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Clinical Abstracts from Overseas: September 2007

OBTN, September 2007, Volume 1, Issue 7

Articles in this issue include: 1) England: GAMEC for Untreated or Relapsed Refractory Germ-Cell Tumors Preventing Oxaliplatin-Induced Peripheral Neuropathy 2) Australia: Immunodeficiency May Be Linked to Multiple Cancer Types 3) Sweden: Long-Term Steroid Use in Rheumatoid Arthritis Has One Benefit, at Least 4) Netherlands: Increasing Survival of Infants With Acute Lymphoblastic Leukemia 5) Israel: Breast Cancer Survival Rates No Worse for Women with BRCA Mutations 6) France: Rituximab Added to CHOP Chemotherapy in Poor-Risk Older Patients with Untreated Diffuse Large B-Cell Lymphoma Results in Good Survival

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â–º ENGLAND

GAMEC for Untreated or Relapsed Refractory Germ-Cell Tumors

The treatment of refractory germ-cell tumors continues to be a challenge to the oncology community, but researchers from St. Bartholomew’s Hospital in London have tested a new approach to combination chemotherapy that appears promising.

Utilizing high-dose methotrexate, actinomycin-D, and etoposide every 14 days, as part of an intensive cisplatin regimen (overall, referred to as GAMEC therapy), these oncologists found that of 27 patients who had been untreated and had a poor prognosis, 20 patients (74%) were progression free after GAMEC and surgery. Of 35 patients who had experienced progression with use of platinum-based chemotherapy, 18 (51%) were progression free after GAMEC and surgery.

However, this approach was found to be toxic: All of the patients receiving GAMEC had at least one episode of febrile neutropenia, and five deaths (8%) were directly attributable to the chemotherapy combination.

The authors concluded that this small study of GAMEC and appropriate surgery resulted in encouraging results in patients with refractory germ-cell tumors and a poor prognosis. However, this intensive regimen is highly toxic and work must be done to determine if risk can be reduced through appropriate patient selection.

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

Shamash J, Powles T, Ansell W, et al: GAMEC: A new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumors. Br J Cancer

Preventing Oxaliplatin-Induced Peripheral Neuropathy

Oxaliplatin-containing medical regimens are commonly used to treat patients with advanced colon cancer, and nerve toxicity, specifically peripheral neuropathy, is a frequent side effect.

The oxaliplatin’s toxicity seems to be related to altered voltage-gated sodium channels inside neurons. British neurologists theorized that a structural analogue to the anticonvulsant carbamazine might be able to inhibit activity of these sodium channels, but with fewer side effects than the parent compound.

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They conducted a controlled study of 32 patients with advanced colorectal cancer, randomized the group to receive oxcarbamazine 600 mg bid or not (but a placebo was not given in its place) as part of their medical regimen. The researchers found 31% of patients receiving oxcarbamazine developed chronic peripheral neuropathy compared with 75% of those not receiving the agent ( = .03). Differences in their total neuropathy scores were significant as well ( = .02).

Mean Total Neuropathy Scores in Patients Receiving Oxcarbamazine as Part of Their Chemotherapy Regimen Mean Total Neuropathy Score

Oxcarbamazine Group

4.1 ± 6.5

No Oxcarbamazine

11.2 ± 9.0

Argyriou A: Efficacy of oxcarbazepine against chronic oxaliplatin-induced peripheral neuropathy: A randomized controlled trial. Presented at the 2007 annual meeting of the European Neurological Society, June 19, 2007, Rhodes, Greece.

â–º AUSTRALIA

Immunodeficiency May Be Linked to Multiple Cancer Types

The Lancet

According to a paper in , patients who have undergone kidney transplants or who have HIV/AIDS have a far higher risk of 20 different cancers compared with the general population.

