Reply to A. Mangla

We are very grateful to Mangla¹ for taking keen interest in our study and highlighting the need of incorporating chemotherapy in selected patients using validated nomograms for the treatment of extremity soft tissue sarcomas (ESTSs) to achieve better outcomes.² Second, they have enumerated many advantages of preoperative radiation therapy (RT) and advocated for neoadjuvant treatment approaches in the management of locally advanced ESTS.

The heterogeneity and rarity of ESTS pose a challenge in decision making and demand a distinct site-specific therapeutic multidisciplinary team (MDT) approach.³ Furthermore, we perform a robust peer review process in the department of radiation oncology to ensure the quality of MDT recommendations and radiation treatment.⁴

Wide surgical excision is the standard definitive treatment, with RT being used as an adjunct modality to enable effective surgical resections or to offset the effects of a positive margin. This combination leads to a local control rate of 85%-90% with good limb function. However, amputation is still performed in some patients with advanced disease, who are elderly and have multiple comorbidities.

Over the years, there has been a diverse opinion among the oncologists regarding the use of chemotherapy in ESTS, particularly in adults. Theoretically, chemotherapy provides a double advantage of making bulky and deep-seated tumors easily resectable, thereby providing good local control and also eradicates any distant micrometastases to decrease the risk of distant recurrences. With 26 of 40 patients in our study presenting with distant recurrences,² there is a desperate need to incorporate any form of systemic treatment to curtail distant metastases, as both surgery and RT are local modalities. Although chemotherapy was given in 35 patients, patient selection needs to be reviewed.

A randomized trial comparing surgery alone and neoadjuvant chemotherapy followed by surgery did not show a major survival advantage for patients receiving preoperative chemotherapy alone.⁵ In another retrospective study, a benefit of neoadjuvant chemotherapy was demonstrated in patients with high-grade tumors larger than 10 cm.⁶ With such conflicting trial designs and results, the use of chemotherapy is still an ongoing debate.

The risk stratification using nomograms helps in providing personalized treatment strategies. Over the years, with the inclusion of new prognostic tools and validation on different populations, these nomograms aid clinicians in selecting patients suitable for intensive treatments.⁷ A randomized study conducted by various European sarcoma groups showed that patient selection for chemotherapy using nomograms results in an improvement in overall survival.⁸

Positive surgical margin is a strong predictor of local recurrence in ESTS. Despite a positive margin in 72% of patients in our data, a complete response was reported in 59%.² We believe that the negative impact of positive margin was effectively offset by adjuvant RT. Since sarcomas are considered relatively radioresistant tumors, we believe that the radiation doses of up to 50 Gy used in the neoadjuvant setting are somewhat suboptimal and higher doses of up to 66 Gy given postoperatively are more effective. The proponents of neoadjuvant RT recommend for a postsurgical RT boost of 16 Gy in cases with positive margins after preoperative RT, but splitting a course of RT results in losing the cumulative impact of biologically effective tumoricidal RT doses. There are data to suggest that postoperative RT boost for positive margins does not improve local control.⁹ Furthermore, RT or chemotherapy, either neoadjuvant or adjuvant, is not a substitute for definitive surgical resection with negative margins and every possible attempt should be considered for a resurgery to achieve negative margins without sacrificing functional outcome.

Our retrospective ESTS patient data are meant for identifying the gaps in our treatment process, based on which a better treatment strategy can be further designed. We agree that there is a need to identify a subset of patients who will benefit from chemotherapy and using nomograms is the way forward. We are still inclined more toward the use of RT in the adjuvant setting as evident by a complete response in 59% of patients in our study.² Our team is grateful to Mangla for bringing this important issue forward via this correspondence. It is a very healthy academic discussion, and we will be happy to discuss it further, if required.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

No potential conflicts of interest were reported.