Almost all patients require multidrug chemotherapy (often including ifosfamide and etoposide), as well as local disease control with surgery and/or radiation. An aggressive approach is necessary because almost all patients with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease.

Treatment often consists of neoadjuvant chemotherapy, which may include vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide. After about three months of chemotherapy, the remaining tumor is surgically resected, irradiated, or both. The surgical resection may involve limb salvage or amputation. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined.

Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at 3-week cycles, but most patients undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks.

Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase "melting like snow", but the main drawback is that it recurs dramatically after some time. Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing's sarcoma resulting from the EWS-ETS gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing's sarcoma cell lines "in vitro" and to delay growth of xenografts in "in vivo" mouse models.

Treatment is usually multimodal, involving surgery, chemotherapy and radiotherapy:

- Surgery, to remove the tumor and a safety margin of healthy tissue. This is the mainstay of synovial sarcoma treatment and is curative in approximately 20–70% of patients, depending on the particular study being quoted.

- Conventional chemotherapy, (for example, doxorubicin hydrochloride and ifosfamide), to reduce the number of remaining microscopic metastases. The benefit of chemotherapy in synovial sarcoma to overall survival remains unclear, although a recent study has shown that survival of patients with advanced, poorly differentiated disease marginally improves with doxorubicin/ifosfamide treatment.

- Radiotherapy to reduce the chance of local recurrence. The benefit of radiotherapy in this disease is less clear than for chemotherapy.

Surgery is important in the treatment of most sarcomas. Limb sparing surgery, as opposed to amputation, can now be used to save the limbs of patients in at least 90% of extremity tumor cases. Additional treatments, including chemotherapy and radiation therapy, may be administered before and/or after surgery. Chemotherapy significantly improves the prognosis for many sarcoma patients, especially those with bone sarcomas. Treatment can be a long and arduous process, lasting about a year for many patients.

- Liposarcoma treatment consists of surgical resection, with chemotherapy not being used outside of the investigative setting. Adjuvant radiotherapy may also be used after surgical excision for liposarcoma.

- Rhabdomyosarcoma is treated with surgery, radiotherapy, and/or chemotherapy. The majority of rhabdomyosarcoma patients have a 50–85% survival rate.

- Osteosarcoma is treated with surgical resection of as much of the cancer as possible, often along with neoadjuvant chemotherapy. Radiotherapy is a second alternative although not as successful.

Treatment depends upon the site and the extent of the disease. Clear cell sarcoma is usually treated with surgery in the first place in order to remove the tumor. The surgical procedure is then followed by radiation and sometimes chemotherapy. Few cases of clear cell sarcoma respond to chemotherapy. Several types of targeted therapy that may be of benefit to clear cell sarcoma patients are currently under investigation.

Treatment consists of surgical excision (the extent of which ranges from tumor excision to limb amputation, depending on the tumor) and in almost all cases radiation. Radiation eliminates the need for limb amputation and there is level I evidence to show that it leads to equivalent rates of survival (Rosenberg et al. NCI Canada). Radiation may be delivered either pre-op or post-op depending on surgeon and multidisciplinary tumor board's recommendations. Radiation can be omitted for low grade, Stage I excised tumors with >1 cm margin (NCCN). Chemotherapy remains controversial in MFH.

The usual site of metastatic disease is the lungs, and metastases should be resected if possible. Unresectable or inoperable lung metastasis may be treated with stereotactic body radiation therapy (SBRT) with excellent local control. However, neither surgery nor SBRT will prevent emergence of additional metastasis elsewhere in the lung. Therefore, role of chemotherapy needs to be further explored to address systemic metastasis.

In general, treatment for soft-tissue sarcomas depends on the stage of the cancer. The stage of the sarcoma is based on the size and grade of the tumor, and whether the cancer has spread to the lymph nodes or other parts of the body (metastasized). Treatment options for soft-tissue sarcomas include surgery, radiation therapy, and chemotherapy.

- Surgery is the most common treatment for soft-tissue sarcomas. If possible, the doctor will remove the cancer and a safe margin of the healthy tissue around it. It is important to obtain a margin free of tumor to decrease the likelihood of local recurrence and give the best chance for eradication of the tumor. Depending on the size and location of the sarcoma, it may, rarely, be necessary to remove all or part of an arm or leg.

- Radiation therapy may be used either before surgery to shrink tumors or after surgery to kill any cancer cells that may have been left behind. In some cases, it can be used to treat tumours that cannot be surgically removed. In multiple studies, radiation therapy has been found to improve the rate of local control, but has not had any influence on overall survival.