Researchers from the University of New South Wales, Australia conducted a meta-analysis that incorporated seven studies of people with HIV/AIDS (N = 444,172) and five studies of kidney-transplant recipients (N = 31,977). They found an alarmingly high risk of cancer caused by infection, and could not identify any similarities in these patients other than the fact that they are markedly immune-compromised either through the disease itself or through medications to prevent rejection.

Those with HIV/AIDS were found to be at 11-fold greater risk than the general population for Hodgkin’s lymphoma. Patients undergoing kidney transplant were found to have a fourfold increased risk.

It has been well documented that patients with HIV/AIDS are at very high risk for Kaposi’s sarcoma (> 3,500 times the risk seen in the overall population). However, the investigators found that patients undergoing kidney transplant were also at significant risk (> 200 times that of the reference population). The researchers revealed that this pattern of risk extended to 20 different types of cancers, all of which are associated with viral infection (e.g., Epstein—Barr virus in Hodgkin’s lymphoma; human papilloma virus in cervical cancer, penile cancer, and oral cancer; hepatic cancer, hepatitis B or C viruses). The incidence of most common epithelial cancers was not increased in these patient groups.

It is not known whether the higher risks for cancers extend to other patients, and the authors of this paper believe that studies of patients with other organ transplants and those with genetic immune deficient conditions should be undertaken.

Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM: Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet 2007;370(9581):59-67.

â–º SWEDEN

Long-Term Steroid Use in Rheumatoid Arthritis Has One Benefit, at Least

Physicians are careful not to continue therapy with chronic steroids for patients with rheumatoid arthritis owing to the side effects of the medications. Corticosteroids are linked to bone loss, immunodeficiency, and other negative effects. However, physicians from Uppsala University Hospital, Sweden, found at least one possible benefit—they mitigate the risk of lymphoma in patients with severe symptoms.

In a presentation at the European Congress of Rheumatology in Barcelona in June, the investigators demonstrated that, if given for more than two years, corticosteroid treatment provided protection from rheumatoid arthritis— associated lymphoma. These 378 patients had only a 40% relative risk of lymphoma compared with 378 patients with rheumatoid arthritis who did not receive steroid therapy. This protective effect was not seen if patients had fewer than two years of steroid treatment. The researchers found that large B-cell lymphoma were most affected by steroid use.

The research also showed that the protective effect was not dependent on the stage of rheumatoid arthritis or when the steroid therapy was initiated. Even if therapy was begun five years after diagnosis of rheumatoid arthritis, the relative risk of lymphoma remained at 60% that of controls.

Baecklund E: The risk of lymphoma in rheumatoid arthritis decreased by long-term steroid use. Presented at the annual meeting of the European Congress of Rheumatology, June 13-16, 2007, Barcelona, Spain.

â–º NETHERLANDS

Increasing Survival of Infants With Acute Lymphoblastic Leukemia

Although chemotherapy has increased cure rates in older children with acute lymphoblastic leukemia (ALL) around 80%, the survival of children younger than one year has been less promising. Physicians from Rotterdam, The Netherlands, studied the use of a new hybrid treatment protocol, which they believe offers far better hope for these youngest patients.

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This multinational trial comprised 482 infants younger than one year. Patients were first administered prednisone pretreatment (part of standard ALL regimens). The hybrid regimen included low-dose and high-dose cytarabine, given sequentially, which has been shown to exert strong effects on infant lymphoblastics . Other components of therapy are part of the treatment of acute myeloid leukemia.

The study resulted in complete remission in 58% at three years; four-year follow-up revealed an event-free survival rate of 47%. Importantly, even infants who responded poorly to prednisone pretreatment demonstrated higher event-free survival than in previous studies of conventional treatment. Toxicity was similar to that of conventional regimens.

The authors believe that this hybrid treatment protocol will eventually replace standard therapy.

Pieters R, Schrappe M, De Lorenzo P, et al: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): An observational study and a multicentre randomised trial

2007;370:240-250.

. Lancet

ISRAEL

â–º

Breast Cancer Survival Rates No Worse for Women with BRCA Mutations

Is the risk of dying from breast cancer worse for patients who have a BRCA mutation compared with women who do not have the mutations? A study performed in Israel revealed that the answer is no.

