Clinical Abstracts From Overseas: June 14, 2010

â–º United Kingdom

Rapid Versus Standard Induction Chemotherapy for Children With Stage 4 Neuroblastoma

Chemotherapeutic treatment for high-risk neuroblastoma generally consists of induction treatments separated by 21-day intervals. Physicians from the U.K. Children’s Cancer and Leukaemia Group sought to determine whether the use of more aggressive protocol would result in better event-free survival in patients older than 12 months.

Twenty-nine centers enrolled 262 children (median age, 2.95 yr) with stage 4 tumors over 10 years. Once enrolled, the patients were randomized to receive higher-dose treatment every 10 days (utilizing cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide or standard treatment with vincristine, carboplatin, etoposide, and cyclophosphamide. The intended total doses of each drug, except vincristine, were the same. Rapid treatment had a dose intensity that was 1.8-fold higher than that of standard treatment.

Surgical tumor resection was attempted in patients who responded to therapy, followed by myeloablation and hemopoietic stem-cell rescue.

Although chemotherapeutic doses were not recorded in all patients, 67% of those in the study group whose doses were recorded received at least 90% of the scheduled dose, compared with 79% in the standard therapy group (but with a relative dose intensity of 94% higher than in the standard therapy group). In terms of event-free survival, the Figure illustrates the differences between the groups. The greatest advantage for the rapid-dosing group came at the 5-year mark, with a 66% difference in survivals. The difference at 10 years was still 49% higher in the rapid-dosing group, but this did not reach statistical significance.

There was no difference in overall survival, according to the investigators. Importantly, myeloablation was provided a median 55 days earlier in the rapid-dosing group compared with the standard care group, which might contribute to an improved outcome.

2008;9:247-256.

Pearson AD, Pinkerton CR, Lewis IJ, et al:High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: A randomized trial. Lancet Oncol

â–º Belgium

Does HPV Remain in Situ After Treatment of Precancerous Lesions?

Human papillomavirus (HPV) is recognized as the primary cause of cervical cancer. With the availability of the HPV vaccine, many experts believe that the incidence of cervical cancer will decrease. However, if patients who did not have the vaccine develop precancerous lesions that are actively treated, do HPV remain after treatment, thus threatening a new cycle of lesion development?

Researchers from the International Center for Reproductive Health, Ghent University, Belgium, attempted to answer this question by studying 122 women who had tested positive for HPV and had cervical intraepithelial neoplasia (CIN)-1 or -2/-3 lesions. Of those with CIN-1 lesions, 55 were treated with cryotherapy and electrosurgical excision. Sixty-seven women with CIN-2/3 lesions were treated similarly. During the follow-up, the women underwent DNA testing, biopsy, and cytology, if needed.

The researchers found that HPV levels dropped considerably just after either type of treatment, although those receiving surgical excision attained a lower HPV concentration. As time passed, any differences in HPV levels diminished. After two years, 17.7% of women in the cryotherapy group were found to have any HPV DNA present compared with 8.4% in the electrosurgical excision group.

The investigators concluded that either cryotherapy or electrosurgical excision resulted in high clearance of HPV at least two years after the procedures.

Aerssens A, Claeys P, Garcia A, et al: Natural history and clearance of HPV after treatment of precancerous cervical lesions.

2008; 52:381-386.

Histopathology

â–º France / Japan

Turning Up the Heat on Lung Tumors

The use of temperature extremes seems like a fertile area of cancer therapy. Cryotherapy, or freezing prostate tumors, has received a good deal of press in the national media. This procedure has also shown promising results in kidney cancer. On the other side of the spectrum, perhaps less is known about the utility of using thermal energy to kill tumors. A new study from France was presented at the meeting of the Society of Interventional Radiology in March, that explored the possibility of using radiofrequency ablation to treat advanced lung cancers that are not resectable.

Two hundred forty-four patients (60% men, 40% women) with either lung metastases or with non—small cell lung cancer enrolled in the study. Using radiofrequency ablation guided by computed tomography, 88% of those undergoing the procedure were alive after 12 months and 70% after 24 months of follow-up, yielding survivals similar to those who are able to undergo surgery.

