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Clinical Abstracts from Overseas

OBTN, November 2007, Volume 1, Issue 9

Articles in this issue include: 1) Italy: Is the Knee Bone Connected to the Lung? 2) Turkey: Gabapentin Helps Opioid Treatment Alleviate Neuropathic Pain 3) China: Is a Blood Test for Early Diagnosis of Liver Cancer Within Reach? 4) Israel: Evidence Supports Finasteride's Utility, not Associated With Advanced Prostate Cancer 5) Spain: Prolonging Survival in Pediatric Patients With High-Grade Brainstem Gliomas 6) Netherlands: Long-Term Study Better Delineates Risks in Testicular Cancer Treatment 7) Sweden: Acupuncture Ineffective for Radiotherapy-Induced Nausea

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â–º ITALY

Is the Knee Bone Connected to the Lung?

A study from the Hospital of Prato, Italy, raises some interesting questions between two disorders not ordinarily considered linked. What does arthritis, which is focally limited to one joint, have to do with a lung cell? It may well predict it.

In this Italian study of 296 patients who experienced arthritis in one knee only over a six-year period, five patients (1.7%) had early stage non—small cell lung cancer. Though this may not seem remarkable, surgical resection of the early tumor seemed to alleviate the arthritic symptoms in each patient.

Each of the patients were middle-aged men, and each had a chronic history of heavy smoking. Drainage of the affected knee revealed nonerosive arthritis. The fluid collected was mildly articular in nature, without inflammatory features.

A median follow-up of 41 months has not revealed any neoplastic or arthritic recurrence. The investigators conclude that “knee monoarthritis may represent in some cases a paraneoplastic syndrome” that heralds non—small cell lung cancer. They suggest that when faced with a patient with arthritic symptoms in one knee who smokes heavily, evaluation for non–small cell lung cancer may turn up surprising results.

Cantini F, Niccoli L, Nannini C, et al: Isolated knee monoarthritis heralding respectable non small-cell lung cancer: A paraneoplastic syndrome not previously described

2007; Sep 3 (E-pub ahead of print).

. Ann Rheum Dis

â–º TURKEY

Gabapentin Helps Opioid Treatment Alleviate Neuropathic Pain

In patients with advanced cancer, neuropathic pain commonly requires multiple drugs, including opioids and narcotics, to improve patients’ quality of life. Sometimes, adjuvant analgesics added to the combination of pain medications provide improved pain relief.

Researchers from Istanbul University, Turkey, sought to compare the effectiveness and safety of gabapentin (Neurontin) combined with an opioid versus opioid monotherapy for the management of neuropathic cancer pain.

Using the World Health Organization analgesic ladder guidelines, these physicians treated 75 patients with advanced cancer who were receiving opioid therapy. The patients had reported receiving adequate alleviation of their nociceptive, but not neuropathic, pain. The 75 patients were assigned to receive either 1) gabapentin in addition to their present opioid monotherapy (in which the gabapentin only was titrated according to pain response) or 2) no gabapentin and only continuation of opioid therapy. Sixty-three patients completed the study, which evaluated treatment effects by the fourth and 13th day of treatment.

P

The researchers found that reduction of pain intensity at Day 4 and Day 13 were similar between the two groups. The opioid-only group had significantly greater mean pain intensity for burning and shooting pain (P = .0001) at both time points compared with the gabapentin group. Interestingly, the gabapentin group had a significant decrease in the rate of allodynia, but only at the day 4 data point ( = .002).

The side effects experienced in the gabapentin group were milder than those receiving opioids only, according to the researchers. On the basis of these results, they conclude that the use of gabapentin added to opioid therapy can offer improved neuropathic pain relief in relief of neuropathic pain in patients with cancer who receive opioid monotherapy alone. Larger investigations are needed to determine if this approach should be used as first-line management of pain in these patients.

Keskinbora K, Pekel AF, Aydinli I: Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: A randomized open trial. J Pain Symptom Manage 2007;34:183-189.

â–º CHINA

Is a Blood Test for Early Diagnosis of Liver Cancer Within Reach?

With the prevalence of hepatitis B virus increasing in Asia, researchers from the Chinese University of Hong Kong have uncovered a marker in the blood that could lead to a blood test that can help detect the presence of early-stage hepatic cancer.

