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Key Words

Hodgkin lymphoma; positron emission tomography; PET; International Prognostic Score; IPS; chemotherapy; doxorubicin; bleomycin; vinblastine; dacarbazine. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary

A positron emission tomography (PET) scan taken after two cycles of standard chemotherapy in patients with advanced Hodgkin lymphoma was able to predict with 92-percent accuracy how effective a complete course of the chemotherapy would be. The PET scan was able to distinguish between patients who would achieve long-term control of their disease and patients whose disease would progress during treatment or immediately thereafter or would later relapse. This procedure can be used to identify Hodgkin lymphoma patients who might benefit from a switch to more-intensive chemotherapy.

Source

Journal of Clinical Oncology, published online July 23, 2007, and in print Aug. 20, 2007 (see the journal abstract ⁴).

Background

Hodgkin lymphoma (HL), a cancer of the immune system, is sensitive to treatment with modern chemotherapy drugs. Patients with advanced HL usually receive treatment with the drugs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which can provide long-term control of the disease for many people. More-intensive chemotherapy regimens can provide better control of HL, but also carry a greater risk of severe side effects and second cancers.

Researchers have been searching for a way to determine, before the end of treatment, which patients' cancers are most likely to be resistant to ABVD. For these patients, the benefits of switching to a more-intensive regimen would likely outweigh the risks.

In 1998, HL experts developed the International Prognostic Score (IPS) to help estimate a patient's risk of disease progression or relapse. The IPS is based on a patient's age, sex, stage of disease, levels of certain proteins in the blood, and number of healthy blood cells. However, almost half the patients predicted by the IPS to have the worst prognosis are able to achieve long-term disease control with just ABVD treatment.

More recently, several small studies have suggested that the results of a PET scan performed early during treatment can strongly predict the response of HL to ABVD chemotherapy.

The Study

The study began in 2001 as two separate clinical trials, one conducted by the Italian Intergruppo Linfomi and the other by the Danish Lymphoma Group, that were merged in 2006 to create a single study. The goal of the study was to determine whether PET could identify patients who are likely to be resistant to ABVD chemotherapy more accurately than the IPS.

All patients enrolled in the study had advanced HL. The participants received an initial PET scan before the start of treatment and were scheduled to receive six cycles of ABVD chemotherapy.

After the first two cycles of chemotherapy, the patients had a second PET scan. At least two doctors reviewed each individual scan, and two additional experts--one in each participating country--reviewed all the positive scans performed in their country. The scans were scored as PET-positive (showing the presence of active cancer cells) or as PET-negative.

The patients continued to receive the planned treatment unless the investigators observed clinical symptoms of cancer progression. All patients were followed for at least 6 months after the completion of treatment. The investigators measured progression-free survival (defined as the time from diagnosis to either cancer progression or relapse, or to death from any cause) and overall survival. They then determined whether the second PET scan or a patient's IPS better predicted the risk of disease progression or relapse.

The study's lead author was Andrea Gallamini, M.D. from the Hematology Department of the Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy.

Results

Between November 2001 and January 2002, 108 patients were enrolled in the Italian trial and 55 patients were enrolled in the Danish trial. After the trials were merged at the beginning of 2006, another 97 patients were enrolled, bringing the total to 260. Following the completion of chemotherapy, 104 of the patients also received radiation therapy.

After a median follow-up period of just over 2 years, 205 patients remained in complete remission, two patients were in partial remission, and 10 patients had relapsed. Forty-three patients had progressed during their treatment or immediately afterwards. Eight patients died from their cancer.

Fifty patients had positive PET scans after two cycles of chemotherapy; 43 of these (86 percent) had progressive disease or experienced a relapse. Among the 210 patients with a negative PET scan after two cycles of treatment, only 10 (less than 5 percent) had progressive disease or experienced a relapse. Among the eight patients who died from Hodgkin lymphoma, seven had a positive PET scan after two cycles of chemotherapy. Only 12.8 percent of patients with a positive PET scan were alive without progression of their disease 2 years after treatment, compared to 95 percent of patients with a negative scan.

