In,. J Rudwron Onmlo&y &d Phw Vol. 24. PP. 65 l-656 Printed in the IJXA. All rights reserved.
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0360.3016192 $5.00 t 00 Cm I992 Pergamon Press Ltd.
??Clinical Original Contribution
SARCOMA
THERAPY: FUNCTIONAL TO TREATMENT
OUTCOME AND RELATIONSHIP PARAMETERS
K. KARASEK, M.D.,’ L. S. CONSTINE, M.D.’ AND R. ROSIER, M.D., PH.D.* ‘Dept. of Radiation
Oncology,
‘Dept. of Orthopedic
Surgery, University
of Rochester
Medical Center,
Rochester,NY
Purpose: To systematically assess the functional outcome of patients treated with surgery and irradiation for extremity or truncal sarcomas, and to correlate this outcome with a detailed analysis of the radiation dose distribution and surgical technique. Conservative surgery and radiation therapy (RT) are known to provide excellent local control, but the relationship of technique to functional outcome requires further study. Methods and MuteriuZsr Forty-one patients were treated for lower extremity (25 patients, 61%), upper extremity (8 patients, 19.5%), and truncal (8, 19.5%) sarcomas from 1983 to 1990. Most patients had malignant fibrous histiocytoma (15), liposarcoma (S), or aggressive fibromatosis (6). Age ranged from 13 to 85 years (median 54). All patients received RT and 39 (95%) had surgery. The mean total RT dose was 59 Gy (range 55.8-64.8 Cy). A protocol for functional assessment was devised and included a 4 point scale (O-3) for each of seven functional parameters (range of motion, fibrosis, edema, pain, skin changes, muscle strength, gait, or upper extremity performance). An aggregate score was obtained by adding the seven parameter scores and compared with both a patient and physician overall functional rating score (excellent, good, fair, poor). Based on this analysis, aggregate scores were defined as 5 3 = excellent, 5 8 = good, I 13 = fair, and > 13 = poor, with 21 as the worst possible score. The same orthopaedic surgeon and radiation oncologist independently examined and rated 22 patients. An additional 17 patients were evaluated by record review. The median time from completion of radiation therapy was 30.5 months (range 7-95 months). A computerized radiation therapy dosimetric analysis was performed on 34 patients. Results: Local control was achieved in 39 patients (95%), including 6 with aggressive fibromatosis. The mean functional outcome score was 5.1 with a range of O-16.34 patients (83%) had good or excellent functional outcomes. The rating system demonstrated minimal interobserver variability. There was a positive relationship between volume irradiated to 2 55 Gy and functional score, strength, fibrosis, and skin changes. Total dose independent of volume was significantly associated with skin changes. Increasing peak dose (hot spot dose) was associated with fibrosis and skin changes. More fibrosis developed as the volume of the peak dose increased. A portion of the joint was treated in 5/33 extremity patients and the entire joint in 24/33 (mean dose 55.8 Gy, range 45-65 Gy). Neither range of motion nor total functional score was correlated with joint dose. Edema and functional score were not related to either the volume or percent of limb spared (receiving 5 40 Gy). The physician functional status ratings generally concurred with patient self-assessments. Concfusions: A system for functional assessment has been developed which is easily performed and provides detailed information about patient functional outcome. This system can be used to evaluate the morbidity of combined modality sarcoma therapy. Doses up to 65 Gy, even over joint spaces, are not associated with significant morbidity. Only a small volume treated to 5 40 Gy is required to maintain good outcome. The most important parameter appears to be the volume treated to 255 Gy. Functional outcome, Sarcoma therapy, Dosimetric analysis.
INTRODUCTION
obtain local control are effective, having evolved over the
Optimal therapy for patients with localized soft tissue sarcomas provides local control and eradicates micrometastatic disease, achieving these objectives with minimal functional disability. While the ability to eliminate distant micrometastases remains limited, current strategies to
past two to three decades. Local control rates achieved by conservative surgery and moderate dose radiotherapy have been excellent, exceeding 80% in several series (13, 17). Limb amputation is now seldom performed. Although the general consensus is that functional outcome and cosmesis have been improved without sacrificing local
Acknowledgements-The
Presented at ASTRO 7 November 199 1 in Washington, DC. Reprint requests to: Kristina Karasek, MD, University of Pittsburgh School of Medicine, Department of Radiation Oncology, Joint Radiation Oncology Center, Presbyterian University Hospital, De Soto at O’Hara Streets, Pittsburgh, PA I52 132582.
authors acknowledge and appreciate the assistance of R. Raubertas, Ph.D., in the statistical analysis of data in this manuscript. Accepted for publication I I June 1992.
