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6/3/2008

With a Tiny Bit of Cancer, Debate on How to Proceed
By LAURA BEIL
New York Times - June 3, 2008

In a cancer patient, lymph nodes are the closest thing to a crystal ball. Gaze into them after removing a tumor. The presence of malignant cells may be a sign that the cancer will recur, leading to more tests and intensive treatment.

As biopsies of the lymph nodes grow more sophisticated and sensitive, oncologists and patients face the unsettling question of what to do with a little bit of cancer. It has become a familiar debate, especially for breast cancer, with no clear answer in sight.

“We can pick up things that we could never pick up before,” said Dr. Minetta Liu, an oncologist at the Georgetown University Medical Center. “But do we need to pick them up?”

Without more data to guide them, doctors worry that some women may be given test results that are actually too good, leading to more medical attention than necessary.

Pathologists have long examined lymph nodes — small grapelike bunches that are part of the immune system — to gain the best sense of whether a tumor, once gone, will reassert itself. If renegade cells become caught in the nodes, the tumor could also be setting up outposts in distant parts of the body.

As recently as the 1990s, doctors took 24 or so nodes to the laboratory for testing, slicing each one and looking for glimpses of cancer. But the more nodes a patient loses, the greater the likelihood of long-term side effects.

In recent years, doctors have tended to focus far more narrowly, on so-called sentinel nodes, the one or two most connected to the internal plumbing of the tumor.

Sentinel node biopsy is growing more and more popular among breast cancer surgeons. The procedure was used in more than 50 percent of patients by 2005, up from about 10 percent in 1998.

Along the way, the field has grown more refined. In one new approach, part of the node is dropped into a high-tech blender, and its genetic material is sifted by computer for signs of cancer.

Now that pathologists have fewer nodes to consider, they have more time to section the tissue. It is as if, after years of skimming a book, doctors could peruse entire chapters. The problem is that the more carefully you read, the less you may know.

“When someone has a very small amount of tumor, what is their actual risk?” asked Dr. Hiram S. Cody III of the Memorial Sloan-Kettering Cancer Center in New York. A tiny bit of cancer could mean that a tumor is going to reignite. Or it could mean very little.

The presence of these so-called micrometastases, and other wisps of tumor too small to count as full-fledged metastases, has been documented in lymph nodes for decades. But only with the popularity of sentinel node testing has the question of micrometastasis entered everyday medical practice.

“Because they are looking at fewer nodes, they can look more carefully,” said Brenda K. Edwards, associate director for surveillance research at the National Cancer Institute.
Dr. Edwards and her colleagues recently found that diagnoses of breast cancer with micrometastatic lymph-node involvement began to increase markedly after 1997 and that it shows no signs of leveling off.

Nowhere are discussions of micrometastases more animated than with breast cancer, where 86 percent of sentinel node biopsies are performed. Scientists are trying to determine whether micrometastases have any effects on survival.

Research is divided, and all the studies have had built-in shortcomings. In The Journal of Clinical Oncology in April, Dr. Cody described a study that looked back at 368 patients from the 1970s. The researchers retrieved stored lymph nodes from the women, examined them for micrometastases and checked to see how the patients had fared.

He and his colleagues found that women with micrometastases did have a slightly worse survival rate than women without any cancer in the nodes. But there are important caveats. Through earlier detection, doctors are diagnosing smaller tumors that are presumably less advanced and less likely to be deadly. Also, none of the subjects received chemotherapy, which has become far more effective in the last 30 years. And the study looked at all nodes, not just the one or two in the sentinel position.

Newer data come from researchers at the John Wayne Cancer Institute in Santa Monica, Calif., home to some of the earliest studies on sentinel node biopsy. Unlike the women in Dr. Cody’s study, these 790 patients underwent chemotherapy and would have received diagnoses on a scale more aligned with modern mammography.

At the annual San Antonio Breast Cancer Symposium in December, researchers reported that women with just micrometastatic cancer in their lymph nodes survived as long, on average, as those with clear nodes.

The problem with that study is that those women and their doctors knew whether micrometastases had been found in their lymph nodes, and that probably influenced the course of treatment.

“We don’t have good answers at this point,” said Dr. Nora Hansen of the Feinberg School of Medicine at Northwestern University, who reported the results.

Other researchers from the John Wayne Institute recently examined breast cancer statistics from 1992 to 2003. They compared how the extent of cancer found in lymph nodes predicted survival.
Writing in December in The Annals of Surgical Oncology, the researchers reported that women with micrometastatic cancer in a sentinel node had a survival rate slightly poorer than women without cancer in the nodes, but better than women with greater node involvement.

Doctors predict that the best insight will come from two national studies involving thousands of participants in which neither the women nor their doctors know about the presence of micrometastases. But those studies are not expected to produce results for years.

So until the issue is settled, oncologists will have to navigate patients through complicated choices. One is whether a node that is positive for micrometastases warrants removing more nodes.

This is no small matter. Women who have been treated for breast cancer often report years of swelling and tightness in the arms just from lymph node removal.

The second dilemma is whether a little cancer is worth a lot of anxiety. Even knowing that its significance is unclear, cancer in a lymph node, no matter how minuscule, can be alarming.
“It’s a hard point for medical oncologists to walk away from,” said Dr. Thomas B. Julian of the Allegheny Cancer Center in Pittsburgh, a leader of one of the two trials that may provide better guidance. “In most centers across the United States, they will treat you for that positive node.”

Dr. Julian and others say that without better answers, micrometastases will continue to affect each doctor and patient differently. Some women, especially younger ones, may want more aggressive treatment, no matter what. Others may decide that the increased risk posed by a micrometastasis is too small and too uncertain to worry about.

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