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From OncoLog, June 2011, Vol. 56, No. 6

Graphic: Compass
Compass, a quarterly supplement to OncoLog, discusses cancer types for which no standard treatment exists or more than one standard treatment is available.

Stage II or III Soft Tissue Sarcoma
Chemotherapy and radiation therapy before or after surgery benefit patients

By Sunni Hosemann

Overview

Soft tissue sarcomas can arise from virtually any connective tissue and can manifest as tumors at almost any anatomical site.

There are at least 50 different histological subtypes of soft tissue sarcoma. This great variety presents unique challenges for developing standard guidelines for treating these tumors.

Experts generally agree that surgical resection is the definitive treatment for soft tissue sarcoma, but surgery alone is not curative for some stage II and III tumors. For those tumors, some combination of additional treatment—chemotherapy and/or radiation therapy—must be considered. However, which additional treatments to use, and in what sequence, remains unclear.

About sarcoma

Sarcomas, which account for less than 1% of cancers in adults, are relatively rare. Only about 10,000 new diagnoses of sarcoma occur annually; of those, about two thirds arise from soft tissues and about one third from bone.

This discussion is limited to American Joint Committee on Cancer (AJCC) stage II or III soft tissue sarcomas that are resectable or potentially resectable. Kaposi sarcoma, desmoid tumors, and gastrointestinal stromal tumors are sarcomas with special characteristics and considerations and are not included in the AJCC staging system; therefore, they are not included in this discussion.

Sarcomas can affect almost any soft tissue—including fat, muscle, nerves, and vascular, lymphatic, and synovial tissues—and tumors are frequently named for the specific tissues they most closely resemble. More than half of soft tissue sarcomas are found in the extremities, about 20% are found in the thorax, 15% are found in the abdomen, and 10% are found in the head and neck. Some soft tissue sarcomas are organ-specific; such tumors arise exclusively in the lungs, liver, kidneys, etc. The specific sarcoma subtype and anatomical site are important factors in treatment choice and outcome.

Soft tissue sarcomas exhibit a wide range of behavior in their patterns of growth and metastasis. Some soft tissue sarcomas tend to grow by spreading locally with microscopic extensions into the surrounding tissue, whereas others are visibly—macroscopically—infiltrative in nature. Some soft tissue sarcomas are slow to metastasize or may never metastasize at all. For example, among patients with retroperitoneal and abdominal soft tissue sarcomas, fewer deaths are attributable to distant metastases than to uncontrolled local recurrence. However, other soft tissue sarcomas are rapidly aggressive in their dissemination.

Flowchart: Standards Options for Stage II or II Resectable Soft Tissue Sarcoma

Most soft tissue sarcomas metastasize hematogenously rather than via regional lymph nodes, as is often the case with carcinomas. The most common site of soft tissue sarcoma metastasis is the lung, but metastases can also appear in nerve, cutaneous, or fat tissue in some patients. Some soft tissue sarcoma metastases, called skip metastases, occur in the soft tissue of the same limb as the primary tumor but at locations that are not adjacent to the primary tumor. Also, the individual metastases themselves may differ in their aggressiveness.

These variations influence and present considerable challenges to the staging of soft tissue sarcomas. For example, because sarcomas generally metastasize hematogenously rather than to regional lymph nodes, the node (N) status has a different significance for sarcomas than it does for carcinomas. According to Raphael Pollock, M.D., Ph.D., a professor in and head of the Division of Surgery at The University of Texas MD Anderson Cancer Center and chair of the AJCC Sarcoma Staging Committee, “An N1 sarcoma may be less ominous than an N1 carcinoma and is a stage III rather than stage IV tumor.”

At least two staging systems for soft tissue sarcoma are in common clinical use. The Musculoskeletal Tumor Society staging system classifies sarcoma according to the tumor grade, extent of tumor spread beyond its anatomical compartment, and presence of metastases. The AJCC stages soft tissue sarcoma using tumor size and grade, lymph node involvement, and presence of distant metastases; tumor depth in relation to tissue fascia is also used to characterize these tumors.

