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Michigan Oncology Journal Fall 97

Biologic Therapies for the Treatment of Soft Tissue Sarcomas and Desmoid Tumors

---Vernon K. Sondak, M.D.

Introduction
Soft tissue sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin. In 1997, an estimated 6,000 cases will occur in the United States, resulting in the deaths of 3,600 patients, which means sarcomas are responsible for the deaths of more patients each year than Hodgkin's disease, testicular cancer and thyroid cancer combined. For most (but not all) types of sarcomas, the major cause of death is metastatic disease, with the lung representing the predominant (and often the only) site of metastasis. There are certain types of sarcomas, particularly low-grade tumors including desmoid tumors, in which metastases rarely occur but uncontrolled local growth represents the major therapeutic problem. In this review, we outline the current standard approaches to metastatic sarcomas and desmoid tumors, and discuss investigational approaches to these difficult tumors being evaluated at the University of Michigan Comprehensive Cancer Center’s Multidisciplinary Sarcoma Clinic.

Standard Therapy for Metastatic Sarcoma
Surgical resection, often combined with adjuvant radiation and/or chemotherapy, is the mainstay of treatment for localized soft tissue and bone sarcomas. Once metastatic disease develops, resection of isolated pulmonary nodules is sometimes feasible, and a small percentage of patients can be cured. This is true even for patients with multiple and bilateral pulmonary metastases, provided that all lung disease can be resected; there are no extrapulmonary metastases and the primary tumor is controlled. Bilateral thoracotomies, thoracoscopic surgery and median sternotomy approaches have all been used to allow removal of bilateral metastases. Preoperative chemotherapy may increase the number of patients who are candidates for resection of their metastases; and in some series has prolonged postoperative disease-free survival as well. Sarcoma patients with isolated pulmonary metastases, especially (but not exclusively) those with four or fewer lesions and/or a long disease-free interval, should be evaluated for potential resection of their metastases as part of an aggressive, multimodality approach.

Many patients with soft tissue sarcomas, however, are not candidates for resection of their metastases, and have more limited treatment options. Aggressive combination chemotherapy is frequently employed, and sometimes results in tumor regression but is almost never curative (1). Ewing’s sarcomas (also called primitive neuroectodermal tumors) and childhood rhabdomyosarcomas are associated with much higher response rates to chemotherapy, and a portion of patients with metastatic disease from these tumors can be cured. Osteogenic sarcoma represents an intermediate situation – there are some reports documenting a higher response rate to certain chemotherapeutic agents than is seen in soft tissue sarcomas, but chemotherapy itself is rarely curative. Thus, while chemotherapy represents the best currently available palliative treatment for most adult sarcoma patients without a surgical option, there is an acute need to develop entirely new treatment strategies for the treatment of metastatic disease (2).

Rationale for Immunotherapy in Sarcomas
Although there has been a great deal of enthusiasm for the use of immunotherapy in the treatment of certain types of cancer, particularly melanoma and renal cell carcinoma, this modality has not been widely applied to sarcomas. This is due at least in part to a lack of clinical response in a small number of patients treated in initial studies of interleukin 2 alone or with lymphokine-activated killer (LAK) cells (3). Recent successes with the use of tumor necrosis factor-a and interferon-g and colony-stimulating factors have led to a rethinking of the possible role for immunotherapy in these tumors (4, 5).

The goal of immunotherapy is to stimulate the immune system to recognize and kill cancer cells by modifying the tumor cells or modifying the host response by expanding the population of lymphocytes that respond specifically to the antigens on the tumor cells. Although sarcomas have traditionally been considered poorly immunogenic, and hence not susceptible to recognition and destruction by the immune system, there is mounting evidence that this is simply not so. In addition to the clinical responses to immunotherapy alluded to previously, sarcoma-associated antigens have been identified that are expressed on human soft tissue and bone sarcoma cells (6, 7).

Current Cancer Center Protocols

UMCC 9612: Adoptive immunotherapy with vaccine-primed lymph node lymphocytes using autologous irradiated tumor plus BCG as a vaccine.