Previous research had revealed that the RASSF1A gene, which is involved in tumor suppression, is turned offin tumor cells through a process referred to as “hypermethylization.” The investigators have designed a new, sensitive method of testing for the specific methylated DNA.

They matched 63 patient pairs (1 with primary hepatocellular cancer and 1 with hepatitis B virus). The new polymerase chain reaction test detected the hypermethylated RASSF1A gene in 93% of those with liver cancer, and 58% of those with chronic hepatitis B infection. The test was also given to healthy volunteers, none of whom tested positive for the altered gene.

In a separate investigation, the scientists evaluated 44 patients who were carriers of hepatitis B virus. Twenty two developed hepatic cancer over time, and their circulating levels of the altered RASSF1A gene increased from baseline to cancer diagnosis. The patients who did not develop hepatic cancer experienced no increase in RAAF1A gene levels.

The researchers conclude that such a blood test, which can result from refinement in the technology and the process they used, would be invaluable as a tool to identify hepatocellular cancer as early as possible in its progression. This could enable the best possible treatment outcomes.

Diminishing returns:Frequency of prostate cancer diagnosis by number ofSequential biopsies in study group.

Hypermethylated RASSF1A gene detected (Percent of Pts)

Liver Cancer

93%

Hepatitis C

58%

Chan KCA: Detection and prognostication of hepatocellular carcinoma by quantitative analysis of aberrantly methylated DNA in serum using a non-bisulfite-based method. Presented at the second annual International Conference on Molecular Diagnostics in Cancer Therapeutic Development. September 17, 2007, Atlanta, GA.

â–º ISRAEL

Evidence Supports Finasteride’s Utility, not Associated With Advanced Prostate Cancer

A previous multicentered, double-blind trial indicated that the use of finasteride reduces the incidence of prostate cancer by one-quarter over seven years but was associated with a 25% increase in the prevalence of high-grade prostate tumors, which dampened enthusiasm for the use of the agent as a preventive treatment. New research from Israel suggests that the latter finding was a result of observational bias, and that finasteride may indeed be a useful preventive agent.

Researchers from Jerusalem, who teamed with those from Merck and Company and University of Illinois, Chicago, found one of the major reasons for the perception that patients taking finasteride was associated with a greater risk of advanced prostate cancer cells was that finasteride also decreased prostate volume by 25% compared with the placebo group (25.1 mL vs. 33.5 mL, respectively). A logistic regression model confirmed that as prostate volume decreases, the likelihood of detection of high-grade cancer cells increased. Recalculation of the odds of finding high-grade prostate cancer revealed a drop from 1.27 in the original Prostate Cancer Prevention Trial odds ratio to 1.03, indicating a nonsignificant risk.

The researchers concluded that adjustments in the number of prostate cores biopsied per patient and the patient’s gland volume accounted for the differences in the prevalence of high-grade cancer in the finasteride and placebo groups.

Cohen YC, Liu KS, Heyden NL, et al: Detection bias due to the effect of finasteride on prostate volume: A modeling approach for analysis of the Prostate Cancer Prevention Trial

2007;99:1366-1374.

: J Natl Cancer Inst

â–º SPAIN

Prolonging Survival in Pediatric Patients With High-Grade Brainstem Gliomas

Brainstem gliomas are a difficult-to-treat category of tumors, partly because the variety of different types seem to have different etiologies. The life expectancy of patients with brainstem gliomas in short, with most dying within 15 months of diagnosis. Clinicians from Barcelona have studied a chemotherapy combination that has shown some promise in a Phase 2 study in patients with brainstem astrocytoma.

Using weekly therapy with irinotecan (Camptosar) 50 mg/m2 (then 65 mg/m2 for the last 2 cycles) and cisplatin (Platinol) 30 mg/m2 for four consecutive weeks (representing 1 cycle), six young patients were treated for four cycles. Four of the patients had pontine neoplasms (50% diffuse, 50% nondiffuse). The other patients had low-grade tumors in the midbrain. Patients with diffuse intrinsic tumors or high-grade tumors were also treated with bevacizumab (Avastin) 5—10 mg/kg biweekly and radiation therapy.

