New Research Presented in Wilms Tumor, Pediatric Sarcoma, Head and Neck Cancer, and Non–Small Cell Lung Cancer

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David B. Dix, MD

Sheri L. Spunt, MD, MBA

In the past few months, numerous presentations from this year’s ASCO Annual Meeting have been covered in depth in the pages of The ASCO Post and online at The brief summaries below capture additional important highlights that have not been covered thus far. We hope you will find them of interest.

Better Outcomes for Wilms Tumor

In a select group of patients with newly diagnosed stage IV Wilms tumor, the addition of cyclophosphamide and etoposide to standard treatment with chemotherapy and radiation improved event-free survival and overall survival, according to the results of the AREN0533 study, conducted by the Children’s Oncology Group.1

AREN0533 evaluated whether therapy can be tailored based on the completeness of the lung metastasis response after 6 weeks of DD4A chemotherapy (vincristine, dactinomycin, and doxorubicin). The study enrolled 391 patients with newly diagnosed stage IV favorable histology Wilms tumor. Of these, 279 had isolated lung metastases, and within this group, 163 (58%) had a “slow incomplete response” to DD4A; the remaining patients had resolution of lung metastases and continued on DD4A alone. In the slow incomplete response group, etoposide with cyclophosphamide and whole-lung irradiation were added to DD4A (called Regimen M). The patients with a slow incomplete response were treated every 3 weeks with Regimen M for an additional 27 weeks.

Based on historic controls, the number of expected events while on treatment was 38.6 for patients with a slow incomplete response. However, only 15 events were recorded in the study. David B. Dix, MD, of the British Columbia Children’s Hospital in Vancouver, reported that the 3-year event-free survival rate in the slow incomplete response group was 88%, while 3-year overall survival in these patients was 92%.

Although the data are not mature, Dr. Dix commented, “The AREN0533 Study Committee is encouraged by these results, and recommends that physicians consider these data when planning treatment for their patients.” Final data are expected in 2016, after a median follow-up of 6 years.

Algorithm for Rare Pediatric Sarcomas

A risk-stratification algorithm appears to accurately segregate pediatric patients with non-rhabdomyosarcoma soft-tissue sarcoma into distinct prognostic subgroups for treatment assignment.2 Use of this algorithm can spare low-risk patients from more toxic therapy, and high-risk patients can be treated with more intensive approaches, according to the first study since the 1990s to be conducted in these rare childhood soft-tissue sarcomas.

The algorithm identifies specific low-risk subsets of patients who can be treated safely with surgery alone, and it shows that patients with intermediate- and high-risk disease can be safely treated with neoadjuvant combined chemotherapy and lower doses of radiotherapy followed by delayed resection without having a negative effect on outcomes.

The risk-stratification scheme applied in the study will be used to determine which children should receive investigational therapies and which ones should not, according to lead author Sheri L. Spunt, MD, MBA, of Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, California. The category of non-rhabdomyosarcoma soft-tissue sarcoma accounts for about 50% of all childhood soft-tissue sarcomas and is a “wastebasket” term for an assortment of more than 30 cancer types that haven’t gotten much research attention, she explained.

ARST0332 enrolled 551 eligible patients with non-rhabdomyosarcoma soft-tissue sarcoma, and is the largest prospective study in the United States conducted in these tumors. Median age was 13.7 years (range, 0.1–29.8 years). Tumor types included all histologic subtypes as well as localized and metastatic disease.

Characteristics including tumor grade, size, extent of resection, margin status, and extent of disease were used to assign newly diagnosed patients into risk groups. Low-risk patients had either surgery alone (ie, those with grossly excised low-grade and ≤ 5 cm widely excised high-grade tumors) or had adjuvant radiotherapy added (ie, those with ≤ 5 cm marginally resected high-grade tumors); patients with ­intermediate-risk (ie, > 5 cm grossly resected tumor or unresected at study entry, without metastases) or high-risk disease (ie, metastatic) were managed with surgery alone or upfront/delayed surgery (based on resection potential) plus adjuvant or neoadjuvant chemoradiotherapy.

At a median of 2.6 years of follow-up, a clear distribution of clinical outcomes was observed. The 4-year survival rates were 97% (surgery alone), 100% (surgery plus radiotherapy), 80% (adjuvant chemoradiotherapy), and 63% (neoadjuvant chemoradiotherapy). There were no deaths; unexpected grade 4 toxicity occurred in 10 patients (2%).

