The follow-up of adult soft-tissue sarcomas

The Follow-Up of Adult Soft-Tissue Sarcomas Shreyaskumar R. Patel, Gunar K. Zagars, and Peter W.T. Pisters Soft-tissue sarcomas are a rare and heterogeneous group of diseases with variable biology and pattern of metastases. These characteristics make it challenging to conduct large, randomized studies that could be used to generate evidence-based guidelines for unique subsets. Much of the data summarized here therefore represents standard practice based on the consensus of a group of experienced specialists and retrospective analysis of large databases. A surveillance guideline should be based on known prognostic factors, outcomes in individual subsets, and patterns of recurrence. It has to be practical and relatively cost-effective. The major goals of such an algorithm for softtissue sarcomas would be early identification of potentially curable recurrences, identification of therapy-related complications, and patient reassurance. Semin Oncol 30:413-416. © 2003 Elsevier Inc. All rights reserved.

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OFT-TISSUE SARCOMAS are a rare and heterogeneous group of mesenchymal tumors originating from connective tissues. The estimated annual incidence in the United States was approximately 8,300 new cases for the year 2002.1 Nearly 60% of these tumors originate in the extremities, followed by 30% in the trunk/retroperitoneum, and about 10% in the head and neck region. The American Joint Commission on Cancer (AJCC) staging system applicable to most soft-tissue sarcomas (except Kaposi’s sarcoma, angiosarcoma, dermatofibrosarcoma protuberans, desmoid tumor, and sarcomas arising in brain, dura, hollow viscera, or parenchymatous organs) is based on important prognostic factors, including primary tumor size, histologic grade, extent of disease, and location in relation to the investing fascia.2 However, this system does not take into account the contribution of histology, for example, small cell sarcomas (Ewing’s/primitive neuroectodermal tumors, rhabdomyosarcomas) that by definition are considered systemic diseases. Within the heterogeneous group of soft-tissue sarcomas, the extremity primaries are the most common, and reasonably uniform in their metastatic patterns and, therefore, form the basis for most guidelines and recommendations. The experience from Memorial Sloan-Kettering Cancer Center (MSKCC) in more than 1,000 patients with extremity soft-tissue sarcomas during the period from July 1982 to June 2000 indicates that the 5-year disease-free and overall survival rates for stage 1 tumors are 86% and 90%, for stage 2 tumors are 72% and 81%, and for stage 3 tumors Seminars in Oncology, Vol 30, No 3 (June), 2003: pp 413-416

are 52% and 56% respectively.2,5 Patients with obvious metastatic disease (AJCC stage 4) are generally incurable; however, there is a small subset of these patients who can be effectively managed with resection and or systemic therapy, resulting in 3- to 5-year survival rates less than 20%. The prognostic factors predicting survival after development of a recurrence subsequent to definitive treatment of the primary tumor tend to depend on the site of recurrence and the time to recurrence. The MSKCC group recently published their analysis of 2,123 patients with resected primary soft-tissue sarcomas from all sites. Median follow-up was 59 months. Two thirds of all recurrences developed within the first 2 years after resection. Time-dependent stepwise regression analysis revealed that risk of tumor-related death decreased significantly for extremity and trunk sites when disease-free interval exceeded 3 years. The influence of known high-risk factors for survival present at diagnosis decreased by 40% for the subset of extremity/trunk lesions at 3 years after resection compared to the influence on other sites, which remained constant over time. The 2-, 5-, and 10-year actuarial disease-specific survivals after complete resection were 89%, 79% , and 71% for extremity/trunk sarcomas, compared to 86%, 69%, and 56%, respectively, for other sites.4 In another series from the M.D Anderson Cancer Center, the authors evaluated the prognostic factors in 504 consecutive patients with relapsed soft-tissue sarcoma following definitive therapy. At a median follow-up of 7.2 years, the 5- and 10-year disease-specific survivals were 51% and 48% for those with isolated local recurrence, compared to 16% and 10%, respectively, for those with distant relapse (P ⬍ .001). Favorable prognostic features for the subset with isolated local recurrence (univariate and multivariate analysis) included ex-

From The Sarcoma Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Shreyaskumar R. Patel, MD, Department of Sarcoma Medical Oncology, Box 450, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3003-0010$30.00/0 10.1016/S0093-7754(03)00101-5 413

