6 TREATMENT


6.1 STAGE I (localized low grade soft tissue sarcomas)


6.1.1
Low grade soft tissue sarcomas tend to recur locally if inadequately excised, and later on in their natural history they can dedifferentiate and thus behave as high grade tumors. Occasionally, a low grade sarcoma may metastatize maintaining its original histological aspect.

6.1.2
The treatment of choice for low grade soft tissue sarcomas is adequate surgery. Since even low grade sarcomas may have "satellites" outside the tumor pseudocapsule, a sufficiently wide excision is the standard option on a type C basis. A wide excision is that which, conceptually, falls outside the "reactive zone", and which, practically, carries out some centimeters (2-3 centimeters) of negative tissue in all potential directions of tumor spread. Such a principle does not apply to resistant anatomic planes, such as muscular fasciae, periostium, serosae, perineurium, vascular external tunica, if they are respected by the tumor. Along such planes it is not necessary to leave centimeters of negative tissue since they offer a natural resistance to tumor spread. On the other hand, since skip lesions outside the reactive zone should be absent, more demolitive resections are ordinarily not required in low grade sarcomas.

6.1.3
A clinical trial is ongoing in USA randomizing no further treatment after surgery against postoperative radiotherapy in low grade adequately excised soft tissue sarcomas. As of today, however, postoperative radiotherapy is investigational for adequately resected (6.1.2) tumors.

6.1.4
If surgery was inadequate, surgical radicalization is standard treatment on a type C basis. If a radicalization is not feasible, postoperative radiotherapy is the standard option on a type R basis. Radiotherapy is usually given at doses >55 Gy.

6.1.5
If adequate surgery is unfeasible, external radiotherapy becomes standard treatment on a type R basis, either preoperatively in an attempt to allow subsequent surgery, at doses of approximately 50 Gy, or as a substitute for surgery, at doses >65 Gy. However, the potential of local control for radiotherapy given alone is definitely lower than for surgery, even if as high as 30in some selected series. Surgery may be particularly difficult in retroperitoneal low grade sarcomas, but radiotherapy at adequate doses will be difficult as well. If both surgery and radiotherapy are unfeasible for a low grade soft tissue sarcoma, standard treatment is chemotherapy, on a type R basis, either preoperatively in an attempt to allow subsequent surgery or as a substitute for surgery. In the latter case, the aim is generally palliative and thus, on clinical grounds, chemotherapy may also be considered investigational or appropriate for individual clinical use, on a type R basis.

6.1.6
Adjuvant chemotherapy is not indicated in low grade sarcomas due to their low systemic potential, their lower responsiveness to chemotherapy, and the absence of positive clinical trials. Some randomized trials included also patients with low grade sarcomas, but failed to demonstrate any advantage in favour of adjuvant chemotherapy. So, adjuvant chemotherapy is currently not recommended in low grade sarcomas.


References

6.1.I
Devereux DF, Wilson RE, Corson JM, Antman KH, Greenberger JS. Surgical treatment of low grade soft tissue sarcomas. American Journal of Surgery 1982; 143, 490-494.

6.1.II
Eilber FR, Eckhardt J, Morton DL. Advances in the treatment of sarcomas of the extremity: current status of limb salvage. Cancer 1984; 54: 2695-2701.

6.1.III
Enneking WF, Spanier SS, Malawer MM. The effect of the anatomic setting on the results of surgical procedures for soft parts sarcoma of the thigh. Cancer 1981; 47: 1005-1022.

6.1.IV
Slater JD, McNeese MD, Peters LG. Radiation therapy for unresectable soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1986; 12:1729-1734.



6.2 STAGE II-III (high grade localized soft tissue sarcomas)


6.2.1
Grade 2 and grade 3 sarcomas differ from each other for their diverse systemic potential and for the interval which can precede the relapse. However, both share a potential of systemic dissemination and a greater aggressiveness than low grade sarcomas, even at the local level, and so can be considered jointly from the therapeutic point of view. Clinical decision making may differentiate the two kinds of disease only with regard to a questionable choice such as whether to administer or not adjuvant chemotherapy (which, theoretically, could seem more justified in grade 3 sarcomas).