651
652
I. J. Radiation Oncology 0 Biology 0 Physics
control rates, verification with a formal analysis is lacking in most patient reports. A reproducible, easily performed system of functional assessment would permit comparisons of outcome provided by various treatment strategies, such as surgery and postoperative radiotherapy, interstitial radiotherapy, or pre- and post-operative radiotherapy. We, therefore, elected to create a system of functional assessment of patients treated for soft tissue sarcoma at the University of Rochester Cancer Center with the intention of addressing the following questions: (a) would such a system be easily performed? (b) would physician and patient assessments be consistent? (c) would the treatment volume or dose correlate with outcome? (d) what percent of the limb should remain relatively spared from radiotherapy in order to obviate morbidity? (e) would inclusion of the joint to high radiation doses correlate with adverse effects on mobility? METHODS
AND MATERIALS
Patient eligibility In order to study the functional outcome of patients treated with surgery and radiation therapy for soft tissue sarcomas, we established the following criteria for patient eligibility: (a) age 13 years or greater, (b) tumors of the trunk (excluding retroperitoneal sites) or extremity, (c) no previous radiation therapy, and (d) histopathologies excluding rhabdomyosarcoma but including Ewing’s sarcoma and chondrosarcoma if the tumor primarily involved soft tissue, and also including aggressive fibromatosis. Patient demographics Forty-one consecutive patients treated between 1983 and 1990 meeting these criteria were evaluated. The radiation was administered at Strong Memorial Hospital (SMH) by a single radiotherapist. Surgery was performed at SMH in all but 11 cases. Seven patients received multiagent chemotherapy which included adriamycin. The study population included 36 previously untreated patients and five who had locally recurrent sarcoma but had never received radiation therapy. The distribution of patients by disease sites was as follows: lower extremity 25 (61%), upper extremity 8 (19.5%), and trunk 8 (19.5%). Patient age ranged from 13 to 85 years with average and median age at diagnosis of 50 and 54 years, respectively. There were twenty-two male and nineteen female patients. Table 1 categorizes the histological subtypes. Almost half of patients were Stage III or greater (44%) using the American Joint Commission staging system (3). Treatment characteristics Surgery. Surgery was wide excision in 22 patients (54%) consisting of tumor removal along with a margin of normal tissue. Marginal excision consisting of gross tumor removal was performed in 16 patients (39%) and intralesional biopsy in two patients. Radical resection of the
Volume 24, Number 4, I992
entire tumor containing compartment was done in one case (6). Amputation was recommended for two patients but limb sparing surgery and large volume irradiation was delivered secondary to patient request. Radiation therapy. Successive field reductions were used as described by Herman Suit (17). All patients received postoperative radiation therapy with the exception of one patient who received both preoperative and postoperative therapy. The target volumes were defined 3-dimensionally using either computer tomographic or magnetic resonance scans. All treatment plans were computerized. The initial target volume included tissue considered at risk for microscopic disease and generally received 45 to 50 Gy. A margin of 5 to 10 cm proximally and distally was added to the tumor volume depending on tumor grade. These volumes ranged from 149 cm3 to 7300 cm3 (mean 2700 cm3 and median 1950 cm3). Either one or two boosts were then delivered to smaller volumes. External beam therapy, in the form of photons, electrons, or both, was delivered using 1.8 Gy daily fractions on megavoltage machines. Cross-sectionally the anatomic compartment as defined by CT and MRI was treated with the exclusion of a small strip of tissue which we defined as the “volume spared” and received < 40 Gy. The mean percent of the limb circumference spared was 30% with a range of one to 78%. Absolute volumes of limb sparing ranged from 26 cm’ to 6990 cm3 with a median of 900 cm’. Total prescribed doses ranged from 55.8 Gy to 64.8 Gy with a mean dose of 59 Gy. Twenty-nine patients of the 33 patients with extremity tumors (88%) received treatment to a joint (24 patients or 73% whole joint and five patients or 15% to < 50% of a joint). The average joint dose was 56 Gy (range 45 to 64.8 Gy, median 55.8 Gy). All patients were fitted with immobilization devices. Beam films were checked on a weekly basis. Patient assessments Functional outcome was assessed by one orthopedic surgeon and one or two radiotherapists independently, without knowledge of the assessment by the other physician. Twenty-four patients (58%) were recalled for evaluation at a median of 30.5 months (range 7-95 months) from completion of therapy. Seventeen were scored by record review. The median and mean followup times were 34.9 and 3 1 months respectively for all patients included Table 1. Histological MFH Liposarcoma Desmoid Chondrosarcoma Ewings Malignant schwannoma Synovial sarcoma Leiomyosarcoma PNET Total
subtypes 15 8 6 4 2 2 2
41
Sarcoma therapy 0 K.
outcome Local tumor control was achieved in 39 patients (95%) including the six with aggressive fibromatosis. Nine of the 35 patients with malignant tumors (26%) developed metastatic disease and eight (23%) of these patients were deceased at the time of chart evaluation. Median survival has not yet been reached by this population using the Kaplan-Meier method.
Disease
outcome Qualitative outcome. Twenty-two patient self-assessments were as follows: excellent 70%, good 15%, fair 7.5%, and poor 7.5%. Physician qualitative assessments of outcome in 4 1 patients were as follows: excellent 5 l%, good 34%, fair lo%, and poor 5%. Quantitative outcome: The mean overall total functional outcome score was 5.1 with a range of 0- 16. Most patients (83%) had good or excellent functional outcomes. The breakdown was as follows: excellent 18 (44%), good 16 (39%) fair 5 ( 12%) and poor 2 (546) and is shown in Figure 1. Correlation between qualitative and quantitative evaluations: Physician and patient qualitative functional scores compared well with the total quantitative scores. Correlation coefficients were .77 0, = .OOOl) and .51 (p = .0006), respectively. Physician qualitative functional scores were related to patient self assessments with a correlation coefficient of .7 1 (p = .OOO1). All seven patients scoring fair or poor had malignant fibrous histiocytoma with the exception of one patient with chondrosarcoma. Five of these patients had lower
Functional
Statistical analysis For the statistical analysis the average score of the two of three physician evaluations was utilized. Associations between functional outcome scores and radiation doses and volumes were assessed using Kendall’s Tau b correlation (1). A correlation coefficient of one indicates a positive correlation between two variables. A 95% confidence interval was selected to determine statistical significance (Q value I .05). Kaplan-Meier analysis was used for survival calculations. Patient and physician scores were compared using the same technique.
Criteria
status evaluation
1
0
Mobility
Normal
Mild loss of motion
Pain
No pain No analgesic
Mild and intermittent Salicylate
Edema
None
Mild and intermittent
Strength Gait
Normal Norma1
Mild loss Slight limp
Normal
Mild impairment Limits some activities Mild Mild: Hyperpigmentation Telangectasia. atrophy
Upper extremity
function
Fibrosis Skin changes
None None
Overall functional
653
er al.
RESULTS
in the study. Seven parameters were scored using a scale from 0 to 3 with a total possible score of 2 1 representing the worst possible outcome (Table 2). Independent of the total quantitative score, both physicians and patients “qualitatively” rated the overall outcome as either excellent, good, fair, or poor. These subjective assessments were then compared to the total functional scores (TFS) in order to derive a quantitative breakdown of the numerical score into functional outcome categories. Aggregate scores were defined as I 3 = excellent, I 8 = good, I 13 = fair, > 13 = poor. This rating system was then used to categorize all quantitative assessments. Isodose curves were analyzed using the central axis or largest diameter contour. Volume calculations were made using digitized contour volumes multiplied by field length. Dosimetric analysis was done on 34 (83%) patients. Volumes receiving ~40 Gy, 50 Gy, 55 Gy, 60 Gy, and 65 Gy, as well as peak dose volumes were calculated. Joint doses (dose to ~50% of joint and whole joint dose) were included in the dosimetry review.
