Early Data Support Neoadjuvant Hypofractionated Radiotherapy in Soft Tissue Sarcoma

Joshua M. Lawrenz, MD

Neoadjuvant hypofractionated radiotherapy was found to have similar complication rates to the current standard conventional radiotherapy and also resulted in a shorter treatment duration in patients with soft tissue sarcoma, according to preliminary results of a small case study,^1,2 explained Joshua M. Lawrenz, MD.

In the study, 16 patients had sarcomas that were located in the extremity, trunk, and retroperitoneum. The median radiation dose was given to 13 patients at 30 Gy in 5 fractions (range, 27.5-50 Gy) on consecutive days. Moreover, the median time to resection following completion of radiation was 1 day (range, 0-7).

Results showed that the median time from initial biopsy results to surgical resection of the primary tumor was 25 days (range, 16- 42), which compares with ≥5 weeks for conventional radiation, Lawrenz said.

Data showed that 10 patients had negative margins and 0 patients had local recurrence at 8 months of follow-up. Four patients had planned marginal excision, and 2 patients had positive margins and underwent R0 re-excision. Three (19%) patients experienced wound complications, receiving reoperations at a mean of 6 weeks, and 2 (12%) patients experienced other toxicity, specifically acute grade 4 tumor lysis syndrome and late grade 3 radiation-induced stress fracture

The next steps of the study, led by Cleveland Clinic researchers, are to accrue more patients and have longer follow-up to determine whether the clinical outcomes of hypofractionated radiotherapy also match conventional radiotherapy, according to Lawrenz. Hypofractionated radiotherapy would provide more convenience to patients with soft tissue sarcomas compared with the current approach, he added.

“One of the advantages of [hypofractionated radiotherapy] is it is a lot more convenient for a lot of patients. About 50% of our cohort were patients who were out of state who came to Cleveland Clinic,” Lawrenz explained. “Often, if you do conventional radiotherapy, that means 25 days over a 5-week period of driving to and from a site where you have your radiation treatment,” said Lawrenz. “In this setting, when patients are from out of state, many of them anecdotally have told us they really liked the idea of going to Cleveland for 2 weeks, [receiving] radiotherapy in week 1 and surgery in week 2.”

In an interview with OncLive® during the 2019 Musculoskeletal Tumor Society Annual Meeting, Lawrenz, a fellow in musculoskeletal oncology at Vanderbilt University Medical Center, discussed the use of hypofractionated radiotherapy versus conventional radiotherapy in soft tissue sarcoma.

OncLive: Could you give an overview of the early outcomes of your study exploring preoperative 5-fraction radiation therapy?

Lawrenz: With soft tissue sarcoma, radiation is usually given either preoperatively or postoperatively. When talking about preoperative radiation, it's often given in a conventional manner, 50 Gy/25 fractions, which takes about 5 weeks to administer. Often after that period, you have a 3- to 6-week window where you wait prior to surgical resection, which averages out to 2 to 3 months before surgical resection [actually takes place].

In our study looking at hypofractionated radiotherapy, patients received 5 days of radiation therapy followed by immediate resection of the tumor. This allows for the entire treatment course of a patient to be taken from 2 to 3 months down to 2 to 3 weeks. This was a key series of 16 patients that we have [been treating] in the last 2 or 3 years at our institution. We had a median of about 8 months of follow-up, which we felt was adequate enough to account for wound complications and toxicity, but not long enough to account for local recurrence rates. We just followed these patients as they received 5 fractions of radiotherapy on 5 consecutive days. Then, they underwent immediate surgical resection anywhere from 0 to 7 days after.

Of the 16 patients, there were 5 who had notable complications, 3 of which were wound complications, 2 were wound dehiscence, and 1 was a wound infection, all of which required reoperation at a mean of about 6 weeks after initial surgery.

There were 2 other toxicities that were notable and required reintervention. One was a medical toxicity called tumor lysis syndrome, which required a readmission to the hospital and hemodialysis. The second was in a patient who developed a stress fracture of their proximal tibia. Radiation likely contributed to that [stress fracture] and so we included it as a complication.

This is a small case series, and we can't draw too many conclusions. However, we can take from these 16 patients that the complication rate was about 30%, which is comparable with conventional radiotherapy. The goal, over the next several months to several years, is to collect more of these patients and follow them for a longer period of time and see whether the outcomes are equivalent to the historical precedent set by conventional therapy. Ideally, if there was a way to have the same outcomes but treat patients in a much shorter time frame, that would be excellent.

What are some additional next steps of this research?

The first is collecting more patients and having longer follow-up. One way to do that is pairing up with other institutions. There are a few other institutions that are doing this [type of study] that are a bit further along than we are in some regards. In tumor or sarcoma research, it's hard because there are only so many patients that get the disease. A meeting like this is great for [collaboration] because you get to talk about [the study] with those institutions and discuss teaming up together. We will keep following these patients long enough to see if we are achieving equivalent outcomes to standard conventional radiotherapy.

We have been utilizing the same methodology for giving chemotherapy for the last few decades. There has been a trend in more preoperative radiation for soft tissue sarcoma than postoperative in the last 10 to 15 years. The only way to advance the field is to try some new things in a safe manner. There is limited evidence in hypofractionated radiotherapy in sarcoma, but there is enough evidence to suggest it warrants being looked at. [With longer follow-up], if [hypofractionated radiotherapy] turned out to have an equal outcome, it certainly could change the field.

What is the key takeaway from this trial for physicians?

The key takeaway is you can only speak to what the data show. Early wound complication and toxicity rate from this series of patients is of an equivalent rate to that of conventional fractionated radiotherapy. We cannot speak more to that [currently]; we can't speak to local recurrence or local control. However, we can say that these patients are tolerating hypofractionated radiotherapy.

References

1. Lawrenz JM, Parsai S, Kilpatrick SE, et al. Early outcomes of preoperative 5-fraction radiation therapy for soft tissue sarcoma with immediate resection. Presented at: 2019 Musculoskeletal Tumor Society Annual Meeting; October 2-4, 2019; Portland, OR. Abstract 7.
2. Lawrenz JM, Parsai S, Kilpatrick SE, et al. Early outcomes of preoperative 5-fraction radiation therapy for soft tissue sarcoma with immediate resection. Presented at: CTOS 2019 Annual Meeting ; November 13-16, 2019; Tokyo, Japan. Abstract 3235168.