Int. J. Radiation
Phys.. Vol. 32, No. 4, pp. 969-976, 1995 Copyright 0 199.5 Elsevier Science Ltd Printed in the USA. All rights reserved [email protected]
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MANAGEMENT OF EXTREMITY SOFT TISSUE SARCOMAS WITH LIMBSPARING SURGERY AND POSTOPERATIVE IRRADIATION: DO TOTAL DOSE, OVERALL TREATMENT TIME, AND THE SURGERY-RADIOTHERAPY INTERVAL IMPACT ON LOCAL CONTROL? DOUGLAS A. FEIN, M.D.,* W. ROBERT LEE, M.D.,* RACHELLE M. LANCIANO, M.D.,* BENJAMIN W. CORN, M.D.,* SCOTT H. HERBERT, M.D.,* ALEXANDRA L. HANLON, M.S.,* JOHN P. HOFFMAN, M.D.,+ BURTON L. EISENBERG, M.D.+ AND LAWRENCE R. COIA, M.D.* *Departmentof RadiationOncology and ‘Departmentof Surgery, Fox ChaseCancerCenter, Philadelphia,PA Purpose: To evaluate potential prognostic factors in the treatment of extremity soft tissue sarcomas that *influence local control, distant metastases, and overall survival. Methods and Materials: Sixty-seven patients with extremity soft tissue sarcomas were treated with curative intent by limb-sparing surgery and postoperative radiation therapy at the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania, between October 1970 and March 1991. Follow-up ranged from 4-218 months. The median external beam dose was 60.4 Gy. In 13 patients, interstitial brachytherapy was used as a component of treatment. Results: The 5-year local control rate for all patients was 87%. The 5-year local control rate for patients who received ~62.5 Gy was 78% compared to 95% for patients who received b62.5 Gy. Patients who received >62.5 Gy had larger tumors (p = 0.008) and a higher percentage of Grade 3 tumors and positive margins than patients who received ~62.5 Gy. The 5-year local control rate for patients with negative or close margins was 100% vs. 56% in patients with positive margins (p = 0.092). Cox proportional hazards regression analysis was performed using the following variables as covariates: tumor dose, overall treatment time, interval from surgery to initiation of radiation therapy, margin status, grade, and tumor size. Total dose (p = 0.04) and margin status @ = 0.02) were found to significantly influence local control. Only tumor size significantly influenced distant metastasis (p = 0.01) or survival @ = 0.03). Conclusion: Postoperative radiation therapy doses >62.5 Gy were noted to significantly improve local control in patients with extremity soft tissue sarcomas. This is the first analysis in the literature to demonstrate the independent influence of total dose on local control of extremity soft tissue sarcomas treated with adjuvant postoperative irradiation. Soft tissue sarcomas,
The use of adjuvant radiotherapy (either preoperatively, intraoperatively, or postoperatively) in the management of extremity soft tissue sarcomas has become standard practice. Previously published reports that have used adjuvant radiation therapy have noted 5year rates of local control and limb salvage ranging between 85-95%, and 5-year survival rates of 70% (3, 5, 14, 15, 25, 26, 29, 30, 32, 36, 39,42). The results with limb-sparing surgery and postoperative irradiation are similar to those reported with radical resection or amputation (30, 34, 37, 38). Despite
general agreement on the role of radiation therapy in the management of extremity soft tissue sarcomas,the influence of several radiation treatment factors including total dose, the surgery-radiotherapy interval, and overall treatment time on local control have not been adequately defined. At the Fox Chase Cancer Center and the Hospital of the University of Pennsylvania,’ surgical resection and radiation are routinely combined in the curative management of extremity soft tissue sarcomas.In this report, we analyze the results of resection and radiation, as well as a number of potential prognosticators, including total dose, overall treatment time, the surgery-radiotherapy interval,
Presentedat the 77th Annual Meeting of the American Radium Society, Paris,France, April 29-May 3, 1995. Reprint requeststo: DouglasA. Fein, M.D., Departmentof RadiationOncology, Fox ChaseCancerCenter,7701Burholme Avenue, Philadelphia,PA 19111.
Accepted for publication 3 March 1995. ’ At the time of analysis,the Departmentof RadiationOncology of the University of Pennsylvaniaencompassed the cancer centersof the University of PennsylvaniaandFox ChaseCancer Center. 969
I. J. Radiation Oncology l Biology l Physics
margins status, tumor size, and tumor grade, and their influence on local control, distant metastasis,and survival.