6.2.2
In high grade soft tissue sarcomas, adequate surgery may be represented by amputation, compartmental resection or wide excision. Classically, "radical" interventions are amputation and compartmental resection. Amputation is done above the joint proximal to the lesion. Compartmental resection is the removal of the whole anatomical compartment in which the tumor arose. A compartmental resection sometimes carries unfavourable sequelae and only a few sites of origin of limb soft tissue sarcomas are contained within anatomical compartments, i.e. are limited by fasciae. So, sarcomas arising in the femoral triangle, in the popliteal fossa, in the feet, hands, elbows and in most trunkal regions are extracompartmental by definition. Therefore, from the '70s onwards, wide excisions, i.e. falling outside the reactive zone, associated with radiotherapy, have been increasingly used with a curative intent. Overall, the combined treatment seems to provide the patients with roughly the same probabilities of long term survival as the more ablative surgery. Local control may be somewhat less, but however local failures are in the range of 5-15%, as compared to 0-5for radical surgery, and survival is the same. There is only one randomized trial comparing conservative surgery versus amputation in limb sarcomas (6.2.XIX), but prospective and retrospective trials are available which confirm the rough equivalence between conservative treatment and demolitive surgery in terms of overall survival. On the contrary, local control is certainly inadequate through marginal surgery, with relapses in >50of cases. Local control is always a goal in treating soft tissue sarcomas, as long as new local relapses do occur there is a risk of progressive worsening of the prognostic features of the disease. If the surgeon feels that a truly complete adequate excision is unfeasible in a conservative way, ablative surgery is the treatment of choice. Studies on quality of life in amputated patients have demonstrated that adaptative resources make it possible for these patients to maintain a quality of life which is not markedly inferior to that of limb spared patients. Therefore, standard treatment in local soft tissue sarcomas is given by the following alternative options: i) compartmental resection, if anatomically feasible, on a type C basis; ii) wide excision combined with pre- or postoperative radiotherapy, on a type 2 level of evidence, as an alternative to compartmental resection (6.2.XIX); iii) amputation, on a type C basis, only if compartmental surgery or wide excision are unfeasible. Decision making may be difficult in some cases, when a complete excision is feasible (i.e. with no macroscopic or microscopic residual disease), but it is "marginal", i.e. inadequate free margins outside the reactive zone are removed, and otherwise ablative surgery must be resorted to. In these cases, marginal excision combined with radiotherapy (postoperatively, and possibly even preoperatively), can be appropriate for individual clinical use in selected patients, on a type R basis, if the patient agrees to run a higher risk of local failure with the likelihood of decreased chances of cure.

6.2.3
Recently, an uncontrolled clinical trial (6.2.XXI) also demonstrated a local recurrence rate <10for wide excision without subsequent radiotherapy for tumors located either subcutaneously or intramuscularly. This may spare the patient those late sequelae of radiotherapy which are sometimes disturbing (edema of the distal limb, etc.). Subcutaneous tumors were removed with a wide margin that included the deep fascia beneath the tumor, while intramuscular tumors were treated by myectomy (without prior incisional or Tru-cut biopsy). This approach, however, should be considered still investigational.

6.2.4
Radiotherapy, if indicated, is generally administered postoperatively at doses >50 Gy (for example, 50 Gy in 25 fractions over 5 weeks, with a boost at 60 Gy to the sites of likely residual microscopic disease). In some institutions, radiotherapy is given preoperatively, at doses of 50 Gy, or both preoperatively and postoperatively. Preoperative treatments may make it easier for the surgeon to adequately excise the tumor, even when it is definitely operable. In many cases, however, a definite judgement of operability cannot be given preoperatively, and the tumor falls in the category of "borderline" resectable lesions. In these cases some kind of preoperative treatment might be reasonable. An alternative option to preoperative radiotherapy may in such cases be chemotherapy. Therefore, splitting adjuvant radiotherapy preoperatively and postoperatively, or employing preoperative chemotherapy may be appropriate for individual clinical use in selected patients on a type R basis, when some surgical difficulties are expected.