- Chemotherapy may be used with radiation therapy either before or after surgery to try to shrink the tumor or kill any remaining cancer cells. The use of chemotherapy to prevent the spread of soft-tissue sarcomas has not been proven to be effective. If the cancer has spread to other areas of the body, chemotherapy may be used to shrink tumors and reduce the pain and discomfort they cause, but is unlikely to eradicate the disease.

Treatment is primarily surgical, with chemotherapy and radiation therapy sometimes used.

The NCCN guideline recommends CCPDMA or Mohs surgery for the best cure rate of DFSP. Mohs surgery can be extremely effective. It will remove the tumor and all related pathological cells without a wide-area excision that may overlook sarcoma cells that have penetrated muscle tissue.

The standard of care for patients with DFSP is surgery. Usually, complete surgical resection with margins of 2 to 4 cm (recommended) is performed. The addition of adjuvant radiotherapy (irradiation) improves local control in patients with close or positive margins during the surgery. A special surgical technique, the "Mohs micrographic surgery" (MMS), can be employed in patients with DFSP. MMS is technically possible if the DFSP is in an anatomically confined area. A high probability of cure of DFSP can be attained with MMS as long as the final margins are negative. Patients who have a recurrent DFSP can have further surgery, but the probability of adverse effects of surgery and/or metastasis is increased in these patients. The Mohs surgery is highly successful.

Imatinib is approved for treatment. As is true for all medicinal drugs that have a name that ends in "ib," imatinib is a small molecular pathway inhibitor; imatinib inhibits tyrosine kinase. It may be able to induce tumor regression in patients with recurrent DFSP, unresectable DFSP or metastatic DFSP. There is clinical evidence that imatinib, which inhibits PDGF-receptors, may be effective for tumors positive for the t(17;22) translocation.

The Stehlin Foundation currently offers DSRCT patients the opportunity to send samples of their tumors free of charge for testing. Research scientists are growing the samples on nude mice and testing various chemical agents to find which are most effective against the individual's tumor.

Patients with advanced DSRCT may qualify to participate in clinical trials that are researching new drugs to treat the disease.

In localized, resectable adult GISTs, if anatomically and physiologically feasible, surgery is the primary treatment of choice. Surgery can be potentially curative, but watchful waiting may be considered in small tumors in carefully selected situations. Post-surgical adjuvant treatment may be recommended. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions. The clinical issues of exact surgical indications for tumor size are controversial. The decision of appropriate laparoscopic surgery is affected by tumor size, location, and growth pattern.

Radiotherapy has not historically been effective for GISTs and GISTs do not respond to most chemotherapy medications, with responses in less than 5%. However, three medications have been identified for clinical benefit in GIST: imatinib, sunitinib, and regorafenib.

Imatinib (Glivec/Gleevec), an orally administered drug initially marketed for chronic myelogenous leukemia based on bcr-abl inhibition, also inhibits both "c-kit" tyrosine kinase mutations and PDGFRA mutations other than D842V, is useful in treating GISTs in several situations. Imatinib has been used in selected neoadjuvant settings. In the adjuvant treatment setting, the majority of GIST tumors are cured by surgery, and do not need adjuvant therapy. However, a substantial proportion of GIST tumors have a high risk of recurrence as estimated by a number of validated risk stratification schemes, and can be considered for adjuvant therapy. The selection criteria underpinning the decision for possible use of imatinib in these settings include a risk assessment based on pathological factors such as tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Following surgical resection of GISTs, adjuvant treatment with imatinib reduces the risk of disease recurrence in higher risk groups. In selected higher risk adjuvant situations, imatinib is recommended for 3 years.

Imatinib was approved for metastatic and unresectable GIST by the US FDA, February 1, 2002. The two-year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.

If resistance to imatinib is encountered, the multiple tyrosine kinase inhibitor sunitinib (marketed as Sutent) can be considered.

The effectiveness of imatinib and sunitinib depend on the genotype. cKIT- and PDGFRA-mutation negative GIST tumors are usually resistant to treatment with imatinib as is neurofibromatosis-1-associated wild-type GIST. A specific subtype of PDGFRA-mutation, D842V, is also insensitive to imatinib.

Regorafenib (Stivarga) was FDA approved in 2013 for advanced GISTs that cannot be surgically removed and that no longer respond to imatinib (Gleevec) and sunitinib (Sutent).

Kaposi sarcoma is not curable, but it can often be treatable for many years. In KS associated with immunodeficiency or immunosuppression, treating the cause of the immune system dysfunction can slow or stop the progression of KS. In 40% or more of peoples with AIDS-associated Kaposi sarcoma, the Kaposi lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain percentage of such people, Kaposi sarcoma may again grow after a number of years on HAART, especially if HIV is not completely suppressed.