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tremity and superficial trunk site, initial tumor size ⱕ 5 cm (T1), greater than 12-month diseasefree interval, and low/intermediate grade. In contrast, for the subset of patients with distant metastases as the first site of relapse, disease-free interval of greater than 12 months was the only predictor of survival. The overall 5-, 10-, and 15-year disease-specific survivals after first relapse (for the entire group of 504 patients) were 27%, 22%, and 19%, respectively.5 This reaffirms the known fact that a small group of patients with relapsed softtissue sarcoma can be long-term survivors. Surveillance of these patients following primary therapy is based on prognostic factors and patterns of recurrence and is designed to identify favorable subsets with resectable recurrences. PATTERNS OF RECURRENCE

The patterns of recurrence vary with anatomic site of the primary tumor. Lymph node metastases are relatively uncommon (⬍5%) in soft-tissue sarcomas. Patients with extremity and superficial trunk primaries have a higher predilection for distant lung metastases and a lower probability of local/regional recurrences. In contrast, patients with retroperitoneal, head and neck, or visceral sarcomas have a higher tendency towards locoregional recurrences compared to distant metastases. The retroperitoneal tumors also have a higher likelihood of metastasizing to the liver. Specific histologic subsets, eg, myxoid liposarcomas, have a tendency to metastasize to other soft-tissues/fatbearing areas requiring more extensive imaging than a typical extremity soft-tissue sarcoma. STAGING AND SURVEILLANCE IN THE LOW-RISK GROUP

The routine use and yield of chest x-rays and computed tomography (CT) of chest to stage a patient with T1 primary extremity soft-tissue sarcoma has been studied retrospectively in a group of 125 consecutive patients at the M.D. Anderson Cancer Center. Seventy percent of these tumors were high grade and the median size was 3 cm. All patients underwent a chest x-ray and only one was suspicious for metastases. Fifty-one patients (41%) underwent a CT scan of the chest, with only one study (in the patient with a suspicious x-ray) demonstrating lung metastases. The incremental costeffectiveness ratio was $59,772 per case of synchronous pulmonary metastases when CT chest was added to a plain chest x-ray. This suggests that

the yield for an added CT scan is very low when a good-quality chest radiograph does not reveal any suspicion for lung metastases. Interestingly, in this cohort of patients, at a median follow-up of 76 months, 19 patients (15%) developed metachronous lung metastases as the only site of documented distant recurrence. Seventeen of these 19 patients had high-grade primary tumors. The probability for development of lung metastases was 19% for high-grade tumors compared to 5% for low- and intermediate-grade tumors. The rate of recurrence was higher (24%) in the group that was staged with x-ray and CT scan compared to chest x-ray alone (9%), reflecting the higher index of suspicion in higher-risk group as perceived by the treating physician. The median disease-free interval was 50 months for the group that was staged with both x-ray and CT chest compared to 29 months for the group staged with chest x-ray alone. The 5-year actuarial overall and metastasesfree survivals for the entire group were 90% and 88%, respectively. The 5-year metastases-free survival for the group staged with x-ray and CT chest was actually lower (65%) compared to the chest x-ray alone group (90%).6 These data suggest that for T1 extremity primary lesions routine use of CT chest for staging at presentation is not cost-effective. It is also reasonable to extrapolate from these data that subsequent follow-up of a patient with T1 extremity primary soft-tissue sarcoma (or other site) who has been treated with curative intent and is free of any gross evidence of disease should not include a routine CT scan of the chest. These patients are best followed by a history and physical examination, cross-sectional imaging of choice encompassing the primary tumor bed, and a chest x-ray at periodic intervals. The debatable issues here include which cross-sectional imaging study if any, at what intervals, and for how long? With regards to imaging of the local site, magnetic resonance imaging (MRI) for head and neck, trunk, and extremity sites, and CT scan for chest and abdominal/retroperitoneal sites is considered appropriate. In the hands of experienced ultrasonographers, ultrasound can provide valuable information at the least cost for extremity and superficial trunk locations. This is, however, operator-dependent and requires experience, expertise and consistency. The National Comprehensive Cancer Network (NCCN) guidelines recommend follow-up with annual scanning of the primary site for 5

FOLLOW-UP OF ADULT SOFT-TISSUE SARCOMAS

years for low-grade, superficial, or small tumors.7 In reality, however, these intervals range from every 3 to 6 months depending on the clinician’s index of suspicion in the immediate postoperative period with extension of the intervals with passage of time. STAGING AND SURVEILLANCE IN THE HIGH-RISK GROUP