Table 2. Functional
KARASEK
form 2
3
Moderate loss of motion Moderate and intermittent Narcotic Mild and constant
Severe loss of motion/fixed contracture Severe and constant Narcotic
Moderate loss Moderate to severe limp cane/crutch Moderate impairment Requires a change in lifestyle Moderate Episodic skin breakdown
Marked (needs compression stocking) Severe loss Nonambulatory Nonfunctional
Severe Chronic ulceration for graft
status
Physician,fimtional
status rating:
0 = Excellent I = Good (slight impairment) 2 = Fair (moderate impairment) 3 = Poor (severe impairment)
Patient functional status rating 0 1 2 3
= = = =
Excellent Good Fair Poor
or need
I. J. Radiation Oncology 0 Biology 0 Physics
654
Volume 24, Number 4, 1992 Table 4. Volume
correlation coefficients outcome parameters
with selected
40 5! %
Volume treated
Strength
Fibrosis
Skin changes
30
50-54 Gy ii ag
Total score
20
55-59 Gy
cc = .21
CC = .23
CC = .34
cc = .30
p = ,097
p = .085
p = .Ol I*
p = .037*
cc = .30 p = .025*
cc = .31
CC = .38
CC = .48
p = .029*
p = .009*
p = .002*
10
CC = Correlation coefficient. *p = .05. 0
outcome
Fig. 1. Treatment
outcome
as described by total functional
score.
extremity tumors. Chronic osteomyelitis was the major contributor to outcome in three patients, two of whom developed infected nonunion fractures following trauma which occurred during RT in one patient and prior to therapy in the other. The third patient with osteomyelitis underwent marginal excision with bone grafting prior to RT. One year later implant failure occurred and allograft was used for replacement. Persistent drainage occurred at the wound and a pathological fracture developed requiring a second graft which ultimately failed, necessitating amputation. A severe contracture of the elbow joint developed immediately after one patient wore a compression bandage to relieve arm edema which developed after adriamycin chemotherapy. The patient rated with the worst outcome (total functional score = 16) had a bulky thigh tumor ( 15 X 8 cm) and received large volume (4190 cm3) postoperative therapy covering both the knee and hip. She developed moderate fibrosis, edema, pain, and contracture. Moderate edema was seen only in one of the patients scoring fair or poor. The mean edema score was .58 for all patients. Dose/Volume correlations with outcome: Increasing peak dose was associated with increasing fibrosis and skin changes. The volume of the peak dose was significantly correlated with fibrosis and not skin changes nor other outcome parameters (Table 3). As treatment volume increased, the scores for overall function, strength, fibrosis, and skin changes worsened. This was most notable for the skin and fibrosis parameters. The treatment volume Table 3. Peak and total prescribed dose correlation with selected outcome parameters Fibrosis Peak dose volume Peak dose
Total dose CC = Correlation *p < .05.
cc p = CC p =
= .27 .027* = .27 .028* cc = .09 p = .49 coefficient.
coefficients
Skin changes cc
= .17
p= .21 cc
= .44
p = .001* cc
= .37
p = .006*
receiving 55 to 59 Gy was more strongly correlated with these parameters than the volume receiving 50 to 55 Gy (Table 4). Total prescribed dose was significantly associated with skin changes (Table 3). Joint doses were not significantly associated with range of motion scores. Similarly, the volume spared could not be related to edema scores or overall functional outcome. Volumes as low as 26 cm3 and corresponding limb volume percentages of one percent were not significantly associated with poor outcomes. The mean total functional score for the patients undergoing marginal excision was 5.5, not significantly different from the mean score of 5.2 for the patients treated with more extensive surgery. DISCUSSION No widely used system exists for analyzing functional outcome of limb preserving therapy of sarcomas. Generally, one can expect to achieve excellent functional outcome following such therapy. This is supported by several recent reports, but detailed descriptions are lacking. For example, in a recent report from the Massachusetts General Hospital, functional status was “judged good by the participating clinicians” ( 17) and later described as good in 75-80% patients who did not require support devices or pain medication (18). In 300 patients treated at M.D. Anderson Cancer Center (15), limb function was maintained in 84.5% of patients and the incidence of severe complications was 6.5%. “Normal function” was maintained in the limbs of 24/26 long-term survivors following postoperative treatment of extremity sarcomas at Mallinckrodt Institute of Radiology (12). In a patient population treated at the National Cancer Institute the functional assessment was based solely on strength and joint motion (5). More detailed descriptions of functional outcomes are found in some reports. In a series of patients treated for distal extremity sarcomas at M.D. Anderson Cancer Center (20), the functional assessment scale was divided into four categories: normal, mild limitation, moderate limitation, severe limitation, and major limitation. Individual criteria included overall function, edema, pain, strength, joint motion, skin ulceration, and fibrosis. Fifty-three of 78 (68%) retained a “normal or fairly normal extremity” and 12 of 78 (16%) had either severe dysfunction or re-
Sarcoma therapy 0 K.
