Originally published as JCO Early Release 10.1200/JCO.2009.19.8655 on February 9 2009

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, P. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, P. Social Bookmarking                            What's this?

A Look in the Mirror

Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Prospective clinical trials can be difficult to conduct, starting with the basic first step of enrollment. Without the structure of a clinical trial, default off-protocol option(s) can be relatively straightforward in some diseases, such as the choice of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or a variant in diffuse large B-cell lymphoma (DLBCL).¹

Conversely, the report by Friedberg et al² in the current issue indicates that the options exercised in the United States in follicular lymphoma (FL) are so diverse as to seem chaotic. We should not be surprised. Published guidelines, such as those of the National Comprehensive Cancer Network,³ show that there is indeed no single standard of care. There are numerous effective options for patients with advanced stage FL, and none is the clear winner (ie, there is no curative option). Hence, a variety of options are selected. The unpleasant surprise is that motivated practitioners, both in community and academic settings, are content to treat FL patients off protocol, rather than seek out pertinent clinical trials that can generate answers about the relative benefits of these various treatment strategies. The problem is not unique to the United States: a report from Germany by Dreyling et al⁴ indicates that only 10% of German patients are enrolled on clinical trials, not much better than the 6% rate reported by Friedberg et al.

What are the issues? Is data collection a deterrent to clinical trial participation? The LymphoCare project shows that many physicians in private practice are motivated to collect information, and are willing to take a self-critical look at their own practice patterns.

To be sure, the LymphoCare project shows that some important and relevant data (eg, some of the components of the Follicular Lymphoma International Prognostic Index [FLIPI] prognostic model⁵) and even key information for basic Ann Arbor stage assignment, are not routinely collected. A disparity between academic and community physicians with respect to stage assignment is noted in the Friedberg et al ² report, which in part relates to a lower frequency of marrow sampling in the community as opposed to the academic setting. Even among academics, marrow sampling was omitted 36% of the time. Why? Perhaps partly because models such as FLIPI and the International Prognostic Index ⁶ lump together stages III and IV: if the stage assignment is already stage III, the importance of sampling the bone marrow is downplayed.

But opting out of performing a baseline bone marrow analysis is a bad idea, for many reasons. First, prognostic models come and go, and get refined. For instance, an eight-factor preliminary version of the FLIPI model included bone marrow involvement.⁷ A new prospective FL prognostic factor project also emphasizes the importance of marrow involvement,⁸ as well as the role of beta-2 microglobulin (B2M). B2M data were not reported in the Friedberg et al ² project, but B2M is another parameter that deserves to be considered as a standard baseline test. B2M is a simple, quantitative, and important predictor that was recognized in the univariate analyses in both the International Prognostic Index and FLIPI projects, and possibly would have been incorporated in the models if more patients' B2M data had been available.

A second reason to sample the bone marrow is that the nuance of stage III versus stage IV is important with respect to radiation therapy, which can sometimes be a valid option in stage III, but is seldom appropriate in stage IV situations. Third, the presence of bone marrow involvement and its extent is important if radioimmunotherapy (RIT) is a treatment consideration, since extensive marrow involvement would be a contraindication to this approach. This is not just an academic issue. There is encouraging recent literature about the effectiveness of incorporating RIT into first-line therapy programs for FL.^9,10

A questionably significant observation in the Friedberg et al² report is the different frequency of grade 3 disease at academic sites compared with community practice. There was no slide review in the LymphoCare project, so this perceived difference should probably be discounted. But the histopathology issue deserves comment, and the grade issue is a convenient starting point, since patients with follicular lymphoma, grade 3 (at least those with grade 3b),¹¹ should be treated aggressively. The clinician, the hematopathologist, and the surgeon have to work together to ensure that adequate biopsy material is obtained. The Friedberg et al article does not report whether their patients' FL diagnoses were based on fine needle aspirate, core biopsy, or excisional biopsy, and this in an important issue.¹² It is also important that the diagnostic biopsy come not necessarily from the most expedient or easy site to biopsy, but from a clinically pertinent site (eg, a growing or bulky site), or one with high metabolic activity if a PET scan is done.

One of the most startling findings of the Friedberg et al² report is the common choice of deferral of therapy for approximately 25% of patients with stage I/II disease. One of the cornerstones of the "watch and wait" argument is the incurability of advanced stage FL. Stage I/II FL is a conspicuous exception, since cure is possible in almost half of patients with stage I/II FL with involved field radiation therapy.¹³ Promising attempts have been made to improve the cure rate by the use of combined-modality therapy.¹⁴ Of course, deferral of therapy can be done, sometimes for years.¹⁵ But if progression occurs as disseminated disease, the opportunity to offer potentially curative therapy has been squandered. The National Comprehensive Cancer Network guidelines suggest that, in stage I/II FL, deferral be considered mainly when there are extenuating circumstances.

