Clinical Abstracts From Overseas: June 16, 2010

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â–º Germany

Drop the Syringe, Pick up the Tattooing Needle

According to a new report on methods of delivering DNA vaccinations, researchers from the Cancer Research Center of Heidelberg, Germany, assert that intramuscular injection is not the best way to go. They suggest a far more unconventional mode of vaccination.

Using a model DNA antigen vaccine, the coat protein from human papillomavirus (HPV), the researchers found that tattooing the vaccine into the skin of mice produced a far greater antibody response compared with standard intramuscular injections.

After three doses of tattooed vaccine, the antibody response was reported to be 16 times greater than the injected vaccine.

They also noted that the use of a molecular adjuvant to help initiate an immune response was helpful with the injected vaccine but did not alter response to the vaccine delivered by tattoo needle.

They believe that the solid vibrating tattoo needle produces bleeding, necrosis, and accompanying inflammation and does a better job of activating the immune system. They also believe that the tattoo administration covers a relatively large area of skin, permitting absorption of the DNA antigen into a greater number of cells.

However, there is no getting around the pain associated with tattooing. This may be the limiting factor in utilizing such a vaccine delivery system.

Pokorna D, Rubio I, Müller M: DNA-vaccination via tattooing induces stronger humoral and cellular immune responses than intramuscular delivery supported by molecular adjuvants.

2008;6:4. E-pub February 7, 2008.

Genetic Vaccines and Therapy

â–º Germany

Infertility Risk for Men With Hodgkin’s Lymphoma

The prognosis for patients with Hodgkin’s lymphoma has steadily improved as treatment has advanced. Clinicians treating these patients, who are typically younger than patients with many other types of cancers, are increasingly considering the longer-term effects of treatment and how they may affect patients later in life. The question of whether cytoxic chemotherapy may affect male fertility is an important consideration, and a group of researchers from Cologne, Germany, published a study recently in Blood to identify the risk involved.

Thirty-eight men (median age, 26 yr; all were younger than 60 yr) with advanced-stage Hodgkin’s disease were given combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (known as BEACOPP) and enrolled in the German Hodgkin Study Group. The majority of patients (84%) also received radiotherapy. Semen analysis was performed before and after starting therapy as well as at regular follow-up visits after therapy was completed.

After treatment, 34 of the 38 men had azoospermia and the remainder had dysspermia. Only four patients who had azoospermia after completing chemotherapy regained the ability to create viable sperm. Those who did regain fertility did so an average of 3.6 years after completing treatment.

Most of the patients had fertility abnormalities before starting therapy (likely linked to the Hodgkin’s lymphoma), so it is difficult to conclude just how the chemotherapy damages fertility, but the scientists pointed out that signs of germ-tissue epithelial damage may provide clues as to how lasting injury is incurred.

Sieniawski M, Reineke T, Nogova L, et al: Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: A report of the German Hodgkin Study Group (GHSG). Blood 2008;111:71-76.

â–º Israel

Putting Women Under the Spotlight: Higher Frequency of Breast Cancer?

An unusual study that linked cancer epidemiology and night-time satellite imagery of the Earth from NASA has lent support to a surprising oncology connection. It appears that women who live in areas with night-time light pollution are subject to higher frequencies of breast cancer than people who live in regions with darker night-time skies, according to an Israeli study from the University of Haifa.

Studies performed in laboratory rats had revealed a connection between light and cancer development; studies in women working in well-lit night-time conditions (such as night-shift employees) had indicated the link in humans. The World Health Organization announced late last year that it considered nightshift work to be a probable carcinogen.

Using highly detailed NASA satellite photographs of night-time illumination and geographic epidemiologic maps of breast and lung cancer incidence in Israeli neighborhoods, the researchers adjusted for a number of factors known to be associated with the risk of these two cancers. Although they found no link with lung cancer incidence, they did report a strong correlation between breast cancer and nighttime lighting, reporting that areas of average light had 37% increased breast cancer rates compared with areas having the least nighttime illumination. Areas with the greatest relative illumination had more than one-quarter greater risk than those of average lighting.

The theory behind this link is that the lighting provides stimulus to the brain to decrease the production of melatonin, a hormone that has been found to suppress tumor growth. The researchers stated that these findings may also have implications for the increased use of indoor fluorescent lighting over standard incandescent bulbs; the former seem to suppress melatonin production to a greater extent. However, the use of indoor lighting was not tested in this study.

Kloog I, Haim A, Stevens RG, et al: Light at night co-distributes with incident breast but not lung cancer in the female population of Israel.

2008;25:65-81.

Chronobiol Int

â–º Japan

Esophagectomy in Patients Older than Age 75

Although most cases of esophageal cancer occur in the elderly, the clinical benefits of esophagectomy are somewhat controversial. Do the risks outweigh the benefits? Researchers from the Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, conducted a retrospective analysis to better understand the clinical outcomes of patients for whom esophagectomy was the primary treatment for their tumors.