6.2.5
For retroperitoneal sarcomas, surgery, though standard treatment, is hardly adequate, and this explains their high recurrence rate and dismal prognosis. For large tumor beds, the only available adjuvant treatment to surgery is intraoperative radiotherapy. This can be regarded as investigational or appropriate for individual non standard clinical use on a type 3 level of evidence (6.2.XIV, 6.2.XI).

6.2.6
With regard to adjuvant chemotherapy in patients adequately operated on, 15 randomized trials were carried out testing its effectiveness against a no-treatment arm after adequate surgery. Only two of such studies (6.2.XVII, 6.2.XVIlI) showed a statistically significant improvement in overall survival and disease free survival, and another two in disease free survival only. Overall, a trend towards improved prognosis in treated patients was demonstrated by most studies. The two trials which showed an improvement in overall survival were relatively small studies and were not published in peer-reviewed journals or were published preliminarily. One was limited to limb sarcomas, while the other included mainly limb sarcomas, and provided a statistically significant advantage only for the limb sarcoma subgroup. Many studies had a limited statistical power, and so they should be considered inconclusive rather than negative. In addition, chemotherapy was often inadequate according to the current standards, since none of the trials, for instance, used Ifosfamide, which is now one of the two most active drugs in soft tissue sarcomas. A meta-analysis was carried out on published data and reported in 1995 (6.2.XlII), showing a 12absolute increase in 5-year survival (confidence interval: 6-17%). This conclusion is felt not to justify the adoption of adjuvant chemotherapy as standard practice in soft tissue sarcomas, mainly due to possible biases inherent to meta-analyses which are carried out on data extracted only from published studies and not on original data. An international collaborative meta-analysis has been therefore initiated gathering both published and unpublished data. In addition, randomized trials are ongoing comparing optimal chemotherapy with Doxorubicin plus Ifosfamide versus no further treatment after surgery. In the meantime, adjuvant chemotherapy is to be considered investigational. Some oncologists in Europe consider adjuvant chemotherapy investigational or appropriate for individual clinical use in selected patients on a type R basis, in patients with bad prognostic factors (high grade, tumor diameter >5-10 cm., deep location) within an individualized shared decision making with a fully informed patient. In other terms, if the physician decides to propose adjuvant chemotherapy outside a randomized clinical trial (which should be the preferred option), he should clearly explain to the patient that standard treatment for the disease is surgery radiotherapy, without chemotherapy, but that there is a still unsatisfactory degree of evidence that adjuvant chemotherapy might give a limited reduction (around 10in absolute terms) of the >50risk of relapse. If adjuvant chemotherapy is given, it is logical to resort to most active schedules, i.e. to the combinations of full dose Doxorubicin and Ifosfamide. Chemotherapy could also be appropriate for individual clinical use on a type R basis in those cases in which a high risk sarcoma could not be treated at best with surgery and radiotherapy, for instance a trunk high grade sarcoma which cannot be treated with truly adequate surgery and full dose radiotherapy. Even in these cases no formal demonstration has been published of the effectiveness of adjuvant chemotherapy in terms of survival and disease free survival. There are some suggestions, however, according to some of the published trials on adjuvant chemotherapy, that the medical treatment might somewhat decrease the local risk of relapse.

6.2.7
There is no reason, today, to administer chemotherapy preoperatively in operable patients, in the absence of a formal demonstration of the effectiveness of chemotherapy in the classical adjuvant postoperative setting. In many cases, however, a definite judgement of operability cannot be given preoperatively, and the tumor falls within the "borderline" resectable lesions. In these cases some kind of preoperative treatment is appropriate for individual clinical use on a type R basis. The probability of a partial response with preoperative full dose chemotherapy averages 40-50%, with an extremely low risk of true progression during treatment. Chemotherapy can be given intravenously or intraarterially, but no evidence has been produced suggesting that intraarterial chemotherapy is superior to the intravenous route of administration. Another option may be preoperative radiotherapy.


