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Dermatofibrosarcoma Protuberans: Long-term Outcomes of 53 Patients Treated With Conservative Surgery and Radiation Therapy
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Sarcoma
Dermatofibrosarcoma Protuberans: Long-term Outcomes of 53 Patients Treated With Conservative Surgery and Radiation Therapy Katherine O. Castle, MD,* B. Ashleigh Guadagnolo, MD, MPH,* C. Jillian Tsai, MD, PhD,* Barry W. Feig, MD,y and Gunar K. Zagars, MD* Departments of *Radiation Oncology and ySurgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas Received Nov 26, 2012, and in revised form Feb 12, 2013. Accepted for publication Feb 19, 2013
Summary Dermatofibrosarcoma protuberans is a rare cutaneous tumor, with surgery as the primary treatment modality but with a propensity for local recurrence. This retrospective study evaluated outcomes of patient treated with conservative surgery and adjuvant radiation therapy (both preoperative and postoperative). Results showed that this combinedmodality approach led to excellent local control even in patients with large or recurrent tumors. Adjuvant radiation should be considered for appropriately selected patients.
Purpose: To evaluate outcomes of conservative surgery and radiation therapy (RT) treatment in patients with dermatofibrosarcoma protuberans. Methods and Materials: We retrospectively reviewed the medical records of 53 consecutive dermatofibrosarcoma protuberans patients treated with surgery and preoperative or postoperative radiation therapy between 1972 and 2010. Median tumor size was 4 cm (range, 1-25 cm). Seven patients (13%) were treated with preoperative RT (50-50.4 Gy) and 46 patients (87%) with postoperative RT (60-66 Gy). Of the 46 patients receiving postoperative radiation, 3 (7%) had gross disease, 14 (30%) positive margins, 26 (57%) negative margins, and 3 (7%) uncertain margin status. Radiation dose ranged from 50 to 66 Gy (median dose, 60 Gy). Results: At a median follow-up time of 6.5 years (range, 0.5 months-23.5 years), 2 patients (4%) had disease recurrence, and 3 patients (6%) had died. Actuarial overall survival was 98% at both 5 and 10 years. Local control was 98% and 93% at 5 and 10 years, respectively. Disease-free survival was 98% and 93% at 5 and 10 years, respectively. The presence of fibrosarcomatous change was not associated with increased risk of local or distant relapse (PZ.43). One of the patients with a local recurrence had gross residual disease at the time of RT and despite RT to 65 Gy developed both an in-field recurrence and a nodal and distant recurrence 3 months after RT. The other patient with local recurrence was found to have in-field recurrence 10 years after initial treatment. Thirteen percent of patients had an RT complication at 5 and 10 years, and 9% had a moderate or severe complication at 5 and 10 years. Conclusions: Dermatofibrosarcoma protuberans is a radioresponsive disease with excellent local control after conservative surgery and radiation therapy. Adjuvant RT should be considered for patients with large or recurrent tumors or when attempts at wide surgical margins would result in significant morbidity. Ó 2013 Elsevier Inc.
Reprint requests to: B. Ashleigh Guadagnolo, MD, MPH, University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Unit 0097, 1515 Holcombe Boulevard, Houston, TX 77030. Tel: (713) 563-8400; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 585e590, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.02.024
Presented in part at the 54th Annual Meeting of American Society for Radiation Oncology, October 28-31, 2012, Boston, MA. Conflict of interest: B.W.F. has received payment for lectures, including service on speakers bureaus from Genomic Health.
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Introduction
Patient and tumor characteristics
Dermatofibrosarcoma protuberans (DFSP) is an uncommon lowgrade cutaneous soft-tissue sarcoma with an incidence rate of 4.5 cases per million persons per year in the United States (1). These tumors tend to exhibit an indolent growth pattern and have little potential for metastatic spread. Because of DFSP’s infiltrative naturedwhich can be clinically difficult to appreciatedit is often characterized by aggressive local behavior. As a result, expert local treatment is paramount to achieving successful outcomes. The primary treatment modality is conservative surgical resection with wide local excision, leading to complete resection of tumor with 1-3-cm margins (depending on anatomic location and approximation to critical structures). The local recurrence rate after surgery ranges from 0 to 63% percent, depending on the nature of the surgery and the ability to obtain widely negative margins (2-4). Negative margins are often not attained as a result of the size or location of the tumor or misdiagnosis at the time of initial resection. In general, when final margins are negative local recurrence is quite low, with ranges from 0 to 13% (3-7). With close or positive margins, however, local recurrence ranges from 21% to 82% according to published series (3-5, 8). The high risk of local recurrence after inadequate surgical resection gives reason to consider adjuvant radiation therapy when re-resection is not an option. Because of the rarity of DFSP, however, there are no prospective randomized studies evaluating adjuvant radiation therapy. Several single-institution series have looked at outcomes after adjuvant radiation therapy. These studies have reported excellent local control (between 80% and 100%), even when patients with positive margins or multiple recurrences are included (5, 9-13). However, these data are limited by small numbers of patients and, in some cases, short follow-up. Nonetheless, these studies collectively suggest that limited surgical resection combined with radiation therapy is an acceptable treatment option when complete surgical resection would be challenging or associated with significant morbidity. The previous analysis of our experience included 19 patients (32% with positive microscopic margins) and found that 10-year actuarial local control was 95% with total radiation doses of 50-60 Gy. We have undertaken an update of this analysis based on our experience treating DFSP patients with conservative surgery and radiation therapy. We report long-term outcomes in the largest series to date of patients with dermatofibrosarcoma protuberans treated with adjuvant radiation therapy.