People with a few local lesions can often be treated with local measures such as radiation therapy or cryosurgery. Weak evidence suggests that antiretroviral therapy in combination with chemotherapy is more effective than either of those two therapies individually. Limited basic and clinical evidence suggest that topical beta-blockers, such as timolol, may induce regression of localized lesions in classic as well as HIV-associated Kaposi sarcoma. In general, surgery is not recommended, as Kaposi sarcoma can appear in wound edges. In general, more widespread disease, or disease affecting internal organs, is treated with systemic therapy with interferon alpha, liposomal anthracyclines (such as Doxil) or paclitaxel.

In women, chemotherapy may damage the ovaries and cause infertility. To avail future pregnancies, the woman may preserve oocytes or ovarian tissue by oocyte cryopreservation or ovarian tissue cryopreservation prior to starting chemotherapy. However, the latter may reseed the cancer upon reinsertion of the ovarian tissue. If it is performed, the ovarian tissue should be examined for traces of malignancy at both the pathological and molecular levels prior to the grafting of the cryopreserved tissue.

The most successful treatment for angiosarcoma is amputation of the affected limb if possible. Chemotherapy may be administered if there is metastatic disease. If there is no evidence of metastasis beyond the lymphedematous limb, adjuvant chemotherapy may be given anyway due to the possibility of micrometastatic disease. Evidence supporting the effectiveness of chemotherapy is, in many cases, unclear due to a wide variety of prognostic factors and small sample size. However, there is some evidence to suggest that drugs such as paclitaxel, doxorubicin, ifosfamide, and gemcitabine exhibit antitumor activity.

Treatment of VAS is through aggressive surgery. As soon as the tumor is recognized, it should be removed with very wide margins to ensure complete removal. Treatment may also include chemotherapy or radiation therapy. The most significant prognostic factor is initial surgical treatment. One study showed that cats with radical (extensive) initial surgery had a median time to recurrence of 325 days versus 79 days for cats with marginal initial excision. The expression of a mutated form of p53, a tumor suppressor gene, is found commonly in VAS and indicates a poorer prognosis.

One such development is in the delivery of doxorubicin. While it is an effective inducer of apoptosis, doxorubicin is quickly filtered out of the body. By loading a PEG-liposome with doxorubicin the circulation time and localization to tumors greatly increases. Cancerous tumors characteristically have extensive angiogenesis and leaky vasculatures, which causes the PEG-liposomes to naturally accumulate in the tumor. This also allows for patients to receive lower and fewer doses of the drug and experience fewer side effects. This is also being attempted with nanoparticles but has not been tested on FDCS. In 2008 COP plus (PEG)-liposomal doxorubicin went into a clinical trial for an FDCS patient to replace the CHOP regimen, and after 5 years the patient remains in CR.

The prognosis for DSRCT remains poor. Prognosis depends upon the stage of the cancer. Because the disease can be misdiagnosed or remain undetected, tumors frequently grow large within the abdomen and metastasize or seed to other parts of the body.

There is no known organ or area of origin. DSRCT can metastasize through lymph nodes or the blood stream. Sites of metastasis include the spleen, diaphragm, liver, large and small intestine, lungs, central nervous system, bones, uterus, bladder, genitals, abdominal cavity, and the brain.

A multi-modality approach of high-dose chemotherapy, aggressive surgical resection, radiation, and stem cell rescue improves survival for some patients. Reports have indicated that patients will initially respond to first line chemotherapy and treatment but that relapse is common.

Some patients in remission or with inoperable tumor seem to benefit from long term low dose chemotherapy, turning DSRCT into a chronic disease.

Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to be resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques. Because of the relatively poor response of epithelioid sarcoma to traditional cancer treatments (surgery, chemotherapy, and radiation), new treatment strategies are being looked to.

Prognosis depends on the primary tumor grade (appearance under the microscope as judged by a pathologist), size, resectability (whether it can be completely removed surgically), and presence of metastases. The five-year survival is 80%.

Newer cases are also starting to be treated by taxotere and gemcitabine. Taxotere is similar to Oncovin used in CHOP; it irreversibly binds beta tubulin halting formation of microtubules. Taxotere has an added benefit though; it also phosphorylates bcl-2 to halt the anti-apoptotic pathway. The dual effect of taxotere on integral cancer pathways makes it a more potent drug than Oncovin. Gemcitabene is a nucleoside analog and when incorporated into DNA during replication leads to apoptosis; the fluorine on the 2’ carbon atom stops other nucleosides from attaching. The most important part of this combination therapy, however, is the synergism between the drugs. While researchers are not entirely sure of the mechanism, there is evidence of synergistic effects of taxotere and gemcitabine when used in combination. This allows for decreased dosages of each single agent with an increased apoptotic response.

2004 research showed that CCSK patients exhibit an improved relapse-free survival from a longer course of therapy when using vincristine, doxorubicin, and dactinomycin, but their long-term survival is unchanged compared with patients receiving 6 months of therapy.