References

6.2.I
Alvegard TA, Sigurdsson H, Mouridsen H, Jolheim O, Unsgaard B, Ringborg V, et al. Adjuvant chemotherapy with doxorubicin in high grade soft tissue sarcoma: a randomized trial of the Scandinavian Sarcoma Group. J Clin Oncol 1989; 7: 1504-1513.

6.2.II
Antman K, Ryan L, Borden E et al. Pooled results from three randomized adjuvant studies of doxorubicin versus observation in soft tissue sarcoma: 10 year results and review of the literature. Proc Sixth International Conf Adjuvant Ther Cancer, 1990; 529-543.

6.2.III
Bramwell VHC. Intraarterial chemotherapy of soft tissue sarcomas. Semin Surg Oncol 1988; 4: 66-72.

6.2.IV
Bramwell V, Rouesse J, Steward W, Santoro A, Schraffordt-Koops H, Buesa J, et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma. Reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1994; 12: 1137-1149.

6.2.V
Chang AE, Kinsella T, Glatstein E, Baker AR, Sindelar WF, Lotze MT, et al. Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity. J Clin Oncol 1988; 6: 1491-1500.

6.2.VI
Edmonson JH. Systemic chemotherapy following complete excision of nonosseous sarcomas: Mayo Clinic experience. Cancer Treat Symp 1985; 3: 89-97.

6.2.VII
Eilber FR, Eckhardt J, Morton DL: Advances in the treatment of sarcomas of the extremity: current status of limb salvage. Cancer 1984; 54: 2695-2701.

6.2.VIII
Eilber FR, Giuliano AE, Huth JF, Morton DL. A randomized prospective trial using postoperative adjuvant chemotherapy (adriamycin) in high-grade extremity soft-tissue sarcoma. Am J Clin Oncol (CCT) 1988; 11: 39-45.

6.2.IX
Enneking WF, Spanier SS, Malawer MM. The effect of the anatomic setting on the results of surgical procedures for soft parts sarcoma of the thigh. Cancer 1981; 47: 1005-1022.

6.2.X
Glenn J, Kinsella T, Glatstein E, Tepper J, Baker A, Sugarbaker P, et al. A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk. Cancer 1985; 55: 1206-1214.

6.2.XI
Gunderson LL, Nagorney DM, McIlrath DC, Fieck JM, Wieand HS, Martinez A, et al. External beam and intraoperative electron irradiation for locally advanced soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1993; 25: 647-656.

6.2.XII
Gustafson P, Rooser B, Rydholm A. Is there no influence of local control on the rate of metastases in high grade soft tissue sarcoma? Cancer 1990; 65: 1727-1729.

6.2.XIII
Tierney JF, Mosseri V, Stewart LA, Souhami RL, Parmar MKB. Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials. Br J Cancer 1995; 72: 469-475.

6.2.XIV
Kinsella TJ, Sindelar WF, Lack E, Glatstein E, Rosenberg SA. Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas. J Clin Oncol 1988; 6:18-25.

6.2.XV
Leibel SA, Tranbaugh RF, Wara WM, Beckstead JH, Bovill EG, Phillips TL. Soft tissue sarcomas of the extremities. Survival and pattern of failure with conservative surgery and postoperative irradiation compared to surgery alone. Cancer 1982; 50: 1076-1083.

6.2.XVI
Omura GA, Blesing JA, Major F, Lieshitz S, Ehrlich CE, Mangan C, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 1985; 3: 1240-1245.

6.2.XVII
Picci P, Bacci G, Gherlinzoni F et al. Results of a randomized trial for the treatment of localized soft tissue tumors (STS) of the extremities in adult patients. In: Recent concepts in sarcoma treatment; Ryan, Baker (eds); p. 144-148, Kluwer, Dordrecht, 1988.

6.2.XVIII
Ravaud A, Bui NB, Coindre JM, Kantor G, Chauvergne J, Maree D. Adjuvant chemotherapy with CYVADIC in high risk soft tissue sarcoma: a randomized prospective trial. Proc Sixth International Conf Adjuvant Ther Cancer, 1990; 556-565.

