Journal of Surgical Oncology 2013;107:723–727

Tumor Size Increase Following Preoperative Radiation of Soft

Tissue Sarcomas Does Not Affect Prognosis

GADINI O. DELISCA, BS,1 VIGNESH K. ALAMANDA, BS,1 KRISTIN R. ARCHER, PhD, DPT,1 YANNA SONG, MS,2

HERBERT S. SCHWARTZ, MD,1 AND GINGER E. HOLT, MD1*

1Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

Background and Objectives: Administration of preoperative radiotherapy for extremity soft tissue sarcoma improves local control, while

allowing for a more conservative surgical resection. During radiation treatment tumor size typically decreases or remains constant. In a subset

of patients, however, a size increase in the tumor occurs. Our goal was to investigate the prognosis of patients who had a size increase of at

least 20% over the course of preoperative radiotherapy versus those who did not.

Methods: This retrospective study evaluated 70 patients treated for localized primary STS of the extremities between January 2000 and

December 2008. Kaplan–Meier curves for disease-specific and metastasis-free survival were calculated for both groups.

Results: Sixty-one patients had stable or decrease local tumor size following preoperative radiotherapy and nine patients had an increase of

at least 20% in tumor size. There were no statistically significant differences found in disease-specific survival and metastasis-free survival

(Gray’s test, P ¼ 0.93 and P ¼ 0.68, respectively) among the two groups.

Conclusion: Our results indicate that a 20% increase in tumor size following preoperative radiotherapy did not result in a worse outcome for

patients when compared to those who had stable or decrease local tumor size following preoperative radiotherapy.

J. Surg. Oncol. 2013;107:723–727. � 2013 Wiley Periodicals, Inc.

KEY WORDS: soft tissue sarcoma; radiation; metastasis; survival

INTRODUCTION

Soft tissue sarcomas (STS) are malignant neoplasms originating

in muscle, fat, nerves, tendons, synovial tissue, and blood vessels.

These rare tumors account for less than 1% of all cancers, and have

an incidence rate of approximately 3 per 100,000 people in United

States [1]. The standard of care for STS of the extremity continues

to be limb salvage surgery (LSS) with wide resection margins often

coupled with preoperative and/or postoperative external-beam radio-

therapy (XRT) [2,3]. Multiple studies have probed the prognostic

effects of marginal excision, preoperative versus postoperative XRT,

primary excision versus re-excision, among other factors, yet few, if

any have investigated the significance of an increase in tumor size

after preoperative radiotherapy on future prognosis [4–6].

Preoperative radiation can result in a reduction in tumor size by

inciting necrosis of the tumor. This results in improved local control

and facilitates a more conservative surgical resection [3]. In a minor-

ity of cases, however, not only is a size reduction not observed, but

an increase in size occurs. An increase in tumor size, secondary to

preoperative radiotherapy, is not always indicative of local disease

progression; rather, it may be attributed to a radiological or histolog-

ical response to treatment [7].

Our goal was to investigate the effects of an increase of at least

20% in tumor diameter in extremity STS following preoperative ra-

diotherapy on future prognosis, mainly survival and distant metasta-

sis. We hypothesized that an increase in tumor size following

radiotherapy would not change overall survival or time to metastasis.

MATERIALS AND METHODS

We conducted a retrospective cohort study at a major sarcoma

center to assess the prognostic effect of a 20% increase in local

tumor size with preoperative radiotherapy in patients who underwent

surgical resection after presenting with a primary localized STS of

the extremity. The 20% cutoff was chosen in accordance with the

RECIST criteria for tumor measurement on categorizing a target le-

sion as progressive disease [8]. All patients who underwent resection

of a primary STS of the extremity, after receiving preoperative radio-

therapy, between January 2000 and December 2008 (n ¼ 90), were

identified based on a retrospective review of medical records in our

institution’s database. Patients were excluded if they were younger

than 18 years of age, if they had metastatic disease (stage IV), if

they lacked sufficient medical records, or if their tumor was incom-

pletely excised elsewhere prior to receiving preoperative radiothera-

py. This study was approved by our Institutional Review Board.

