Grandround

Managing adult soft tissue and gastrointestinal stromal tumours

Sarcomas and gastrointestinal stromal tumours include a wide variety of biologically diverse cancers, many of them very rare. Paolo Casali, a leading expert, presents an update of the latest evidence on the best way to manage them.

This is an edited version of a presentation by Paolo Casali, from the National Cancer Institute, Milan, Italy, that was first transmitted to the nd2 ESO–ESMO Latin-American Masterclass in Clinical for the European School of Oncology. It is edited by Susan Mayor.

arcomas and gastro-intestinal true for a range of soft tissue lesions, surgery that is not compartmental stromal tumours (GISTs) are such as uterine leiomyosarcomas, surgery, then is Srare cancers. The incidence whose benign counterpart – uterine indicated in principle. Use of adjuvant of soft tissue sarcomas in adults is leiomyomas (fibroids) – is one of the plus is not 4.5 per 100,000 population per year, most common conditions in women. standard treatment, although it can be and for GIST it is 1.5 per 100,000 used on an individualised basis. population per year. Osteosarcoma has an incidence of 0.3, Ewing’s Treating localised tumours 0.2, and rhabdomyosarcoma (RMS) Treating advanced disease 0.1 per 100,000 per year. Surgery is the standard approach The very low incidence of these rare for treating localised adult soft tissue Surgery is standard treatment cancers contrasts with an incidence sarcomas. Radiation therapy is used for isolated metastatic disease to rate of 300 per 100,000 per year quite frequently, although possibly the lung. Standard chemotherapy is for benign tumours. This poses a less frequently in current practice. doxorubicin, although doxorubicin plus challenge for clinicians and inevitably However, when soft tissue sarcomas are ifosfamide is widely used, depending results in delays in diagnosis. This is high grade, deeply located and require on a patient’s presentation. Histology- September / October 2016 33 Grandround

is no evidence behind this, but it seems Dedifferentiated liposarcoma logical. The question as to whether or not to add chemotherapy to surgery has not yet been settled by clinical studies. We generally give chemotherapy before surgery in these cases, to help ascertain if the patient is responsive to chemotherapy in order to tailor the overall strategy.