One hundred and ninety-eight patients with soft tissue sarcomasof all siteswere treated at the Fox ChaseCancer Center and the Hospital of the University of Pennsylvania between October 1970 and March 1991. Patients excluded from this analysis include those treated for recurrent disease (25 patients), metastatic disease (8 patients), those treated with palliative intent (14 patients), and those who did not receive the full course of their radiation therapy at the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania (7 patients). Also excluded from this analysis were patients with a histologic diagnosis of rhabdomyosarcoma (four patients), cutaneous angiosarcoma of the skin (five patients), and patients with visceral sarcomas of the uterus (nine patients) or other sites(three patients). One patient, who received a previous course of whole abdominal irradiation for ovarian carcinoma 15 years before a malignant fibrous histiocytoma developed in the buttock (within the prior radiation ports), and was treated with interstitial brachytherapy alone, was excluded. Of the 123 patients available for analysis, this study focuses on the 67 patients with extremity soft tissue sarcomaswho were treated with curative intent with postoperative irradiation. All radiation therapy was performed at either the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania. Follow-up ranged from 4 to 218 months (median 31 months). Five patients with evidence of tumor recurrence were lost to follow-up. These patients were listed as dead of diseaseat the time of last follow-up. All patients underwent a comprehensive work-up, which included a physical examination, complete blood cell count and serum chemistries, chest roentgenogram, and scanning of the involved extremity and lung with computed tomography or magnetic resonance imaging. Twenty-four patients were diagnosed by an incisional biopsy, 42 by an excisional biopsy, and 1 by a needle biopsy. All histopathologic slides were reviewed at the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania. Histologic type and distribution are shown in Table 1. Sixteen tumors were Grade 1, 15 were Grade Table 1. Histologic Histologic
Malignant fibrous histiocytoma Liposarcoma Synovial Malignant schwannoma Epithelioid Hemangiopericytoma Leiomyosarcoma Undifferentiated Fibrosarcoma
of soft tissue sarcomas No. 21 22 8 6 2 2 2 2 2
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2, and 36 were Grade 3. One patient presented with a clinically positive lymph node. Forty patients presented with tumors
Extremity soft tissue sarcomas 0 D. A.
chemotherapy neoadjuvantly, three patients after completion of limb-sparing surgery and postoperative irradiation, and one patient after wide excision but before irradiation. Estimates of rates for local control, distant metastases, and survival were calculated using the Kaplan-Meier product-limit method, and the log-rank test was used to evaluate differences in survival (18, 23, 35). To examine the effect of clinical and treatment variables upon local control, survival, and distant metastasis, Cox regression models were calculated using these outcome measuresas the dependent variable (17, 35). The parameters included as covariates were margins (negative or close vs. positive), tumor grade (1 or 2 vs. 3), tumor size (
Local Control -- I - f&,
tions were those that necessitatedhospitalization or a surgical procedure.