A total of 70 patients met the inclusion criteria. The cohort was

then divided into two groups: Group A—those who had stable or

decreased local tumor size (n ¼ 61), and Group B - those who had

at least a 20% increase in tumor size (n ¼ 9). In the latter subset, a

20% increase was defined as a difference equal to or greater than

20% from pre-radiotherapy to post-radiotherapy tumor size. The pre-

radiotherapy and post-radiotherapy tumor size was determined by

measuring the maximum tumor diameter using T1 weighted magnet-

ic resonance imaging (MRI).

Each patient in our study was managed by a multidisciplinary

oncology team in a manner consistent with the current standard of

care. Upon referral for a consultation with one of our orthopedic

*Correspondence to: Ginger E. Holt, MD, Vanderbilt University MedicalCenter, Department of Orthopaedics and Rehabilitation, 1215 21st Ave.South, Medical Center East, South Tower, Suite 4200, Nashville, TN37232-8774. Fax: 615-343-1028. E-mail: ginger.e.holt@vanderbilt.edu

Received 4 November 2012; Accepted 7 January 2013

DOI 10.1002/jso.23322

Published online 11 February 2013 in Wiley Online Library(wileyonlinelibrary.com).

� 2013 Wiley Periodicals, Inc.

oncologists, the customary work up consisted of an open or core

needle biopsy, followed by a histological diagnosis, an MRI scan of

the tumor and a computed tomography (CT) scan of the chest. Each

patient subsequently underwent preoperative radiotherapy. The medi-

an preoperative radiation dose administered was 50 Gy with a range

of 45–62 Gy. Patients were then restaged. The STS was surgically

resected within 6 weeks of completion of preoperative radiotherapy.

Patient demographics and tumor characteristic were collected

from a retrospective review of medical records. Patient characteris-

tics included age at time of surgery, sex, and race. Tumor character-

istics consisted of pre-radiotherapy sarcoma size, post-radiotherapy

sarcoma size, depth (superficial or deep to investing fascia of under-

lying muscle), site (upper or lower extremity), histology grade (low,

intermediate, or high), and histological subtype. Staging of the sarco-

mas was also carried out as specified in the guidelines recommended

by the American Joint Committee on Cancer (AJCC) [9]. Patients

were staged according to their presentation prior to the initiation of

preoperative radiotherapy. Surgical margins were recorded as either

positive or negative for each patient. A positive margin was defined

as the presence of malignant cells at the inked margins. Additional

therapies (neoadjuvant chemotherapy, adjuvant chemotherapy and

postoperative radiation) received by the patient was also recorded. In

order to assess the prognostic effect of size change, we collected

data on survival status and distant metastasis rates.

Descriptive statistics were used to summarize variables and to as-

sess normality, identify outliers, determine appropriate summaries of

location and spread, and assess the need for nonparametric analysis.

Patient demographics, tumor characteristics, and prognostic out-

comes of disease-specific death and distant metastasis were com-

pared across groups (stable or decrease local tumor size versus 20%

increase in local tumor size) using Wilcoxon rank sum tests for con-

tinuous variables and chi-square or Fisher’s exact tests for dichoto-

mous and categorical variables. Survival curves for disease free

survival and metastasis free survival were calculated and presented

using the Kaplan–Meier method [10]. For the disease free survival

curve, the primary end point of the study was designated as death

due to sarcoma. Gray’s test was calculated and used to compare the

disease-specific hazards of death and distant metastasis between

patients with a decrease or no change in tumor size and patients with

an increase in tumor size [11,12]. Statistical software R (version

1.11.1, www.r-project.org) was used for all data analysis. Reported

P-values were two-sided and a P-value of less than 0.05 was consid-

ered to indicate statistical significance.

RESULTS

A total of 70 patients, with surgical resections performed between

January 2000 and December 2008, were included in our retrospective

study. Sixty-one of the patients, Group A, had stable or decrease

local tumor size following preoperative XRT. The remaining nine

patients, Group B, had at least a 20% increase in local tumor size

following preoperative XRT. A 20% increase in size was defined as a

growth of at least 20% from preoperative radiotherapy to post-preop-

erative radiotherapy maximum tumor diameter. A summary of the

cohort’s demographics and tumor characteristics are presented in

Table I. The median follow-up time for all patients was 2.77 years

(IQR, 1.11–4.58 years).