Eligibility: Patients must have advanced, mea-surable soft tissue sarcoma, adequate performance status, and autologous tissue that is available for processing into a vaccine (this can be cryopreserved tissue from a prior procedure). Adult patients with osteogenic sarcoma or Ewing’s sarcoma, and all patients under 16, are excluded from participation.

Protocol schema: Patients will have surgical excision of tumor for establishment of the vaccine, which can include prior surgical specimens cryopreserved for this purpose. Seven to 10 days after vaccination by intradermal inoculation of irradiated autologous tumor cells plus BCG, patients will undergo excision of inguinal lymph nodes draining the vaccine site for in vitro activation. Activation of lymph node cells requires two to three weeks, after which time patients are admitted as inpatients to the U-M’s General Clinical Research Center (GCRC) for five to seven days to receive their activated cells and IL-2 through a central line. Retreatment will be offered if disease responds or remains stable, by administration of additional activated cells (derived from cryopreserved material) and IL-2.

UMCC 9636: Phase I/II evaluation of inter-leukin-2 DNA/DMRIE/DOPE as an immunother-apeutic agent in cancer by direct gene transfer.

Eligibility: Patients must have advanced, mea-surable soft tissue sarcoma, adequate performance status, and disease that is accessible for direct intratumoral injection (this can be palpable tumor for direct injection or disease in liver, lung or other sites amenable to radiologically-guided injection). Adult patients with osteogenic sarcoma or Ewing’s sarcoma, and all patients under 18, are excluded from participation.

Protocol schema:Eligible patients will undergo injections directly into tumor nodules with a total of six doses of Leuvectin, a mixture of plasmid DNA encoding human interleukin 2 plus a lipid vector (DMRIE/DOPE), at one of three dose levels (300, 750 or 1500mg). Leuvectin injections will be administered once per week for six weeks followed by a three-week observation period. The injections are performed after administration of a local anesthetic. When necessary, injections will be performed with the aid of sonographic or CAT scan visualization of the metastatic tumor. Patients will be monitored for toxicity for two hours post-injection, but in the absence of adverse events will receive their injections as an outpatient. Retreatment will be offered if disease responds or remains stable, by administration of an additional six injections of Leuvectin.

Non-Surgical Therapy of Desmoid Tumors
Desmoid tumors are unusual soft tissue lesions with unique characteristics but definite similarities to low-grade soft tissue sarcomas. Although clinical reports of low-grade soft tissue sarcomas often include desmoid tumors, in fact, desmoids virtually never metastasize even after multiple local recurrences. Desmoids have also been referred to as “aggressive fibromatosis,” reflecting the uncertainty that exists about their malignant potential. But whatever name is chosen, some facts are clear. Desmoid tumors present in a fashion identical to soft tissue sarcomas, as an enlarging, often painless, soft tissue mass. Clinically and radiographically, there is generally nothing to distinguish a desmoid tumor from a soft tissue sarcoma. Like low-grade sarcomas, wide excision is the mainstay of treatment, but local recurrence after surgical treatment is very common. Deaths due to desmoids are infrequent, since the tumors do not metastasize, but can occur due to local recurrence in a critical area such as the neck or abdomen.

Little is known regarding the etiology of desmoid tumors. There are two specific clinical settings in which desmoids arise that have provided insights into both the causation and therapy of these lesions. The first is during or just after pregnancy. Desmoid tumors are more common in women than men, and frequently present within one to two years of delivery, occasionally arising in the vicinity of a Cesarean section scar. These facts, combined with isolated reports of spontaneous regression of desmoids at menopause and the demonstration of estrogen receptors on some tumors, suggest a hormonal component to their development. Based on this, hormonal therapy with a variety of agents — most notably tamoxifen — has been employed with occasional success. We and others have seen either complete disappearance, marked shrinkage, or stabilization of tumor growth combined with marked symptomatic improvement after treatment with tamoxifen alone or in combination with other agents (8, 9) (see below).