Concerning the general topic of deferral of therapy for patients with advanced stage FL, the Friedberg et al² report makes an interesting geographic observation. Practitioners in the northeastern United States are much more likely to elect to defer therapy than those in other regions. Another geographic observation is that German practice patterns differ from those in the United States with respect to the use of anthracyclines. Italian practitioners, as well, employ anthracyclines much more commonly for patients with FL.¹⁶ But, as mentioned previously, Europeans and Americans share a poor track record of recruitment of FL patients to clinical trials. Recently, it seems that we in the United States often look abroad for large-scale trial results that establish new practice patterns. For answers about FL, we need to look to ourselves.

Purists who look askance at a pharmaceutical company-sponsored project like LymphoCare need to reflect on the design of our available clinical trials. Are the trial designs too restrictive? Trials should not only address important questions, but also do it in a format that is inviting to participation. Perhaps a lesson can be learned from the design of a European RIT trial,¹⁰ in which enrollment occurred at the time of remission, rather than pretreatment.

The willingness of US practitioners to participate in a project like the LymphoCare study is surely a good sign about the motivation and curiosity of both the academic and community participants. The optimistic view is that we are poised to do more than look in the mirror at how we have done, which is basically what the observational LymphoCare project accomplishes. It is time to look to the future, by designing prospective therapeutic trials that enroll more than just a selected 6% of our patients. The Friedberg et al² report highlights what a wealth of information is out there. From the current prevailing therapeutic chaos in the FL world, we need to strive for some order.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Peter McLaughlin, Millennium Pharmaceuticals (C), Bayer HealthCare Pharmaceuticals (C), Genentech (C) Stock Ownership: None Honoraria: Peter McLaughlin, Bayer HealthCare Pharmaceuticals, Millennium Pharmaceuticals, Bayer Pharmaceuticals, Genentech Research Funding: Peter McLaughlin, Bayer HealthCare Pharmaceuticals, Bayer Pharmaceuticals, OSI Pharmaceuticals, Millennium Pharmaceuticals, Biogen Idec, Genentech Expert Testimony: None Other Remuneration: None

REFERENCES

1. Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23:4117–4126, 2005.[Abstract/Free Full Text]

2. Friedberg JW, Taylor MD, Cerhan JR, et al: Follicular lymphoma in the United States: First report of the National LymphoCare Study. J Clin Oncol 27:1202–1208, 2009.[Abstract/Free Full Text]

3. Zelenetz AD, Advani RH, Byrd JC, et al: Non-Hodgkin's lymphomas. Journal of the Natl Compr Canc Netw 6:356–421, 2008.

4. Dreyling M, Fetscher S, Kornek P, et al: Treatment of indolent non-Hodgkin's lymphoma in Germany: Results of a representative population-based survey. Blood 110:407a; 2007 (suppl) abstr 1353.

5. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258–1265, 2004.[Abstract/Free Full Text]

6. Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive non-Hodkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994, 1993.[Abstract/Free Full Text]

7. Solal-Celigny P: International prognostic index for follicular lymphomas. Proc Am Soc Clin Oncol 21:281a; 2002 (suppl) abstr 1121.

8. Federico M, Bellei M, Marcheselli L, et al: F2 prognostic index. Ann Oncol 19:101–102, 2008 (suppl 4) abstr 058.

9. Press OW, Unger JM, Braziel RM, et al: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24:4143–4149, 2006.[Abstract/Free Full Text]

10. Hagenbeek A, Bischof-Delaloye A, Radford JA, et al: ⁹⁰Y-Ibritumomab tiuxetan consolidation of first remission in advanced stage follicular non-Hodgkin's lymphoma: First results of the international randomized phase 3 first-line indolent trial in 414 patients. Blood 110:198a; 2007 (suppl) abstr 643.

11. Wahlin BE, Sander B, Christensson B, et al: Grading follicular lymphoma: No difference between 1,2 and 3a, but 3b is something else. Blood 110:768a; 2007 (suppl) abstr 2611.

12. Hehn ST, Grogan TM, Miller TP: Utility of fine-needle aspirations as a diagnostic technique in lymphoma. J Clin Oncol 22:3046–3052, 2004.[Abstract/Free Full Text]

13. Peterson PM, Gospodarowicz M, Tsang R, et al: Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone. Proc Am Soc Clin Oncol 22:561; 2004 (suppl) abstr 6521.

14. Seymour JF, Pro B, Fuller LM, et al: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 21:2115–2122, 2003.[Abstract/Free Full Text]

15. Soubeyran P, Eghbali H, Trojani M, et al: Is there any place for a wait-and-see policy in stage I₀ follicular lymphoma? A study of 43 consecutive patients in a single center. Ann Oncol 7:713–718, 1996.[Abstract/Free Full Text]

16. Rigacci L, Federico M, Martelli M, et al: The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: Retrospective study of the Intergrupo Italiano Linformi on 761 cases. Leuk Lymphoma 44:1911–1917, 2003.[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, P. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, P. Social Bookmarking                            What's this?