quired an amputation for complications. Outcome was significantly worse for the lower extremity lesions. Jentzsch et al. (8) evaluated leg function of patients surviving at least two years following therapy for Ewing’s Sarcoma. Soft tissue changes were rated by circumference measurements which in our experience is a confusing endpoint because of the effect of edema and surgery. Muscle strength, joint motion, pain, edema, and quality of gait were quantified with a three point scale. These investigators did not use numerical scores, but instead placed patients into four functional groups described as fully functional, moderately limited, severely limited, or nonfunctional. This format has been used by subsequent investigators ( 11). Most recently, Stinson et al. (15) published a retrospective review of the long-term limb function of 145 patients treated at the National Cancer Institute. Lampert et al. (9) had previously reported on 26 of these patients using an elaborate standardized battery of measurements of range of motion, muscle strength, functional category, edema, and pain. Stinson et al. (15) used a similar comprehensive list of criteria with either “yes” or “no” ratings except for range of motion and muscle strength deficits which were classified as either “mild” or “moderate/severe” deficits. In 1982, a system of functional evaluation of surgically managed musculoskeletal tumors was proposed to the Musculoskeletal Tumor Society. This system has been subsequently modified and consists of seven factors: motion, pain, stability, deformity, strength, functional activities/emotional acceptance, and complications (7). These were rated with a four point scale. This system has been applied by Bell et al. in Toronto (4). A total of 88 patients were evaluated following surgery and radiotherapy. Sixtyeight had functional scores of 21 or better (with 35 representing the best possible outcome). Numerical scores were not defined in terms of descriptors such as excellent, fair, or poor. Six patients were felt to have unsatisfactory outcomes. Three of these patients suffered from late fractures. No information was given about the radiation therapy techniques or doses. We found this system to be cumbersome and difficult to apply. The system for functional assessment developed at our institution is easy to perform and provides detailed information about functional outcome. It incorporates both quantitative and qualitative evaluations which were reproducible. It is impossible to clearly distinguish the impact of surgery from late radiation effects. The sequelae one would expect following radiotherapy, such as fibrosis and skin changes, were related to the treatment volume and peak dose. The correlation became stronger with increasing dose except for the greater than 60 Gy category in which there were few cases. Strength is a parameter largely impacted by extent of surgery. Since more extensive surgeries were followed by larger radiation treatment portals for the postoperative phase of therapy, an inverse association between strength and increasing radiation treatment vol-
KARASEK
et al.
655
ume might be expected. Our data suggest this. LOSSof strength should therefore be largely a consequence of surgery. Total radiation dose was not a predictor for functional outcome in this study. Stinson et al. ( 15) found that doses greater than 63 Gy at 1.8 Gy fractions were positively correlated with chronic pain, skin telangectasias, edema, decrease in muscle strength, and loss of range of motion. Doses exceeding 64.8 Gy were not used in the current study, thus such a relationship between high dose and outcome would not have been detected. The limb volume receiving high radiation dose, as quantified from digitization of isodose curves, was the most important parameter for predicting functional outcome. It was the only aspect of therapy which was clearly associated with the total functional score. Unfortunately the large patient series reviewed by Stinson et al. ( 15) did not include information about treatment volumes, although the length of the treatment field was found to significantly contribute to edema, tissue induration, and decreased muscle strength. All our radiation portals were devised to protect a small strip of tissue to allow for lymphatic drainage. Only a few patients developed edema, making it difficult to draw conclusions about the relationship of edema with treatment parameters. As there was no correlation between volume spared and outcome, we conclude that only a small volume of tissue must be spared to prevent lymphedema. This finding was also apparent in Stinson’s report ( 15). The percent of limb diameter irradiated was quantified as 0% to 25%, 26% to 50%, 51% to 75%, and no association with the development of extremity edema was found. Our data indicate that the joint can tolerate moderately high doses of RT without adverse effects on mobility. This is in contrast to the conclusion made by Stinson et al. ( 15). They did not quantify the doses delivered to joints, which may have received higher doses since boost fields were treated to 70 Gy. Five of seven patients with only fair or poor outcomes were treated for lower extremity tumors. Despite this finding, the tumor site was not found to correlate with outcome. Other series have found the functional outcome to be worse for lower extremity sarcomas (9, 15, 20). In general, lower extremity tumors are larger when detected and therefore require more extensive therapy. The local control rates obtained in this series were similar to those cited in other reports using similar techniques (14, 19). Most patients maintained good to excellent functional outcomes using such treatment strategies. We will continue to assess these patients to evaluate possible changes in the outcome parameters over time. It is of interest that some of our patients have demonstrated a decrease in subcutaneous fibrosis with elapsed time. As more patients are evaluated using our assessment protocol, we should be able to more clearly define the relationship of dosimetric parameters to functional outcome.
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1. J. Radiation Oncology 0 Biology 0 Physics
Volume 24, Number 4. 1992
REFERENCES 1. Agresti, A. Analysis of ordinal categorical data. New York, NY: John Wiley and Sons; 1984: 16 1. 2. Barkley, H. T.; Martin, R. G.; Romsdahl, M. M.; Treatment of soft tissue sarcomas by preoperative irradiation and conservative resection. Int. J. Radiat. Oncol. Biol. Physics. 14: 693-699;1988. 3. Beahrs, 0. H.; Henson, D. E.; Hutter, R. V.; eds. Manual for staging of cancer. Philadelphia, PA: J. B. Lippincott Company; 1988: 127-131. 4. Bell, R. S.; O’Sullivan, B.; Davis, A.; I-anger, F.; Cummings, B.; Fornasier, V. L. Functional outcome in patients treated with surgery and irradiation for soft tissue tumours. J. Surgical Oncol. 48:224-23 1;199 1. 5. Chang, A. E.; Steinberg, S. M.; Culnane, M.; Lampert, M. H. Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas. J. Clin. Oncol. 7:1217-1728;1989. 6. Enneking, W. F. Staging of musculoskeletal neoplasms. Current concepts of diagnosis and treatment of soft tissue tumors. Heidelberg: Springer-Verlag; 1984. 7. Enneking, W. F. Modification of the system for functional evaluation of surgical management of musculoskeletal tumors. In Enneking, W. F., ed. Limb salvage in musculoskeletal oncology. New York: Churchill Livingstone, 1987: 626-639. 8. Jentzsch, J.; Binder, H.; Cramer, H. Leg function after radiotherapy for Ewing’s sarcoma Cancer. 47: 1268-278; 198 1. 9. Lampert, M. H.; Gerber, L. H.; Glatstein, E.; Rosenberg, S. A.; Danoff, J. V. Soft tissue sarcoma: Functional outcome after wide local excision and radiation therapy. Arch. Phys. Med. Rehabil. 65477-480; 1984. 10. Lindberg, R. D.; Martin, R. G.; Romsdahl, M. M.; Barkley, H. T. Conservative surgery and postoperative radiotherapy in 300 adults with soft tissue sarcomas. Cancer 47:23912397;1981. 11. Marcus, R. B.; Cantor, A.; Heare, T. C.; Graham-Pole, J.; Mendenhall, N. P.; Million, R. R. Local control and function
12.
