Adult-type soft tissue sarcomas are a variegate group of

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1 Adjuvant Chemotherapy for Soft Tissue Sarcoma Paolo G. Casali, MD OVERVIEW Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence. Adult-type soft tissue sarcomas are a variegate group of malignancies. They are highly heterogeneous, because they are made up of several histologies and arise from virtually all body sites. 1 In addition, they are rare, and their incidence is approximately 4 per 100,000 per year. 2 This incidence does not prevent controlled trials, but pooling together different histologies and possibly different primary sites is often the price to pay. It is true that more than half of STS cases are high-grade and undifferentiated pleomorphic sarcomas, liposarcomas, leiomyosarcomas, myxofıbrosarcomas, synovial sarcomas, or malignant peripheral nerve sheath tumors, and more than half of them arise in the limbs. However, a high degree of heterogeneity remains, even after selecting a group of patients with these types of STS, and other relevant subgroups (e.g., uterine sarcomas) are left behind. This contributes to major limitations of available evidence on adjuvant chemotherapy in STS and, thus, a considerable degree of uncertainty on its clinical value, although several randomized clinical trials have been performed in the last 40 years. When one singles out high-grade STS, the mortality rate exceeds 50%. In addition to the malignancy grade, other main prognostic factors are size and presentation for example, deep fascial extension. By combining these three factors, it is easy to select a population in which two-thirds of patients may die of their disease. Prognostic nomograms are available to refıne the prognosis with a view toward adjuvant decisions. 3-6 Currently, the treatment of metastatic disease is unsatisfactory. Surgery of lung metastases is the main option when secondary lesions are isolated in the lungs, and the number of such lesions is relatively low. A cure may be achieved in a minority of patients with these metastases, and the course of disease may be slowed down in a subgroup of others; however, most patients will experience relapse in a matter of months. Chemotherapy is based on anthracyclines and ifosfamide, though other cytotoxics and even molecularly targeted agents are available, which have interesting antitumor activity in selected histologies. Indeed, there is currently a trend in favor of an histology-driven approach in the medical therapy of STS. However, the effect of medical therapy in the metastatic setting is essentially palliative, though improving over the last years. The median survival of patients with metastatic disease often has been reported to be in the range of 1 year. Undoubtedly, there are subgroups who benefıt from surgery of lung metastases and currently available medical therapies, but a cure is essentially precluded in most cases, and though possibly higher than once reported overall survival remains unsatisfactory, if one leaves aside the tails of curves. In addition, STS often pose challenging problems regarding surgery of localized disease. In a minority of cases, one may hope to convert mutilating surgery into limb-sparing procedures by means of preoperative cytoreduction. In several other cases, cytoreduction is felt by the surgeon to be potentially useful to minimize sequelae and improve the local control rate. This is why chemotherapy is resorted to preoperatively in a proportion of patients, which may vary from an From the Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Paolo G. Casali, MD, Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, Milano, Italy; paolo.casali@istitutotumori.mi.it by American Society of Clinical Oncology. e629

2 PAOLO G. CASALI institution to another, with a view toward local cytoreduction, in addition to its possible systemic effects. In conclusion, there is a huge need for effective adjuvant and/or neoadjuvant treatments in STS. The proportion of potentially amenable patients may roughly amount to onehalf of cases. This applies to adult-type STS, because extraskeletal Ewing sarcomas and embryonal or alveolar rhabdomyosarcoma fall in a distinct group of sarcomas, even when they occur in the adult, which deserves chemotherapy in all cases as a key component of the standard treatment. AVAILABLE EVIDENCE Several randomized, controlled trials have been performed with adjuvant chemotherapy for STS, starting from the 1970s, when chemotherapy was shown to be crucial in revolutionizing the prognosis of childhood sarcomas, (i.e., osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma). Trials performed in STS can be divided into two generations. Firstgeneration trials used anthracycline-based regimens that is, either doxorubicin alone or combinations that today would be regarded as exploiting doxorubicin as virtually the only, or nearly only, active drug. Second-generation trials have been based on combinations of anthracyclines and ifosfamide. Doses varied substantially, but at least the two main active drugs in STS were incorporated. A high degree of heterogeneity can be found in all these studies also, as far as the patient populations are concerned, and the number of patients ranged from a few dozens to hundreds. A meta-analysis of these randomized clinical trials, published in 2008, confırmed the benefıt that a previous metaanalysis, done on individual patient data, had already shown in terms of local and distant relapse rate; the 2008 publication also noted a statistically signifıcant benefıt in terms of overall KEY POINTS Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS), but it is an option to share with the patient in conditions of uncertainty when the risk of relapse is high. Controlled evidence is available, and was also pooled in meta-analyses, but its weakness is that studies have been conflicting. If the decision is to resort to chemotherapy in the patient with localized high-risk STS, chemotherapy can be administered preoperatively if cytoreduction is felt to help improve the quality of surgical margins and/or sequelae. Personalization of adjuvant chemotherapy across diverse STS subgroups is worth testing in clinical research as a way forward, to improve its efficacy. Personalized, rational decision making in conditions of uncertainty on adjuvant treatment for patients with STS is the every-day challenge that multidisciplinary tumor boards face at reference sarcoma centers or within sarcoma networks. survival for doxorubicin plus ifosfamide (p 0.01). 