The treatment seems to have lingering effects as well: 85% treated with radiofrequency ablation did not have detectable tumors after 12 months, and 77% remained tumor free after 24 months. Local tumors progressed in 6.1% of patients after 12 months and 11% after 24 months.

In a separate investigation, radiologists from Japan tested the effect of this procedure on lung function. They found that of 35 patients, nine patients experienced pneumothorax (which resolved within 3 wk, without the need for surgery in 8). The only indicator of lung function that seemed affected by the procedure was partial oxygen pressure, which was significantly reduced. According to the investigators, the overall clinical implication of this effect is minor.

deBaère T, Palussière J, Hakime A, et al: Longterm follow-up after percutaneous pulmonary radiofrequency ablation. Presented at the 2008 annual meeting of the Society of Interventional Radiology. Washington, DC, March 17, 2008.

Matsuoka T, Okuma T, Yamamoto A, et al: Influences on radiofrequency ablation for lung tumors on pulmonary function. Presented at the 2008 annual meeting of the Society of Interventional Radiology. Washington, DC,

March 17, 2008.

â–º The Netherlands

Are Women Treated for Breast Cancer at Higher Risk for New Tumors Appearing Elsewhere?

Treatment of early-stage breast cancer can often achieve excellent long-term remission rates and even cure. However, that is not a guarantee against other tumors developing elsewhere in the body. Dutch oncologists sought to quantify that risk, in a large surveillance trial with a median follow-up of more than five years.

A total of 58,068 Dutch women with invasive breast cancer that was diagnosed between 1989 and 2003 were studied by these researchers from multiple oncology centers in the Netherlands. In these patients, 2,578 primary tumors developed in places other than the breast, for a cumulative 10-year risk of 5.4%. Compared with the general Dutch population, this represented a 22% increased risk for tumor development. Many tumor types and locations were registered, including solid tumors and soft-tissue sarcomas. No one tumor location predominated.

The researchers revealed that in women who had breast cancer and who were younger than 50 and exposed to radiation therapy, the risk for lung cancer was elevated (hazard ratio, 2.31). In the younger age group, chemotherapy actually decreased the risk of other cancer development (hazard ratio, 0.78). In those older than 50 years, radiation therapy raised the risk for soft-tissue sarcomas (hazard ratio, 3.43). In this age group, chemotherapy raised the risk of melanoma, uterine cancer, and acute myelogenous leukemia.,

Although it should be pointed out that treatments for breast cancer changed radically from the beginning of the study period until its conclusion in 2003, the authors did not study this aspect. However, it does seem that patients who were diagnosed with breast cancer during this period have a small increased risk of developing non—breast primary tumors.

2008;26:1239-1246.

Schaapveld M, Visser O, Louwman MJ, et al: Risk of new primary nonbreast cancers after breast cancer treatment: A Dutch population-based study. J Clin Oncol

â–º Italy

Radioimmunotherapy Converts Partial Response to Complete Response in Follicular Lymphoma

Follicular non-Hodgkin lymphoma (NHL) is the most common form of lymphoma in the United States. A group of Italian researchers conducted a prospective, open-label trial of a combination of fludarabine and mitoxantrone for first-line therapy for follicular NHL. Patients who only obtained partial remissions were given radio-immunotherapy to see if the remissions could be advanced to complete status and to better understand the effects of such therapy on patients already attaining complete remissions.

Sixty-one patients with stage III or IV untreated follicular NHL were enrolled in this phase II study over 22 months at Italian institutions throughout the country. All patients were treated with oral fludarabine 40 mg/m² on the first three days of the 28-day cycle and intravenous mitoxantrone 10 mg/m² on the first day of the cycle for six cycles.

Fifty-seven patients attained at least a partial response and had platelet counts above 100 X 109/L, granulocyte levels higher than 1.5 X 109/L, and bone-marrow infiltration of below 25% after completion of the sixth cycle of chemotherapy and were deemed eligible for the next stage of treatment. A total of 43 patients attained a complete response and 14 of the 61 patients experienced a partial response with the initial combined chemotherapy.