13.
14.
15.
16.
17.
18.
19. 20.
after twice-a-day radiotherapy for Ewing’s sarcoma of bone. Int. J. Radiat. Oncol. Phys. 2 1: 1509- I5 15; I99 1. Pao, W. J.; Pilepich, M. V. Postoperative radiotherapy in the treatment of extremity soft tissue sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 19:907-9 11;1990. Robinson, M.; Barr, L.; Fisher, C.; Fryatt, I.; Stotter, A.; Harmer, C.; Wiltshaw, E.; Westbury, G. Treatment of extremity soft tissue sarcomas with surgery and radiotherapy. Radiotherapy Oncol. l&221-233;1990. Rosenberg, S. A.; Tepper, J.; Glatstein, E. The treatment of soft tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann. Surgery 196:304-3 14;1982. Stinson, S. F.; DeLaney, T. F.; Greenberg, J.; Yang, J. C.: Lampert, M. H.; Hicks, J. E.; Venzon, D.; White, D. E.; Rosenber, S. A.; Glatstein, E. J. Acute and long-term effects on limb function ofcombined modality limb sparing therapy for extremity soft tissue sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 21:1493-1499;1991. Suit, H. D.; Mankin, H. J.; Wood, W. C.; Proppe, K. H. Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcoma. Cancer. 55: 2659-2667; 1985. Suit, H. D.; Mankin, H. J.; Wood, W. C. Treatment of the patient with stage MO soft tissue sarcoma. J. Clin. Oncol. 6:854-862; 1988. Suit, H. P. The role of radiation therapy in the management of patients with sarcoma of soft tissue in 1988. In: Pinedo, H. M., Verweig, J., eds. Treatment of soft tissue sarcomas. Boston, MA: Klower Academic. 1989:65-74. Suit, H. D. Sarcoma of soft tissue in the adult. ASTRO Refresher Course No. 105; 1990. Talbert, M. L.; Zagars, G. K.; Sherman, N. E.; Romsdahl, M. M. Conservative surgery and radiation therapy for soft tissue sarcoma of the wrist, hand, ankle. and feet. Cancer 66:2482-249 1; 1990.
Copynghr
0360.3016192 $5.00 t 00 Cm I992 Pergamon Press Ltd.
??Clinical Original Contribution
SARCOMA
THERAPY: FUNCTIONAL TO TREATMENT
OUTCOME AND RELATIONSHIP PARAMETERS
K. KARASEK, M.D.,’ L. S. CONSTINE, M.D.’ AND R. ROSIER, M.D., PH.D.* ‘Dept. of Radiation
Oncology,
‘Dept. of Orthopedic
Surgery, University
of Rochester
Medical Center,
Rochester,NY
Purpose: To systematically assess the functional outcome of patients treated with surgery and irradiation for extremity or truncal sarcomas, and to correlate this outcome with a detailed analysis of the radiation dose distribution and surgical technique. Conservative surgery and radiation therapy (RT) are known to provide excellent local control, but the relationship of technique to functional outcome requires further study. Methods and MuteriuZsr Forty-one patients were treated for lower extremity (25 patients, 61%), upper extremity (8 patients, 19.5%), and truncal (8, 19.5%) sarcomas from 1983 to 1990. Most patients had malignant fibrous histiocytoma (15), liposarcoma (S), or aggressive fibromatosis (6). Age ranged from 13 to 85 years (median 54). All patients received RT and 39 (95%) had surgery. The mean total RT dose was 59 Gy (range 55.8-64.8 Cy). A protocol for functional assessment was devised and included a 4 point scale (O-3) for each of seven functional parameters (range of motion, fibrosis, edema, pain, skin changes, muscle strength, gait, or upper extremity performance). An aggregate score was obtained by adding the seven parameter scores and compared with both a patient and physician overall functional rating score (excellent, good, fair, poor). Based on this analysis, aggregate scores were defined as 5 3 = excellent, 5 8 = good, I 13 = fair, and > 13 = poor, with 21 as the worst possible score. The same orthopaedic surgeon and radiation oncologist independently examined and rated 22 patients. An additional 17 patients were evaluated by record review. The median time from completion of radiation therapy was 30.5 months (range 7-95 months). A computerized radiation therapy dosimetric analysis was performed on 34 patients. Results: Local control was achieved in 39 patients (95%), including 6 with aggressive fibromatosis. The mean functional outcome score was 5.1 with a range of O-16.34 patients (83%) had good or excellent functional outcomes. The rating system demonstrated minimal interobserver variability. There was a positive relationship between volume irradiated to 2 55 Gy and functional score, strength, fibrosis, and skin changes. Total dose independent of volume was significantly associated with skin changes. Increasing peak dose (hot spot dose) was associated with fibrosis and skin changes. More fibrosis developed as the volume of the peak dose increased. A portion of the joint was treated in 5/33 extremity patients and the entire joint in 24/33 (mean dose 55.8 Gy, range 45-65 Gy). Neither range of motion nor total functional score was correlated with joint dose. Edema and functional score were not related to either the volume or percent of limb spared (receiving 5 40 Gy). The physician functional status ratings generally concurred with patient self-assessments. Concfusions: A system for functional assessment has been developed which is easily performed and provides detailed information about patient functional outcome. This system can be used to evaluate the morbidity of combined modality sarcoma therapy. Doses up to 65 Gy, even over joint spaces, are not associated with significant morbidity. Only a small volume treated to 5 40 Gy is required to maintain good outcome. The most important parameter appears to be the volume treated to 255 Gy. Functional outcome, Sarcoma therapy, Dosimetric analysis.