Patients ranged in age from 19 to 76 years (mean, 41 years; median, 38 years), and 57% were male. Seventy-two percent of all patients were white, 26% black, and 2% Asian (Table 1). The anatomic distribution of lesions was as follows: 19 (36%) were located in the trunk, 11 (21%) on the scalp, 8 (15%) on other headand-neck sites (neck, parotid, preauricular, infraorbital, cheek, and chin), 8 (15%) on the upper extremities, and 7 (13%) on the lower extremities (Fig. 1). Tumor size was documented in 51 patients and ranged from 1 to 25 cm in maximal dimension. The mean and median sizes were 5.1 and 4 cm, respectively. Tumor size was 5 cm in 36 patients (68%) and >5 cm in 15 patients (28%). No patients had clinical evidence of lymphatic or hematogenous spread of disease at the time of initial treatment. Fifty-one patients (96%) had surgical excision or biopsy before referral to MD Andersoon Cancer Center (MDACC), and 19 patients had a biopsy only. Twenty-four patients (45%) had 1 or more recurrences before referral. According to physical examination, evaluation of submitted slides, and outside operative/biopsy reports, 13 patients (25%) had gross disease, 22 (42%) had positive margins, 11 (21%) had negative margins, and 7 (13%) had uncertain margin status. The evaluating surgeon established the need for re-excision on the basis of the adequacy of the prior surgical excision, the location and extent of any residual disease, and morbidity associated with additional surgery. For patients with gross tumor at the time of presentation, preoperative irradiation was preferred for larger lesions. Otherwise, patients received postoperative irradiation. Thirty-four patients (64%) underwent re-excision at our institution, whereas 19 (36%) received radiation after the surgical resection at an outside institution (2 of these patients had gross disease, 7 positive margins, 8 negative margins, and 2 uncertain margin status). Thirteen patients (25%) were found to have fibrosarcomatous change. If patients had radiation before re-excision at MDACC, regardless of previous outside management, they were considered to have had preoperative radiation. In total, 7 patients (13%) received preoperative radiation followed by surgery, and 46
Methods and Materials Patients were identified through a search of the Department of Radiation Oncology database. Approval was obtained from our institution’s institutional review board before review of these data. Between 1972 and 2010, 53 consecutive patients with DFSP received radiation therapy as a component of their definitive treatment (adjuvant to surgical resection). Patients were worked up according to the current standard of care at the time of their assessment. This typically included a full history, complete physical examination, and appropriate imaging. Before radiation treatment, all cases were reviewed by a pathologist at our institution, and histopathologic diagnosis of DFSP was confirmed.
Table 1 Patient and tumor characteristics N Age (y), median (range) Sex Male Female White Black Asian Tumor size (cm), median (range) Tumor size (cm) 5 >5 Surgical excision or biopsy before referral to MDACC 1 recurrence before referral to MDACC
53 38 (19-76) 30 23 38 14 5 4
(57) (43) (72) (26) (2) (1-25)
36 (68) 15 (28) 51 (96) 24 (45)
Abbreviation: MDACC Z University of Texas MD Anderson Cancer Center. Values are number (percentage) unless otherwise noted.
Volume 86 Number 3 2013
Conservative surgery and adjuvant RT for DFSP Table 2
Treatment characteristics
N Re-excision at MDACC Treatment sequence Preoperative radiation Postoperative radiation Margin status at postoperative RT Gross disease Positive margin Negative margin Uncertain Radiation dose (Gy), median (range) Preoperative RT Postoperative RT Radiation technique Appositional electrons alone Mixed electrons þ photons Conventional photons Other
Fig. 1.
Anatomic location of lesions.
patients (87%) underwent surgical resection followed by postoperative radiation. (See Table 2 for all treatment-related characteristics.) Of the 46 patients receiving postoperative radiation, 3 (7%) had gross disease, 14 (30%) had positive margins, 26 (57%) negative margins, and 3 (7%) had uncertain margin status. The majority of patients, 53%, were treated with appositional electrons alone, whereas 28% were treated with mixed electron and photon plans, and 9% were treated with conventional photons alone. In general, the clinical target volume consisted of the gross tumor or tumor bed with a 5-cm radial margin and 2-cm-deep margin. The median total radiation dose was 60 Gy (range, 50-66 Gy) for all patients. The median dose was 50 Gy (range, 50-60 Gy) for patients receiving preoperative radiation and 60 Gy (range, 50-66 Gy) for those receiving postoperative radiation. Dose per fraction (fx) ranged from 1.1 Gy/fx to 2.5 Gy/fx. Only 5 patients total were treated with radiation doses greater than 60 Gy: 2 patients with gross disease and 3 patients with positive margins after surgery. Only 1 patient received systemic therapy. This patient presented with gross residual disease and fibrosarcomatous features on pathology after an outside excisional biopsy and was treated with preoperative radiation therapy with concurrent imatinib, followed by a margin-negative wide local excision and adjuvant imatinib.
