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Should Patients with Advanced Follicular Lymphoma Receive Consolidation with Radioimmunotherapy after Initial Responses to Systemic Chemotherapy?

Carlson, Robert H.

doi: 10.1097/01.COT.0000343992.12383.3b
Report from ‘Great Debates & Updates in Hematology’ Conference

CHICAGO—There are two anti-CD20 radioimmunotherapy drugs currently approved for treatment of refractory non-Hodgkin's lymphoma: tositumomab/Iodine-131 tositumomab (Bexxar), and 90Y-ibritumomab tiuxetan (Zevalin). Should either of those be used as consolidation therapy in patients with advanced follicular lymphoma who have responded to initial systemic chemotherapy? That was the question discussed by two experts here at the “Great Debates and Updates in Hematology” conference, sponsored by the American School of Oncology.

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Recent clinical trials point to response and survival advantages in giving radioimmunotherapy following chemotherapy, noted Christopher R. Flowers, MD, MS, Director of the Lymphoma Program and Medical Director of the Oncology Data Center at Winship Cancer Institute of Emory University School of Medicine, who favored the use of radioimmunotherapy in this setting.

But, said Jonathan W. Friedberg, MD, Director of Hematological Malignancy Clinical Research at James P. Wilmot Cancer Center of the University of Rochester, with the prognosis for patients with follicular lymphoma greatly improving in recent years, clinicians should wait for definitive answers from larger trials before moving beyond standard therapy.

Both debaters were chosen for this question and assigned their positions by meeting co-chairs Hagop Kantarjian, MD, James O. Armitage, MD, and Robert Z. Orlowski, MD.

CHRISTOPHER R. FLOWERS, MD, MS, argued his point mainly by citing recent clinical trials in which radioimmunotherapy appeared to improve outcomes.

Figure. C

Figure. C

The first example was the Phase II Southwest Oncology Group (SWOG) S9911 study of 90 previously untreated patients with advanced-stage follicular lymphoma who received six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by tositumomab/I-131 tositumomab, reported by Oliver W. Press, MD, PhD, and colleagues in 2006 in the Journal of Clinical Oncology (24:4143-4149).

The progression-free survival rate in that study was 67% for patients who completed treatment with CHOP and tositumomab/I-131 tositumomab, compared with 44% in historical CHOP studies.

And overall survival at five years with CHOP plus RIT was 87 percent, compared with a CHOP historical overall-survival rate of 64 percent.

A trial of the other approved RIT drug, 90Y-ibritumomab tiuxetan, used it in front-line therapy—reported by Dianna Shipley, MD, at the 2005 ASCO Annual Meeting (Abstract 6577)—showing impressive survival rates, Dr. Flowers said. The 42 patients with untreated follicular lymphoma first received a short course of chemotherapy plus rituximab, and those who responded then received 90Y-ibritumomab tiuxetan.

There was a 28% complete response rate after chemotherapy and rituximab, which rose to 67% after the addition of the radiopharmaceutical.

The actuarial overall-survival rates were 98% at one year and 95% at two years, and actuarial progression-free survival was 98% at one year and 85% at two years.

The radioimmunotherapy trial receiving the most attention, Dr. Flowers said, used tositumomab/I-131 tositumomab as a single agent in front-line treatment of follicular lymphoma—reported by Mark S. Kaminski, MD, at ASCO's 2007 Annual Meeting—a study that accrued 76 patients.

The one-week course of front-line single-agent tositumomab/I-131 tositumomab regimen was associated with a complete response rate of 75% and a five-year progression-free survival rate of approximately 60%.

Dr. Flowers said another trial to watch is SWOG's Phase III S0016 trial of R-CHOP versus CHOP with tositumomab I-131/tositumomab for treatment of patients with newly diagnosed follicular lymphoma.

A SWOG spokesperson contacted after the meeting for this article said that the trial completed accrual in August with 564 patients registered, and that outcomes would be reported as the data mature.

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JONATHAN W. FRIEDBERG, MD, said his main contention is that it is premature to use radioimmunotherapy as consolidation for all patients based on the clinical trial data currently available, although there are, he added, selected patients in whom it could be considered.



A bold statement to make, considering that Dr. Friedberg is protocol chair for the ongoing SWOG-S0433 Phase II study testing iodine I 131/tositumomab and R-CHOP in patients with advanced diffuse large B-cell lymphoma—and also because the primary investigator of that study, Richard I. Fisher, MD, Director of the Wilmot Center and a strong proponent of radioimmunotherapy, was sitting right in front of Dr. Friedberg in the audience.

In fact, Dr. Friedberg's first words were to thank the meeting chairmen “for the invitation to argue against my boss here [Dr. Fisher]—fortunately we're not on the same plane going home.”

After that awkward moment Dr. Friedberg went to his task.

He noted that Dr. Flowers had cited completed radioimmunotherapy studies with favorable outcomes in patients with follicular lymphoma.

“The problem is, the historical controls used [in those studies] were less effective than our current standards,” Dr. Friedberg said. “Our current standards combining rituximab plus chemotherapy are so good that it's going to be very difficult to prove that radioimmunotherapy adds to that.”

He said that since many patients today have an excellent prognosis, the current standards have set a high bar for radioimmunotherapy to compete against. This is something to consider if a novel treatment has significant side effects in patients who would otherwise have a good prognosis anyway with standard treatment, he said.

Non-Hodgkin's lymphoma is sensitive to radiation and radioimmunotherapy can kill both bound and neighboring tumor cells, overcoming the problem of access in bulky or poorly vascularized tumors, he noted, adding that radioimmunotherapy regimens are very well tolerated, with treatment lasting only one week and with fewer side effects than after chemotherapy.

But potential toxicities include hematologic toxicities and infection, hypothyroidism due to the iodine-31 tositumomab, second malignancies, and decreased marrow reserve for subsequent treatments such as autologous stem cell transplant and chemotherapy.

Dr. Friedberg also mentioned the Phase III SWOG S0016 trial, as did Dr. Flowers, saying that the results will dictate the future of radioimmunotherapy in non-Hodgkin's lymphoma. “I'm optimistic that the trial may be positive, and that's why I put a lot of patients on that trial,” Dr. Friedberg said.

But he reiterated his main point, that “I think it's premature to move in that direction until we see the results.”

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Voting to Choose 1 of 4 Treatment Options

Before the debate, the audience was presented with the case of a 52-year-old physician with Stage IV follicular lymphoma, a hemoglobin of 10.5 gm/dl, and 15% bone marrow involvement. Serum LDH is normal, but she has nodal involvement above and below the diaphragm. She requests therapy with R-CHOP, and after four cycles she has done well with no serious adverse events. She achieves a clinical complete response, and her bone marrow is clear of disease on repeat biopsy.

Members of the audience were asked to choose one of four treatment options for this patient, assuming no financial restrictions (an important factor given treatment cost). The voting before and after both debaters spoke indicated a strong wait-and-see attitude about radioimmunotherapy:

  • No further therapy for now: Before the debate, 17% of the audience members agreed with this; afterwards, 8% did.
  • Two additional cycles of R-CHOP consolidation: Before, 8%; afterwards, 8%.
  • Maintenance rituximab for two years: Before, 61%; afterwards, 69%.
  • Radioimmunotherapy: Before, 14%; afterwards, 15%.
© 2009 Lippincott Williams & Wilkins, Inc.
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