Bench to Bedside: Surgery Without a Knife

This image shows a patient with pancreatic cancer that has spread locally and cannot be removed because it engulfs a critical blood vessel. This scan was taken before the patient began treatment in the original clinical trial that studied gemcitabine plus radiation. The patient is lying down—note how concave the abdomen is (top of the image), indicating the patient has lost weight due to the pancreatic cancer.

This image shows the same patient after completing the clinical trial. Compare the size of the tumor (circled) with the first image. It is smaller and no longer engulfs the blood vessel as a result of treatment with gemcitabine plus focused radiation. Note, too, the rounded abdomen, indicating the patient has tolerated the combination of radiation and chemotherapy well, eating more and gaining 10 pounds. While this, the original study, was taking place, the Lawrence team was already working in the lab to prove their theory that gemcitabine plus a second chemotherapy agent produces even better results when combined with radiation therapy. This sequencing of laboratory research and clinical trials has resulted in three clinical trials in about seven years, consistently advancing our understanding of pancreatic cancer treatment, patient comfort and longevity.

The Concept
Historically, few patients with pancreatic cancer live more than 10 months following diagnosis. Ted Lawrence, M.D., Ph.D., and his research team are changing that dismal outlook one month at a time through a marriage of technology research and biology research. Lawrence, the Isadore Lampe Professor and chair of Radiation Oncology, and his team have harnessed the sophisticated power of radiation therapy with radiationsensitizing chemotherapy drugs to extend the lives of patients with pancreatic cancer that has spread to nearby lymph nodes.

In 1995, Lawrence and colleague Donna S. Shewach, Ph.D., professor of pharmacology, found that the chemotherapy drug gemcitabine makes cancerous cells more sensitive to radiation. That led Lawrence to question how these two treatments could be better used together to improve patients’ outcomes. He started by focusing the radiation and adding full chemotherapeutic doses of gemcitabine. The new therapy would increase the amount of chemotherapy traveling through the body compared to previous approaches using radiation while decreasing the radiation exposure to normal, healthy tissue. In effect, this strategy would treat patients through chemotherapy and use radiation like surgery without a knife.

Proof of Concept
After testing this concept in the lab, the team brought it into a clinical trial, publishing their initial clinical results in 2001. The team found that this new approach increased survival in patients to close to a year—a significant step forward for a disease that has seen little success. In addition, patients saw improved quality of life with the new therapy, noting less nausea and weight loss and better pain management.

Treatment Today
In recent studies, the Lawrence team has built on the original research in two different ways. First, other drugs have been combined with gemcitabine to boost the effects of chemotherapy. Second, each of the three to four radiation beams used in standard treatment are now replaced by about 100 “beamlets,” each with the ability to pack its own punch (called “intensity modulated” radiation). Radiation at U-M, already customdesigned to match the area needing treatment, is now even more precise. Each beamlet carries a different dose of radiation treatment so that the radiation wraps around the tumor while sparing the neighboring tissues with almost unimaginable precision.

Treatment Tomorrow
Can other cancer centers adopt these findings? Yes, if investigators are willing to invest the time in careful radiation planning and to assemble a skilled and collaborative team of surgeons, medical oncologists, radiation oncologists, radiologists and pathologists. Lawrence does hope these findings will be subjected to a randomized trial, although the treatment can definitely be exported to the rest of the world now.

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