RESULTS The actuarial 5-year local control rate for all patients was 87% (Fig. 1). Six of the 67 patients experienced a local recurrence. The overall 5-year survival for all patients was 67%. There was a suggestion of an association between local control and survival, as 4 of the 6 patients (67%) who experienced a local failure had died of carcinoma or intercurrent diseaseat the time of evaluation vs. 13 of 61 patients (21%) who had their tumors locally controlled @ = 0.03). Twenty-three of 28 patients (82%) who received a total dose (external beam plus brachytherapy) ~62.5 Gy had their tumors locally controlled at the time of analysis, compared to 38 of 39 patients (97%) who received >62.5 Gy @ = 0.04). The 5-year local control rate for patients who received 562.5 Gy was 78% compared to 95% for patients who received >62.5 Gy (Fig. 2). Patients who received ~62.5 Gy had a median tumor size of 7.01 cm compared to 10.00 cm in the group of patients who received >62.5 Gy @I = 0.004). Twenty-one percent of patients who received ~62.5 Gy had tumors 210 cm vs. 53.8% in the group who received >62.5 Gy (p = 0.008). Furthermore, 46% of patients who received ~162.5 Gy had Grade 3 tumors vs. 59% for patients who received >62.5 Gy. Seventy-six percent of patients who received a total dose ~62.5 Gy had negative or close margins compared to 67% of patients who received >62.5 Gy. Forty-two of 44 patients (98%) who had negative or close margins had their tumors locally controlled vs. 13
ia+++* I. .a
ij E 8 ii P
Years from Initiation
Fig. 1. Local control of extremity
soft tissue sarcomas after postoperative
I. J. Radiation
By Total Dose Groups l.O-
Totd Dose > 62.5 Gy
Fig. 2. Local control by total dose group of extremity
of 18 patients (72%) who had positive margins of resection @ = 0.007). The 5-year local control rate for patients with negative or close margins was 100% compared to 56% for patients with positive margins of resection (p = 0.002) (Fig. 3). The only failure in the group with close or negative margins occurred after 5.7 years. There was an associationbetween local control and survival for patients with close or negative margins, as 86% of patients with negative or close margins remained alive at the time of
soft tissue sarcomas after postoperative
analysis vs. 61% with positive margins (p = 0.04). The 5-year overall survival rate in patients with negative or close margins was 76% compared to 62% for patients with positive margins (p = 0.08). Thirty-six of 40 patients (90%) with tumors ~10 cm experienced local control of their tumor vs. 25 of 27 patients (93%) with tumors 210 cm (p = NS). Tumor size did influence overall survival as 85% of patients with tumors
By Margin Status
Fig. 3. Local control by margin status of extremity
sarcomas after postoperative
0 D. A. FEIN et al.
After Postoperative By Tumor
:; , , , zzy1 2
Fig. 4. Survival by tumor size of extremity soft tissue sarcomas after postoperative irradiation.
59% of patients with tumors 210 cm (p = 0.02) (Fig. 4). The 5-year overall survival rates for patients presenting with tumors ~10 cm was 80% compared to 48% in patients with tumors 2 10 cm @ = 0.01). Patients with tumors
patients (89%) who had Grade 3 tumors (p = NS). Six of the 54 patients (11%) treated with external beam irradiation alone failed locally compared to 0 of 13 patients who received an implant (p = NS). The effects of margin status (negative or close vs. positive), tumor Grade (1 or 2 vs. 3), tumor size (< 10 cm vs. 2 10 cm), tumor dose (on a continuum), overall radiation therapy treatment time (on a continuum), and interval from surgery to initiation of radiation therapy (on a con-
After Postoperative By Tumor
Fig. 5. Distant metastasis by tumor size of extremity soft tissue sarcomas after postoperative irradiation.
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tinuum) on local control were evaluated for all 67 patients by stepwise model-building using Cox regression. Margin status @ = 0.02) and total dose 0, = 0.04) significantly influenced local control. A second multivariate analysis was performed excluding the 13 patients who had a brachytherapy implantation. In this analysis, margin status (p = 0.03) and total dose (p = 0.04) again significantly influenced local control. Similar multivariate analyses were performed for the endpoints of distant metastasis and survival. Tumor size significantly influenced distant metastasis (p = 0.01) and survival (p = 0.03). None of the other variables contributed significantly to these endpoints. Fourteen patients failed at distant sites. The 5-year actuarial rate of distant metastasis was 23%. Three of 40 patients (8%) with tumors
DISCUSSION To our knowledge, this is the first report that demonstrates the independent impact of total dose on local control. Despite the fact that patients who received >62.5 Gy had significantly larger tumors (p = 0.008) compared to patients who received 562.5 Gy, local control was significantly improved (JJ = 0.04) for the patients receiving the higher dose. In addition, in the multivariate analysis, total dose again was found to significantly influence local control (p = 0.04). Other authors have not demonstrated a local control advantage with increasing total dose (25, 26, 29, 32). Carabell and Goodman theorized that the dose-response relationship for soft tissue sarcomas was fairly flat (7). The Mallinckrodt Institute of Radiology reported local control in 13 of 17 patients (76%) who received postoperative irradiation doses between 50 Gy and <60 Gy compared to 26 of 31 patients (84%) who received between 60-68 Gy (29). Both patients who received a total dose <50 Gy experienced a local failure. In the University of California San Francisco series in which patients received 50-70 Gy, the only in-field recurrence among patients treated with surgery and postoperative irradiation occurred in an