New Pediatric Hodgkin's Treatment - ABVE-PC

In what may be the year's most significant breakthrough in the treatment of pediatric Hodgkin's Lymphoma (HL), researchers have identified a new and less toxic chemotherapy regimen. But can it help older Hodgkin's patients?

Treatment of Hodgkin's Lymphoma (HL) could be seen as having grown a little too comfortable over the years as curative chemotherapy regimens (i.e. ABVD or MOPP) became standard.¹ This is after all cancer, and when a curative treatment modality is found, why mess with a good thing?

Yet in the cancer world every 'good thing' invariably has a dark side. Young HL patients, living longer thanks to these treatments, were also entering adulthood dealing with their toxic side effects—sterility, cardiopulmonary toxicity, secondary leukemia—hardly the kind of karma you would hope to be visited on childhood cancer survivors.

Thus researchers with the Children’s Oncology Group, led by Cindy Schwartz, MD of Hasbro Children’s Hospital, undertook a multi-year study involving over 200 patients under age 22 with either intermediate or high-risk HL. The aim was to identify a new regimen that would be as effective in curing the cancer as previous regimens, but much less toxic.²

The outcome is the ABVE-PC regimen which, when followed by low-dose radiation, produced some impressive results (a summary can be found at the Hasbro Children's Hospital website), what Dr Schwartz calls "a significant advance in the treatment of HL."

HL Regimens: A Compare-and-Contrast

The new ABVE-PC regimen brings together six chemo drugs—doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide—into a single 'dose-dense' regimen. Now, compare this to the drugs used in the most common HL regimens (all drugs in red are drugs also used in the ABVE-PC regimen):

The MOPP regimen:

mechlorethamine,vincristine, procarbazine and prednisone

The ABVD regimen:

doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine

The BEACOPP regimen:

bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine and prednisone

Clearly the drugs themselves in ABVE-PC are hardly new to the treatment of HL, but at least three aspects differentiate it from prior treatments.

I. The Absence of Procarbazine

The absence of procarbazine in ABVE-PC (found in MOPP and BEACOPP) means a great deal to young patients hoping to one day have kids. Procarbazine is a known fertility killer, rendering virtually all men sterile and most women infertile and in premature menopause over age 25, and it also carries the risk of secondary leukemia later in life.⁸

II. The Dose-Dense Model of Chemotherapy

You'll notice that ABVE-PC and ABVD share bleomycin and doxorubicin, drugs that can lead to cardiopulminary (heart and lung) toxicity.⁸

But herein lies a key to understanding how ABVE-PC works: It's dose-dense chemotherapy, which is defined as a chemo plan in which "drugs are given with less time between treatments than in a standard chemotherapy treatment plan."

A number of years ago, a mathematical model of the growth of tumor cells known as the Norton-Simon model predicted that the best way to kill a diverse population of cancer cells would be to go after the fast-reproducing cells first, and then go after the slower, more resistant ones.^5,6 Dose-dense chemotherapy was developed according to this model, and the intensive ABVE-PC regimen relies on it.

The researchers focused on achieving rapid early response (RER), meaning in this case that the efficacy of the chemo regimen was evaluated after just 9 weeks. According to Dr. Schwarz, "This early detection allows for a reduction in therapy for those who respond well to the dose-dense treatment, and therefore, individual response can be tailored for maximum efficacy."

III. Cumulative drug dosages

In an ABVE-PC regimen cycle, patients received higher doses of the chemotherapy drugs than they would have normally received in a cycle of the older regimens, and the time between cycles were shorter. However, the cumulative doses they received in ABVE-PC—across the full treatment spectrum—were:

• A) substantially lower than what they would receive in older, longer regimens, and
• B) below the recognized thresholds known for causing long-term toxicity.

For this reason, ABVE-PC can share the likes of bleomycin and doxorubicin with ABVD and benefit from their cancer-killing qualities, but avoid their negative long-term effects.

Consider that, of the 209 patients evaluated at study's end, 63% of them (132) needed just those 9 weeks of chemotherapy. Set that against 6 months or more of exposure in the ABVD regimen.

Applications beyond the pediatric population

The new regimen appears to serve the younger HL population well, but it summons an obvious question: If the regimen is effective and less toxic, is there any reason why older HL patients couldn't benefit from it? After all, when framed this way, no patient would refuse such a regimen.

I put the question to Dr. Schwartz, and in an email to me she said that because there is "very little if any biologic difference between adolescent HL and young adult (21-45) HL", she believes ABVE-PC "could easily be extended to the adult population." Whether it will or not remains to be seen.

She noted that the BEACOPP regimen, which has been used successfully to treat adult HL^3,4, is similar in dose-density to ABVE-PC but does expose patients to procarbazine.

I didn't ask Dr. Schwartz about much older HL patients (those over the age of 60). They make up a very small percentage of total HL patients (as few as 15%), making so-called Elderly Hodgkin's a fairly rare disease, one for which no standard treatment recommendations exist and for whom the prognosis, when set against the younger population, is typically not very good.⁷

Addendum

Lead author Cindy Schwarz MD is the director of pediatric hematology/oncology at Hasbro Children's Hospital, the pediatric center at Rhode Island Hospital. Dr. Schwartz is also a professor of pediatrics at Brown University's school of medicine.

The study was published in Blood, the weekly medical journal of the American Society of Hematology and among the most widely-cited medical journals in the field of hematology.

Resources:

• ^1. Ansell, S, Armitage, J, Management of Hodgkin Lymphoma. Mayo Clin Proc. 2006;81(3):419-426
• ^2. Schwartz et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate and high risk Hodgkin lymphoma: the results of P9425 from the Children's Oncology Group. Blood, Jul 2009; doi:10.1182/blood-2008-10-184143
• ^3. Diehl V, Sieber M, Ruffer U, et al, German Hodgkin's Lymphoma Study Group. BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin's disease. Ann Oncol. 1997;8:143-148.
• ^4. Diehl V, Franklin J, Pfreundschuh M, et al, German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease [published correction appears in N Engl J Med. 2005;353:744]. N Engl J Med. 2003;348:2386-2395.
• ^5. Norton, L., R. Simon, J. Brereton, A. Bogden. Predicting the course of Gompertzian growth. Nature 1976;264:542-5.
• ^6. Norton, L. A Gompertzian model of human breast cancer growth. Cancer Research. 1988;48:7067-71.
• ^7. Evens AM, Sweetenham JW, Horning SJ. Hodgkin lymphoma in older patients: an uncommon disease in need of study. Oncology, 2008 Nov 15;22(12):1369-79.
• ^8. Ko, Andrew et al. (2008). Everyone's Guide to Cancer Therapy, 5th Edition. Kansas City: Andrews McMeel Publishing.