The scientists evaluated the clinical records of 1,000 patients with esophageal cancer who underwent esophagectomy from 1964 to 2006. The patients were categorized by age (age 75 was the threshold). Based on this demographic split, overall morbidity between the younger and older groups was similar (39% and 41%, respectively). However, using logistic regression analysis, the investigators found that both age and year of operation were correlated with pulmonary complication frequency. Patients at least 75 years of age had 75% greater odds of having pulmonary complications arising from the esophagectomy compared with younger patients, but this correlation was strongest in patients having the operation between 1964 and 1980, decreasing steadily with more recent operations.

Incidence of pulmonary complications decreases with time in elderly patients(> 75 yr) undergoing esophagectomy.

Operation Performed

Pulmonary Complication 30-Day Incidence

Mortality

1964 - 1980

50%

6.2%

1981 - 1993

25%

5.2%

1994 - 2006

11%

0%

They found that the frequency of all significant pulmonary complications decreased as the operations were performed into the 21st Century. Overall survival rates did not differ significantly between the two age groups, particularly for those with operations in the recent past.

The scientists concluded that esophagectomy was associated with more pulmonary complications in patients at least 75 years of age compared with younger patients; however, the frequency of complications has decreased and the overall prognosis for the two groups of patients has improved with better technique and experi- ence of the recent past. Therefore, they believe that esophagectomy should be considered effective treatment in appropriate elderly patients.

Morita M, Yoshida K, Ohgaki K, et al: Clinical significance of an esophagectomy in patients 75 years of age or older based on an analysis of 1,000 operative cases with esophageal cancer. Presented at the ASCO Gastrointestinal Cancers Symposium, January 25—27, 2008, Orlando, Florida.

â–º Multiple Sites in Asia

Combination Treatment With Cetuximab for Colorectal Cancer Refractory to Irinotecan

The successful use of a combination of cetuximab and irinotecan has been reported previously for patients with metastatic colorectal cancer. However, the use of this combination has not been heavily reported in patients with inadequate response to irinotecan-based regimens. A group of researchers from China, Taiwan, Australia, and other countries from the region conducted a nonblinded, single-arm phase II study of patients from Asia and Oceania to evaluate the safety and efficacy of cetuximab plus irinotecan in cases where irinotecan-based therapy was not effective. Preliminary results of this study, presented at a recent ASCO symposium on gastrointestinal cancer, indicate that this combination offers some promise in these patients.

The investigators sought primarily to measure disease progression after 12 weeks of therapy. Patients were included for study if they had metastatic colorectal cancer and experience disease progression within three months of starting an irinotecan-based regimen and if their tumors tested positive for epithelial growth factor receptor. One hundred twenty-three patients (73 men, 50 women; mean age, 56 yr; median Karnofsky performance status score, 90) were administered cetuximab 400 mg/m² in the first week of therapy followed by irinotecan 250 mg/m2/wk at the treatment schedule during which the patient’s tumor demonstrated disease progression. Nearly half of the patients had received at least two previous treatment regimens.

After 12 weeks, the patients’ progression-free survival rate was 50%. The patients’ experienced a median duration of response of 32 weeks. Fifty-two patients (42%) patients were still alive at the end of follow-up for this study. The investigators reported a median survival of 9.5 months.

They indicated that the most common grade 3 or 4 adverse events were diarrhea in 12%, neutropenia 9%, acne-like rash 8%, and vomiting 6%. Grade 3 or 4 infusion-related reactions were seen in only 3 (2%) patients. The researchers concluded that a combination of cetuximab and irinotecan can have favorable effects on disease progression and be well tolerated in those with refractory metastatic colorectal cancer.

Lim RS, Sun Y, Im SA, et al: Cetuximab in combination with irinotecan in the treatment of patients with metastatic colorectal carcinoma refractory to irinotecan: Preliminary data from the ELSIE study. Presented at the ASCO Gastrointestinal Cancers Symposium, January 25—27, 2008, Orlando, Florida.

â–º Italy

Clinical Benefit of Sorafenib in Patients With Advanced Hepatocellular Carcinoma and Hepatitis C

Subgroup Analysis of the SHARP Trial

Hepatitis C virus (HCV) is a key risk factor for hepatocellular carcinoma (HCC), and accounts for 50% to 70% of cases in Europe and North America.

Luigi Bolondi, MD, Professor and Chair of Internal Medicine, University of Bologna, Bologna, Italy, presented the results of a SHARP (Sorafenib HCC Assessment Randomized Protocol) study subanalysis evaluating the clinical benefit and safety profile of sorafenib (Nexavar) in patients with HCC and hepatitis C.