When the predictive power of a PET scan after two cycles of chemotherapy and factors included in the IPS were examined in a statistical analysis, only the presence of stage IV disease (from the IPS) and a PET scan could significantly predict the risk of progression or relapse. In the study, results from the PET scan after the second cycle of chemotherapy were 92 percent accurate in predicting progression-free survival during the 2-year period following the completion of treatment.

Limitations

Currently, standards do not exist that specifically define what makes a PET scan 'PET positive' or 'PET negative', explained Eric Seifter, M.D., Associate Professor of Internal Medicine and Oncology at the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center. “This study worked because they had all their PET scans centrally reviewed…and they agreed on the criteria [for what made a PET scan positive or negative],” he said. “How do you know that you're replicating what they did when you're relying on someone who usually reads PET scans for other, more common cancers? People who do PET scanning obviously want to get this figured out and standardized so that everyone can do it in the same way.”

In addition, said Wyndham H. Wilson, M.D., Ph.D, head of the Lymphoma Therapeutics Section in NCI's Center for Cancer Research, “the investigators did not report what percentage of PET-positive and PET-negative patients received radiation therapy, and hence did not assess the role of radiation in progression-free survival. Furthermore, while the results of a negative PET look excellent, the relatively short follow-up period in this study precludes an accurate estimate of late relapses. Indeed, early aggressive intervention is more likely to benefit patients who have a late relapse (the PET negative group) than an early relapse (the PET positive group).”

Comments

Despite these limitations, said Dr. Seifter, “This study does show that, when properly read, the PET scan can really help define who is likely to relapse [early] and who isn't, better than any other test we have right now.”

“In conclusion,” stated the authors, “an early interim [PET] scan seems to be the most useful prognostic factor in advanced HL. This prognostic tool is a surrogate test for the chemosensitivity of the tumor, and it identifies two different categories of patients for which different therapeutic strategies are appropriate.”

Glossary Terms

The active ingredient in a drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. It comes from the bacterium Streptomyces verticillus. Bleomycin damages DNA and may kill rapidly growing cancer cells. It is a type of antineoplastic antibiotic.

Treatment with drugs that kill cancer cells.

A drug that is used to treat Hodgkin lymphoma and malignant melanoma and is being studied in the treatment of other types of cancer. It attaches to DNA in cells and may kill cancer cells. It is a type of alkylating agent. Also called DTIC-Dome.

A drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages DNA and may kill cancer cells. It is a type of anthracycline antitumor antibiotic. Also called Adriamycin PFS, Adriamycin RDF, doxorubicin hydrochloride, hydroxydaunorubicin, and Rubex.

Cancer that begins in cells of the immune system. There are two basic categories of lymphomas. One kind is Hodgkin lymphoma, which is marked by the presence of a type of cell called the Reed-Sternberg cell. The other category is non-Hodgkin lymphomas, which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin lymphomas can be further divided into cancers that have an indolent (slow-growing) course and those that have an aggressive (fast-growing) course. These subtypes behave and respond to treatment differently. Both Hodgkin and non-Hodgkin lymphomas can occur in children and adults, and prognosis and treatment depend on the stage and the type of cancer.

A procedure in which a small amount of radioactive glucose (sugar) is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the body where the glucose is used. Because cancer cells often use more glucose than normal cells, the pictures can be used to find cancer cells in the body. Also called positron emission tomography scan.

A procedure in which a small amount of radioactive glucose (sugar) is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the body where the glucose is used. Because cancer cells often use more glucose than normal cells, the pictures can be used to find cancer cells in the body. Also called PET scan.

The length of time during and after treatment in which a patient is living with a disease that does not get worse. Progression-free survival may be used in a clinical study or trial to help find out how well a new treatment works. Also called PFS.

The active ingredient in a drug used together with other drugs to treat several types of cancer, including advanced Hodgkin lymphoma and advanced testicular germinal-cell cancers. It is also being studied in the treatment of other types of cancer. Vinblastine comes from the periwinkle plant Vinca rosea Linn. It blocks cell growth by stopping cell division and may kill cancer cells. It is a type of vinca alkaloid and a type of antimitotic agent.