Treatment Regimen Effective for Metastatic Testicular Cancer

Researchers from Indiana University and the Walther Cancer Institute have developed an effective treatment for metastatic or relapsed testicular cancer, using high-dose chemotherapy with carboplatin and etoposide, supplemented by peripheral-blood stem-cell rescue. Their retrospective review, published in the July 26 New England Journal of Medicine by Dr. Larry Einhorn and colleagues, includes 184 consecutive patients from 1996-2004 who did not respond to first-line treatment. (Most patients with metastatic testicular cancer respond to initial treatment.)

Positive results in disease-free survival were found in both patients with seminomas and in those with nonseminomas. After a median follow-up of 48 months, 116 of the patients remained in complete remission.

The favorable outcomes varied according to some significant prognostic factors, however. More patients who received second-line therapy were disease-free, compared with those who received later therapy (70 vs. 45 percent). Also responding better were patients whose tumors were sensitive to cisplatin (68 vs. 45 percent); those who had a better response to initial chemotherapy (73 vs. 55 percent); and those with a more favorable prognosis (80 vs. 55 percent).

The researchers developed a new algorithm to capture the relevant prognostic factors present before salvage treatment that are associated with long-term survival. Their model includes the International Germ Cell Cancer Collaborative Group stage status and, they explained, effectively stratifies patients into low-, intermediate-, and high-risk groups.

PET Can Predict Hodgkin Lymphoma Relapse

A positron emission tomography (PET) scan performed after two cycles of standard chemotherapy for Hodgkin lymphoma (HL) was able to predict, with 92-percent accuracy, which patients' cancer would progress during treatment or relapse immediately afterward, according to study results published online July 23 in the Journal of Clinical Oncology. Doctors can use this prognostic data to determine which high-risk patients might benefit from a switch to more intensive chemotherapy.

Investigators enrolled 260 patients into a prospective, single-arm clinical trial. All patients had advanced HL and were scheduled to receive six cycles of the chemotherapy drugs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Participants received a baseline PET scan and a second scan after the second cycle of chemotherapy.

At least two different experts scored the scans as PET-positive (showing residual cancer activity) or PET-negative, and those scored as positive were reviewed by a third expert. The investigators recorded progression-free survival and overall survival over a median follow-up period of 2 years and determined whether the second PET scan or a patient's International Prognostic Score (IPS) could better predict the risk of disease progression or relapse.

Fifty patients had positive PET scans after 2 cycles of treatment; 43 of these (86 percent) had disease progression during treatment or relapsed after treatment. Of the 210 patients with a negative PET scan after 2 cycles of treatment, only 10 (less than 5 percent) experienced disease progression or relapse. In a multivariate analysis, the IPS did not add any prognostic information.

"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."

Inactivated Gene May Indicate Aggressive Lung Cancer

Inactivation of a gene known to have a role in tumor suppression in some cancers may indicate an aggressive form of lung cancer, researchers from the Dana-Farber Cancer Institute reported online in Nature on August 5.

Using mouse models of the three subtypes of non-small-cell lung cancer (NSCLC), the researchers demonstrated that inactivation of the gene LKB1 in combination with mutations in the gene KRAS - which is commonly seen in NSCLC - led to increased differentiation of tumor cells and metastasis compared with mice in which LKB1 was unaffected. Additional studies in NSCLC cell lines found that LKB1 was often inactivated or mutated in all three NSCLC subtypes.

In the NSCLC mouse models, mutated forms of KRAS "cooperated" with two other genes commonly inactivated in lung cancer, p53 and Ink4a/Arf, to develop tumors and metastases. However, lead investigator Dr. Kwok-Kin Wong and colleagues explained, "the strongest cooperation was seen with homozygous (both gene copies) inactivation of Lkb1." Tumors with mutated KRAS and inactivated LKB1 took less time to develop, progressed into all three NSCLC subtypes, and were more likely to generate metastases.

Gene expression profiling of the mouse model tumor samples and tumor cell lines identified several genes whose expression levels were significantly affected by LKB1, including NEDD9 and CD24, and that influenced tumor initiation, differentiation, and progression. When the researchers used short hairpin RNAs to reduce NEDD9 levels in an NSCLC cell line in which LKB1 was inactivated, tumor cell migration and invasion were decreased by more than half.

"These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis," the authors concluded.

Guidelines Address Neurocognitive Problems in Childhood Cancer Survivors

More than a quarter-million children diagnosed with cancer are alive 5 years after treatment, but 50 to 60 percent of these survivors are at risk for neurocognitive impairment because of toxic treatments to the developing brain. A Children's Oncology Group (COG) task force recently issued long-term, risk-based, exposure-related guidelines to help caregivers identify these effects, and to guide intervention and advocacy for such children.

At highest risk are survivors of brain tumors and acute lymphoblastic leukemia, the most common childhood cancer. Impairments to thinking and reasoning probably stem from treatments that are standard for a number of childhood cancers - cranial radiation therapy, chemotherapy with drugs such as methotrexate and cytarabine, and corticosteroids such as prednisone and dexamethasone.

The problems can be subtle or dramatic, and often emerge as late effects years after treatment. Scientists believe they come primarily from the effect of therapies and surgery on brain functions that are still developing in children - such as attention and concentration, processing speed, visual perceptual skills, executive function, and memory.

The authors urge that these difficulties "be recognized and addressed in a timely and appropriate manner. Primary care practitioners who care for survivors should be aware of those at greatest risk, be able to recognize the school difficulties associated with these outcomes, and have an approach to screening, intervention and advocacy."

These recommendations emerged from the COG Long-Term Follow-Up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer. They are published in the August Archives of Pediatrics and Adolescent Medicine. The guidelines can be found also in the COG master document containing all long-term follow-up guidelines.