SAN FRANCISCO, June 24 — Even high-risk childhood acute lymphoblastic leukemia (ALL) can be safely treated without prophylactic cranial irradiation when using personalized chemotherapy, researchers found.

In a prospective clinical trial, risk-based intensification of therapy without cranial irradiation yielded a five-year cumulative risk of isolated central nervous system relapse of 2.7% (95% confidence interval 1.1 to 4.3), according to a study reported in the June 25 issue of the New England Journal of Medicine.

This relapse rate was well within the 1.5 to 4.5% range in clinical trials that used prophylactic cranial irradiation, Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues said.

Children who would have received prophylactic cranial irradiation under prior treatment criteria had significantly longer continuous complete remission than historical controls who were irradiated (five-year rate 90.8% versus 73.0%, relative risk 0.34, P=0.04).

These clinical findings further chip away at the once standard use of prophylactic cranial irradiation, Dr. Pui’s group wrote.

• Explain to interested patients that cranial irradiation was once standard for all childhood cases of ALL to prevent cancer recurrences in the central nervous system.
• Explain that new treatment regimens can now achieve the same or better results without it.
• Note that the trial provided comparisons only with historical controls rather than an active comparator arm.

Radiation-associated late complications such as second cancers, cognitive deficits, and endocrine problems, have led researchers to progressively reduce dosages and limit use to only the highest-risk children.

Now only about 20% of childhood ALL cases in the U.S. are treated with cranial irradiation to prevent central nervous system relapse, Dr. Pui said.

But his group saw potential to eliminate its use entirely.

Their Total Therapy XV trial tested whether intensified systemic treatment for central nervous system control plus optimal intrathecal treatment would be enough to maintain overall survival rates without prophylactic cranial irradiation in 498 consecutive children with newly diagnosed ALL.

The intensity of the treatment regimen followed an algorithm based on each child’s level of risk determined by presenting features and sequential measurements of minimal residual disease after remission-induction treatment.

All patients were successfully measured for levels of minimal residual disease, which resulted in reclassification of risk status from low to standard risk for 30 patients, from low to high risk for six patients, and from standard to high risk for 22 patients.

Chemotherapy doses were adjusted on the basis of pharmacogenetics and pharmacokinetics.

The overall five-year survival rate of 93.5% (95% CI, 89.8 to 97.2) for all 498 patients under this treatment strategy was “superior to results of all major studies reported to date,” the researchers noted.

This rate also compared favorably with the 87.5% survival rate reported by the Surveillance, Epidemiology, and End Results Program for patients younger than 15 treated in clinical practice between 2000 and 2004, they noted.

They found an estimated five-year rate of event-free survival of 85.6% (95% CI 79.9% to 91.3).

Overall, only 9.3% of the treated children had any relapse (95% CI, 6.0 to 12.6), and just 3.9% had any central nervous system relapse (95% CI 1.9 to 5.9).

Of the 11 patients who had an isolated central nervous system relapse, all remained alive and in a second remission for 0.4 to 5.5 years (median 2.5).

Independent factors in isolated central nervous system relapse included T-cell ALL, black race, the genomic translocation t(1;19)(TCF3-PBX1), and any central nervous system involvement.

However, the researchers argued against prophylactic cranial irradiation even for patients with these risk-associated features because “approximately 90% of such patients would have received unnecessary irradiation.”

Also, “since central nervous system and hematologic relapses are competing events,” they wrote, “eradication of occult central nervous system leukemia by means of cranial irradiation alone may allow overt systemic relapse from residual leukemia in the bone marrow or other sites,” which is more difficult to treat with salvage therapy.

Despite intensive treatment, the strategy was associated with a cumulative risk of death from toxic effects during chemotherapy of only 1.4% (95% CI 0.4 to 2.4).

The higher doses of dexamethasone (Decadron, Intensol, Dexpak) and asparaginase (Elspar) given to the standard- and high-risk groups caused more osteonecrosis, thrombosis, and hyperglycemia than seen in the low-risk group.

“Rates of disseminated fungal infection and thrombosis were substantial, but no patient died of these complications,” Dr. Pui’s group noted.

Notably, they said they expected a low rate of therapy-induced cancers since etoposide (Etopophos, Vepesid) and irradiation were given only to the small subgroup of patients who underwent hematopoietic stem cell transplantation.