It had been thought that the existence of BRCA mutations may imply resistance to hormone therapy for breast cancer, and that this may be associated with a poorer prognosis compared with women who do not have the mutations. The researchers evaluated the 10-year survival of 1,545 Israeli women who were diagnosed with invasive breast cancer in the 1980s, as part of a national registry project. This enabled them to evaluate survival without regard to mutation-specific treatment, because the BRCA mutations had not yet been discovered at that time.

They found that 33% of non-carriers, 33% of BRCA1 carriers and 44% of BRCA2 carriers had not survived. The use of chemotherapy positively influenced overall survival rates of patients with BRCA1 mutations, compared with noncarriers. Interestingly, the BRCA2 patients and patients without any BRCA mutations had similar survival rates, regardless of whether chemotherapy was used. The authors believe that chemotherapy may be especially benefi-cial to women with a BRCA1 mutation, regardless of age or tumor size.

Rennert G, Bisland-Naggan S, Barnett-Griness O, et al: Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations

2007;357:115-123.

. N Engl J Med

â–º FRANCE

Rituximab Added to CHOP Chemotherapy in Poor-Risk Older Patients with Untreated Diffuse Large B-Cell Lymphoma Results in Good Survival

Roughly half of patients newly diagnosed with lymphoma are >60 years of age, and many are >80 years of age. Older patients treated for lymphoma may not tolerate the high-dose therapies used in younger patients, often because of the presence of concomitant diseases. Diffuse large B-cell lymphoma represents >60% of all lymphomas seen in older patients. Response rate is usually lower in elderly patients than in younger patients, even when treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Recently, rituximab added to CHOP (R-CHOP) has been shown to dramatically improve the survival of older patients without increasing toxicity.

Dr. Bertrand Coiffier, Hematology Department, Hospices Civils de Lyon and Claude Bernard University, Pierre-Benite, France, presented 7-year follow-up results of the GELA (Groupe d’Etude des Lymphomes de l’Adulte) study at this year’s American Society of Clinical Oncology annual meeting in Chicago, Illinois Enrolled patients (n=399) had untreated diffuse large B-cell lymphoma and were 60 to 80 years old (median age at diagnosis, 69 years). Sixty percent of enrollees had poor-risk lymphoma as defined by an age-adjusted International Prognostic Index (aaIPI) risk score of 2 or 3. Patients were randomized to receive either CHOP (n=197) or R-CHOP (n=202).

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At a median follow-up of 7 years, eventfree survival in the R-CHOP and CHOP groups was 42% and 25%, respectively ( < 0.001). Progression-free survival was 52% and 29%, respectively ( < 0.001). Disease-free survival was 66% and 42%, respectively ( = 0.001). Sixty-five percent of patients in the CHOP arm died, compared with 47% in R-CHOP arm.

Patients treated with R-CHOP experienced good survival even with poor risk parameters. Among patients aged >75 years, 43% are alive at 7 years; among those with Stage IV disease, 47% are alive; among those with a high lactate dehydrogenase level, 54% are alive; among those with a serum hemoglobin concentration <10 g/dL, 54% are alive; and among those with a high aaIPI score, 42% are alive.

Dr. Coiffier concluded that this analysis confirms the long-term benefit associated with the combination of rituximab and CHOP, and shows that older patients must be treated as younger patients even in presence of high-risk characteristics. He stated, “The benefit of the addition of rituximab to the CHOP regimen persists with time, even in elderly patients. R-CHOP is the gold-standard regimen. Older patients should be treated for cure.”

Presented at American Society of Clinical Oncology, June, 2007. Abstract #8009, Oral Presentation.