587
53 34 (64) 7 (13) 46 (87) 3 14 26 3
(7) (30) (57) (7)
50 (50-60) 60 (50-66) 28 15 5 5
(53) (28) (9) (9)
Abbreviations: MDACC Z University of Texas MD Anderson Cancer Center; RT Z radiation. Values are number (percentage) unless otherwise noted.
Local control was defined as no regrowth of tumor. Overall survival was defined as death from any cause. Radiation-related complications were graded as mild (self-limited and requiring no treatment), moderate (requiring conservative medical management), or severe (requiring surgical intervention or hospitalization).
Results Overall outcomes Of 53 patients, 2 (4%) experienced local relapse after radiation therapy. Actuarial local control and disease-free survival rates were 98% and 93% at 5 and 10 years, respectively (Fig. 2). Fifty patients (94%) were alive at last follow-up, and 3 had died. One
Statistical analysis, follow-up, and complication grading The median follow-up time from the completion of radiation therapy was 6.5 years (range, 0.5 months-23.5 years). The Kaplan-Meier method was used to determine local control, survival, disease-free survival, and complications. The significance of difference between proportions was determined using c2 or Fisher’s exact test as appropriate. A P value of .05 was considered statistically significant. Patients were censored at the time of last documented follow-up or correspondence.
Fig. 2. Actuarial local control for all patients with dermatofibrosarcoma protuberans.
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completing radiation therapy the patient developed a 3-cm lesion on the left foot within the prior irradiation field. He underwent radical resection, and pathology confirmed DFSP. He has no evidence of recurrent disease 2.5 years after surgical management of his recurrence.
Treatment complications
Fig. 3. Actuarial overall survival for all patients with dermatofibrosarcoma protuberans. patient died as a result of metastatic disease, with the circumstances described below. Actuarial overall survival rates were 98% at both 5 and 10 years (Fig. 3). Median overall survival was 22 years (range, 18-25 years). Fibrosarcomatous change was not associated with increased risk of either local or distant relapse (PZ.43).
Local recurrences One patient who experienced local relapse presented with a 25-cm ulcerating mass involving the right vulva and a biopsy consistent with DFSP. She underwent a margin-negative wide local excision and was observed until an 8-cm local recurrence was identified 6 months later (Table 3). She underwent re-excision with focally positive margins. Her postoperative course was complicated by delayed wound healing, and before initiating postoperative radiation therapy she developed a multifocal local recurrence. She was then treated with 65 Gy over 6.5 weeks and had a complete clinical response. However, 3 months later she developed multiple nodules within and adjacent to the radiation treatment field, as well as nodal disease and subsequently metastatic disease. Pathology from the recurrence revealed spindle cell sarcoma, without the classic appearance of DFSP seen in her index lesion. The patient ultimately died of metastatic disease less than 2 years after the completion of her radiation therapy. The other patient who developed a local recurrence presented with a 3-cm lesion on the left foot that was biopsy-proven DFSP. Five weeks after undergoing excision with positive margins the patient was treated with 60 Gy in 30 fractions. Ten years after
Table 3 Age (y) 76 31
Radiation-related complications occurred in 6 patients (11%), with a median time to complications of 9.5 months (range, 2.5 months-3.5 years) (Table 4). Actuarial rates of all radiationinduced complications were 13% at both 5 and 10 years. Four of the 6 patients had severe complications. The actuarial rates of severe radiation related complications were 9% at both 5 and 10 years. Five of the 6 patients with complications were treated with 60 Gy in 30 fractions, whereas the sixth patient was treated with 54 Gy in 26 fractions. Three patients had skin graft failure (2 of whom also had associated soft-tissue necrosis). All 3 necessitated additional surgical intervention, despite a minimum of 6 weeks between surgery and the start of radiation.
Discussion For patients with biopsy-proven DFSP, surgical resection in the form of wide local excision is the mainstay of treatment. However, depending on the type of surgery as well as the size and location of the tumor, negative margins may be unachievable without significant morbidity. If these patients are not candidates for reresection, National Comprehensive Cancer Network guidelines recommend that adjuvant therapy in the form of radiation therapy or imatibib mesylate be considered (14). Our present series demonstrates that the combination of conservative surgery and adjuvant radiation therapy provides excellent long-term disease control, with 10-year actuarial local control of 93% for patients with a clinical history of multiple recurrences or positive margins after surgery. This adds to a growing body of literatured consisting primarily of small single-institution retrospective studiesdthat evaluates the role of adjuvant radiation therapy in the treatment of DFSP. To date, this is the largest series of patients treated with adjuvant radiation therapy after conservative surgery for DFSP. Our data, in agreement with a growing body of literature, support the use of adjuvant radiation therapy in appropriately selected patients with DFSP. Three of the published series looking at adjuvant radiation have included patients with recurrent disease, often times multiply recurrent. These series demonstrated excellent local control, as was observed in our series (5, 9, 10). The role of radiation therapy as sole therapy for DFSP remains unclear. There are few reported cases in the literature in
Local recurrences Lesion size (cm) 25 3
Lesion site Vulva Foot
Abbreviation: RT Z radiation.