INTRODUCTION
obtain local control are effective, having evolved over the
Optimal therapy for patients with localized soft tissue sarcomas provides local control and eradicates micrometastatic disease, achieving these objectives with minimal functional disability. While the ability to eliminate distant micrometastases remains limited, current strategies to
past two to three decades. Local control rates achieved by conservative surgery and moderate dose radiotherapy have been excellent, exceeding 80% in several series (13, 17). Limb amputation is now seldom performed. Although the general consensus is that functional outcome and cosmesis have been improved without sacrificing local
Acknowledgements-The
Presented at ASTRO 7 November 199 1 in Washington, DC. Reprint requests to: Kristina Karasek, MD, University of Pittsburgh School of Medicine, Department of Radiation Oncology, Joint Radiation Oncology Center, Presbyterian University Hospital, De Soto at O’Hara Streets, Pittsburgh, PA I52 132582.
authors acknowledge and appreciate the assistance of R. Raubertas, Ph.D., in the statistical analysis of data in this manuscript. Accepted for publication I I June 1992.
651
652
I. J. Radiation Oncology 0 Biology 0 Physics
control rates, verification with a formal analysis is lacking in most patient reports. A reproducible, easily performed system of functional assessment would permit comparisons of outcome provided by various treatment strategies, such as surgery and postoperative radiotherapy, interstitial radiotherapy, or pre- and post-operative radiotherapy. We, therefore, elected to create a system of functional assessment of patients treated for soft tissue sarcoma at the University of Rochester Cancer Center with the intention of addressing the following questions: (a) would such a system be easily performed? (b) would physician and patient assessments be consistent? (c) would the treatment volume or dose correlate with outcome? (d) what percent of the limb should remain relatively spared from radiotherapy in order to obviate morbidity? (e) would inclusion of the joint to high radiation doses correlate with adverse effects on mobility? METHODS
AND MATERIALS
Patient eligibility In order to study the functional outcome of patients treated with surgery and radiation therapy for soft tissue sarcomas, we established the following criteria for patient eligibility: (a) age 13 years or greater, (b) tumors of the trunk (excluding retroperitoneal sites) or extremity, (c) no previous radiation therapy, and (d) histopathologies excluding rhabdomyosarcoma but including Ewing’s sarcoma and chondrosarcoma if the tumor primarily involved soft tissue, and also including aggressive fibromatosis. Patient demographics Forty-one consecutive patients treated between 1983 and 1990 meeting these criteria were evaluated. The radiation was administered at Strong Memorial Hospital (SMH) by a single radiotherapist. Surgery was performed at SMH in all but 11 cases. Seven patients received multiagent chemotherapy which included adriamycin. The study population included 36 previously untreated patients and five who had locally recurrent sarcoma but had never received radiation therapy. The distribution of patients by disease sites was as follows: lower extremity 25 (61%), upper extremity 8 (19.5%), and trunk 8 (19.5%). Patient age ranged from 13 to 85 years with average and median age at diagnosis of 50 and 54 years, respectively. There were twenty-two male and nineteen female patients. Table 1 categorizes the histological subtypes. Almost half of patients were Stage III or greater (44%) using the American Joint Commission staging system (3). Treatment characteristics Surgery. Surgery was wide excision in 22 patients (54%) consisting of tumor removal along with a margin of normal tissue. Marginal excision consisting of gross tumor removal was performed in 16 patients (39%) and intralesional biopsy in two patients. Radical resection of the
Volume 24, Number 4, I992
entire tumor containing compartment was done in one case (6). Amputation was recommended for two patients but limb sparing surgery and large volume irradiation was delivered secondary to patient request. Radiation therapy. Successive field reductions were used as described by Herman Suit (17). All patients received postoperative radiation therapy with the exception of one patient who received both preoperative and postoperative therapy. The target volumes were defined 3-dimensionally using either computer tomographic or magnetic resonance scans. All treatment plans were computerized. The initial target volume included tissue considered at risk for microscopic disease and generally received 45 to 50 Gy. A margin of 5 to 10 cm proximally and distally was added to the tumor volume depending on tumor grade. These volumes ranged from 149 cm3 to 7300 cm3 (mean 2700 cm3 and median 1950 cm3). Either one or two boosts were then delivered to smaller volumes. External beam therapy, in the form of photons, electrons, or both, was delivered using 1.8 Gy daily fractions on megavoltage machines. Cross-sectionally the anatomic compartment as defined by CT and MRI was treated with the exclusion of a small strip of tissue which we defined as the “volume spared” and received < 40 Gy. The mean percent of the limb circumference spared was 30% with a range of one to 78%. Absolute volumes of limb sparing ranged from 26 cm’ to 6990 cm3 with a median of 900 cm’. Total prescribed doses ranged from 55.8 Gy to 64.8 Gy with a mean dose of 59 Gy. Twenty-nine patients of the 33 patients with extremity tumors (88%) received treatment to a joint (24 patients or 73% whole joint and five patients or 15% to < 50% of a joint). The average joint dose was 56 Gy (range 45 to 64.8 Gy, median 55.8 Gy). All patients were fitted with immobilization devices. Beam films were checked on a weekly basis. Patient assessments Functional outcome was assessed by one orthopedic surgeon and one or two radiotherapists independently, without knowledge of the assessment by the other physician. Twenty-four patients (58%) were recalled for evaluation at a median of 30.5 months (range 7-95 months) from completion of therapy. Seventeen were scored by record review. The median and mean followup times were 34.9 and 3 1 months respectively for all patients included Table 1. Histological MFH Liposarcoma Desmoid Chondrosarcoma Ewings Malignant schwannoma Synovial sarcoma Leiomyosarcoma PNET Total
subtypes 15 8 6 4 2 2 2
41
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outcome Local tumor control was achieved in 39 patients (95%) including the six with aggressive fibromatosis. Nine of the 35 patients with malignant tumors (26%) developed metastatic disease and eight (23%) of these patients were deceased at the time of chart evaluation. Median survival has not yet been reached by this population using the Kaplan-Meier method.