Desmoid tumors occur with greatly increased frequency in patients with familial adenomatous polyposis. The association of familial polyposis with desmoids and other soft tissue tumors was originally given the name Gardner’s syndrome. It is now realized, however, that all patients with familial polyposis are at risk for the development of desmoids, and that the genetic defect in polyposis patients with and without desmoids is identical, so the term Gardner’s syndrome has fallen into disuse. The desmoid tumors in polyposis patients tend to occur within the abdomen, often in the colonic mesentery after proctocolectomy. Patients with familial polyposis are born with one defective copy of the apc gene, a tumor suppressor gene. As with other tumor suscep-tibility syndromes, the second, normal copy of the gene must be lost for a tumor (either an adenomatous polyp or a desmoid) to develop. It is likely that surgical trauma increases the chance that a desmoid tumor will actually develop in a predisposed individual. This may explain both the predilection for mesenteric tumors in polyposis patients and abdominal wall tumors in some women after Cesarean section.

Another non-surgical therapy for desmoids was suggested by studies in familial polyposis patients: sulindac (Clinoril). Some patients with familial polyposis have undergone significant reduction in the number of colonic polyps after treatment with oral sulindac. During treatment, anecdotal regressions of coexisting desmoid tumors have been seen. Alone or in combination with tamoxifen, objective regression of as many as 50 percent of polyposis-associated desmoid tumors has been reported (9). Sporadic desmoids, not associated with familial polyposis, will also respond on occasion to this combination. Other therapeutic modalities have been utilized in the treatment of desmoid tumors. Radiotherapy has been employed both as primary treatment and as postop-erative adjuvant therapy. Cytotoxic chemotherapy regimens have been employed, with some successes reported using relatively non-toxic regimens (10).

Currently, we are treating all desmoid tumors in a similar fashion, regardless of their etiology. Resection with a histologically negative margin is done when-ever possible, but not sacrificing major neurovascular structures or adjacent organs unless absolutely necessary. If pathologic analysis of the resected specimen reveals close approximation of tumor to the surgical margin, either re-excision or postoperative radiation are employed. Unresectable or recurrent desmoids are treated first with the combination of tamoxifen and sulindac. Resection or radiation are used for failures of this therapy or to eliminate residual disease after partial responses. Chemotherapy is reserved as a “last resort,” in patients who have failed all other therapies and are severely symptomatic or in danger of dying because of compression of vital structures by tumor.

References

1. Sondak VK, Chang AE. Clinical Evaluation and Treatment of Soft Tissue Tumors. In: Enzinger FW, Weiss SA (eds): The Soft Tissue Tumors (ed 3)., pg 17, C.V. Mosby, St. Louis, Missouri, 1995.
2. Edmonson JH. Needed: Qualitative improvement in antisarcoma therapy. J Clin Oncol. 13:1531, 1995.
3. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high dose interleukin-2 alone. N Engl J Med. 316:889, 1987.
4. Lienard D, Ewalenko P, Delmotte JJ, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 10:52, 1992.
5. Redman BG, Flaherty L, Chou TH, et al. Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer. J Immunother. 12:50, 1992.
6. Song S, Stastny JJ, Chen H, Das Gupta TK. Expression of two sarcoma-associated antigens in various human sarcoma cell lines. Pro Am Assoc Cancer Res. 36:477 (2843), 1995.
7. Ward P, Misra V, Bruland O, Haines D. Characterization of an osteosarcoma-associated antigen: Role in tumori-genesis and suitability as a target for immunotherapy. Proc Am Assoc Cancer Res. 36:477 (2844), 1995.
8. Sondak VK. Sarcomas of Soft Tissue and Bone. In: Greenfield LJ, Mulholland MW, Oldham KT, Zelenock GB, Lillemoe KD (eds): Surgery: Scientific Principles and Practice, (ed 2)., pg 2246, Lippincott-Raven, Philadelphia, Pennsylvania, 1997.
9. Tsukada K, Church JM, Jagelman DG, et al. Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum. 35:29, 1992.
10. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer. 64:1192, 1989.

Vernon K. Sondak, M.D., is an associate professor of Surgery and director of the Cancer Center’s Multidisciplinary Sarcoma Clinic.

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