EditorialPublication Exclusive

Data-based medicine: When data and ‘opinion’ collide

As a hematology/oncology fellow, I was fortunate enough to have a remarkable medical oncologist, Ben Mead, FRCR, FRCP, as a mentor.

His approach to oncology was strongly evidence-based and grounded in the available literature, and he upheld a level of intellectual honesty in his clinical care and clinical research that is, frankly, quite uncommon in academic medicine.

I owe a great deal to Ben. He taught me the importance of critical thought in our approach to treating our patients and interpreting the literature. I have tried and frequently failed to live up to the standard that he set.

John Sweetenham, MD, PhD

John Sweetenham

There have, of course, been many times when published results have failed to confirm my own beliefs and prejudices. The natural reaction in this situation is to look for problems with the methodology or interpretation of the research, until the weight of evidence becomes unequivocal and one has to accept a new reality.

I reflected on this as data emerged from the ASTRO Annual Meeting in September. Like others, my email was flooded with reports from the meeting that highlighted new and potentially practice-changing findings.

Among these was a report of a retrospective study — based on data from the National Cancer Data Base (NCDB) — that concluded OS for patients with early-stage Hodgkin’s lymphoma was superior if they received a treatment regimen that included radiation therapy.

Although heralded by some websites and magazines as the first study to demonstrate this, a systematic review and meta-analysis from the Cochrane Collaboration, published in 2011, reached the same conclusion. The authors of the Cochrane study concluded that “adding radiotherapy to chemotherapy improves … overall survival in patients with early-stage [Hodgkin’s lymphoma].”

The authors of the study presented at ASTRO went slightly further and concluded that “combined-modality therapy (CMT) contributes significantly to the cure for early-stage Hodgkin’s disease and that radiotherapy should remain standard practice.”

Current controversy

In the interest of full disclosure, I am an advocate for avoiding radiation therapy in selected patients with early-stage Hodgkin’s lymphoma, so upon seeing the results of both of these studies, I am inclined to “trash” them based on their retrospective nature, the lack of detailed treatment information intrinsic to NCDB studies, and the misgivings that many of us have with meta-analyses (unless they happen to confirm our prejudices!).

Putting my own biases to one side, the results of this recent study add new data to an area that has become very polarized in recent years. Like most published studies, the devil is in the details, but there are some big-picture issues that have led to the current controversy in managing these patients.

Hodgkin’s lymphoma is a highly curable disease that typically affects individuals in their late teens, 20s and 30s. For early-stage disease, cure rates of 90% or more are now expected. Late toxicity of therapy is, therefore, a major concern in this population.

Historical studies of patients treated in the 1960s, 1970s and 1980s demonstrated an excess risk of late second malignancy and, for those patients who receive mediastinal radiation, cardiovascular disease. The second malignancies were partly related to chemotherapy — which was predominantly alkylator-based — and partly related to radiation therapy.

Consequently, chemotherapy and radiation strategies have evolved to minimize the risk for late toxicity but maintain excellent disease control rates. Alkylating agents largely have been excluded from Hodgkin’s lymphoma therapy.

Sequential randomized controlled trials from many organizations worldwide have demonstrated that, for most patients with early-stage Hodgkin’s lymphoma, CMT is the standard of care. Total doses of chemotherapy, and doses and fields of radiation therapy, have been reduced in sequential studies based on pre-treatment risk factors. Data from the German Hodgkin Lymphoma Study Group H10 study showed two cycles of ADVB chemotherapy — which consists of adriamycin, bleomycin, vinblastine and dacarbazine — followed by 20 Gy involved-field radiation therapy should be considered standard for many patients with good-risk, early-stage Hodgkin’s lymphoma.

Early data suggested that highly selected, favorable-risk patients with limited-stage Hodgkin’s lymphoma achieve excellent DFS and OS with chemotherapy alone, avoiding any potential — albeit diminished — risk from radiation therapy.

The advent of functional imaging, particularly FDG-PET scanning, has allowed early response assessment of patients with limited-stage Hodgkin’s lymphoma and may identify low-risk patients with whom radiation therapy can be safely omitted, with no effect on disease control compared with CMT. This is now the subject of prospective, randomized trials in several countries.

Advocates for the use of radiation in all patients point out, appropriately, that patients who relapse after a chemotherapy-only approach likely will require salvage therapy that includes stem cell transplantation, which is highly undesirable in this young patient population.