In addition to preoperative radiotherapy, 49% (n ¼ 30) of patients

in Group A and 67% (n ¼ 6) in Group B received a postoperative

radiation boost. One patient in Group B received neoadjuvant che-

motherapy. Adjuvant chemotherapy was administered to 10%

(n ¼ 6) of patients in Group A and to 33% (n ¼ 3) of those in

Group B. Positive resection margins were noted in 5% (n ¼ 3) of

the patients in Group A and in 11% (n ¼ 1) of those in Group B.

The median pre-radiotherapy tumor size in Group A was 14.2 cm

with 25% of the tumors measuring at or below 11.0 cm and 75%

measuring at or below 18.0 cm. In Group B, the median pre-radio-

therapy tumor size was 12.0 cm with 25% measuring at or below

12.0 cm and 75% measuring at or below 19.0 cm (Fig. 1). A total of

three (5%) patients in Group A and zero patients in Group B had

local recurrences. This difference was not statistically significant

(P ¼ 0.50). Three patients (5%) in Group A and one patient (11%)

in Group B had amputations where limb-sparing surgery was no lon-

ger deemed feasible.

Statistically significant differences in the two groups were noted

in post-radiotherapy size (P ¼ 0.003), change in tumor size

(P < 0.001), treatment with neoadjuvant chemotherapy (P ¼ 0.009)

and treatment with adjuvant chemotherapy (P ¼ 0.049). No other

statistically significant differences between patients in Groups A and

B were noted.

Sarcoma-Specific Death

Survival analysis indicated that the time to sarcoma-specific death

by tumor size change was not statistically significant (Gray’s test,

P ¼ 0.93; Fig. 2). At 6 years of follow-up, 22 out of 55 (40%)

Group A patients and three out of eight (37.5%) Group B patients

had died as a result of the disease.

Distant Metastasis

Survival analysis found no difference in the time to metastasis for

the two groups (Gray’s test, P ¼ 0.68; Fig. 3). At 6 years of follow-

up, 28 out of 56 (50%) Group A patients and three out of eight

(37.5%) Group B patients had developed distant metastasis.

Histology

The pathology reports for eight out of nine the patients in Group

B indicated tumor necrosis ranging from 10% to 95%. Hemorrhage

was noted in the pathologic evaluation of four out the nine tumors.

Cystic regions were indicated in three out of the nine tumors and

fibrosis was noted in 1.

Sub-Analysis: High Grade Sarcomas

A sub-analysis restricted to high grade sarcomas was conducted.

At 6 years follow up, 19 out of 41 (46.3%) patients with stable or

decrease tumor size and three out of seven (42.9%) patients with at

least a 20% increase in tumor size had died as a result of the disease

(Gray’s test, P ¼ 0.96). At 6 years follow-up, 24 out of 42 (57.1%)

patients with stable or decrease tumor size and three out of seven

(42.9%) patients with at least a 20% increase in tumor size had de-

veloped distant metastasis (Gray’s test, P ¼ 0.66).

DISCUSSION

Tumor size is a well-established prognostic factor in patients with

STS of the extremity with larger tumors portending a worse outcome

[13,14]. Further, preoperative radiotherapy has been shown to

improve local control in patients with STS [3]. The prognostic effect

between preoperative radiotherapy and change in tumor size, howev-

er, has yet to be definitively elucidated. An increase in tumor size

during preoperative radiotherapy is not the desired response and

maybe misperceived as disease progression. Thus, it is important to

determine whether or not an increase in tumor size secondary to

preoperative radiotherapy is detrimental to a patient’s prognosis.

The results of our retrospective cohort study found no statistically

significant differences in prognosis between patients in Group A

(those with stable or decrease local tumor size) and Group B (those

724 Delisca et al.

Journal of Surgical Oncology

with a 20% increase in local tumor size) as measured by disease-

specific survival and metastasis-free survival. Furthermore, a sub-

analysis restricted to high grade sarcomas yielded similar results.

While these results are consistent with the study by Miki et al. [15],

they used 10% as their size increase cut-off where we used 20%. It

should also be noted that in the Miki et al. study T-2 weighted scans

where used to measure tumor diameter, whereas we utilized T-1

measurements. T1 measurements were used since it provides a more

accurate depiction of tumor extent [16]. These differences notwith-

standing, both of our studies suggest that an increase in tumor size

following preoperative radiotherapy does not necessarily have a neg-

ative effect on the prognosis of a patient.

