BOSTON (FRONTLINE MEDICAL NEWS) – Neoadjuvant chemotherapy and radiation appear to offer long-term benefits in patients with high-risk soft tissue sarcomas of the extremities.

The key word is “appear,” however, because the idea is drawn more from inference than from evidence, and not all sarcoma specialists are convinced that neoadjuvant chemotherapy and radiation add anything more than toxicity.

In studies presented at the annual meeting of the American Society of Radiation Oncology, including a retrospective case series and a national database review, investigators found evidence supporting the use of combined modality therapy with radiation and chemotherapy in patients with soft tissue sarcomas of the extremities.

“Large high-grade extremity soft-tissue sarcomas are at high risk of failure and death compared to our typical high-risk patients who present with one [risk] factor,” said Omar Mahmoud, MD, PhD , from the Rutgers Cancer Institute of New Jersey, New Brunswick.

He and his colleagues combed through the National Cancer Database to identify 3,840 otherwise healthy patients with grade 3 or 4 soft-tissue sarcomas (STS) of the extremities of various histologies larger than 8 cm, who underwent surgical resections during 2004-2013.

They looked at overall survival in patients who received no neoadjuvant or adjuvant therapy and those who received either neoadjuvant or adjuvant chemotherapy and/or radiation therapy. They used propensity score matching to adjust for imbalances of covariates across treatment subgroups.

They found that chemotherapy was associated with significantly better 5-year overall survival, at 57%, compared with 45% with no chemotherapy (P less than .001)

In multivariate analysis, age older than 50 years, positive tumor margins, larger tumors, and tumors located in the trunk or pelvis were associated with worse prognosis, whereas receipt of chemotherapy and radiotherapy were associated independently with better prognosis.

Out to 100 months (8.3 years) of follow-up, overall survival was significantly higher for patients who received combined modality adjunctive therapies, compared with either single modality therapy (chemotherapy or radiotherapy alone) or no therapy (P less than .001).

Using propensity score matching to compare patients who received combined vs. single-modality therapy, the investigators found that combined therapies were associated with significantly better overall survival, with a hazard ratio of 0.72 (95% confidence interval, 0.62-0.84).

There was no difference in survival according to the timing of therapy, whether preoperative, postoperative, or concurrent), however.

Finally, looking at survival among all subgroups, they saw that combined therapies remained significantly better than single-modality therapies (P less than .001).

Drop the ‘D’ in MAID?

In a separate study, Neilayan Sen, MD, and colleagues from Rush University Medical Center in Chicago reported that a modified protocol involving neoadjuvant chemotherapy interdigitated with radiation followed by surgery and adjuvant chemotherapy was associated with good disease control and survival and lower toxicity in patients with large STS of the extremities or abdominal wall.

The original protocol, dubbed MAID (mesna, doxorubicin, ifosfamide, dacarbazine), was shown in the RTOG 9514 trial to be associated with higher rates of disease-free, distant disease-free, and overall survival than older regimens, but at the price of high short-term toxicities. Among 64 evaluable patients, 97% had grade 3 or higher toxicities, including three deaths, two of which were from myelodysplasia.

To see whether they could match the efficacy of MAID while reducing toxicity, the Rush team modified the MAID protocol by dropping the dacarbazine. For the radiation component, they used either 3-D conformal radiation therapy or intensity-modulated radiation therapy, set the maximum dose penetration (Dmax) at 112% or less, and used reduced volumes while maintaining the dose and fractions (44 Gy delivered in 22 fractions, 11 each between chemotherapy cycles 1-2 and 2-3). Patients then underwent surgery, followed by three additional cycles of chemotherapy.

In a retrospective analysis of 26 patients treated with the modified protocol, there were no toxicity-related amputations, and no amputations were required for tumor management. Two patients had in-field fractures.

At a median follow-up of 39 months, 25 of the 26 patients were still alive and there were no cases of treatment-related malignancies or myelodysplasia.

The 3-year actuarial results with MAI also compared favorably with those of RTOG 9514, with locoregional recurrence-free survival rates of 87.2% with the modified protocol vs. 82.4% for the original MAID protocol, distant metastasis-free survival of 67.9% vs. 64.%, respectively, disease-free survival of 67.9% vs. 56.6%, and overall survival of 93.3% vs. 75.1%.

“The omission of dacarbazine does not compromise any disease-control endpoints. With the integration of 3-D techniques as well as intensity modulation and smaller fields than were used in [RTOG] 9514, there’s a significantly reduced grade 4 and 5 toxicity rate. We think that the integration of image guidance with reduced target volume parameters further,” Dr. Sen said.

Better Agents Needed

Elizabeth H Baldini, MD, MPH , from the Dana-Farber/Brigham & Women’s Cancer Center, Boston, the invited discussant, agreed that there is a need for better systemic therapy to reduce the risk of distant recurrence in patients with high-risk localized sarcomas.

“But the bottom line is that the benefit of chemotherapy with the agents we have today is uncertain,” she said.

Assessment of systemic chemotherapy in sarcoma is hampered by the rarity of the tumors, with more than 50 different histologic subtypes, and wide tumor heterogeneity, and although the studies reported here appear to show benefit for chemotherapy, they appear to overlap with those for surgery and radiation alone, she said.

Session comoderator Yen-Lin Evelyn Chen, MD , a radiation oncologist at Massachusetts General Hospital Cancer Center, Boston, said in an interview that studies presented during the session show that, “chemotherapy in experienced hands can be delivered safely.”

Dr. Chen added, however, that the local control rates reported by Dr. Sen and colleagues were a little lower than she would have expected in the modern era, suggesting that either the radiation modification or elimination of dacarbazine may have played a role.


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