The researchers administered yttrium-90-labelled ibritumomab tiuxetan between six and 10 weeks following the final cycle of combined chemotherapy. The agent was administered with an initial infusion of intravenous rituximab 250 mg/m² on day 1 and a second 250 mg/m² infusion on day 7, 8, or 9. After this second infusion, ibritumomab tiuxetan was administered as a weight-based intravenous dose.

Twelve of the 14 patients (86%) who had a partial response with initial treatment achieved complete response with radio-immunotherapy. The investigators reported that three-year progressionfree survival was estimated to be 76% and three-year overall survival was 100%, based on a median follow-up of 30 months.

This therapy was not without hematologic toxicity: Sixty-three percent of the 57 patients had grade 3 or 4 thrombocytopenia, neutropenia, and anemia; blood transfusions were required in 21.

Effect of Radioimmunotherapy on Patients Obtaining Partial Responses

Patients With Previous Partial Response Who Obtained a Complete Response

86%

All Patients Obtaining Complete Response

96%

Zinzani PL, Tani M, Pulsoni A, et al: Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: A phase II non-randomised trial (FLUMIZ).

2008;9:352-358.

Lancet Oncol

Italy / China

Adjuvant Chemotherapy Fails to Improve Survival in Some Gastric Cancers

In patients with localized gastric cancer, surgery appears to be the only efficacious approach. In patients who are not cured, overall long-term survival remains poor. Recent research suggested that a chemotherapy combination may have a positive influence on the outcomes of patients with advanced metastatic disease; therefore, would the same chemotherapy in combination with surgery improve long-term survival in patients with less-advanced disease?

Italian oncologists from multiple centers conducted a phase III trial of the chemotherapy combination of cisplatin, epirubicin, 5-fluorouracil, and leucovorin (PELF) as adjuvant therapy in patients with histologically proven adenocarcinoma of the stomach (stages IB—IV). All 258 patients in the study underwent tumor resection and were randomly assigned to monitoring or to receive four cycles of intravenous PELF treatment, consisting of cisplatin 40 mg/m2 and epirubicin 30 mg/ m2 on days 1 and 5, and leucovorin 100 mg/m2 and 5-fluorouracil 300 mg/m2 on days 1 through 4. The cycles were repeated every 21 days.

Patients were followed for a median 73 months. The researchers found that 48% of patients undergoing adjuvant chemotherapy with PELF experienced disease progression compared with 52% in the surgery-only group. Overall survivals were 47% and 45%, respectively. Those receiving adjuvant chemotherapy did not experience statistically significant increases in either disease-free survival (hazard ratio, 0.92) or overall survival (hazard ratio, 0.90). Yet those undergoing chemotherapy did experience significant toxicity (grade 3 or 4) from the PELF regimen.

They concluded that adjuvant chemotherapy with PELF did not significantly improve overall survival or disease-free survival compared with surgery alone. Although there was some improvement with adjuvant chemotherapy, the modest level of improvement and the toxic effects of the agents may not justify their use.

In a related meta-analysis, researchers from Shanghai, China, evaluated the benefit of adjuvant chemotherapy in 4,919 patients with gastric cancer from 23 trials. This study did not specify chemotherapy combinations; however, they reported a 53% overall survival in those receiving surgery alone compared with 61% in the adjuvant chemotherapy arm. Patients receiving surgery alone seemed to have a longer diseasefree survival (relative risk of recurrence, 0.88) compared with the chemotherapy results in the study.

Adjuvant PELF Therapy or Surgery Alone forLocalized Gastric Tumors

Therapy

DFS

Overall Survival

Chemotherapy + Surgery

52%

47%

Surgery Alone

48%

45%

Note: These differences are not statistically significant.

PELF = Cisplatin, epirubicin, 5-fluorouracil, and leucovorin.

Di Costanzo F, Gasperoni S, Manzione L, et al: Adjuvant chemotherapy in completely resected gastric cancer: A randomized phase III trial conducted by GOIRC.

2008;100:388-98.

J Natl Cancer Inst

Liu TS, Wang Y, Chen SY, et al: An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.

March 17, 2008 [Epub ahead of print].

Eur J Surg Oncol

DFS = Disease-free Survival.