6.2.XIX
Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M et al. 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 Surg 1982; 196: 305-315.

6.2.XX
Ruka W, Emrich LJ, Driscoll DL, Karakousis CP. Prognostic significance of lymph node metastasis and bone, major vessel, or nerve involvement in adults with high-grade soft tissue sarcomas. Cancer 1988; 62: 999-1006.

6.2.XXI
Rydholm A, Gustafsan P, R÷÷ser Bo, WillÚn H, ┼kerman M, Herrlin K et al. Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 1991; 9: 1757-1765.

6.2.XXII
Stinson SF, DeLaney TF, Greenberg J, Yang JC, Lampert MH, Hicks JE, et al. Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. International Journal of Radiation Oncology, Biology, Physics 1991; 21: 1493-1499.

6.2.XXIII
Suit HD, Mankin HJ, Wood WC, Gebhardt MC, Harmon DC, Rosenberg A, et al. Treatment of the patient with stage M0 soft tissue sarcoma. J Clin Oncol 1988; 6: 854-862.

6.2.XXIV
Tepper JE, Suit HD. Radiation therapy of soft tissue sarcomas. Cancer 1985; 55: 2273-2277.

6.2.XXV
Tepper JE, Suit HD, Wood WC, Proppe KH, Harmon D, McNulty P. Radiation therapy of retroperitoneal soft tissue sarcomas. International Journal of Radiation Oncology,Biology, Physics 1984; 10: 825-830.

6.2.XXVI
Terjanian TO, Benjamin RS, Barkley HT, Evans HL, Murphy WK, Martin RG. VACAR adjuvant chemotherapy for poor-prognosis soft-tissue sarcomas of the extremities. A prospective randomized trial with 10-year follow-up. Proc Am Soc Clin Oncol 1987; 6: 129.



6.3 STAGE IVA (local regional soft tissue sarcoma with regional lymph node metastases)

6.3.1
Stage IVA disease is infrequent (<5overall), even if some histotypes, such as epithelioid sarcoma, angiosarcoma, synovial sarcoma, and others are associated with a higher probability to metastatize to regional lymph nodes (10-20%). The prognosis of these patients is definitely worse than for the localized disease without regional lymph node involvement, and in some series it was close to that of patients with distant metastases.

6.3.2
In patients with lymph node metastases, standard treatment, on a type R basis, can be represented by surgery for the primary lesion according to the same criteria for limited disease, lymphadenectomy, and radiotherapy if necessary. Lymph node involvement in soft tissue sarcomas is considered a very poor prognostic factor and these patients are thus to be considered poor-prognosis patients, close to patients with advanced disease. Therefore those oncologists who feel that adjuvant chemotherapy (6.2.6) can be proposed to high-risk patients, informing them that it is not standard practice, may consider chemotherapy in addition to surgery and radiotherapy as appropriate for individual non standard clinical use on a type R basis when lymph nodes are involved.


References

6.3.I
Mazeron JJ, Suit HD. Lymph node as sites of metastases from sarcomas of soft tissue. Cancer 1987; 60: 1800-1808.

6.3.II
Ruka W, Emrich LJ, Driscoll DL, Karakousis CP. Prognostic significance of lymph node metastasis and bone, major vessel, or nerve involvement in adults with high-grade soft tissue sarcomas. Cancer 1988; 62: 999-1006.

6.3.III
Weingrad DN, Rosenberg SA. Early lymphatic spread of osteogenic and soft tissue sarcomas. Surgery 1978; 84: 231-240.



6.4 STAGE I-IVA (4.1.3) inoperable locally advanced disease

6.4.1
Inoperable lesions entail a very poor prognosis in a disease in which surgery is the treatment mainstay. In these cases, therefore, it is reasonable to resort to all the available resources which can give a partial response and thereby convert an inoperable disease into an operable one. Even a marginal excision can represent a goal in such cases, especially if radiotherapy can follow thereafter. In some cases even debulking surgery may be useful to the individual patient, at least as far as his quality of life is concerned.