Induction Therapy in Head and Neck Cancer

Induction therapy follwed by concomitant treatment improved survival and other outcomes compared with concomitant therapy alone in patients with locally advanced squamous cell carcinoma of the head and neck, according to a multicenter phase II/III study presented by Maria Grazia Ghi, MD, of Ospedale Civile, Venice, Italy.3

The phase II part of the study was previously published and supported the use of three cycles of induction therapy with TPF (docetaxel, cisplatin, and fluorouracil) without compromising delivery of chemoradiotherapy. In the phase III study, concomitant therapy with cetuximab (Erbitux) plus radiation therapy was added to the induction and noninduction arms (2×2 factorial design). This is the first study to compare these two regimens, she stated.

The phase III trial included 421 patients with stage III or IV unresectable squamous cell carcinoma of the head and neck randomly assigned from the beginning to induction with TPF followed by chemoradiotherapy or cetuximab/radiotherapy vs concomitant treatment alone. The treatment arms (induction vs no induction) were well balanced for demographics and disease characteristics.

Median progression-free survival was 29.7 months in the induction arm vs 18.5 in the noninduction arm (P = .0155). Median overall survival was 53.7 months vs 30 months, respectively (P = .025). Overall response rate was not different in the induction and noninduction arms after concomitant therapy, but the complete response rate was significantly higher in the induction arm: 43.5% vs 28% (P = .0023).

Induction therapy did not affect compliance with concomitant therapy, she said. The study was not powered to compare the two concomitant regimens, and a larger study would be required to do that.

Toxicity was not significantly different in the two arms, with the exception of more grade 4 neutropenia in the TPF arm (4% vs 1%, respectively, P = .037).

Ceritinib in ALK-Positive Lung Cancer

In the ASCEND-1 trial, ceritinib (Zykadia) produced positive results in ALK-positive patients with non–small cell lung cancer (NSCLC), including those previously treated with an ALK inhibitor (crizotinib [Xalkori]) as well as those who were crizotinib-naive.4 With ceritinib, tumor shrinkage was also observed in brain metastases present at baseline.

The overall response rate was 58%, and median progression-free survival was 8.2 months; results were similar in patients who previously received an ALK inhibitor and those who were ALK inhibitor–naive at baseline.

Dong-Wan Kim, MD, of Seoul National University Hospital, South Korea, who presented these results, emphasized that this drug works in both pre–ALK inhibitor–treated and ALK inhibitor–naive patients, and he was especially impressed with the drug’s activity in metastatic brain cancer. “This [ie, brain metastasis] is currently one of the biggest challenges in treating ALK-positive NSCLC,” he said.

“Ceritinib achieved a high rate of durable responses and prolonged progression-free survival in both ALK inhibitor–treated and ALK inhibitor–naive patients. In ALK inhibitor–naive patients, median duration of response and median progression-free survival have not yet been reached,” he noted.

ASCEND-1 was a global phase I trial conducted at 20 centers in 11 countries that included 255 patients with ALK-positive tumors. Of these, 163 had received an ALK inhibitor, while 83 where ALK inhibitor–naive at baseline.

Mean age was 53, 62% were never smokers, and 92.7% had adenocarcinoma histology. Median time from initial diagnosis was 18 months. At the time of cutoff, 52% of patients were still on treatment. Median duration of response was 9.7 months.

Most common toxicities were gastrointestinal and included nausea, vomiting, diarrhea, and constipation (mostly grades 1 and 2). Approximately 34% of patients reported decreased appetite.

Ceritinib is the only U.S. Food and Drug Administration–approved therapy for patients with ALK-positive metastatic NSCLC who have had disease progression on or are intolerant to crizotinib. Two phase II trials of ceritinib have been completed, and two phase III trials are ongoing. ■

Disclosure: Drs. Dix, Spunt, and Ghi reported no potential conflicts of interest. Dr. Kim is a consultant or advisor for Novartis.


1. Dix DB, Gratias EJ, Seibel N, et al: Treatment of stage IV favorable histology Wilms tumor with incomplete lung metastases response after chemotherapy. ASCO Annual Meeting. Abstract 10001. Presented May 31, 2014.

2. Spunt SL, Million L, Anderson JR, et al: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients under 30 years of age. ASCO Annual Meeting. Abstract 10008. Presented May 31, 2014.

3. Ghi MG, Paccagnella A, Ferrari D, et al: Concomitant chemoradiation (CRT) or cetuximab/RT (EET/RT) followed by induction docetaxel/cisplatin/5-fluorouracil (TPF) followed by CT or CET/RT in patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN). ASCO Annual Meeting. Abstract 6004. Presented June 2, 2014.

4. Kim D, Mehra R, Tan DS, et al: Ceratinib in anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC). ASCO Annual Meeting. Abstract 8003. Presented June 2, 2014.