Data-driven decisions

If ever there was an example of a situation in which our approach to treatment should be guided by carefully conducted prospective trials rather than strongly held opinion, this is it. Treatment of limited-stage Hodgkin’s lymphoma is, in many respects, the most challenging clinical situation those of us in the lymphoma world face. The balance of risks for recurrence vs. risks for late toxicity or second-line treatment is complex and requires careful discussion with patients and — when possible — inclusion in prospective studies.

Unfortunately, systematic study of this issue has been clouded by strongly held opinion. One recent example is a publication on this subject in which the title describes the omission of radiation therapy as “misguided.” At best, it’s disheartening that the literature on such an important issue should include emotive language, even though, no doubt, it’s sincere on the part of the author and written with the noblest of intentions.

The author of the ASTRO abstract that prompted this editorial should be congratulated on a nice study that contributes important new data on this subject.

The message from the study needs to be clear: CMT remains the standard of care, but we owe it to this young group of patients to explore the potential of omitting a potentially toxic, damaging treatment modality whenever possible. Our efforts should be directed toward identifying the minority of good-risk patients who derive true benefit from radiation rather than treating 100% of patients, most of whom probably don’t need it. Prospective studies using functional imaging currently offer the most promise to do this.

The take-home message from this experience is partly related to Hodgkin’s lymphoma but, more importantly, relates to the need for all of us to keep our eye on the ball.

Strong opinions drive innovation in oncology and make the subject controversial, interesting and fun. Clinical decision-making needs to be driven by data whenever possible.

The above is an example in which there are now ample data to show the issue deserves careful evaluation in well-designed randomized trials rather than position statements. That’s definitely the way Ben would approach it.

References:

Engert A. N Engl J Med. 2010;363:640-652.

Herbst C. Cochrane Database Syst Rev. 2011;2:CD007110.

Meyer RM. N Engl J Med. 2012;366:399-408.

Parikh RR. Int J Radiat Oncol Biol Phys. 2014;doi:10.1016/j.ijrobp.2014.06.026.

Parikh RR. Abstract #1042. Presented at: ASTRO Annual Meeting; Sept. 14-17, 2014; San Francisco.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor, Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.

As a hematology/oncology fellow, I was fortunate enough to have a remarkable medical oncologist, Ben Mead, FRCR, FRCP, as a mentor.

His approach to oncology was strongly evidence-based and grounded in the available literature, and he upheld a level of intellectual honesty in his clinical care and clinical research that is, frankly, quite uncommon in academic medicine.

I owe a great deal to Ben. He taught me the importance of critical thought in our approach to treating our patients and interpreting the literature. I have tried and frequently failed to live up to the standard that he set.

John Sweetenham, MD, PhD

John Sweetenham

There have, of course, been many times when published results have failed to confirm my own beliefs and prejudices. The natural reaction in this situation is to look for problems with the methodology or interpretation of the research, until the weight of evidence becomes unequivocal and one has to accept a new reality.

I reflected on this as data emerged from the ASTRO Annual Meeting in September. Like others, my email was flooded with reports from the meeting that highlighted new and potentially practice-changing findings.

Among these was a report of a retrospective study — based on data from the National Cancer Data Base (NCDB) — that concluded OS for patients with early-stage Hodgkin’s lymphoma was superior if they received a treatment regimen that included radiation therapy.

Although heralded by some websites and magazines as the first study to demonstrate this, a systematic review and meta-analysis from the Cochrane Collaboration, published in 2011, reached the same conclusion. The authors of the Cochrane study concluded that “adding radiotherapy to chemotherapy improves … overall survival in patients with early-stage [Hodgkin’s lymphoma].”

The authors of the study presented at ASTRO went slightly further and concluded that “combined-modality therapy (CMT) contributes significantly to the cure for early-stage Hodgkin’s disease and that radiotherapy should remain standard practice.”

Current controversy

In the interest of full disclosure, I am an advocate for avoiding radiation therapy in selected patients with early-stage Hodgkin’s lymphoma, so upon seeing the results of both of these studies, I am inclined to “trash” them based on their retrospective nature, the lack of detailed treatment information intrinsic to NCDB studies, and the misgivings that many of us have with meta-analyses (unless they happen to confirm our prejudices!).