6.4.2
Available therapeutic options are cytoreductive chemotherapy or irradiation. Chemotherapy may be given intravenously or as an intraarterial infusion. In both cases a systemic (therapeutic and toxic) effect will concur. Otherwise, chemotherapy can be given as an intraarterial perfusion, without any major systemic effect. Radiotherapy can be combined with chemotherapy, or hyperthermia can be added to radiotherapy and chemotherapy. All these approaches are still investigational and no evidence has been provided so far that one of them is superior to the others. Overall, a combined approach with a preoperative intravenous cytoreductive chemotherapy and/or radiotherapy, followed by some kind of surgery may be regarded as standard treatment on a type R basis. Intraarterial infusion or perfusion (possibly with TNF), as well as hyperthermia, should be considered investigational options, to be given only within clinical trials.


References

6.4.I
Bramwell VHC. Intraarterial chemotherapy of soft tissue sarcomas. Semin Surg Oncol 1988; 4: 66-72.

6.4.II
Suit HD, Mankin HJ, Wood WC, Proppe KH. Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcoma. Cancer 1985; 55: 2659-2667.

6.4.III
van Haelst-Pisani CM, Buckner JC, Reiman HM, Schaid DJ, Edmonson JH, Hahn RG. Does histologic grade in soft tissue sarcoma influence response rate to systemic chemotherapy? Cancer 1991; 68: 2354-2358.



6.5 STAGE IVB with isolated lung metastases

6.5.1
A conspicuous fraction of high grade sarcoma patients (as high as 80%) show isolated lung metastases as their first distant relapse. In these cases, if at a computerized tomography scan the lung lesions look completely resectable to an experienced thoracic surgeon, an attempt should be made to remove them surgically. A bilateral surgical exploration, by means of a median sternotomy or a bilateral thoracotomy, is recommended, given the unsatisfactory sensitivity of computerized tomography scan for small lung nodules. Patients who underwent complete removal of their lung metastases (possibly constituting 80of all patients with distant relapses) were shown in uncontrolled prospective trials to have at least a 20long term disease free survival, i.e. possibly a cure rate in the range of one fourth or one fifth. Given the dismal prognosis associated with every other therapeutic option in the metastatic disease, surgery of completely resectable lung lesion is therefore standard treatment on a type 3 level of evidence (6.5.I, 6.5.lI, 6.5.III, 6.5.VI). No prognostic factor was definitely demonstrated to be of value in selecting patients for surgery, save for the feasibility of a complete excision of visible nodules. However, the number of lung nodules (more or less than four), the doubling time or the free interval (more or less than one year) have been shown to provide some prognostic value in some series, but should not be used as selection criteria for surgery.

6.5.2
"Adjuvant" chemotherapy was used in some prospective uncontrolled clinical trials on surgery of lung metastases, but no evidence has been provided that it adds to surgery alone. Ongoing randomized trials are comparing surgery of lung metastases alone against surgery plus anthracyclines and Ifosfamide. In this perspective, chemotherapy is to be considered investigational in these patients. Actually, many medical oncologists find it difficult not to employ chemotherapy in an already systemic disease, as long as they consider that patients with lung metastases truly belong to the advanced disease setting. Indeed, the risk of relapse after surgery of lung metastases is obviously high. In this perspective, "adjuvant" chemotherapy can therefore be regarded as investigational or appropriate for individual clinical use in selected patients on a type R basis within an individualized shared decision making. If this is the case, the patient should be informed of the lack of evidence in favour of a beneficial effect. Selected patients should be those presenting with bad prognostic factors. These prognostic factors may be represented by the tumor doubling time, the free interval after the last definitive treatment for local disease, the number of lung nodules.

6.5.3
When lung lesions are inoperable, an attempt can be made to convert them to resectability, but this will prove feasible in very few cases, if any. Chemotherapy is therefore standard treatment on a type R basis. The clinical goal is a good response, as long as there is some theoretical chance of converting the case to a completely resectable one. Therefore, regimens associated with the highest predicted response rate should be resorted to. According to two, out of three, randomized trials, polychemotherapy with Doxorubicin and Ifosfamide gives higher response rates by comparison with monochemotherapy with Doxorubicin, and therefore one of the regimens which include Doxorubicin and Ifosfamide Dacarbazine can be used when the goal is a partial response. Studies are needed, however, to assess the degree of clinical benefit that chemotherapy can provide in the patients with unresectable isolated lung lesions.