Extrapolating from long-term results of prior studies, the investigators predicted five- to 10-year major adverse event rates of no more than 4% and a 10-year survival rate — “and perhaps a cure rate”– of 90%.

The study was supported by grants from the National Institutes of Health and an American Cancer Society F.M. Kirby Clinical Research Professorship and by the American Lebanese Syrian Associated Charities. Dr. Pui reported receiving lecture fees from Enzon Pharmaceuticals. Co-authors reported conflicts of interest with Enzon Pharmaceuticals, Genzyme, sanofi-aventis, EUSA Pharma, the American Society for Investigative Pathology, Genome Explorations, and a patent concerning molecular diagnosis of thiopurine-S-methyltransferase deficiency.

Primary source: New England Journal of Medicine

Source reference:

Pui C-H, et al “Treating childhood acute lymphoblastic leukemia without cranial irradiation” N Engl J Med 2009; 360: 2730-41.

WHEELING, W.Va., June 24 — Ewing’s sarcoma strikes white Americans at nearly 10 times the rate it affects blacks and about double that in Pacific Islanders, researchers said.

• Explain to interested patients that Ewing’s sarcoma is a rare form of cancer that primarily affects children and young adults.
• Explain that five- and 10-year survival rates are both about 50%.
• Note that the study was a retrospective analysis of database records, which could be faulty or incomplete.

Annual age- and population-adjusted incidence of the disease from 1973 to 2005 was 0.155 per 100,000 in whites, 0.017 in blacks, and 0.082 in Pacific Islanders, reported Sean P. Scully, MD, PhD, of the University of Miami, and colleagues online in Cancer.

Moreover, the rate among whites has been increasing significantly — by an average of 0.84% annually (P<0.05), the researchers found.

Rates for other racial groups have not changed significantly, although the small number of patients — a total of 1,631 cases were analyzed in the study, 92% white — may have made significance impossible.

Hispanic ethnicity did not markedly affect incidence among whites.

The study was the first comprehensive epidemiological and outcomes study of Ewing’s sarcoma, using data from the Surveillance, Epidemiology and End Results database maintained by the CDC.

The disease afflicts mostly children and young adults. The highest incidence was in 10- to 19-year-olds, at about 0.95 cases per 100,000.

Incidences between 0.3 and 0.4 per 100,000 were found for children younger than 10 and for people in their 20s. Starting at age 30, rates fell below 0.1 per 100,000 and declined steadily with increasing age.

In addition to the incidence data, the researchers examined survival records and their relation to patient and disease characteristics:

• Five- and 10-year survival rates were 55% and 53%, respectively, and did not differ with age.
• Survival rates were significantly lower for males — 10-year rates were 50% for males and 58% for females (P<0.004).
• Blacks showed poorer survival than whites — 46% versus 52% — but the difference was not significant, perhaps because there were only 35 blacks with the disease.
• Tumor size greater than 8 cm reduced survival probabilities by 25% (P<0.001).
• Distant metastasis cut survival rates by more than half (P<0.001).
• Patients treated surgically had higher survival rates — 62% versus 43% for nonresected patients at 10 years (P<0.001).
• Survival rates have improved substantially over time, from 39% at five years in 1973-1975 to 57% in 1996-2005 (P<0.001).

Cox proportional hazards analysis identified local or regional disease confinement, an appendicular location, and tumor size of 8 cm or less as independent and significant predictors of improved survival.

Dr. Scully and colleagues said the reasons for the racial differences and the rising incidence among whites were unclear.

“Environmental factors and exposures to potential mutagens or viruses change over time, and Caucasians could carry a genetic propensity to respond to specific kinds of mutagens that cause Ewing’s sarcoma,” the researchers speculated.

Ewing’s sarcoma is characterized by a particular chromosomal alteration, which may or may not actually cause the disease, they said.

However, if it is causal, “then explanations for the racial disparities in incidence and sex disparities in outcome could be explained by differences in genetic replication machinery,” Dr. Scully and colleagues wrote.

They said more research is needed to clarify these issues.

Dr. Scully and colleagues noted several limitations of the study, including its retrospective nature and its reliance on database information that may be faulty or incomplete.

No external funding for the study was reported. No potential conflicts of interest were reported.

Primary source: Cancer

Source reference:

Jawad M, et al “Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005″ Cancer 2009; DOI: 10.1002/cncr.24388.