The similar results between patients in Groups A and B may be

explained, in part, by the fact that an increase in tumor size after

radiation does not always indicate a non-response to treatment. Fac-

tors other than tumor progression that can lead to an increase in

tumor size include necrosis, hemorrhage, and edema [7,15,17]. Thus,

an increase in tumor size can be attributed to, in some cases, what

would be considered favorable histopathological processes.

Histology review of the patients in Group B indicated tumor ne-

crosis ranging from 10% to 95%. Hemorrhage, cystic regions and

fibrosis were also seen. These findings confirm that a majority of the

tumors that had a 20% increase in maximal tumor diameter were still

undergoing favorable pathological processes indicative of treatment

TABLE I. Patient Demographics and Tumor Characteristics

Variable Group A (N ¼ 61) Group B (N ¼ 9) P-value Total (N ¼ 70)

Age, years, median (IQR) 57 (47.0–66.0) 59 (43.0–69.0) 0.94 57 (46.25–66.75)

Sex 1

Male 41 (67%) 6 (67%) 47 (67%)

Female 20 (33%) 3 (33%) 23 (33%)

Race 0.66

Caucasian 53 (87%) 8 (89%) 61 (87%)

African American 4 (7%) 1 (11%) 5 (7%)

Other 4 (7%) 0 (0%) 4 (6%)

Site 0.88

Upper extremity 12 (20%) 1 (11%) 13 (19%)

Lower extremity 49 (80%) 8 (89%) 57 (81%)

Size, cm, median (IQR)

Pre-radiotherapy 15.0 (11.0–20.0) 12.0 (10.0–19.0) 0.28 15.0 (11.0–18.75)

Post-radiotherapy 11.0 (7.5–15.5) 19.0 (16.0–23.0) 0.003 12.0 (8.13–16.0)

Tumor size change �3.0 (�7.0 to �1.0) 6.0 (4.0–7.0) <0.001 �2.5 (�6.0-0)

Depth 0.84

Superficial 2 (3%) 1 (11%) 3 (4%)

Deep 59 (97%) 8 (89%) 67 (96%)

Grade 0.46

I 5 (8%) 1 (11%) 6 (9%)

II 9 (15%) 0 (0%) 9 (13%)

III 47 (77%) 8 (89%) 55 (79%)

AJCC stage 0.72

I 13 (21%) 1 (11%) 14 (20%)

II 4 (7%) 1 (11%) 5 (7%)

III 44 (72%) 7 (78%) 51 (38%)

Microscopic margins 0.46

Negative 58 (95%) 8 (89%) 66 (92%)

Positive 3 (5%) 1 (11%) 6 (8%)

Histology type 0.30

Fibrosarcoma 1 (2%) 0 (0%) 1 (1%)

Leiomyosarcoma 6 (10%) 0 (0%) 6 (9%)

Liposarcoma 18 (30%) 4 (44%) 22 (31%)

Malignant fibrous histiocytoma (MFH) 30 (49%) 4 (44%) 34 (49%)

Synovial sarcoma 2 (3%) 0 (0%) 2 (3%)

Vascular sarcoma 0 (0%) 1 (11%) 1 (1%)

Rhabdomyosarcoma 2 (3%) 0 (0%) 2 (3%)

Others 2 (3%) 0 (0%) 2 (3%)

Neoadjuvant chemotherapy 0 (0%) 1 (11%) 0.009 1 (1%)

Adjuvant chemotherapy 6 (10%) 3 (33%) 0.049 9 (13%)

Postoperative radiotherapy 30 (49%) 6 (67%) 0.33

Survival status 0.97

Alive 32 (52%) 5 (56%) 37 (53%)

Died of disease 23 (38%) 3 (33%) 26 (37%)

Died of other causes 6 (10%) 1 (11%) 7 (10%)

Local recurrence 0.50 3 (4%)

Yes 3 (5%) 0 (0%) 3 (4%)

No 58 (95%) 9 (100%) 67 (96%)

Distant metastasis 0.48

Yes 28 (46%) 3 (33%) 31 (44%)

No 33 (54%) 6 (66%) 39 (56%)

Follow-up time, years, median (IQR) 2.70 (1.14–5.12) 3.02 (0.98–4.22) 0.65 2.77 (1.11–4.58)

Preoperative XRT of STS 725

Journal of Surgical Oncology

response. Hemorrhage and the cystic regions may, in fact, have con-

tributed to the size increase. The one case of fibrosis was likely pre-

cipitated by inflammatory processes which may account for a

transient increase in size. Extensive fibrosis, on the other hand,

which is rarely present, can account for a long term increase in size.