individual who received 66 Gy (25). Lindberg er al. were unable to demonstrate a decrease in local control when the total dose was reduced from 70-75 Gy to 60-65 Gy (26). Similarly, the Royal Marsden did not demonstrate a relationship between total dose and local control (32). In the treatment of retroperitoneal sarcomas, both Fein et al. and Tepper et al. have demonstrated a dose-response, although the total dose used was significantly less than that used in the treatment of extremity soft tissue sarcomas (11, 40). Our analysis confirms the importance of margin status as a prognosticator of local control (1, 5, 9, 10, 15, 29). In our study, 98% of patients with negative or close margins had their tumors locally controlled vs. 72% who had positive margins (p = 0.007). Similarly, Pao and Pilepich reported local failure in 4 of 8 patients (50%) with gross residual disease, 6 of 3 1 patients (19%) with microscopically positive margins, and 1 of 10 patients (10%) with negative margins (29). Suit et al. noted that for patients with Stage IIB, IIIB, and IVA disease that local control was 79% with negative margins vs. 57% with positive margins (39). Abbatucci et al., who reported on sarcomas involving a number of sites, noted local control rates of 98% for negative margins and 56% for microscopically positive margins (1). The National Cancer Institute reported that margin status did not influence local control, but cautioned that margin status was not available for 27 of the 143 patients, including 6 of the 12 patients who failed locally after a limb-sparing procedure (30). Other variables analyzed did not significantly influence local control. Contrary to the results reported at other treatment sites, the overall treatment time did not influence local control (2, 12, 13, 22, 24). This finding is similar to that demonstrated in the treatment of Hodgkin’s
soft tissue sarcomas
disease and prostate carcinoma, where prolonging the overall treatment time did not adversely influence local control (21, 33). A plausible basis behind this finding is that the cellular kinetics as measured by labeling indices for sarcomas is lower than that reported for squamous cell carcinomas (27). Therefore, prolonging overall treatment time may not lead to accelerated repopulation. Furthermore, sarcomas, in contrast to squamous cell carcinomas of the head and neck and uterine cervix, have a propensity for metastatic failure rather than local failure. This was demonstrated in our series in which 6 patients failed locally while 14 patients had a distant component of failure. There was no evidence from our data that a relationship existed between the risk of recurrence and the surgeryradiotherapy interval. This is in conflict with some of the reports of breast cancer, which suggest that recurrence rates may be higher among patients who have had a long delay between surgery and radiotherapy, although conflicting evidence exists (6, 28, 31). These findings should not dissuade oncologists from implementing treatment even when postoperative irradiation cannot be initiated prior to 6 weeks following surgery due to poor wound healing or logistical problems. Nevertheless, we continue to believe that radiation therapy should be started as soon as possible after surgery to minimize the amount of tumor cell proliferation that is permitted to occur during the surgery-radiotherapy interval. The use of interstitial brachytherapy may enhance local control by enabling the clinician to increase the tumor dose while minimizing the dose to the surrounding normal tissue by taking advantage of the inverse square law. None of the 13 patients who received an interstitial implantation as a component of their treatment failed locally compared to 6 of 54 patients treated with external beam irradiation alone. A number of authors have successfully used interstitial brachytherapy in the treatment of extremity soft
0 D. A. FEIN er al.
tissue sarcomas (14, 16, 36, 42). Our results confirm that improving local control may lead to an enhancement in patient survival as proposed by Suit et al., although this contention is not supported by data from Memorial SloanKettering Cancer Center (14, 39). In our analysis, tumor size significantly influenced overall survival as well as distant metastases. Harrison et al. reported that high grade tumors r5 cm had a higher rate of death due to disease (p = 0.004) as well as a higher rate of distant metastasis07 = 0.002) (14). Collin et al. and Potter et al. demonstrated a significant relationship between tumor size and survival (8, 30). Both Lindberg et al. and Suit et al. reported an associationbetween tumor size and the incidence of distant metastasis(26, 39). The 7% incidence of complications reported in our seriesis similar to that reported by other authors (19, 26, 29, 32). Our data suggeststhat dosesof ~-65 Gy may be associatedwith an increasedrisk of complications, as four of the five complications in our series occurred in this group of patients. Karasek et al. reported in a meticulous analysis of functional outcome that doses up to 65 Gy, even over joint spaces,are not associatedwith significant morbidity (20). The results of Wiklund et al. suggestthat dose per fraction may play an important role in contributing to the complication rate (41). Wiklund et al. reported a 3-year complication incidence of 35% for patients receiving postoperative irradiation to a total dose of 51 Gy in 17 fractions (41). Adjuvant radiation therapy using doses >62.5 Gy should be considered for all patients with extremity soft tissue sarcomasfollowing surgical resection. This analysis argues for the use of higher dosesin the treatment of extremity soft tissue sarcomasto improve the local control rates. Notwithstanding, the improvement in local control as a function of higher dose may also be associatedwith an increased rate of complications.