No. of excisions before RT 2 1
Margin status at time of RT Gross disease Positive
RT dose (Gy) 65 60
RT technique
Time to event
Photons Mixed appositional photons/electrons
21 wk 10 y
Volume 86 Number 3 2013 Table 4
Conservative surgery and adjuvant RT for DFSP
Treatment-related complications
Site (size)
No. of excisions
Time from surgery to RT (wk)
30
Breast (2 cm)
2
6
WLE þ pectoralis flap
64
Cheek (4 cm)
2
6
64
Chin (3 cm)
3
3.5
WLE þ rotational flap reconstruction WLE/marginal mandibulectomy þ flap reconstruction
66
Forehead (5 cm)
3
9
56
Scalp (2.5 cm)
3
6
47
Back (7 cm)
1
25
Age (y)
589
Surgery
Dose/technique 60 Gy, appositional electrons 60 Gy, appositional electrons 60 Gy, photons
Time to event 15 mo 9 mo 9 mo
Moh’s surgery þ delayed 54 Gy, mixed 3.5 y split thickness graft appositional electrons reconstruction and photons WLE þ split thickness 60 Gy, appositional 2.5 mo skin graft electrons WLE þ skin graft 60 Gy, appositional 6 mo electrons
Complication (severity) Breast implant asymmetry (mild) Edema þ xerostomia (mild) Osteoradionecrosis þ fracture requiring mandibulectomy (severe) Soft-tissue necrosis requiring surgery (severe) Graft failure (severe) Soft-tissue necrosis þ graft failure (severe)
Abbreviations: RT Z radiation; WLE Z wide local excision.
which radiation alone was used. Suit et al (5) included 3 patients with tumors ranging from 4 to 8.5 cm who were treated with radiation therapy alone to total doses ranging from 66.7 Gy to 74 Gy. Local control was achieved in all of these cases. In our series, 3 patients had gross disease ranging from 0.5 cm to 4 cm after surgical resection and were treated with external beam radiation therapy with total doses between 60 and 65 Gy. One of 3 patients had documented local recurrence of disease after 60 Gy radiation. The benefit of adjuvant radiation therapy must be weighed against the risk of toxicity. Several studies that included patients treated with adjuvant radiation therapy did not report on toxicity from radiation therapy (2, 5, 15). In the previously published series from our institution consisting of 19 patients with a median follow-up of 6 years, there were no clinically significant sequelae of radiation therapy (9). In the series published by Sun et al (12), 6 patients were found to have moderate (grade 2) fibrosis or telangiectasias within the radiation treatment field. All had been treated with electron beam therapy. Marks et al (10) looked at 10 patients treated with adjuvant radiation therapy and found that 1 patient developed wound breakdown 4 years after radiation therapy. In our series, radiation-related complications occurred in 6 patients (11%). Our single-institution retrospective study has inherent limitations. First, because of the rarity of the disease this series spans multiple treatment eras. Although radiation planning for this disease site has not drastically changed over the course of time, the adaption of CT-based treatment planning provides better visualization of the tumor or operative bed and allows for optimal target coverage and potential reduction in toxicity relative to older treatment techniques, and our series does not distinguish 2dimensional from 3-dimensional planning. Furthermore, this cohort of patients represents a heterogeneous group selected by surgeons and radiation oncologists according to specific patient and tumor characteristics, leading to selection bias regarding treatment recommendations. Additionally, given the indolent nature of the disease and its radiosensitivity, there were very few events. This attests to the excellent local control of
conservative surgery and radiation therapy but prevents further exploration of prognostic factors as well as the effect of specific treatment strategies and dose.
Conclusion Dermatofibrosarcoma protuberans is a radioresponsive disease with excellent local control after conservative surgery in combination with radiation therapy. Radiation therapy should be considered for patients with large (>5 cm) or recurrent tumors. Radiation therapy should also be considered for patients when complete resection with negative margins is not possible or when repeated attempts at wide surgical margins would result in significant morbidity. Radiation therapy can be delivered either preoperatively (50 Gy in 25 fractions) or postoperatively (60 Gy in 30 fractions; with higher doses up to 66 Gy in 33 fractions for patients with positive resection margins).
References 1. Rouhani P, Fletcher CD, Devesa SS, et al. Cutaneous soft tissue sarcoma incidence patterns in the U.S.: An analysis of 12,114 cases. Cancer 2008;113:616-627. 2. Rutgers EJ, Kroon BB, Albus-Lutter CE, et al. Dermatofibrosarcoma protuberans: Treatment and prognosis. Eur J Surg Oncol 1992;18:241248. 3. Connelly JH, Evans HL. Dermatofibrosarcoma protuberans. A clinicopathologic review with emphasis on fibrosarcomatous areas. Am J Surg Pathol 1992;16:921-925. 4. Lindner NJ, Scarborough MT, Powell GJ, et al. Revision surgery in dermatofibrosarcoma protuberans of the trunk and extremities. Eur J Surg Oncol 1999;25:392-397. 5. Suit H, Spiro I, Mankin HJ, et al. Radiation in management of patients with dermatofibrosarcoma protuberans. J Clin Oncol 1996;14:23652369.