The fact that more than one staging system for sarcomas is in common use highlights the difficulties in categorizing these very diverse tumors. According to Dr. Pollock, MD Anderson physicians have found that considering histology when classifying sarcoma may provide more robust prognostic information than grade alone. He also said that a need exists for continued refinements in staging approaches to identify additional prognostic factors that can guide treatment decisions.

Refinements in the staging of soft tissue sarcomas have been limited by the paucity of large data sets for these rare tumors. An initiative of the National Cancer Institute aimed at addressing this concern is The Cancer Genome Atlas, a tissue procurement program that links tissue specimens with clinical data regarding treatment responses, disease progression, and survival. Upon completion of this project in several years, it is hoped that the National Cancer Institute will make The Cancer Genome Atlas data freely available to researchers and clinicians throughout the world.

Technological advances have helped as well: high-throughput molecular analysis and tissue microarrays have enabled researchers to rapidly evaluate large collections of specimens for many hundreds of molecular markers. Dr. Pollock believes these advances will yield valuable genetic and molecular prognostic information that could be integrated with clinical information to better stratify and stage sarcomas, which in turn could lead to better-informed treatment recommendations for individual patients.

Treatment options and decisions

Surgery alone is curative for many soft tissue sarcomas that can be resected en bloc with microscopically negative margins. The possibility of such optimal resection is determined by the size and location of the tumor; however, tumor histology and grade also yield prognostic information about the risk of recurrence and metastasis.

Type of surgery is an additional concern when planning optimal treatment for soft tissue sarcoma. When a sarcoma is located in an extremity, the surgeon must decide whether to perform limb-sparing surgery or amputation. Limb-sparing surgery should be considered if complete resection of the tumor can be performed without seriously compromising the function of the limb. The surgical expertise needed to perform limb-sparing surgery is a limiting factor that affects the rate of amputations for sarcoma, which varies from 3% to 10% at most hospitals but is 0.1% at MD Anderson and other major sarcoma centers.

However, even when limb-sparing surgery is possible, patient preferences play a role in determining the type of surgery to be performed. Because the recovery and rehabilitation period after some limb-sparing procedures can be substantially longer than that after amputation, some patients opt for amputation as a shorter, simpler form of surgery. For example, in some patients, radiation therapy would be required with limb-sparing surgery—and thus prolong treatment—but not with amputation. The location and extent of limb loss, prosthetic possibilities, and lifestyle issues all play a part in this very individualized decision.

In most patients with stage II or III soft tissue sarcoma, surgery alone is not sufficient, and radiation therapy and/or chemotherapy are also employed. The grade and size of the tumor, in addition to its location in relation to the deep fascia, are considered when determining the need for additional, nonsurgical therapies. Shreyaskumar Patel, M.D., a professor in the Department of Sarcoma Medical Oncology, said, “Tumors that are high-grade, deep, and large are all bad actors that are likely to require additional therapy.”

According to Gunar Zagars, M.D., a professor in the Department of Radiation Oncology, radiation therapy is considered a standard adjuvant therapy for sarcomas when surgery alone is believed to be insufficient. Targeting radiation to sarcomas can be challenging because of their wide variation in anatomical locations and depths in the body. However, Dr. Zagars said that precise radiation delivery systems such as intensity-modulated radiation therapy and proton therapy make it possible to treat soft tissue sarcomas that cannot be treated with conventional external-beam radiation therapy. Given these options, Dr. Zagars said, “It is exceedingly rare today to see a tumor that I can’t access to treat.”

The addition of chemotherapy as an adjuvant to surgery for soft tissue sarcoma is less well accepted by clinicians worldwide. “The standard of care has been surgery with or without radiation therapy,” Dr. Patel said, “but this is clearly inadequate because we know that up to half of patients with stage III soft tissue sarcoma will have a recurrence and will die of the disease within 3–5 years.” However, given the rarity of soft tissue sarcomas, not enough large, randomized clinical trials have been conducted in homogeneous populations to provide the evidence needed to establish firm guidelines for the use of chemotherapy in these patients.

