

Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712).

Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA.

Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH.

Recent studies have suggested that rituximab has clinical activity and modulates antiapoptotic proteins associated with drug resistance in chronic lymphocytic leukemia (CLL). We performed a randomized phase 2 study to determine the efficacy, safety, and optimal administration schedule of rituximab with fludarabine in previously untreated CLL patients. Patients were randomized to receive either 6 monthly courses of fludarabine concurrently with rituximab followed 2 months later by 4 weekly doses of rituximab for consolidation therapy or sequential fludarabine alone followed 2 months later by rituximab consolidation therapy. A total of 104 patients were randomized to the concurrent (n = 51) and sequential (n = 53) regimens. During the induction portion of treatment, patients receiving the concurrent regimen experienced more grade 3 or 4 neutropenia (74% versus 41%) and grade 3 or 4 infusion-related toxicity (20% versus 0%) as compared with the sequential arm. The consolidation rituximab therapy was tolerated well in both arms. All other toxicities were similar in the 2 arms. The overall response rate with the concurrent regimen was 90% (47% complete response [CR], 43% partial response [PR]; 95% confidence interval [CI], 0.82-0.98) compared with 77% (28% CR, 49% PR; 95% CI, 0.66-0.99) with the sequential regimen. With a median follow-up time of 23 months, the median response duration and survival have not been reached for either regimen. Rituximab administered concurrently with fludarabine in previously untreated CLL patients demonstrates marked clinical efficacy and acceptable toxicity. Phase 3 studies using this combination approach for patients with CLL are warranted.

PMID: 12393429
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