Most histiocytomas will regress within two or three months. Surgical removal may be necessary if the tumor does not regress or if it is growing rapidly to a large size. Histiocytomas should never be treated with an intralesional injection of a corticosteroid, as remission relies on recognition of the tumour by the body's immune system which is suppressed by steroids.

Based on a survey of >800, surgical removal of the entire involved kidney plus the peri-renal fat appeared curative for the majority of all types of mesoblastic nephroma; the patient overall survival rate was 94%. Of the 4% of non-survivors, half were due to surgical or chemotherapeutic treatments. Another 4% of these patients suffered relapses, primarily in the local area of surgery rare cases of relapse due to lung or bone metastasis.. About 60% of these recurrent cases had a complete remission following further treatment. Recurrent disease was treated with a second surgery, radiation, and/or chemotherapy that often vincristine and actinomycin treatment. Removal of the entire afflicted kidney plus the peri-renal fat appears critical to avoiding local recurrences. In general, patients who were older than 3 months of age at diagnosis or had the cellular form of the disease, stage III disease, or involvement of renal lymph nodes had a higher recurrence rate. Among patients with these risk factors, only those with lymph node involvement are recommended for further therapy.

It has been suggested that mesoblastic nephroma patients with lymph node involvement or recurrent disease might benefit by adding the ALK inhibitor, crizotinib, or a tyrosine kinase inhibitor, either larotrectinib or entrectinib, to surgical, radiation, and/or chemotherapy treatment regimens. These drugs inhibit NTRK3's tyrosine kinase activity. Crizotinib has proven useful in treating certain cases of acute lymphoblastic leukemia that are associated with the "ETV6-NTRK3" fusion gene while larotrectinib and entrectinib have been useful in treating various cancers (e.g. a metastatic sarcoma, papillary thyroid cancer, non-small-cell lung carcinoma, gastrointestinal stromal tumor, mammary analog secretory carcinoma, and colorectal cancer) that are driven by mutated, overly active tyrosine kinases. Relevant to this issue, a 16-month-old girl with infantile fibrosarcoma harboring the "ETV6–NTRK3" fusion gene was successfully trated with larotrectinib. The success of these drugs, howwever, will likely depend on the relative malignancy-promoting roles of ETV6-NTRK3 protein's tyrosine kinase activity, the lose of ETV6-related transcription activity accompanying formation of ETV6-NTRK3 protein, and the various trisomy chromosomes that populate mesoblastic nephroma.

The disease used to be uniformly fatal, with a 5-year survival rate between 10 and 35%. As a result, treatment was radical surgery. New multidrug chemotherapy regimens with or without radiation therapy are now used in combination with less radical surgery with good results, although outcome data are not yet available.

10 to 20% of patients treated for anal cancer will develop distant metastatic disease following treatment. Metastatic or recurrent anal cancer is difficult to treat, and usually requires chemotherapy. Radiation is also employed to palliate specific locations of disease that may be causing symptoms. Chemotherapy commonly used is similar to other squamous cell epithelial neoplasms, such as platinum analogues, anthracyclines such as doxorubicin, and antimetabolites such as 5-FU and capecitabine. JD Hainsworth developed a protocol that includes Taxol and Carboplatinum along with 5-FU. Median survival rates for patients with distant metastases ranges from 8 to 34 months.

Proton pump inhibitors (such as omeprazole and lansoprazole) and histamine H2-receptor antagonists (such as famotidine and ranitidine) are used to slow acid secretion. Once gastric acid is suppressed, symptoms normally improve.

Localised disease (carcinoma-in-situ) and the precursor condition, anal intraepithelial neoplasia (anal dysplasia or AIN) can be ablated with minimally invasive methods such as Infrared Photocoagulation.

Previously, anal cancer was treated with surgery, and in early-stage disease (i.e., localised cancer of the anus without metastasis to the inguinal lymph nodes), surgery is often curative. The difficulty with surgery has been the necessity of removing the internal and external anal sphincter, with concomitant fecal incontinence. For this reason, many patients with anal cancer have required permanent colostomies.

Current gold-standard therapy is chemotherapy and radiation treatment to reduce the necessity of debilitating surgery. This "combined modality" approach has led to the increased preservation of an intact anal sphincter, and therefore improved quality of life after definitive treatment. Survival and cure rates are excellent, and many patients are left with a functional sphincter. Some patients have fecal incontinence after combined chemotherapy and radiation. Biopsies to document disease regression after chemotherapy and radiation were commonly advised, but are not as frequent any longer. Current chemotherapy consists of continuous infusion 5-FU over four days with bolus mitomycin given concurrently with radiation. 5-FU and cisplatin are recommended for metastatic anal cancer.