The risk of distant metastases to lungs is much higher for T2 (⬎5 cm) primary tumors and, therefore, routine use of CT chest for staging at the time of diagnosis is considered the standard of care. The M.D. Anderson group reviewed their experience in 600 consecutive patients with T2, primary, extrathoracic soft-tissue sarcomas who underwent both chest x-ray and a CT scan of the chest to detect the presence of lung metastases.8 The yield of routine use of CT chest was higher (19.2% v 16%) compared to selective use of CT chest based on chest x-ray findings. The incremental costeffectiveness ratio calculated as the cost per additional patient with lung metastases identified by routine versus selective use of CT chest was $27,594. As expected there was significant variation in yield and cost for different subsets based on grade, size, and site. The authors concluded that for patients with T2 soft-tissue sarcomas, routine use of CT chest for staging purposes was most cost-effective in patients with high-grade lesions and extremity primaries. On the contrary, routine use of CT chest was not recommended for all low-grade or retroperitoneal soft-tissue sarcomas. The group from Roswell Park Cancer Institute reviewed their experience with follow-up strategies in 150 patients with extremity soft-tissue sarcomas. The median follow-up was 69 months, 49% of the tumors were high-grade, and the median size was 8 cms. Their postoperative surveillance strategy included a clinical assessment, laboratory tests (complete blood cell count, electrolytes, and liver function tests), and a chest x-ray every 3 months for years 1 and 2, every 4 months for year 3, every 6 months for years 4 and 5, and annually thereafter for life. MRI or CT scan of the primary site was performed annually. More than 90% of the recurrences occurred in the first 5 years postresection. Eighteen percent of patients had local recurrences at a median of 14 months and 89% of these occurred within 5 years. Almost all of these recurrences were detected on physical examination and 86% of these were deemed resectable. Forty per-

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cent of patients developed distant metastases at a median time of 18 months. Ninety-four percent of these were detected within 5 years, and 93% had pulmonary metastases. Thirty-seven percent had pulmonary symptoms, while 63% had asymptomatic lung metastases. The authors analyzed the utility and cost-effectiveness ratio of chest x-ray surveillance in 74 patients with high-grade tumors whose first recurrence was confined to lungs. The cost per quality-adjusted life-years saved for a 6-year surveillance program was $30,000, which compares favorably to the arbitrary suggested cutoffs of $50,000 to $100,000.9 The NCCN guidelines for large, high-grade tumors recommend imaging of the primary tumor site every 4 to 6 months for the first 3 years followed by long-term annual follow-up including consideration for CT scan or MRI following resection. Chest x-rays are recommended every 3 to 6 months for 5 years.6 Our standard practice is to monitor these patients with a history, physical examination, laboratory tests (including a complete blood cell count, liver function tests, electrolytes, and creatinine [especially for those who have undergone systemic chemotherapy]), a chest x-ray, and a cross-sectional imaging study of choice (as described above for low-risk tumors) at 3-month intervals for 1 to 2 years, 4-month intervals for the next 1 to 2 years, 6-month intervals for the next 1 to 2 years, and yearly thereafter. Since most local recurrences are likely to occur within 5 years, it is reasonable to omit the cross-sectional imaging for extremity and superficial trunk sites after that time. The debate as to the appropriate tests, intervals, and duration can only be resolved with prospective studies in large cohorts of homogeneous populations. DISCUSSION

The major objectives of surveillance after curative therapy in a potentially curable patient include early identification of curable recurrences, reversible/treatable complications of therapy, identification of second primary tumors (especially where risk is high, eg, upper aerodigestive tract cancers) and increasingly for reassurance of the patient. In the current era of cost-containment, there is ever-increasing pressure and responsibility on the shoulders of the health care provider to be cost-effective and base their practice patterns only on evidence-based recommendations. Accomplishing both is particularly difficult in a disease like soft-tissue sarcomas, where the required