6.5.4
Isolated surgically removable further relapses to the lungs can be dealt with by further surgical attempts, with the aim to remove all visible nodules as well. It is difficult to state at which point in the patient history of relapses it is most reasonable to add chemotherapy, if not used before. Surgery of lung lesions is standard treatment on a type 3 level of evidence (6.5.II) as long as it is feasible, but clinical skill is needed to decide when there is no longer any reason for it to be useful to the patient.

6.5.5
The concurrence of local disease (either primary or relapsing) and isolated lung metastases is best treated by a combined approach following the same criteria mentioned above for each of the two settings. Sometimes, ablative surgery can be suggested to an informed patient with concurrent isolated lung metastases, in an attempt to provide them with some chances of cure. Therefore, adequate local surgery and surgery of lung metastases are standard treatment, on a type R basis, when local disease and isolated lung metastases are present. Studies are needed to assess the clinical benefit that an aggressive approach can provide in this patient setting. If one multiplied chances of cure for local disease (40%) by chances of cure for lung disease (20%), a 8probability of cure should be expected. It is therefore logical not to leave these cases to palliative approaches only, even if, in this population overall, the expected benefit is low.


References

6.5.I
Casson AG, Putnam JB, Natarajan G, Johnston DA, Mountain C, McMurtrey M, et al. Efficacy of pulmonary metastasectomy for recurrent soft tissue sarcoma. J Surg Oncol 1991; 47: 1-4.

6.5.II
Feldman PS, Kyriakos M. Pulmonary resection for metastatic sarcoma. J Thorac Cardiovasc Surg 1972; 64:784-799.

6.5.III
Jablons D, Steinberg SM, Roth J, Pittaluga S, Rosenberg SA, Pass HJ. Metastasectomy for soft tissue sarcoma. J Thorac Cardiovasc Surg 1989; 97: 695-705.

6.5.IV
Pastorino U, Valente M, Santoro A, Gasparini M, Azzarelli A, Casali P, et al. Results of salvage surgery for metastatic sarcomas. Ann Oncol 1990; 1: 269-273.

6.5.V
Potter DA, Glenn J, Kinsella T, Glatstein E, Lack EE, Restrepo C, et al. Patterns of recurrence in patients with high-grade soft-tissue sarcomas. J Clin Oncol 1985; 3: 353-366.

6.5.VI
Robinson MH, Sheppard M, Moskovic E, Fisher C. Lung metastasectomy in patients with soft tissue sarcoma. Br J Radiol 1994; 794: 129-135.

6.5.VII Roth JA, Putnam JB, Wesley MN, Rosenberg SA. Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma patients. Cancer 1985; 55: 1361-1366.

6.5.VIII
van Geel AN, Pastorino U, Pietraszek A, Schmitz PIM. Surgery of lung metastases from soft tissue sarcoma. Eur J Cancer 1993; 29A(Suppl 6): S183.



6.6 STAGE IVB extrapulmonary disease

6.6.1
Soft tissue sarcomas metastatize to lungs, bone, and liver, in addition to soft tissues and other organs with decreasing frequency. Median survival for these patients is generally <12 months and the 5-year survivors are exceptional (definitely <5%). Chemotherapy has been widely used in these patients as a standard option, basically with a palliative intent, but is clearly inadequate. Chances of a partial response do not exceed 20-40%. However, no study has been initiated comparing chemotherapy to best supportive care. Indeed, many oncologists feel that best supportive therapy without chemotherapy may be a reasonable option at least in a subset of advanced sarcoma patients, i.e. those with poor performance status, for whom chances of response are lower and toxicity is higher; those for whom, on clinical grounds, even a partial response is likely to be useless with regard both to survival (because the disease is too advanced) and to quality of life (because no symptomatic improvement is expected). Therefore, an attempt with a first line chemotherapy regimen (6.6.2) may be considered a standard option, on a type C basis, at least for good performance status patients and/or patients in whom some clinical benefit is reasonably expected if a partial response does occur. Indeed, best supportive care can well be appropriate for individual clinical use in selected patients, on a type R basis, e.g. in patients with poor performance status, those with very advanced disease, those in which even a partial response is not expected to improve quality of life.