In most, if not all, cancers, a reduction in tumor size is a favor-

able determinant in assessing local control. In both radiotherapy and

chemotherapy the goal is to target rapidly dividing cells, thereby

effectively reducing the number of viable cancer cells. A study by

Eilber et al. [18] showed that treatment-induced necrosis correlated

with a lower rate of local recurrence and an improvement in overall

survival in patients receiving neoadjuvant therapy for high grade

STS of the extremity. Thus, in the case of STS, a reduction in

cancerous cells, in the setting of preoperative radiotherapy, not only

improves local control, but also improves patient outcomes. The spe-

cific causes and effects of radiation-induced necrosis (RIN) have

been described in many studies [19,20]. RIN occurs in tumors that

show either an increase or decrease in size in response to neoadju-

vant radiotherapy. This demonstrates the importance of determining

whether an increase in tumor size is attributed to a favorable patho-

logical process versus progression of the cancer.

Since tumor size may not always adequately reflect tumor re-

sponse, imaging modalities can be used to help determine the patho-

logical effects of neoadjuvant therapy [21]. MRI and positron

emission tomography (PET) can be used to monitor cellular activity

of malignant cells [22,23]. Choong et al. found that Thallium-201

scintigraphy maybe a good predictor of STS histological response to

preoperative radiotherapy [23]. Although these imaging modalities

can potentially help characterize tumor response, they often are not

employed (with the exception of MRI) due to costs to the patient,

risks, or other feasibility concerns. Further, the efficacy of these tools

as predictors of prognosis is still being investigated.

Three long-term side effects of preoperative radiotherapy include

wound complications, decrease range of motion, and bone fractures

[24,25]. When a complication of preoperative radiotherapy is cou-

pled with an increase in tumor size, the chances of discontinuing

radiation treatment is increased. In many cases, discontinuing radio-

therapy is justified, especially when side effects are severe. Termina-

tion of preoperative radiotherapy of a STS mainly due to a size

increase, however, may not always be warranted. Since preoperative

radiotherapy can improve local control, it is important to determine

Fig. 1. Box plots comparing pre-radiotherapy and post-radiotherapytumor measurements.

Fig. 2. Survival curves for disease-specific survival for patientshaving at least a 20% increase in tumor size versus those who didnot following preoperative radiotherapy.

Fig. 3. Metastasis curves for patients having at least a 20% increasein tumor size versus those who did not following preoperativeradiotherapy.

726 Delisca et al.

Journal of Surgical Oncology

whether the size increase is due to disease progression or due to a

favorable tumor response to treatment. To help delineate the differ-

ences, gadolinium enhanced MRI may be used. In the event the

enhanced MRI findings are equivocal, a tissue biopsy should be con-

sidered. Those considerations notwithstanding, more research on the

prognostic effects of size change following preoperative radiotherapy

needs to be done.

Since this study looks at the prognostic effects tumor size change

after preoperative radiotherapy at a single institution, it is inherently

underpowered in some of the analyses conducted. Thus, a beta error

cannot be ruled out with certainty. Additional therapies such as

chemotherapy and postoperative radiation were not applied to all

patients. Both chemotherapy and postoperative radiotherapy could

influence prognosis. Furthermore, in our study the proportion of

patients in Group A versus Group B receiving neoadjuvant or adju-

vant chemotherapy were statistically significant. Patients in Group B

may have received adjuvant chemotherapy at a higher rate than those

in Group A due to the perception that the size increase portended a

worse outcome, thus necessitating adjuvant treatment.

In conclusion, our findings show that a 20% increase in the size

of a localized primary STS of the extremity after preoperative radio-

therapy does not result in a worse outcome for the patient. This find-

ing can be attributed to the fact that an increase in tumor size does

not always indicate disease progression; rather, it could be indicative

of a favorable tumor response to treatment. When disease progres-

sion is suspected due to increased local tumor size, verification

through imaging, re-staging, or a biopsy is critical.

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