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6. DuBay D, Cimmino V, Lowe L, et al. Low recurrence rate after surgery for dermatofibrosarcoma protuberans: A multidisciplinary approach from a single institution. Cancer 2004;100:1008-1016. 7. Nouri K, Lodha R, Jimenez G, et al. Mohs micrographic surgery for dermatofibrosarcoma protuberans: University of Miami and NYU experience. Dermatol Surg 2002;28:1060-1064. discussion 1064. 8. Meguerditchian AN, Wang J, Lema B, et al. Wide excision or Mohs micrographic surgery for the treatment of primary dermatofibrosarcoma protuberans. Am J Clin Oncol 2010;33:300-303. 9. Ballo MT, Zagars GK, Pisters P, et al. The role of radiation therapy in the management of dermatofibrosarcoma protuberans. Int J Radiat Oncol Biol Phys 1998;40:823-827. 10. Marks LB, Suit HD, Rosenberg AE, et al. Dermatofibrosarcoma protuberans treated with radiation therapy. Int J Radiat Oncol Biol Phys 1989;17:379-384.
International Journal of Radiation Oncology Biology Physics 11. Khatri VP, Galante JM, Bold RJ, et al. Dermatofibrosarcoma protuberans: Reappraisal of wide local excision and impact of inadequate initial treatment. Ann Surg Oncol 2003;10:1118-1122. 12. Sun LM, Wang CJ, Huang CC, et al. Dermatofibrosarcoma protuberans: Treatment results of 35 cases. Radiother Oncol 2000;57: 175-181. 13. Dagan R, Morris CG, Zlotecki RA, et al. Radiotherapy in the treatment of dermatofibrosarcoma protuberans. Am J Clin Oncol 2005;28: 537-539. 14. Miller SJ, Alam M, Andersen JS, et al. Dermatofibrosarcoma protuberans. J Natl Compr Canc Netw 2012;10:312-318. 15. Haas RL, Keus RB, Loftus BM, et al. The role of radiotherapy in the local management of dermatofibrosarcoma protuberans. Soft Tissue Tumours Working Group. Eur J Cancer 1997;33: 1055-1060.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Sarcoma
Dermatofibrosarcoma Protuberans: Long-term Outcomes of 53 Patients Treated With Conservative Surgery and Radiation Therapy Katherine O. Castle, MD,* B. Ashleigh Guadagnolo, MD, MPH,* C. Jillian Tsai, MD, PhD,* Barry W. Feig, MD,y and Gunar K. Zagars, MD* Departments of *Radiation Oncology and ySurgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas Received Nov 26, 2012, and in revised form Feb 12, 2013. Accepted for publication Feb 19, 2013
Summary Dermatofibrosarcoma protuberans is a rare cutaneous tumor, with surgery as the primary treatment modality but with a propensity for local recurrence. This retrospective study evaluated outcomes of patient treated with conservative surgery and adjuvant radiation therapy (both preoperative and postoperative). Results showed that this combinedmodality approach led to excellent local control even in patients with large or recurrent tumors. Adjuvant radiation should be considered for appropriately selected patients.
Purpose: To evaluate outcomes of conservative surgery and radiation therapy (RT) treatment in patients with dermatofibrosarcoma protuberans. Methods and Materials: We retrospectively reviewed the medical records of 53 consecutive dermatofibrosarcoma protuberans patients treated with surgery and preoperative or postoperative radiation therapy between 1972 and 2010. Median tumor size was 4 cm (range, 1-25 cm). Seven patients (13%) were treated with preoperative RT (50-50.4 Gy) and 46 patients (87%) with postoperative RT (60-66 Gy). Of the 46 patients receiving postoperative radiation, 3 (7%) had gross disease, 14 (30%) positive margins, 26 (57%) negative margins, and 3 (7%) uncertain margin status. Radiation dose ranged from 50 to 66 Gy (median dose, 60 Gy). Results: At a median follow-up time of 6.5 years (range, 0.5 months-23.5 years), 2 patients (4%) had disease recurrence, and 3 patients (6%) had died. Actuarial overall survival was 98% at both 5 and 10 years. Local control was 98% and 93% at 5 and 10 years, respectively. Disease-free survival was 98% and 93% at 5 and 10 years, respectively. The presence of fibrosarcomatous change was not associated with increased risk of local or distant relapse (PZ.43). One of the patients with a local recurrence had gross residual disease at the time of RT and despite RT to 65 Gy developed both an in-field recurrence and a nodal and distant recurrence 3 months after RT. The other patient with local recurrence was found to have in-field recurrence 10 years after initial treatment. Thirteen percent of patients had an RT complication at 5 and 10 years, and 9% had a moderate or severe complication at 5 and 10 years. Conclusions: Dermatofibrosarcoma protuberans is a radioresponsive disease with excellent local control after conservative surgery and radiation therapy. Adjuvant RT should be considered for patients with large or recurrent tumors or when attempts at wide surgical margins would result in significant morbidity. Ó 2013 Elsevier Inc.
Reprint requests to: B. Ashleigh Guadagnolo, MD, MPH, University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Unit 0097, 1515 Holcombe Boulevard, Houston, TX 77030. Tel: (713) 563-8400; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 585e590, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.02.024
Presented in part at the 54th Annual Meeting of American Society for Radiation Oncology, October 28-31, 2012, Boston, MA. Conflict of interest: B.W.F. has received payment for lectures, including service on speakers bureaus from Genomic Health.