Primary endpoints of the subanalysis were overall survival (OS) and time to symptomatic progression (TTSP). Secondary endpoints were time to progression (TTP), disease control rate (DCR; complete or partial response, or stable disease confirmed >28 days from first determination), and safety.

Of 602enrollees, 178 (93 in the sorafenib group and 85 in the placebo group) were HCV-positive. Median OS was 14.0 and 7.9 months in the sorafenib and placebo groups, respectively. TTSP was similar in both arms. Median TTP was 7.59 months in the sorafenib group, compared with 2.76 months in the placebo group. DCR was greater in the sorafenib group compared with that in the placebo group (44% vs. 31%).

The most frequent grade 3—4 adverse events (AEs) were hand–foot skin reaction (12.9% and 0% in the sorafenib and placebo groups, respectively), diarrhea (10.8% and 2.4%, respectively), hyperbilirubinemia (9.7% and 2.4%, respectively), ascites (6.5% and 9.4%, respectively), and fatigue (6.5% and 8.2%, respectively). AEs resulted in a dose reduction in 32% of sorafenib-treated patients and 8% of those who received placebo.

Dr. Bolondi and his team of investigators concluded that the results in HCV-positive patients with HCC treated with sorafenib are consistent with results in the overall analysis, thereby confirming the benefit of sorafenib in this important subset of patients. The safety profile in the HCV subpopulation was also similar to that in the overall population, with mostly predictable and manageable Grade 1—2 events. According to the investigators, these findings support the efficacy and safety results reported in the SHARP trial in patients with HCC and demonstrate a consistent clinical benefit irrespective of HCV status.

Bolondi L, Venook AP: Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): Subgroup analysis of the SHARP trial. Presented at the 2008 Gastrointestinal Cancers Symposium, Orlando, Florida, January 2008.

â–º SwedenDietary Fiber: Does It Mitigate Breast Cancer Risk?

According to a Swedish study, dietary fiber intake does affect the risk of breast cancer— perhaps based on estrogen- and progesterone receptor status. Investigators from the Karolinska Institute of Stockholm evaluated the demographics, risk factors, and dietary fiber intake of nearly 52,000 postmenopausal women.

Participant’s fiber intake was self-reported, using a questionnaire that was applied in 1987 and 1997. Nearly 1,200 cases of breast cancer were recorded in this population, in which estrogen and progesterone receptor status was known.

Multivariate risk ratios for breast cancer with fiber intake

Variable

Relative Risk

All Fiber Types

0.85

ER+/PR+

0.85

Highest vs. Lowest Intake of Fruit-Based Fiber

All Fiber Types

0.66

ER+/PR+

0.62

Patients with cancer were then stratified according to multiple risk factors and total fiber intake. The researchers did not find a significant correlation between total fiber intake when all breast cancer types were considered, but a significant relationship existed for estrogen- and progesterone-positive receptor status and fiber type, specifically fruit-based fiber.

The investigators also revealed that the overall risk of breast cancer in ever-users of postmenopausal hormones was inversely related to the participants’ intake of cereal-based fiber (adjusted relative risk, 0.50). A risk correlation could not be detected in women who never used postmenopausal hormones.

They concluded that postmenopausal women seem to be able to lower their risk of breast cancer by increasing their dietary fiber intake.

Suzuki R, Rylander-Rudqvist T, Ye W, et al: Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status: A prospective cohort study among Swedish women.

2008;122:403-412.

Int J Cancer

â–º IndiaIndoor Air Pollution and Cancer Risk in Developing Countries

Economically active, developing countries are at high risk for increased pollution in many forms: air, water, and ground. One of the greatest contributors to indoor air pollution has been identified as the burning of wood and coal for energy. Three-quarters of India use some solid fuel for cooking, but little information has been provided on its contribution to cancer risk.

Scientists from the International Agency for Research on Cancer in Lyon, France, studied Indian patients with lung or throat cancer (1,861 cases) and compared them with Indian residents (718 controls) without cancer to determine the contribution of indoor air pollution from solid fuels to cancer risk. They found the people who always used coal as fuel had nearly four times (odds ratio, 3.76) the risk of lung cancer than people who never used coal. Residents who used coal for more than 50 years had a 3.47 higher risk of developing hypopharyngeal tumors and 3.65 higher odds of developing laryngeal tumors.

The use of wood as a fuel was associated with a 1.62 higher risk of hypopharyngeal cancer. Furthermore, increasing levels of smoke in the dwelling directly correlated with higher cancer rates.

Based on these findings, a novel cancer prevention initiative in India might involve active steps to reduce indoor air pollution related to solid-fuel use in the home.

Sapkota A, Gajalakshmi V, Jetly D, et al: Indoor air pollution from solid fuels and risk of hypopharyngeal/ laryngeal and lung cancers: A multicentric case−control study from India.

2008; Jan 30 [E-pub ahead of print].

Int J Epidemiol