WHEELING, W.Va., June 24 — Women with rare, placental site trophoblastic tumors (PSTT) are unlikely to survive if the disease is diagnosed more than four years after their last pregnancy, British researchers found.

• Explain to interested patients that placental site trophoblastic tumors, which occur in women following pregnancy, are extremely rare.
• Explain that, according to this study, outcomes are poor when the disease is diagnosed more than four years after pregnancy, but most such tumors are found sooner than that and are usually curable.

In fact, all women diagnosed with the disease more than four years after pregnancy were dead within 65 months, while the 10-year survival rate among those diagnosed within four years of pregnancy was 98% according to Peter Schmid, MD, PhD, of Imperial College London, and colleagues.

The findings, reported online in The Lancet, were based on records for all PSTT cases in Great Britain from 1976 to 2006 — a total of 62 — as obtained from national registry data.

Thirteen women were diagnosed more than four years after pregnancy. Of the other 49 diagnosed sooner, only one died, the researchers found.

As those numbers indicate, PSTT is an extremely rare complication of pregnancy, arising months or even years afterward. The outcome of the pregnancy — normal delivery, abortion, miscarriage, or hydatidiform mole — does not seem to matter.

Dr. Schmid and colleagues examined outcomes for the 62 patients with PSTT, out of a total of about 36,000 gestational trophoblastic disease cases.

Those diagnosed at stage I had a 10-year survival rate of 90% (95% CI 77% to 100%), with no evidence that postoperative chemotherapy improved outcomes.

Later-stage patients appeared to benefit from surgery and adjuvant chemotherapy, the researchers found.

Among five patients with stage II disease, the two who were treated exclusively with surgery both had disease recurrence, while three patients who had surgery plus chemotherapy have survived recurrence-free, Dr. Schmid and colleagues said.

Of 23 patients with stage III or IV metastatic disease, 14 had both surgery and chemotherapy. The combined approach led to durable remissions in eight patients, with recurrence seen in five and no response at all in one.

Among eight patients receiving just chemotherapy, only two had long-term disease control. The sole patient treated exclusively with surgery has survived recurrence-free.

Dr. Schmid and colleagues calculated overall 10-year survival for stage III and IV disease to be 49% (95% CI 26% to 72%).

For all disease stages, recurrence was a bad omen. Only one-third of patients relapsing could achieve a second, durable remission, the researchers found.

Multivariate analysis indicated that time from last pregnancy to diagnosis was by far the strongest predictor of survival, even after controlling for tumor size, depth of myometrial invasion, and other factors that might influence prognosis.

The area under the receiver-operator characteristic curve for time since antecedent pregnancy as a prognostic measure was 0.981 (95% CI 0.942 to 1.019).

Using four years as the cutoff, the positive predictive value was 100% and negative predictive value was 98%.

Dr. Schmid and colleagues said time from pregnancy to diagnosis could perhaps guide treatment.

In particular, they recommended that patients diagnosed more than four years after pregnancy receive adjuvant chemotherapy, even for those with stage I disease.

Such an approach for early-stage patients would also make sense when there are other risk factors for poor outcomes, such as vascular invasion or serosal involvement, they said.

In an accompanying commentary, Ernest Kohorn, MD, of Yale University, noted that careful diagnosis, including histological confirmation, is essential in dealing with potential PSTT cases.

“It is now accepted that placental-site trophoblastic tumors differ from other trophoblastic neoplasms in that the tumor load is not accurately correlated with the concentration of hCG, and that the tumor might be less sensitive to chemotherapy that is effective in the other types of trophoblastic neoplasia,” he wrote.

He also applauded Dr. Schmid and colleagues for recommending aggressive treatment of PSTT.

“It is gratifying to find that the investigators advocate adjuvant chemotherapy even for stage I disease,” Dr. Kohorn said.

The study was funded by the National Commissioning Group. No potential conflicts of interest were reported by the study authors or Dr. Kohorn.

Primary source: The Lancet

Source reference:

Schmid P, et al “Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study” Lancet 2009; DOI: 10.1016/S0140-6736(09)60618-8.

Additional source: The Lancet

Source reference:

Kohorn E “Long-term outcome of placental-site trophoblastic tumours” Lancet 2009; DOI: 10.1016/S0140-6736(09)60791-1.