7,8 The magnitude of benefıt was in the 5% to 10% range. Although small, this could well justify the choice of using chemotherapy in high-risk patients, and a meta-analysis of several randomized clinical trials could be regarded as suffıcient evidence to back this choice. Methodologically, the last meta-analysis was not done on individual patient data. However, the main limitation of any meta-analysis of adjuvant chemotherapy in STS is that the pooled trials are conflicting, and the largest trials point to a lack of benefıt. Clearly, this substantially undermines any positive conclusion. Conversely, small trials were less heterogeneous in their patient population and/or were carried out by single institutions with more expertise with the disease. In rare cancers, large trials enrolling patients from a variety of institutions with different expertise levels may pose substantial problems in terms of quality of care. Random assignment is not a guarantee that this clinical bias is offset just because it is operating in both arms, because the most effective treatment may be more penalized by shortcomings in quality of care (e.g., in the adjuvant setting, by surgical treatment). In 2012, a large, randomized trial was published by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group, which provided a negative result by using a regimen of doxorubicin plus ifosfamide at full doses, though the latter was given at 5 g/m 2 in 24 hours. 9 The relapse rate of the study patient population was in the 50% range; thus, it was at a level that may be slightly lower than the one selected by some positive studies. By updating the meta-analysis using aggregate data for overall survival of this and other new studies, a statistically significant benefıt was still apparent in terms of survival in favor of chemotherapy (p 0.02). A randomized trial performed by the Italian Sarcoma Group (ISG) and the Spanish Sarcoma Group (GEIS), published in 2008, compared fıve cycles (three preoperatively and two postoperatively) of full-dose epirubicin (an analog of doxorubicin) plus ifosfamide with 3 preoperative cycles of the same regimen. 10 Both relapse-free survival and overall survival were superimposable, but they also were superimposable to the treatment arm (fıve postoperative cycles of the same regimen) of a previous randomized trial carried out by ISG that had a no-chemotherapy control arm. 11 That trial had been closed in advance because of an early major benefıt in survival in favor of the adjuvant treatment arm. With a longer follow-up time, the statistical signifıcance was lost, though a trend was preserved. 12 The patient population of the ISG trials was defınitely in the high-risk group, and it was calculated that the prognosis expected without chemotherapy for patients enrolled on the most recent trial, estimated through available nomograms, was compatible with the performance of the control group in the fırst study. This may be taken as indirect evidence that three courses of a full-dose regimen of anthracycline plus ifosfamide can give some prognostic benefıt in a truly high-risk STS patient population. It is interesting that several trials on adjuvant chemotherapy in STS detected some benefıt in terms of local relapses. 8,13 e ASCO EDUCATIONAL BOOK asco.org/edbook

3 This observation is diffıcult to explain, especially in the presence of a questionable benefıt for distant relapse. However, one should recall that the local control in some patients with high-risk STS may be challenging. In addition, some local relapses in STS may well lead to death. This might explain the differences in survival in the absence of comparable differences in distant relapses. In addition, this could add to the rationale of placing chemotherapy preoperatively, as long as the decision has been made in the single case to use it as an adjunct to surgery. The ISG trial allowed the combination of neoadjuvant chemotherapy with preoperative radiation therapy, and this proved to be tolerable in the proportion of patients in whom it was used. With an incidence in the range of 0.5 per 100,000 per year, uterine sarcomas are a relevant subgroup in the STS family. They entail a signifıcant risk of relapse. Leiomyosarcoma is the main subgroup, if one excludes mixed mullerian tumors (carcinosarcomas), which are currently held to be epithelial in nature. Other highly malignant subgroups are high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas. Recent, uncontrolled evidence was provided on a regimen employing four cycles of gemcitabine plus docetaxel and another that was based on four cycles of the same chemotherapy followed by four cycles of doxorubicin. 