The clinicians noted “complete and rapid clinical responses” to the regimen, with better than 20% reduction in tumor size after completion of the regimen. Three of the patients’ gliomas had progressed and needed additional therapy, with a progression-free survival of nine months. However, all six patients survived after a median follow-up of 12 months.

Mora J: Successful treatment of childhood brainstem gliomas with cisplatin and irinotecan. Presented at the European Cancer Conference, Barcelona, Spain, September 23—27, 2007.

â–º NETHERLANDS

Long-Term Study Better Delineates Risks in Testicular Cancer Treatment

When faced with newly diagnosed solid tumors, oncologists have generally been focused on tumor response, tumor remission, progression-free survival of various lengths, and five-year remission rates. A study from The Netherlands took a much longer view: What was the outcome of therapy 20 years later in patients treated for testicular cancer?

The researchers followed 2,707 Dutch patients who were five-year survivors of testicular cancer for a mean 17.6 years. Specifically, they sought the incidence of second malignant neoplasms or cardiovascular disease in patients, and correlated the risk of these outcomes with the types of treatment the patients received.

The researchers revealed that the incidence of second malignant neoplasms overall was 70% higher than in the general population. The risk for second malignancies was 2.6- times higher if the patient had received subdiaphragmatic radiotherapy and 2.1-times higher after receiving chemotherapy (compared with patients who received surgery only). If the patient had undergone subdiaphragmatic radiotherapy, the risk of either a secondary malignant tumor or cardiovascular disease was 1.8 fold higher than surgery alone. If the patient had been given chemotherapy, the increased risk of either second malignancy or cardiovascular disease was 1.9-fold, compared with surgery only. This is similar to the increased long-term risk seen with smoking, noted the researchers.

Few chemotherapy or radiotherapy treatments have been exposed to this duration of follow-up; it is hoped that this type of information can better inform physician and patient decision making at the time of treatment.

van den Belt-Dusebout AW, de Wit R, Gietema JA, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5- year survivors of testicular cancer

2007;25:4370-4378.

. J Clin Oncol

â–º SWEDEN

Acupuncture Ineffective for Radiotherapy-Induced Nausea

Medical science is still grappling with the utility of complementary medicine. Acupuncture is thought to be a promising tool for modulating central nervous system function, but scientists from Linköping University Hospital and University, Linköping, and the Karolinska Institute, Stockholm, Sweden, have found that it does work better than placebo in one area: the treatment of radiotherapy-induced nausea in patients with cancer.

Two hundred thirty-seven patients who received radiotherapy in the abdominal or pelvic region were assigned in this randomized study to receive either active or sham acupuncture for 30 minutes, two to three times per week for the duration of the radiotherapy. The radiotherapy treatments lasted for a median of 5 weeks. Treatment focused on acupuncture point PC6.

Information about nausea symptoms were collected through a series of questionnaires and patient self-reported symptom diaries that were maintained for the duration of the radiotherapy and at least two weeks beyond it. Of the 237 patients, 215 had completed the study (110 receiving the study treatment and 105 receiving sham therapy).

The investigators found that 68% receiving the study treatment experienced nausea for a mean of 19 days compared with 61% of those in the placebo group who experienced nausea for 17 days. Vomiting occurred in 24% and 28% of the patients, respectively.

Does acupuncture alleviate radiotherapy-inducednausea and vomiting? *Patient would want to receive acupuncture if Radiotherapy was necessary in the future.

Incidence of:

Nausea Vomiting

Patient Satisfaction

Active acupuncture

68%

24%

66%

Sham acupuncture

61%

28%

77%

A subset of 58 patients were receiving chemotherapy along with radiotherapy during the study period. In this cohort, 82% of those in the active treatment group reported nausea over a mean of 19 days compared with 80% in the sham treatment group reported symptoms of nausea over 13 days.

Interestingly, the investigators stated, even though acupuncture was not more effective than placebo in alleviating nausea and vomiting in patients receiving radiotherapy, these patients indicated high satisfaction with the treatment and specified that they would be very interested in receiving it if radiotherapy was again required.

Enblom A: Invasive acupuncture for radiotherapy-induced nausea and vomiting is not more effective than placebo acupuncture. Presented at the European Cancer Conference Barcelona, Spain, September 23—27 2007.