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evidence-based data are difficult to obtain. We are therefore forced to settle for a so-called consensus, frequently not uniform, since it has to allow for clinical judgment. Somewhere between 20% and 38% of patients with soft-tissue sarcomas will develop isolated pulmonary metastases.9-11 Complete surgical resection of these pulmonary metastases have resulted in actuarial projected 3-year survivals of 20% to 54%11,12 and 5-year survival rates of 21% to 26%.13,14 Pulmonary metastasectomy is therefore considered a standard practice since there is indeed a small population that can be cured and the morbidity and mortality of this procedure in experienced hands is very low. The prognostic factors that have favored better outcome following metastasectomy include a longer disease-free interval (⬎12 months), fewer metastases (less than five per lung field), and a shorter tumor doubling time.15 None of these studies have estimated the benefit of metastasectomy on the patient’s quality of life. The psychosocial impact of being disease-free compared to having demonstrable metastatic disease cannot be underestimated. Based on this logic, resection of metastases at any one isolated site is frequently considered for patients with softtissue sarcomas. The actual impact of such a strategy on survival is difficult to establish given the small numbers. For those patients with multiple sites of disease, the proportion of long-term survivors is significantly smaller and therefore therapeutic strategies are geared at expectant palliation and improvement in overall quality of life. RECOMMENDATIONS

Acknowledging the very limited data available to make firm recommendations and the tremendous heterogeneity amongst soft-tissue sarcomas requiring individualized clinical judgment, the following surveillance strategies are suggested. Patients with low-risk soft-tissue sarcomas who have undergone curative therapy could be followed with a history, physical examination, and chest x-ray at 3- to 4-month intervals for 2 years, 4- to 6-month intervals for 2 years, and yearly thereafter. Crosssectional imaging should be individualized based on the reliability of physical examination and suspicion for deep-seated recurrence. Patients with nonextremity sites frequently require cross-sectional imaging for routine follow-up. Patients with a very low-risk of recurrence could stop surveillance after 5 to 10 years as clinically appropriate.

Patients with high-risk soft-tissue sarcomas could be followed with a history, physical examination, laboratory tests (including a complete blood cell count, electrolytes, liver function tests, and creatinine [especially if they have undergone systemic therapy]), chest x-ray, and a cross-sectional imaging of choice every 3 months for 2 years, every 4 months for 2 years, every 6 months for the fifth year, and yearly thereafter. The costeffectiveness of many of these tests and their impact on survival remains unknown. REFERENCES 1. Jemal A, Thomas A, Murray T, et al: Cancer statistics. CA Cancer J Clin 52:23-47, 2002 2. Soft-tissue sarcoma, in Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual (ed 6). New York, NY, Springer Verlag, 2002, pp 193-197 3. Brennan MF: Staging of soft-tissue sarcomas. Ann Surg Oncol 6:8-9, 1999 4. Stojadinovic A, Leung DHY, Allen P, et al: Primary adult soft-tissue sarcoma: Time-dependent influence of prognostic variables. J Clin Oncol 20:4344-4352, 2002 5. Zagars GK, Ballo MT, Pisters PWT, et al: Prognostic factors for disease-specific survival after relapse of soft-tissue sarcoma: An analysis of 504 patients with disease relapse following initial conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys (submitted) 6. Fleming JB, Cantor SB, Varma DGK, et al: Utility of chest computed tomography for staging in patients with T1 extremity soft-tissue sarcomas. Cancer 92:863-868, 2001 7. Demetri GD, Delaney T: Sarcoma. Cancer Control 8:94-101, 2001 8. Porter GA, Cantor SB, Ahmad SA, et al: Cost-effectiveness of staging computed tomography of the chest inpatients with T2 soft-tissue sarcomas. Cancer 94:197-204, 2002 9. Whooley BP, Gibbs JF, Mooney MM, et al: Primary extremity sarcoma: What is the appropriate follow-up? Ann Surg Oncol 7:9-14, 2000 10. Gadd MA, Casper ES, Woodruff JM, et al: Development and treatment of pulmonary metastases in adult patients with extremity soft-tissue sarcomas. Ann Surg 218:705-712, 1993 11. Billingsley KG, Burt ME, Jara E, et al: Pulmonary metastases from soft-tissue sarcoma: Analysis of patterns of disease post-metastasis survival. Ann Surg 229:602-612, 1999 12. Jablons D, Steinberg SM, Roth J, et al: Metastasectomy for soft-tissue sarcoma. J Thorac Cardiovasc Surg 97:695-705, 1989 13. Verazin GT, Warneke JA, Driscoll DL, et al: Resection of lung metastases from soft-tissue sarcomas: A multivariate analysis. Arch Surg 127:1407-1411, 1992 14. Casson AG, Putnam JB, Natarajan G, et al: Five-year survival after pulmonary metastasectomy for adult soft-tissue sarcoma. Cancer 69:662-668, 1992 15. Putnam JB, Roth JA, Wesley MN, et al: Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft-tissue sarcomas. J Thorac Cardiovasc Surg 87:260-268, 1984