14,15 The latter regimen was associated with an interesting relapse-free survival rate compared with external controls, though the rate decreased with a longer follow-up time. A randomized trial is ongoing to compare this regimen to a nochemotherapy arm in uterine leiomyosarcomas. CURRENT RECOMMENDATIONS The 2014 National Comprehensive Cancer Network (NCCN) clinical practice guidelines state that adjuvant chemotherapy for STS greater than 5 cm and intermediate to high grade in the extremities, superfıcial trunk, or head and neck, can be viewed as an appropriate intervention on the basis of lowerlevel evidence marked by limited and conflicting data. 16 Thus, adjuvant chemotherapy is a legitimate option, but is not standard. In essence, the same applies to uterine leiomyosarcomas or undifferentiated sarcomas. The 2015 European Society for Medical Oncology (ESMO) clinical practice guidelines state that chemotherapy can be regarded as an option for patients with high-grade, deep STS that is greater than 5 cm as adjuvant or neoadjuvant treatment, but they acknowledge no consensus on its role, given the conflicting results of available studies. 17 In uterine leiomyosarcomas, the value of adjuvant chemotherapy also is said to be undetermined. In brief, clinical practice guidelines must take into account that some evidence was provided on the potential value of adjuvant chemotherapy in STS but that this evidence is insuffıcient to make chemotherapy standard practice. Thus, a clinical decision shared with the patient to resort to adjuvant chemotherapy in the presence of a high risk of relapse is fully justifıed according to current consensus recommendations, provided that the patient is aware that it is not standard treatment. ISSUES Available studies mainly refer to the most typical presentations, that is, limb and superfıcial trunk STS. Their results are conflicting, and uncertainty has not been settled, but at least they can help by providing direct evidence. In clinical practice, one may be challenged by patients with STS who fall outside the average STS patient. In general, the primary site can be regarded as a minor source of discrepancy for the effıcacy of systemic therapy, because there is no major reason, ultimately, why the same histology should benefıt differently depending on the primary site. Sometimes, an atypical site entails an additional risk of relapse. For example, a pleural synovial sarcoma is likely to entail a higher risk than a limb synovial sarcoma because of the additional locoregional risk of pleural spread. Thus, one may estimate that an additional reason for selecting adjuvant chemotherapy is in place. It goes without saying that the reverse may be true as well; that is, the additional risk is even less likely to be covered by available adjuvant treatments. Some rare histologies may pose further uncertainty, because their behavior may be less known and, most important, their chemotherapy sensitivity may deviate from that of average STS. Indeed, some histologies (e.g., epithelioid sarcoma, or alveolar soft part sarcoma) are less sensitive to standard chemotherapy for STS, and this may be a good reason to refrain from using adjuvant chemotherapy for them, when the lack of any tumor lesion prevents one from the opportunity to check tumor response (i.e., tumor sensitivity). In these cases, delaying chemotherapy to the time of relapse may be a reasonable choice, though the pursued effect of chemotherapy as an adjuvant would be different by defınition. Sometimes, these histologies are less sensitive to anthracyclines plus ifosfamide but may be sensitive to other agents (e.g., leiomyosarcoma is less sensitive to ifosfamide and more sensitive to dacarbazine). In these cases, one may try to personalize the choice of the medical therapy. Of course, this adds to the uncertainty of adjuvant chemotherapy in STS, and the patient needs to be informed accordingly within a deeply shared decision-making process. In general, because the approach to the medical therapy of STS is increasingly histology driven, the assessment of whether an histology-driven approach to the adjuvant therapy of STS may improve its effectiveness is a priority for clinical research. However, when single histologies are considered, the number of eligible patients for clinical studies further diminishes, and conventional statistics faces major challenges. With regard to the regimen choice in the adjuvant setting, aside from the possible role of histology-driven options, fulldose anthracycline-plus-ifosfamide combinations should be regarded as standard. Certainly, this conclusion may be challenged by the unclear superiority of the combination of these two drugs over single-agent doxorubicin in advanced disease, as recently suggested by a randomized trial. 18 How- e631

4 PAOLO G. CASALI ever, this trial showed a clear superiority of the combination in terms of antitumor activity (response rate and progression-free survival). Thus, it is logical to resort to most active regimens in the adjuvant setting, aside from their superiority in terms of survival in the setting of advanced disease. Therefore, if the decision is made to use adjuvant chemotherapy in the single patient, in the absence of a personalized choice in favor of an histology-driven regimen, a full-dose combination of an anthracycline and ifosfamide can be regarded as the most logical selection today. In many institutions, this means doses of doxorubicin in the range of 60 to 75 mg/m 2, or equivalents, plus ifosfamide in the range of 6,000 to 7,500 mg/m 2. CONCLUSION The rarity and the heterogeneity of STS have been formidable obstacles to generating reliable evidence in favor of or against adjuvant and neoadjuvant chemotherapy. Available data are consistent with a limited degree of effectiveness, but a lack of benefıt cannot be ruled out. In fact, several institutions worldwide propose systemic therapy to selected patients with STS in a shared decision-making process in conditions of uncertainty. Eligible patients are