ABSTRACT: In asymptomatic disease, overall survival is often the same with immediate treatment vs watch and wait. The deciding factor may be what patients are willing to tolerate.
New therapies for follicular lymphoma, including rituximab (Rituxan), have led to improved outcomes but have also fueled a controversy: Is it still appropriate to withhold treatment early in the course of disease?
Four experts debated the watch and wait approach at ECCO/ESMO 2009 in Berlin. But reading between their stated positions, it was clear all of the participants agreed that watchful waiting is appropriate for some low-risk patients. However, those who took the "con" position set the bar much higher to determine who qualifies as low risk.
The standard for asymptomatic patients
Despite what drug companies would have people believe, there is not always a sense of urgency when it comes to treatment, said Michele Ghielmini, MD, from the Oncology Institute of Southern Switzerland in Lugano. "Marketers would like to sell you these new drugs today, but follicular lymphoma remains an incurable disease, even when treated with the five most potent drugs available plus stem cell transplant and rituximab," he said. "You can watch and wait and then catch up later with chemotherapy and stem cell transplant."
Median survival after diagnosis of follicular lymphoma is 12 to 15 years. One argument for starting therapy immediately is that delaying therapy will lead to problems such as irreversible organ damage, resistant disease, transformation, and less robust response to delayed therapy.
But Dr. Ghielmini argued that these fears are unfounded. Organ damage is very rare in follicular lymphoma. The key is to take the "watch" part very literally, following patients closely and often. Regarding resistance and transformation, response rates are not influenced by tumor stage, he said, adding that in one study, the reported incidence of transformation in 600 patients was only 3% per year (J Clin Oncol 26:5165-5169, 2008).
"Side effects of therapy are not increased when you delay therapy," he said. "The majority of side effects, including alopecia, nausea, and infection, depend on the drug itself and are not influenced by disease stage."
Advantages of waiting include delaying acute and late adverse effects of therapy and delaying impaired fertility. Perhaps the most important point is that there is no survival difference in patients who are managed by watch and wait vs upfront treatment, according to three studies (Semin Hematol 25 (suppl 2):11-16, 1988; J Clin Oncol 15:1110-1117, 1997; Lancet 362:516-522, 2003).
"Thanks to rituximab, follicular lymphoma has an improved prognosis. Nevertheless, starting therapy immediately in asymptomatic patients anticipates toxicity without improved survival," Dr. Ghielmini said.
Criteria for management
Philippe Solal-Celigny, MD, from the Centre J. Bernard in Le Mans, France, also spoke in favor of watchful waiting. He agreed with Dr. Ghielmini that asymptomatic patients have to be carefully followed, including a visit to the hematology clinic every three months.
He explained that at his institution, "we take a moderate position. We believe that not all patients need to be treated initially. We use several criteria to decide which patients should be managed by watch and wait."
For stage I disease, excisional biopsy is curative and patients can be observed after surgery, Dr. Solal-Celigny said. The watch and wait strategy is appropriate for patients with stage I or II nonbulky disease (< 5 cm) in a site with a high risk of radiation treatment toxicity, such as the mediastinum or peritoneum. It is also appropriate for elderly patients with comorbidities, he added.