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International Journal of Radiation Oncology Biology Physics
Introduction
Patient and tumor characteristics
Dermatofibrosarcoma protuberans (DFSP) is an uncommon lowgrade cutaneous soft-tissue sarcoma with an incidence rate of 4.5 cases per million persons per year in the United States (1). These tumors tend to exhibit an indolent growth pattern and have little potential for metastatic spread. Because of DFSP’s infiltrative naturedwhich can be clinically difficult to appreciatedit is often characterized by aggressive local behavior. As a result, expert local treatment is paramount to achieving successful outcomes. The primary treatment modality is conservative surgical resection with wide local excision, leading to complete resection of tumor with 1-3-cm margins (depending on anatomic location and approximation to critical structures). The local recurrence rate after surgery ranges from 0 to 63% percent, depending on the nature of the surgery and the ability to obtain widely negative margins (2-4). Negative margins are often not attained as a result of the size or location of the tumor or misdiagnosis at the time of initial resection. In general, when final margins are negative local recurrence is quite low, with ranges from 0 to 13% (3-7). With close or positive margins, however, local recurrence ranges from 21% to 82% according to published series (3-5, 8). The high risk of local recurrence after inadequate surgical resection gives reason to consider adjuvant radiation therapy when re-resection is not an option. Because of the rarity of DFSP, however, there are no prospective randomized studies evaluating adjuvant radiation therapy. Several single-institution series have looked at outcomes after adjuvant radiation therapy. These studies have reported excellent local control (between 80% and 100%), even when patients with positive margins or multiple recurrences are included (5, 9-13). However, these data are limited by small numbers of patients and, in some cases, short follow-up. Nonetheless, these studies collectively suggest that limited surgical resection combined with radiation therapy is an acceptable treatment option when complete surgical resection would be challenging or associated with significant morbidity. The previous analysis of our experience included 19 patients (32% with positive microscopic margins) and found that 10-year actuarial local control was 95% with total radiation doses of 50-60 Gy. We have undertaken an update of this analysis based on our experience treating DFSP patients with conservative surgery and radiation therapy. We report long-term outcomes in the largest series to date of patients with dermatofibrosarcoma protuberans treated with adjuvant radiation therapy.
Patients ranged in age from 19 to 76 years (mean, 41 years; median, 38 years), and 57% were male. Seventy-two percent of all patients were white, 26% black, and 2% Asian (Table 1). The anatomic distribution of lesions was as follows: 19 (36%) were located in the trunk, 11 (21%) on the scalp, 8 (15%) on other headand-neck sites (neck, parotid, preauricular, infraorbital, cheek, and chin), 8 (15%) on the upper extremities, and 7 (13%) on the lower extremities (Fig. 1). Tumor size was documented in 51 patients and ranged from 1 to 25 cm in maximal dimension. The mean and median sizes were 5.1 and 4 cm, respectively. Tumor size was 5 cm in 36 patients (68%) and >5 cm in 15 patients (28%). No patients had clinical evidence of lymphatic or hematogenous spread of disease at the time of initial treatment. Fifty-one patients (96%) had surgical excision or biopsy before referral to MD Andersoon Cancer Center (MDACC), and 19 patients had a biopsy only. Twenty-four patients (45%) had 1 or more recurrences before referral. According to physical examination, evaluation of submitted slides, and outside operative/biopsy reports, 13 patients (25%) had gross disease, 22 (42%) had positive margins, 11 (21%) had negative margins, and 7 (13%) had uncertain margin status. The evaluating surgeon established the need for re-excision on the basis of the adequacy of the prior surgical excision, the location and extent of any residual disease, and morbidity associated with additional surgery. For patients with gross tumor at the time of presentation, preoperative irradiation was preferred for larger lesions. Otherwise, patients received postoperative irradiation. Thirty-four patients (64%) underwent re-excision at our institution, whereas 19 (36%) received radiation after the surgical resection at an outside institution (2 of these patients had gross disease, 7 positive margins, 8 negative margins, and 2 uncertain margin status). Thirteen patients (25%) were found to have fibrosarcomatous change. If patients had radiation before re-excision at MDACC, regardless of previous outside management, they were considered to have had preoperative radiation. In total, 7 patients (13%) received preoperative radiation followed by surgery, and 46
Methods and Materials Patients were identified through a search of the Department of Radiation Oncology database. Approval was obtained from our institution’s institutional review board before review of these data. Between 1972 and 2010, 53 consecutive patients with DFSP received radiation therapy as a component of their definitive treatment (adjuvant to surgical resection). Patients were worked up according to the current standard of care at the time of their assessment. This typically included a full history, complete physical examination, and appropriate imaging. Before radiation treatment, all cases were reviewed by a pathologist at our institution, and histopathologic diagnosis of DFSP was confirmed.
Table 1 Patient and tumor characteristics N Age (y), median (range) Sex Male Female White Black Asian Tumor size (cm), median (range) Tumor size (cm) 5 >5 Surgical excision or biopsy before referral to MDACC 1 recurrence before referral to MDACC
53 38 (19-76) 30 23 38 14 5 4
(57) (43) (72) (26) (2) (1-25)
36 (68) 15 (28) 51 (96) 24 (45)
Abbreviation: MDACC Z University of Texas MD Anderson Cancer Center. Values are number (percentage) unless otherwise noted.
Volume 86 Number 3 2013
Conservative surgery and adjuvant RT for DFSP Table 2
Treatment characteristics
N Re-excision at MDACC Treatment sequence Preoperative radiation Postoperative radiation Margin status at postoperative RT Gross disease Positive margin Negative margin Uncertain Radiation dose (Gy), median (range) Preoperative RT Postoperative RT Radiation technique Appositional electrons alone Mixed electrons þ photons Conventional photons Other
Fig. 1.