6.6.2
For patients (6.6.1) in whom one decides to resort to chemotherapy, there is continuing uncertainty as to the best regimen to use. Two active drugs are available, Doxorubicin and Ifosfamide. Each of them is able to provide a 20response rate in the advanced disease. Many uncontrolled prospective trials have evaluated their combination, sometimes in addition to Dacarbazine, which is another marginally active drug. In the Dana Farber's series of 105 patients, a 47response rate was obtained with the MAID regimen (Ifosfamide plus Mesna + Doxorubicin + Dacarbazine). However complete responses are rare (<10%), even with most intensive regimens. Three randomized trials are available which compared Doxorubicin or Doxorubicin-based chemotherapy with Doxorubicin plus Ifosfamide. Two of them, from ECOG and SWOG/CALGB, demonstrated a statistically significant higher response rate for the Doxorubicin plus Ifosfamide arm (roughly, 30vs 20%) but no survival advantage. The third one, from EORTC, did not show either a survival or a response benefit, but the doses of Ifosfamide and Doxorubicin were lower than in the former two studies. However, since an advantage in terms of partial responses was demonstrated with the combination of Doxorubicin and Ifosfamide at full doses, the medical oncologist may well suggest such an approach to the patient whenever he feels that a partial response could be useful, in terms of survival (e.g., when an inoperable patient might be converted into an operable one after chemotherapeutic cytoreduction) or quality of life (e.g., when metastases are directly associated with symptoms disturbing the patient's ordinary life: pain, etc.). Therefore, monochemotherapy with Doxorubicin is currently standard treatment on a type 1 level of evidence (6.6.III, 6.6.IV,6.6.VI) at least when a partial response is not a clinical goal. If a partial response represents a goal on clinical grounds, polychemotherapy with Doxorubicin and Ifosfamide may give higher response rates on comparison with monochemotherapy with Doxorubicin, and therefore may be resorted to in the individual patient. Thus regimens including Doxorubicin and Ifosfamide Dacarbazine may be considered investigational or appropriate for individual clinical use in selected patients on a type R basis.

6.6.3
A standard second line chemotherapy is not available today. An EORTC phase II trial suggested that Taxotere might be an active drug in pretreated patients. Another experimental option is constituted by Ifosfamide at higher than standard doses (>12,000 mg/sqm). The response rate in these settings is however <20%. Since the survival benefit was not assessed and is indeed doubtful, second line chemotherapy, particularly with high dose Ifosfamide or investigational drugs and regimens, should be regarded as investigational or appropriate for individual clinical use in selected patients on a type R basis. In fact, when a partial response is a clinical goal for palliative reasons (pain or other symptoms), a second line treatment may be chosen within an individualized shared decision making with the patient. When the progression free interval has been sufficiently long (i.e. >12 months), the clinician may resort to the same chemotherapy already used in the first line.


References

6.6.I
Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A et al. An Intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcoma. J Clin Oncol 1993; 11: 1276-1285.

6.6.II
Antman KH, Ryan L, Elias A, Sherman D, Grier HE. Response to ifosfamide and mesna in 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 1989; 7: 126-131.

6.6.III
Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5: 840-850.

6.6.IV
Edmonson JH, Ryan LM, Blum RH, Brooks JSJ, Shiraki M, Frytak S et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993; 11: 1269-1275.

6.6.V
Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 1989; 7: 1208-1216.

6.6.VI
Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13: 1537-1545.

6.6.VII
van Hoesel QGCM, Verweij J, Catimel G, Clavel M, Kerbrat P, van Oosterom AT, et al. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. Ann Oncol 1994; 5: 539-542.



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ę European School of Oncology, 1996

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