â–º

GERMANY

New Protection Against Oncogenic Human Papillomavirus Infections

Cervarix—GlaxoSmithKline’s AS04 adjuvant-adsorbed human papillomavirus (HPV) vaccine— is designed to prevent infection from HPV types 16 and 18, which cause about 70% of HPV-related cervical cancer cases. In addition, substantial protection against virus strains 45 and 31 have been demonstrated in clinical trials.

Cervarix is created using the L1 protein of the viral capsid. Recombinant activity in a baculovirus vector produces L1 protein spheres, which are very immunogenic. The viral proteins induce the formation of neutralizing antibodies. AS04 is a proprietary adjuvant that has been found to boost the immune-system response. The vaccine contains no live virus and no DNA; hence, it cannot infect the patient.

At this year’s American Society of Clinical Oncology annual meeting in Chicago, Illinois, Dr. Tino F. Schwarz, Stifung Hospital, Wuerzburg, Germany, presented an interim analysis of the results of an extension study of a multinational Phase III trial performed to evaluate the efficacy and safety of the Cervarix vaccine in women up to the age of 55 years. Dr. Schwarz was the principal investigator of the study.

In the 12-month primary study, the Cervarix vaccine was highly immunogenic and well tolerated in women 15 to 55 years of age (n=666). The extension study is evaluating the persistence of immune response and safety. Healthy women aged 15—55 years who had received three doses of the Cervarix vaccine at Months 0, 1, and 6 in the primary study were invited to participate in the extension trial. A total of 517 women were enrolled in the extension trial (169 aged 15–25 years, 83 aged 26–35 years, 89 aged 36–45 years, and 176 aged 46–55 years). Data through 18 months after the first vaccine dose are included in the interim analysis.

At 18 months, 100% of enrollees in all age groups remained seropositive for both antigens. The Cervarix vaccine was well tolerated among all age groups.

“Serum antibody responses against anti-HPV-16 and anti-HPV-18 elicited by the HPV-16/18 AS04 candidate vaccine are likely to represent an important, if not essential, aspect of providing protection against HPB-16 and/or HPV-18 cervical infections,” stated Dr. Schwarz. He added, “One additional aspect of protection may be the detection of antibodies at disease-relevant sites, namely the genital mucosa. One possible mechanism of protection of the cervix is transudation of serum IgG into cervical secretions.”

These results provide strong evidence that in women up to age 55, the HPV-16/18 AS04 candidate vaccine may protect against new infections with oncogenic HPV types that can cause cervical cancer. The 100% efficacy rate across all age groups is an important finding because, as Dr. Schwarz explained, “the older a woman is when infected, the more likely the infection will become persistent, which may lead to the development of precancerous lesions.”

Presented at American Society of Clinical Oncology, June 5, 2007. Abstract #3007, Oral Presentation.

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MULTIPLE SITES IN EUROPE

Can Radiotherapy Be Avoided in Young Children With Brain Tumors?

Some experts worry that the use of radiotherapy for brain tumors in children younger than two years of age may harm brain development, but they have had little evidence to support the use of chemotherapy in these very young patients. That may change with the published results of a 10-year trial involving children from the Netherlands, Scandinavia, and the United Kingdom.

Researchers tested whether the use of adjuvant chemotherapy after surgery would obviate (or at least delay) the need for radiotherapy in toddlers with newly diagnosed ependymomas. Radiotherapy was given to only those children whose cancers had progressed. A total of 42% of the children did not receive any radiation treatment, and the five-year survival was 64%. Importantly, in those requiring radiation treatment, the use of pharmacologic therapy delayed the need for radiotherapy by at least 18 months, meaning that they were first exposed to radiotherapy when they were more than 3.5 years old.

The authors concluded that a significant proportion of children with ependymomas can be spared radiotherapy, which can result in learning disabilities and altered brain development. Even if the need for radiotherapy can be delayed, they believe, this would be a real improvement in treatment safety.

Grundy RG, et al: A prospective trial of primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children under three years of age: A UKCCSG/ SIOP study

2007;July 20, 2007 (E-pub, ahead of print).

. Lancet Oncology