Disease
outcome Qualitative outcome. Twenty-two patient self-assessments were as follows: excellent 70%, good 15%, fair 7.5%, and poor 7.5%. Physician qualitative assessments of outcome in 4 1 patients were as follows: excellent 5 l%, good 34%, fair lo%, and poor 5%. Quantitative outcome: The mean overall total functional outcome score was 5.1 with a range of 0- 16. Most patients (83%) had good or excellent functional outcomes. The breakdown was as follows: excellent 18 (44%), good 16 (39%) fair 5 ( 12%) and poor 2 (546) and is shown in Figure 1. Correlation between qualitative and quantitative evaluations: Physician and patient qualitative functional scores compared well with the total quantitative scores. Correlation coefficients were .77 0, = .OOOl) and .51 (p = .0006), respectively. Physician qualitative functional scores were related to patient self assessments with a correlation coefficient of .7 1 (p = .OOO1). All seven patients scoring fair or poor had malignant fibrous histiocytoma with the exception of one patient with chondrosarcoma. Five of these patients had lower
Functional
Statistical analysis For the statistical analysis the average score of the two of three physician evaluations was utilized. Associations between functional outcome scores and radiation doses and volumes were assessed using Kendall’s Tau b correlation (1). A correlation coefficient of one indicates a positive correlation between two variables. A 95% confidence interval was selected to determine statistical significance (Q value I .05). Kaplan-Meier analysis was used for survival calculations. Patient and physician scores were compared using the same technique.
Criteria
status evaluation
1
0
Mobility
Normal
Mild loss of motion
Pain
No pain No analgesic
Mild and intermittent Salicylate
Edema
None
Mild and intermittent
Strength Gait
Normal Norma1
Mild loss Slight limp
Normal
Mild impairment Limits some activities Mild Mild: Hyperpigmentation Telangectasia. atrophy
Upper extremity
function
Fibrosis Skin changes
None None
Overall functional
653
er al.
RESULTS
in the study. Seven parameters were scored using a scale from 0 to 3 with a total possible score of 2 1 representing the worst possible outcome (Table 2). Independent of the total quantitative score, both physicians and patients “qualitatively” rated the overall outcome as either excellent, good, fair, or poor. These subjective assessments were then compared to the total functional scores (TFS) in order to derive a quantitative breakdown of the numerical score into functional outcome categories. Aggregate scores were defined as I 3 = excellent, I 8 = good, I 13 = fair, > 13 = poor. This rating system was then used to categorize all quantitative assessments. Isodose curves were analyzed using the central axis or largest diameter contour. Volume calculations were made using digitized contour volumes multiplied by field length. Dosimetric analysis was done on 34 (83%) patients. Volumes receiving ~40 Gy, 50 Gy, 55 Gy, 60 Gy, and 65 Gy, as well as peak dose volumes were calculated. Joint doses (dose to ~50% of joint and whole joint dose) were included in the dosimetry review.
Table 2. Functional
KARASEK
form 2
3
Moderate loss of motion Moderate and intermittent Narcotic Mild and constant
Severe loss of motion/fixed contracture Severe and constant Narcotic
Moderate loss Moderate to severe limp cane/crutch Moderate impairment Requires a change in lifestyle Moderate Episodic skin breakdown
Marked (needs compression stocking) Severe loss Nonambulatory Nonfunctional
Severe Chronic ulceration for graft
status
Physician,fimtional
status rating:
0 = Excellent I = Good (slight impairment) 2 = Fair (moderate impairment) 3 = Poor (severe impairment)
Patient functional status rating 0 1 2 3
= = = =
Excellent Good Fair Poor
or need
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Volume 24, Number 4, 1992 Table 4. Volume
correlation coefficients outcome parameters
with selected
40 5! %
Volume treated
Strength
Fibrosis
Skin changes
30
50-54 Gy ii ag
Total score
20
55-59 Gy
cc = .21
CC = .23
CC = .34
cc = .30
p = ,097
p = .085
p = .Ol I*
p = .037*
cc = .30 p = .025*
cc = .31
CC = .38
CC = .48
p = .029*
p = .009*
p = .002*
10
CC = Correlation coefficient. *p = .05. 0
outcome
Fig. 1. Treatment
outcome
as described by total functional
score.
extremity tumors. Chronic osteomyelitis was the major contributor to outcome in three patients, two of whom developed infected nonunion fractures following trauma which occurred during RT in one patient and prior to therapy in the other. The third patient with osteomyelitis underwent marginal excision with bone grafting prior to RT. One year later implant failure occurred and allograft was used for replacement. Persistent drainage occurred at the wound and a pathological fracture developed requiring a second graft which ultimately failed, necessitating amputation. A severe contracture of the elbow joint developed immediately after one patient wore a compression bandage to relieve arm edema which developed after adriamycin chemotherapy. The patient rated with the worst outcome (total functional score = 16) had a bulky thigh tumor ( 15 X 8 cm) and received large volume (4190 cm3) postoperative therapy covering both the knee and hip. She developed moderate fibrosis, edema, pain, and contracture. Moderate edema was seen only in one of the patients scoring fair or poor. The mean edema score was .58 for all patients. Dose/Volume correlations with outcome: Increasing peak dose was associated with increasing fibrosis and skin changes. The volume of the peak dose was significantly correlated with fibrosis and not skin changes nor other outcome parameters (Table 3). As treatment volume increased, the scores for overall function, strength, fibrosis, and skin changes worsened. This was most notable for the skin and fibrosis parameters. The treatment volume Table 3. Peak and total prescribed dose correlation with selected outcome parameters Fibrosis Peak dose volume Peak dose
Total dose CC = Correlation *p < .05.
cc p = CC p =
= .27 .027* = .27 .028* cc = .09 p = .49 coefficient.
