Neoadjuvant Therapy Improves Survival of Large Sarcomas in Extremities



MIAMI BEACH – Preoperative chemotherapy or radiation – take your pick or both – improves overall survival of patients with large, soft-tissue sarcomas of the extremities, retrospective studies from two cancer centers suggest.

Looking at a cohort of 112 patients, investigators at the Mayo Clinic in Scottsdale, Ariz., saw no significant differences by treatment type in local control rates or overall survival.

But among patients with tumors measuring longer than 5 cm, the 3-year overall survival rate was 63% for those who had neoadjuvant radiation and surgery and 70% for those who had chemoradiotherapy and surgery, versus 40% with surgery alone (P = .03), radiation oncologist Jonathan B. Ashman and colleagues reported at the annual meeting of the American Society for Radiation Oncology.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/radiation – have bigger tumors, so they’re more aggressive tumors, but the local control is the same, so we think that the neoadjuvant therapy is helping more than we would expect from surgery alone," Dr. Ashman said in an interview.

In a separate study, Johns Hopkins Hospital investigators reported excellent local control and good overall survival rates for patients with large sarcomas of the extremities that were treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy.

The estimated 3-year overall survival rate was 66%, the estimated disease-free survival rate 58%, and estimated the local control rate 100% among 16 patients treated with interdigitated neoadjuvant chemotherapy and radiation using the MAID protocol (mesna, doxorubicin, ifosfamide and dacarbazine), reported radiation oncologist Dr. Raju Raval and colleagues from Johns Hopkins Hospital in Baltimore.

The Mayo Experience

The Mayo investigators retrospectively looked at whether adding chemotherapy to external beam radiation therapy and limb-sparing surgery added benefit for patients with stage II or III soft-tissue sarcomas of the extremities. The center’s sarcoma team recommends either neoadjuvant radiation or chemoradiotherapy for patients who have high-grade tumors and are likely to have narrow resection margins based on preoperative MRI imaging showing large tumor size or unfavorable location of the tumor relative to bone or to neurovascular structures.

"We found that patients who are treated with either neoadjuvant strategy – either radiation or chemotherapy/ radiation – have bigger tumors."

The investigators reviewed the charts of 91 patients treated for primary disease, and 21 treated for tumor recurrence from 1998 through 2009. Median follow-up was 22.1 months. Overall, 39 of the patients received neoadjuvant chemoradiotherapy, 37 neoadjuvant radiation, and 36 surgery alone. The majority of tumors in each treatment group were pathologic grade 3 or 4, and most were 5 cm or greater in their longest dimension.

Of the 39 patients who received some form of chemotherapy, 20 had concurrent weekly cisplatin 20-40 mg/m2, with the remainder receiving other protocols, including MAID and MAP (methotrexate, doxorubicin, and cisplatin).

Dr. Ashman said that although there is no clear evidence to support the use of weekly cisplatin in sarcoma, "our practice has been over the last 5-8 years to have patients who have large and high-risk tumors but otherwise have good performance status, with good renal function and no other contraindications to receive weekly cisplatin, because it’s such a well-tolerated regimen. The rationale is that there hasn’t been really good data to show a benefit from the more toxic protocols."

Cisplatin is known to sensitize tumor cells to radiation, he noted. "When you’re looking at just radiosensitization, and you’re looking at just local outcomes and not trying to affect the distant metastasis rate, then let’s try to use a therapy that’s less toxic, so that patients don’t have to break therapy."

In all, 92 patients had surgery with limb-preservation attempt, and the majority (88%) had disease-free surgical margins (R0 resections); rates of R0 resections did not differ among the treatment groups.

The overall 3-year local control rate was 87%, distant metastasis-free survival was 69%, and overall survival was 68%. Patients who received a neoadjuvant therapy had higher rates of wound complications, which occurred in 11% of surgery-only patients, compared with 50% of patients who received chemoradiotherapy (P = .003) and 42% of those who received radiation (P = .02). There was no significant difference in wound complications between the two neoadjuvant therapy types, however, and no factors predicted these complications.

The Johns Hopkins Experience

Dr. Raval and colleagues from Johns Hopkins reported on 16 patients with high-grade soft-tissue sarcomas treated with interdigitated neoadjuvant chemotherapy and radiation, surgery, and adjuvant chemotherapy.

The therapy consists of three cycles of chemotherapy, with 44 Gy radiation divided into 22 fractions, 11 of which are delivered following the first chemotherapy cycle, and 11 following the second cycle. Surgery is performed about 80 days after the start of therapy, and an additional 11 Gy or radiation is given if an R0 resection was not achieved. If the patient can tolerate it, three additional adjuvant chemotherapy cycles are given.