Anatomic location of lesions.
patients (87%) underwent surgical resection followed by postoperative radiation. (See Table 2 for all treatment-related characteristics.) Of the 46 patients receiving postoperative radiation, 3 (7%) had gross disease, 14 (30%) had positive margins, 26 (57%) negative margins, and 3 (7%) had uncertain margin status. The majority of patients, 53%, were treated with appositional electrons alone, whereas 28% were treated with mixed electron and photon plans, and 9% were treated with conventional photons alone. In general, the clinical target volume consisted of the gross tumor or tumor bed with a 5-cm radial margin and 2-cm-deep margin. The median total radiation dose was 60 Gy (range, 50-66 Gy) for all patients. The median dose was 50 Gy (range, 50-60 Gy) for patients receiving preoperative radiation and 60 Gy (range, 50-66 Gy) for those receiving postoperative radiation. Dose per fraction (fx) ranged from 1.1 Gy/fx to 2.5 Gy/fx. Only 5 patients total were treated with radiation doses greater than 60 Gy: 2 patients with gross disease and 3 patients with positive margins after surgery. Only 1 patient received systemic therapy. This patient presented with gross residual disease and fibrosarcomatous features on pathology after an outside excisional biopsy and was treated with preoperative radiation therapy with concurrent imatinib, followed by a margin-negative wide local excision and adjuvant imatinib.
587
53 34 (64) 7 (13) 46 (87) 3 14 26 3
(7) (30) (57) (7)
50 (50-60) 60 (50-66) 28 15 5 5
(53) (28) (9) (9)
Abbreviations: MDACC Z University of Texas MD Anderson Cancer Center; RT Z radiation. Values are number (percentage) unless otherwise noted.
Local control was defined as no regrowth of tumor. Overall survival was defined as death from any cause. Radiation-related complications were graded as mild (self-limited and requiring no treatment), moderate (requiring conservative medical management), or severe (requiring surgical intervention or hospitalization).
Results Overall outcomes Of 53 patients, 2 (4%) experienced local relapse after radiation therapy. Actuarial local control and disease-free survival rates were 98% and 93% at 5 and 10 years, respectively (Fig. 2). Fifty patients (94%) were alive at last follow-up, and 3 had died. One
Statistical analysis, follow-up, and complication grading The median follow-up time from the completion of radiation therapy was 6.5 years (range, 0.5 months-23.5 years). The Kaplan-Meier method was used to determine local control, survival, disease-free survival, and complications. The significance of difference between proportions was determined using c2 or Fisher’s exact test as appropriate. A P value of .05 was considered statistically significant. Patients were censored at the time of last documented follow-up or correspondence.
Fig. 2. Actuarial local control for all patients with dermatofibrosarcoma protuberans.
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completing radiation therapy the patient developed a 3-cm lesion on the left foot within the prior irradiation field. He underwent radical resection, and pathology confirmed DFSP. He has no evidence of recurrent disease 2.5 years after surgical management of his recurrence.
Treatment complications
Fig. 3. Actuarial overall survival for all patients with dermatofibrosarcoma protuberans. patient died as a result of metastatic disease, with the circumstances described below. Actuarial overall survival rates were 98% at both 5 and 10 years (Fig. 3). Median overall survival was 22 years (range, 18-25 years). Fibrosarcomatous change was not associated with increased risk of either local or distant relapse (PZ.43).
Local recurrences One patient who experienced local relapse presented with a 25-cm ulcerating mass involving the right vulva and a biopsy consistent with DFSP. She underwent a margin-negative wide local excision and was observed until an 8-cm local recurrence was identified 6 months later (Table 3). She underwent re-excision with focally positive margins. Her postoperative course was complicated by delayed wound healing, and before initiating postoperative radiation therapy she developed a multifocal local recurrence. She was then treated with 65 Gy over 6.5 weeks and had a complete clinical response. However, 3 months later she developed multiple nodules within and adjacent to the radiation treatment field, as well as nodal disease and subsequently metastatic disease. Pathology from the recurrence revealed spindle cell sarcoma, without the classic appearance of DFSP seen in her index lesion. The patient ultimately died of metastatic disease less than 2 years after the completion of her radiation therapy. The other patient who developed a local recurrence presented with a 3-cm lesion on the left foot that was biopsy-proven DFSP. Five weeks after undergoing excision with positive margins the patient was treated with 60 Gy in 30 fractions. Ten years after
Table 3 Age (y) 76 31
Radiation-related complications occurred in 6 patients (11%), with a median time to complications of 9.5 months (range, 2.5 months-3.5 years) (Table 4). Actuarial rates of all radiationinduced complications were 13% at both 5 and 10 years. Four of the 6 patients had severe complications. The actuarial rates of severe radiation related complications were 9% at both 5 and 10 years. Five of the 6 patients with complications were treated with 60 Gy in 30 fractions, whereas the sixth patient was treated with 54 Gy in 26 fractions. Three patients had skin graft failure (2 of whom also had associated soft-tissue necrosis). All 3 necessitated additional surgical intervention, despite a minimum of 6 weeks between surgery and the start of radiation.