Still, said Dr. Patel, a number of smaller studies support the addition of chemotherapy for patients at a high risk of recurrence, even if such therapy does not necessarily result in a cure. For example, a 1997 meta-analysis of 14 trials that were conducted in the 1970s and 1980s concluded that the addition of doxorubicin-based therapy, while not conferring a statistically significant overall survival advantage, did increase local control rates and relapse-free intervals. In the subset of extremity soft tissue sarcomas, however, there was a survival advantage. An update in 2008 that included four newer trials found that the modern combination of doxorubicin and ifosfamide offered an overall survival benefit for the entire population of soft tissue sarcoma patients. And a prospective study conducted by the Italian Sarcoma Group found a 19% increase in the 5-year overall survival rate following aggressive therapy with anthracycline, ifosfamide, and growth factor support in patients with extremity and superficial trunk tumors that had a high risk of recurring. However, with follow-up beyond 7 years, the overall survival benefit lost its statistical significance owing to late recurrences.

“It’s important to note that overall survival is not the only measure we should consider,” Dr. Patel said. “Longer disease-free intervals—lengthening the time to relapse—are important for patients.” The short- and long-term toxicities associated with chemotherapy and radiation therapy must also be considered when adding these therapies to a patient’s treatment plan.

Treatment sequence

Soft tissue sarcomas are best treated by collaborative multidisciplinary teams in comprehensive cancer centers. However, treatment strategies at such centers vary considerably in terms of whether radiation therapy, chemotherapy, or both should precede or follow surgery. At MD Anderson, preoperative therapies are preferred.

“In cases where all three modalities are brought to bear, radiation therapy and chemotherapy are oriented toward achieving a successful surgery,” said Dr. Zagars. “Treatment hinges on realizing that surgery is necessary and building around that.”

At MD Anderson, the preferred sequence begins with chemotherapy followed by radiation therapy and then surgery. This treatment sequence has notable advantages. For example, when chemotherapy is delivered preoperatively, its effect on the tumor can be observed directly when the tumor is resected. In contrast, the effectiveness of chemotherapy given after surgery cannot be gauged by direct observation. “When chemotherapy is delivered postoperatively, we are only guessing about its benefit for an individual patient,” Dr. Patel said. “But we can actually see the effect of preoperative chemotherapy and thus stop treatment for patients who are not benefiting.”

Giving radiation therapy before surgery also has advantages. For example, preoperative radiation therapy uses a lower dose of radiation than does postoperative therapy. Also, the radiation field is usually smaller for preoperative radiation therapy than for postoperative radiation therapy, in which the radiation field would have to encompass the entire surgical field to control the tumor’s microscopic extensions into surrounding tissue.

According to Dr. Zagars, radiation oncologists at MD Anderson do not routinely employ postoperative radiation boosts because the required time lapse between the last preoperative radiation treatment and the boost renders the boosts less effective.

Despite the advantages of preoperative radiation therapy in patients with soft tissue sarcomas, the potential for complications can limit its use. When radiation precedes surgery, postoperative wound healing is delayed, and the potential for wound complications is higher. Therefore, Dr. Zagars said, preoperative radiation therapy requires close collaboration and a high degree of trust between medical, surgical, and radiation oncologists. “Complications from preoperative radiation therapy heal faster than those resulting from postoperative radiation therapy,” he said. “But the surgeon and patient have to be comfortable with the risk of complications and agree to it.”

In the absence of universally accepted treatment guidelines for stage II and III soft tissue sarcomas, a multidisciplinary approach can help determine which combination of surgery, radiation therapy, and chemotherapy will benefit each individual patient.

References

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Soft Tissue Sarcoma V1.2011.
Altekruse SF, Kosary CL, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2007. Bethesda, MD: National Cancer Institute, 2010.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. Shreyaskumar Patel

Shreyaskumar Patel, M.D.
Professor, Sarcoma Medical Oncology

Photo: Dr. Raphael Pollock

Raphael Pollock, M.D., Ph.D.
Professor and Division Head, Surgery

Photo: Dr. Gunar Zagars

Gunar Zagars, M.D.
Professor, Radiation Oncology

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, June 2011 issue:

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