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I. J. Radiation Oncology 0 Biology 0 Physics Hoffman, J. P.; Coia, L. R. Management of retroperitoneal sarcomas: Does dose escalation impact on locoregional control? Int. J. Radiat. Oncol. Biol. Phys. 31: I29- 134; 1995. Fowler, J. F.; Lindstrom, M. J. Loss of local control with prolongation in radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 23:457-467; 1992. Girinsky, T.; Rey, A.; Roche, B.; Haie, C.; Gerbaulet, A.; Randrianarivello, H.; Chassagne, D. Overall treatment time in advanced cervical carcinomas: A critical parameter in treatment outcome. Int. J. Radiat. Oncol. Biol. Phys. 27:1051-1056; 1993. Harrison, L. B.; Franzese, F.; Gaynor, J. J.; Brennan, M. F. Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superhcial trunk. Int. J. Radiat. Oncol. Biol. Phys. 27:259-265; 1993. Herbert, S. H.; Corn, B. W.; Solin. L. J.; Lanciano, R. M.; Schultz, D. J.; McKenna, W. G.; Coia, L. R. Limbpreserving treatment for soft tissue sarcomas of the extremities. Cancer 72:1230-1238; 1993. Hilaris, B.; Shiu, M.; Nori, D.; Anderson, L.; Manolatos, S. Limb sparing therapy for locally advanced soft tissue sarcomas. Endocur. Hyperther. Oncol. 1:17-24; 1985. Kalbfleisch, J. D.; Prentice, R. L. The statistical analysis of failure time data. New York: John Wiley & Sons; 1980. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-481; 1958. Karakousis, C. P.; Emrich, L. J.; Rao, U.; Krishnamsetty, R. M. Feasibility of limb salvage and survival in soft tissue sarcomas. Cancer 57:484-491; 1986. Karasek, K.; Constine, L. S.; Rosier, R. Sarcoma therapy: Functional outcome and relationship to treatment parameters. Int. J. Radiat. Oncol. Biol. Phys. 24:651-656; 1992. Lai, P. P.; Pilepich, M. V.; Krall, J. M.; Asbell, S. 0.; Hanks, G. E.; Perez, C. A.; Rubin, P.; Sause, W. T.; Cox, J. D. The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: The Radiation Therapy Oncology Group 75-06 and 77-06 experience. Int. J. Radiat. Oncol. Biol. Phys. 21:925-933; 1991. Lanciano, R. M.; Pajak, T. F.; Martz, K.; Hanks, G. E. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A Patterns-of-Care study. Int. J. Radiat. Oncol. Biol. Phys. 25:391-397; 1993. Lawless, J. F. Statistical models and methods for lifetime data. New York: John Wiley & Sons; 1982. Lee, W. R.; Marcus, R. B.; Sombeck, M. D.; Mendenhall, W. M.; Morgan, L. S.; Freeman, D. E.; Million, R. R. Radiotherapy alone for carcinoma of the vagina: The importance of overall treatment time. Int. J. Radiat. Oncol. Biol. Phys. 29:983-988; 1994. Leibel, S. A.; Tranbaugh, R. F.; Wara, W. M.; Beckstead, J. H.; Bovill, E. G.; Phillips, T. L. Soft tissue sarcomas of the extremities: Survival and patterns of failure with conservative surgery and postoperative irradiation compared to surgery alone. Cancer 50: 1076- 1083; 1982. Lindberg, R. D.; Martin, R. G.; Romsdahl, M. M.; BarkIey, H. T., Jr. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 47:2391-2397; 1981. Meyer, J. S. Cell kinetic measurements of human tumors. Hum. Pathol. 3874-877; 1982.
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