Discussion For patients with biopsy-proven DFSP, surgical resection in the form of wide local excision is the mainstay of treatment. However, depending on the type of surgery as well as the size and location of the tumor, negative margins may be unachievable without significant morbidity. If these patients are not candidates for reresection, National Comprehensive Cancer Network guidelines recommend that adjuvant therapy in the form of radiation therapy or imatibib mesylate be considered (14). Our present series demonstrates that the combination of conservative surgery and adjuvant radiation therapy provides excellent long-term disease control, with 10-year actuarial local control of 93% for patients with a clinical history of multiple recurrences or positive margins after surgery. This adds to a growing body of literatured consisting primarily of small single-institution retrospective studiesdthat evaluates the role of adjuvant radiation therapy in the treatment of DFSP. To date, this is the largest series of patients treated with adjuvant radiation therapy after conservative surgery for DFSP. Our data, in agreement with a growing body of literature, support the use of adjuvant radiation therapy in appropriately selected patients with DFSP. Three of the published series looking at adjuvant radiation have included patients with recurrent disease, often times multiply recurrent. These series demonstrated excellent local control, as was observed in our series (5, 9, 10). The role of radiation therapy as sole therapy for DFSP remains unclear. There are few reported cases in the literature in
Local recurrences Lesion size (cm) 25 3
Lesion site Vulva Foot
Abbreviation: RT Z radiation.
No. of excisions before RT 2 1
Margin status at time of RT Gross disease Positive
RT dose (Gy) 65 60
RT technique
Time to event
Photons Mixed appositional photons/electrons
21 wk 10 y
Volume 86 Number 3 2013 Table 4
Conservative surgery and adjuvant RT for DFSP
Treatment-related complications
Site (size)
No. of excisions
Time from surgery to RT (wk)
30
Breast (2 cm)
2
6
WLE þ pectoralis flap
64
Cheek (4 cm)
2
6
64
Chin (3 cm)
3
3.5
WLE þ rotational flap reconstruction WLE/marginal mandibulectomy þ flap reconstruction
66
Forehead (5 cm)
3
9
56
Scalp (2.5 cm)
3
6
47
Back (7 cm)
1
25
Age (y)
589
Surgery
Dose/technique 60 Gy, appositional electrons 60 Gy, appositional electrons 60 Gy, photons
Time to event 15 mo 9 mo 9 mo
Moh’s surgery þ delayed 54 Gy, mixed 3.5 y split thickness graft appositional electrons reconstruction and photons WLE þ split thickness 60 Gy, appositional 2.5 mo skin graft electrons WLE þ skin graft 60 Gy, appositional 6 mo electrons
Complication (severity) Breast implant asymmetry (mild) Edema þ xerostomia (mild) Osteoradionecrosis þ fracture requiring mandibulectomy (severe) Soft-tissue necrosis requiring surgery (severe) Graft failure (severe) Soft-tissue necrosis þ graft failure (severe)
Abbreviations: RT Z radiation; WLE Z wide local excision.
which radiation alone was used. Suit et al (5) included 3 patients with tumors ranging from 4 to 8.5 cm who were treated with radiation therapy alone to total doses ranging from 66.7 Gy to 74 Gy. Local control was achieved in all of these cases. In our series, 3 patients had gross disease ranging from 0.5 cm to 4 cm after surgical resection and were treated with external beam radiation therapy with total doses between 60 and 65 Gy. One of 3 patients had documented local recurrence of disease after 60 Gy radiation. The benefit of adjuvant radiation therapy must be weighed against the risk of toxicity. Several studies that included patients treated with adjuvant radiation therapy did not report on toxicity from radiation therapy (2, 5, 15). In the previously published series from our institution consisting of 19 patients with a median follow-up of 6 years, there were no clinically significant sequelae of radiation therapy (9). In the series published by Sun et al (12), 6 patients were found to have moderate (grade 2) fibrosis or telangiectasias within the radiation treatment field. All had been treated with electron beam therapy. Marks et al (10) looked at 10 patients treated with adjuvant radiation therapy and found that 1 patient developed wound breakdown 4 years after radiation therapy. In our series, radiation-related complications occurred in 6 patients (11%). Our single-institution retrospective study has inherent limitations. First, because of the rarity of the disease this series spans multiple treatment eras. Although radiation planning for this disease site has not drastically changed over the course of time, the adaption of CT-based treatment planning provides better visualization of the tumor or operative bed and allows for optimal target coverage and potential reduction in toxicity relative to older treatment techniques, and our series does not distinguish 2dimensional from 3-dimensional planning. Furthermore, this cohort of patients represents a heterogeneous group selected by surgeons and radiation oncologists according to specific patient and tumor characteristics, leading to selection bias regarding treatment recommendations. Additionally, given the indolent nature of the disease and its radiosensitivity, there were very few events. This attests to the excellent local control of
conservative surgery and radiation therapy but prevents further exploration of prognostic factors as well as the effect of specific treatment strategies and dose.
Conclusion Dermatofibrosarcoma protuberans is a radioresponsive disease with excellent local control after conservative surgery in combination with radiation therapy. Radiation therapy should be considered for patients with large (>5 cm) or recurrent tumors. Radiation therapy should also be considered for patients when complete resection with negative margins is not possible or when repeated attempts at wide surgical margins would result in significant morbidity. Radiation therapy can be delivered either preoperatively (50 Gy in 25 fractions) or postoperatively (60 Gy in 30 fractions; with higher doses up to 66 Gy in 33 fractions for patients with positive resection margins).
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