those with a high risk of relapse, which largely is dictated by the malignancy grade and the clinical presentation. There are some rare histologies that are poorly sensitive to chemotherapy: in patients who have these histologies, adjuvant chemotherapy usually is not proposed, even when the risk would be high enough to justify adjuvant treatment, if available. There is some evidence that systemic therapy may be placed before or after surgery with similar results, with the obvious advantage for preoperative chemotherapy to exert a local effect, which sometimes may be benefıcial for the quality of surgical margins. Chemotherapy may be combined with radiation therapy preoperatively so that the local effect is maximized. Evidence provided by one randomized trial would support a short course of three cycles of chemotherapy, which clearly is more acceptable for decision making in a setting of so much uncertainty over its effıcacy. Overall, chemotherapy has a limited antitumor activity in STS. Although this explains the diffıculty in fınding any major effect of adjuvant chemotherapy, it is clear that systemic therapy is undergoing improvements in STS. A major way forward seems to lie in histology-driven approaches. Thus, an ongoing, randomized trial is comparing three cycles of full-dose epirubicin plus ifosfamide with three cycles of an histology-driven chemotherapy regimen (i.e., gemcitabine plus dacarbazine in leiomyosarcoma; trabectedin in myxoid liposarcoma; high-dose continuous-infusion ifosfamide in synovial sarcoma; ifosfamide plus etoposide in malignant peripheral nerve sheath tumors; gemcitabine plus docetaxel in pleomorphic sarcomas). Likewise, an above-mentioned randomized trial that is ongoing in uterine leiomyosarcoma is histology-driven. In principle, molecularly targeted agents shown to be active in STS might be tested in the adjuvant setting, though they face all of the limitations that targeted therapy may encounter in solid tumors when used as an adjuvant, as demonstrated with gastrointestinal stromal tumors. 19,20 Thus, there is room to test the effectiveness of more variegated medical therapies in the adjuvant treatment of STS, but standard practice continues to face a high degree of uncertainty. All the rules of rational decision making in conditions of uncertainty should be exploited while we look forward to the implementation of new methods for clinical studies in rare cancers. 21 Disclosures of Potential Conflicts of Interest Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate family member; those marked B are held by the author and an immediate family member. Institutional relationships are marked Inst. Relationships marked U are uncompensated. Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Paolo G. Casali, Novartis, Pfizer, PharmaMar. Consulting or Advisory Role: Paolo G. Casali, Amgen Dompé, ARIAD/Merck, Bayer, Blueprint Medicines, GlaxoSmithKline, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar. Speakers Bureau: None. Research Funding: Paolo G. Casali, Amgen Dompé (Inst), Bayer (Inst), Eisai (Inst), GlaxoSmithKline (Inst), MolMed S.p.A. (Inst), Novartis (Inst), Pfizer (Inst), PharmaMar (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Paolo G. Casali, Novartis, PharmaMar. Other Relationships: None. References 1. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al (eds). WHO Classifıcation of Tumours of Soft Tissue and Bone. Lyon: IARC; Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer. 2011;47: Eilber FC, Brennan MF, Eilber FR, et al. Validation of the postoperative nomogram for 12-year sarcoma-specifıc mortality. Cancer. 2004;101: Mariani L, Miceli R, Kattan MW, et al. Validation and adaptation of a nomogram for predicting the survival of patients with extremity soft tissue sarcoma using a three-grade system. Cancer. 2005;103: Gronchi A, Miceli R, Shurell E, et al. Outcome prediction in primary e ASCO EDUCATIONAL BOOK asco.org/edbook

5 resected retroperitoneal soft tissue sarcoma: histology-specifıc overall survival and disease-free survival nomograms built on major sarcoma center data sets. J Clin Oncol. 2013;31: Iasonos A, Keung EZ, Zivanovic O, et al. External validation of a prognostic nomogram for overall survival in women with uterine leiomyosarcoma. Cancer. 2013;119: Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350: Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113: Woll PJ, Reichardt P, Le Cesne A, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13: Gronchi A, Frustaci S, Mercuri M, et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30: Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19: Frustaci S, De Paoli A, Bidoli E, et al. Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology. 2003;65: Bramwell V, Rouesse J, Steward W, 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: Hensley ML, Ishill N, Soslow R, et al. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol. 2009; 112: Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for highgrade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer. 2013;119: von Mehren M, Randall RL, Benjamin RS, et al. Soft tissue sarcoma, version J Natl Compr Canc Netw. 2014;12: ESMO/European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 (suppl 3):iii102-iii Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensifıed doxorubicin plus ifosfamide for fırst-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial. Lancet Oncol. 2014;15: van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet. 2012;379: Casali PG, Fumagalli E, Gronchi A. Adjuvant therapy of gastrointestinal stromal tumors (GIST). Curr Treat Options Oncol. 2012;13: Casali PG, Bruzzi P, Bogaerts J, et al. Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann Oncol. 2015;26: e633