Putting my own biases to one side, the results of this recent study add new data to an area that has become very polarized in recent years. Like most published studies, the devil is in the details, but there are some big-picture issues that have led to the current controversy in managing these patients.

Hodgkin’s lymphoma is a highly curable disease that typically affects individuals in their late teens, 20s and 30s. For early-stage disease, cure rates of 90% or more are now expected. Late toxicity of therapy is, therefore, a major concern in this population.

Historical studies of patients treated in the 1960s, 1970s and 1980s demonstrated an excess risk of late second malignancy and, for those patients who receive mediastinal radiation, cardiovascular disease. The second malignancies were partly related to chemotherapy — which was predominantly alkylator-based — and partly related to radiation therapy.

Consequently, chemotherapy and radiation strategies have evolved to minimize the risk for late toxicity but maintain excellent disease control rates. Alkylating agents largely have been excluded from Hodgkin’s lymphoma therapy.

Sequential randomized controlled trials from many organizations worldwide have demonstrated that, for most patients with early-stage Hodgkin’s lymphoma, CMT is the standard of care. Total doses of chemotherapy, and doses and fields of radiation therapy, have been reduced in sequential studies based on pre-treatment risk factors. Data from the German Hodgkin Lymphoma Study Group H10 study showed two cycles of ADVB chemotherapy — which consists of adriamycin, bleomycin, vinblastine and dacarbazine — followed by 20 Gy involved-field radiation therapy should be considered standard for many patients with good-risk, early-stage Hodgkin’s lymphoma.

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Early data suggested that highly selected, favorable-risk patients with limited-stage Hodgkin’s lymphoma achieve excellent DFS and OS with chemotherapy alone, avoiding any potential — albeit diminished — risk from radiation therapy.

The advent of functional imaging, particularly FDG-PET scanning, has allowed early response assessment of patients with limited-stage Hodgkin’s lymphoma and may identify low-risk patients with whom radiation therapy can be safely omitted, with no effect on disease control compared with CMT. This is now the subject of prospective, randomized trials in several countries.

Advocates for the use of radiation in all patients point out, appropriately, that patients who relapse after a chemotherapy-only approach likely will require salvage therapy that includes stem cell transplantation, which is highly undesirable in this young patient population.

Data-driven decisions

If ever there was an example of a situation in which our approach to treatment should be guided by carefully conducted prospective trials rather than strongly held opinion, this is it. Treatment of limited-stage Hodgkin’s lymphoma is, in many respects, the most challenging clinical situation those of us in the lymphoma world face. The balance of risks for recurrence vs. risks for late toxicity or second-line treatment is complex and requires careful discussion with patients and — when possible — inclusion in prospective studies.

Unfortunately, systematic study of this issue has been clouded by strongly held opinion. One recent example is a publication on this subject in which the title describes the omission of radiation therapy as “misguided.” At best, it’s disheartening that the literature on such an important issue should include emotive language, even though, no doubt, it’s sincere on the part of the author and written with the noblest of intentions.

The author of the ASTRO abstract that prompted this editorial should be congratulated on a nice study that contributes important new data on this subject.

The message from the study needs to be clear: CMT remains the standard of care, but we owe it to this young group of patients to explore the potential of omitting a potentially toxic, damaging treatment modality whenever possible. Our efforts should be directed toward identifying the minority of good-risk patients who derive true benefit from radiation rather than treating 100% of patients, most of whom probably don’t need it. Prospective studies using functional imaging currently offer the most promise to do this.

The take-home message from this experience is partly related to Hodgkin’s lymphoma but, more importantly, relates to the need for all of us to keep our eye on the ball.

Strong opinions drive innovation in oncology and make the subject controversial, interesting and fun. Clinical decision-making needs to be driven by data whenever possible.

The above is an example in which there are now ample data to show the issue deserves careful evaluation in well-designed randomized trials rather than position statements. That’s definitely the way Ben would approach it.

References:

Engert A. N Engl J Med. 2010;363:640-652.

Herbst C. Cochrane Database Syst Rev. 2011;2:CD007110.

Meyer RM. N Engl J Med. 2012;366:399-408.

Parikh RR. Int J Radiat Oncol Biol Phys. 2014;doi:10.1016/j.ijrobp.2014.06.026.

Parikh RR. Abstract #1042. Presented at: ASTRO Annual Meeting; Sept. 14-17, 2014; San Francisco.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor, Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.