coefficients
Skin changes cc
= .17
p= .21 cc
= .44
p = .001* cc
= .37
p = .006*
receiving 55 to 59 Gy was more strongly correlated with these parameters than the volume receiving 50 to 55 Gy (Table 4). Total prescribed dose was significantly associated with skin changes (Table 3). Joint doses were not significantly associated with range of motion scores. Similarly, the volume spared could not be related to edema scores or overall functional outcome. Volumes as low as 26 cm3 and corresponding limb volume percentages of one percent were not significantly associated with poor outcomes. The mean total functional score for the patients undergoing marginal excision was 5.5, not significantly different from the mean score of 5.2 for the patients treated with more extensive surgery. DISCUSSION No widely used system exists for analyzing functional outcome of limb preserving therapy of sarcomas. Generally, one can expect to achieve excellent functional outcome following such therapy. This is supported by several recent reports, but detailed descriptions are lacking. For example, in a recent report from the Massachusetts General Hospital, functional status was “judged good by the participating clinicians” ( 17) and later described as good in 75-80% patients who did not require support devices or pain medication (18). In 300 patients treated at M.D. Anderson Cancer Center (15), limb function was maintained in 84.5% of patients and the incidence of severe complications was 6.5%. “Normal function” was maintained in the limbs of 24/26 long-term survivors following postoperative treatment of extremity sarcomas at Mallinckrodt Institute of Radiology (12). In a patient population treated at the National Cancer Institute the functional assessment was based solely on strength and joint motion (5). More detailed descriptions of functional outcomes are found in some reports. In a series of patients treated for distal extremity sarcomas at M.D. Anderson Cancer Center (20), the functional assessment scale was divided into four categories: normal, mild limitation, moderate limitation, severe limitation, and major limitation. Individual criteria included overall function, edema, pain, strength, joint motion, skin ulceration, and fibrosis. Fifty-three of 78 (68%) retained a “normal or fairly normal extremity” and 12 of 78 (16%) had either severe dysfunction or re-
Sarcoma therapy 0 K.
quired an amputation for complications. Outcome was significantly worse for the lower extremity lesions. Jentzsch et al. (8) evaluated leg function of patients surviving at least two years following therapy for Ewing’s Sarcoma. Soft tissue changes were rated by circumference measurements which in our experience is a confusing endpoint because of the effect of edema and surgery. Muscle strength, joint motion, pain, edema, and quality of gait were quantified with a three point scale. These investigators did not use numerical scores, but instead placed patients into four functional groups described as fully functional, moderately limited, severely limited, or nonfunctional. This format has been used by subsequent investigators ( 11). Most recently, Stinson et al. (15) published a retrospective review of the long-term limb function of 145 patients treated at the National Cancer Institute. Lampert et al. (9) had previously reported on 26 of these patients using an elaborate standardized battery of measurements of range of motion, muscle strength, functional category, edema, and pain. Stinson et al. (15) used a similar comprehensive list of criteria with either “yes” or “no” ratings except for range of motion and muscle strength deficits which were classified as either “mild” or “moderate/severe” deficits. In 1982, a system of functional evaluation of surgically managed musculoskeletal tumors was proposed to the Musculoskeletal Tumor Society. This system has been subsequently modified and consists of seven factors: motion, pain, stability, deformity, strength, functional activities/emotional acceptance, and complications (7). These were rated with a four point scale. This system has been applied by Bell et al. in Toronto (4). A total of 88 patients were evaluated following surgery and radiotherapy. Sixtyeight had functional scores of 21 or better (with 35 representing the best possible outcome). Numerical scores were not defined in terms of descriptors such as excellent, fair, or poor. Six patients were felt to have unsatisfactory outcomes. Three of these patients suffered from late fractures. No information was given about the radiation therapy techniques or doses. We found this system to be cumbersome and difficult to apply. The system for functional assessment developed at our institution is easy to perform and provides detailed information about functional outcome. It incorporates both quantitative and qualitative evaluations which were reproducible. It is impossible to clearly distinguish the impact of surgery from late radiation effects. The sequelae one would expect following radiotherapy, such as fibrosis and skin changes, were related to the treatment volume and peak dose. The correlation became stronger with increasing dose except for the greater than 60 Gy category in which there were few cases. Strength is a parameter largely impacted by extent of surgery. Since more extensive surgeries were followed by larger radiation treatment portals for the postoperative phase of therapy, an inverse association between strength and increasing radiation treatment vol-
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et al.
655
ume might be expected. Our data suggest this. LOSSof strength should therefore be largely a consequence of surgery. Total radiation dose was not a predictor for functional outcome in this study. Stinson et al. ( 15) found that doses greater than 63 Gy at 1.8 Gy fractions were positively correlated with chronic pain, skin telangectasias, edema, decrease in muscle strength, and loss of range of motion. Doses exceeding 64.8 Gy were not used in the current study, thus such a relationship between high dose and outcome would not have been detected. The limb volume receiving high radiation dose, as quantified from digitization of isodose curves, was the most important parameter for predicting functional outcome. It was the only aspect of therapy which was clearly associated with the total functional score. Unfortunately the large patient series reviewed by Stinson et al. ( 15) did not include information about treatment volumes, although the length of the treatment field was found to significantly contribute to edema, tissue induration, and decreased muscle strength. All our radiation portals were devised to protect a small strip of tissue to allow for lymphatic drainage. Only a few patients developed edema, making it difficult to draw conclusions about the relationship of edema with treatment parameters. As there was no correlation between volume spared and outcome, we conclude that only a small volume of tissue must be spared to prevent lymphedema. This finding was also apparent in Stinson’s report ( 15). The percent of limb diameter irradiated was quantified as 0% to 25%, 26% to 50%, 51% to 75%, and no association with the development of extremity edema was found. Our data indicate that the joint can tolerate moderately high doses of RT without adverse effects on mobility. This is in contrast to the conclusion made by Stinson et al. ( 15). They did not quantify the doses delivered to joints, which may have received higher doses since boost fields were treated to 70 Gy. Five of seven patients with only fair or poor outcomes were treated for lower extremity tumors. Despite this finding, the tumor site was not found to correlate with outcome. Other series have found the functional outcome to be worse for lower extremity sarcomas (9, 15, 20). In general, lower extremity tumors are larger when detected and therefore require more extensive therapy. The local control rates obtained in this series were similar to those cited in other reports using similar techniques (14, 19). Most patients maintained good to excellent functional outcomes using such treatment strategies. We will continue to assess these patients to evaluate possible changes in the outcome parameters over time. It is of interest that some of our patients have demonstrated a decrease in subcutaneous fibrosis with elapsed time. As more patients are evaluated using our assessment protocol, we should be able to more clearly define the relationship of dosimetric parameters to functional outcome.
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