Continuous-infusion high-dose ifosfamide has been shown to be active in The choice of chemotherapy in dedifferentiated liposarcoma advanced disease driven chemotherapy may be a choice low. These are the best prognostic Doxorubicin plus ifosfamide. A as second- or later line therapy. factors. However, there are a variety randomised trial carried out by the Surgery for lung metastases may be of clinical presentations, so it is always EORTC Soft Tissue and Bone Sarcoma the used when lesions are isolated in questionable as to whether to resort to Group compared the standard treatment the lungs. The indication for surgery is surgery or not. of doxorubicin (75mg/m2) alone with higher in patients where the previous We are inclined to use chemotherapy doxorubicin (75mg/m2) plus ifosfamide disease-free interval was long and in addition to surgery in cases where (7.5g/m2). The results showed a the number of lesions reasonably prognostic factors are favourable. There difference in progression-free survival in favour of the combination; however, the difference in overall survival was Myxoid liposarcomas not statistically significant Lancet( Oncol 2014, 15:415). This means that single-agent doxorubicin could still be regarded as the standard treatment. Depending on the clinical presentation, the combination of doxorubicin plus ifosfamide may be used, particularly if it is believed that a tumour response could be useful. This randomised trial put together all histologies, but the question is how far we need to take account of the complexity of the histology of soft tissue sarcomas. This is a particular challenge for managing the disease and also for clinical trials. The more you put the different histologies together, the less likely you are to see differences that may apply only to some histologies and not others. Ifosfamide. In terms of the main drugs used in soft tissue sarcomas, ifosfamide is not active in leiomyosarcomas according to retrospective evidence (JCO 2007, 25:3144–50). As a result, many Trabectedin is approved for treating soft tissue sarcomas and has been shown to institutions do not use ifosfamide in induce a strong pathological response in myxoid liposarcomas (upper ) and in some cases also tumour shrinkage (lower ) leiomyosarcomas. In contrast, ifosfamide 34 September / October 2016 Grandround is very active in synovial sarcoma. It is also Dacarbazine. Dacarbazine is active active given as a continuous high-dose in leiomyosarcoma, but much less so in Leiomyosarcoma infusion over 14 days in dedifferentiated liposarcoma. Doxorubicin liposarcoma (see figure opposite,top ). . Gemcitabine is active Two retrospective series suggest efficacy in leiomyosarcomas although not in of high-dose continuous infusion in any other soft tissue sarcomas, with the Gemcitabine dedifferentiated liposarcomas (Sarcoma exception of angiosarcoma. One study 2013, doi.org/10.1155/2013/868973; Clin has shown improved progression-free Trabectedin Sarcoma Res 2014, 4:16). survival with gemcitabine plus docetaxel Trabectedin. Trabectedin is another compared to gemcitabine alone (JCO Dacarbazine drug that is now approved in the US 2007, 25: 2755–63), but other studies and Europe for soft tissue sarcomas. did not confirm this. An option, which This agent is active in dedifferentiated we follow at our institution, is to use liposarcoma, but probably primarily in gemcitabine alone in leiomyosarcomas. those with less aggressive behaviour. It is This is much better tolerated. especially active in myxoid liposarcomas, Pazopanib. The antiangiogenic drug Undifferentiated more so than in dedifferentiated pazopanib has demonstrated improved pleomorphic sarcoma liposarcoma, with tumour shrinkage progression-free survival in a phase III in some cases and very convincing study of all soft tissue sarcomas, with the Doxorubicin ± ifosfomide pathological response – despite lack exception of liposarcomas, which were of tumour shrinkage – in other cases not included (Lancet 2012, 378:1879). High-dose ifosfomide (see figure opposite,bottom ). This Some histologies, including uterine may be because trabectedin has a leiomyosarcomas and synovial sarcomas, Some sarcomas have many more treatment targeted mechanism of action in myxoid are more responsive. However, the options than others liposarcoma, in which the drug displaces rebound effect that can occur with the fusion transcript specific to this antiangiogenic agents may limit the use agonist. The evidence is only anecdotal, type of tumour from target genes and of pazopanib. but this type of sarcoma is very rare. promotes a type of differentiation (Mol In summary, in some histologies This type of sarcoma has a non- Cancer Therap 2009, 8:449). of soft tissue sarcomas, such as random chromosomal change. High- Trabectedin is active in metastatic leiomyosarcoma, it is possible to use grade endometrial stromal sarcoma liposarcoma and leiomyosarcoma, several chemotherapy drugs. Some of has a different chromosomal change. after failure of conventional chemo­ these drugs can be used for a relatively Undifferentiated endometrial sarcoma, therapy (JCO 2015, doi: 10.1200/ long time. Other histologies, such as another type, is very aggressive and not JCO.2015.62.4734). This includes undifferentiated pleomorphic sarcoma, responsive to hormonal therapy. uterine leiomyosarcomas (Gynecol Oncol have far fewer options for medical Desmoid tumours may be 2011; 123: 553–56). therapy. responsive to hormonal therapy, but Eribulin. More recently there has their natural history is very erratic, been some evidence to show eribulin Rarer histologies sometimes progressing and sometimes may be active in liposarcoma, providing Certain rarer histologies may respond spontaneously regressing. We are using an increase of seven months in overall to specific drugs: less and less surgery in desmoid tumours survival compared to dacarbazine (Lancet Angiosarcoma responds to taxanes, and have published a consensus- 2016, 387:1629–37)). However, it is not which have no effect on other soft based algorithm of drug options (Ann clear why there is less improvement tissue sarcomas, at least as single Oncol 2014, 25:578–83). Different in progression-free survival. This drug agents. Angiosarcoma also responds to histologies respond to different drugs. has now been approved by the US gemcitabine. For example, dermatofibrosarcoma has regulators, the FDA, and has received Low-grade endometrial stromal a chromosomal translocation, with an a positive opinion from the Committee sarcomas respond to hormonal therapy overproduction of PDGF-beta, and for Human Medicinal Products of the with progestins or aromatase inhibitors, responds to . European regulators, the EMA. but not to tamoxifen, because it is an This underlines the importance September / October 2016 35 Grandround

sarcomas (Cancer 2008, 113:573). Histology-driven chemotherapy However, the studies included showed divergent results, with some being Leiomyosarcoma: gemcitabine, trabectedin, DTIC (& temozolamide) … negative and others positive. Liposarcoma, dedifferentiated: ci-hd ifosfomide, trabectedin … A study in our centre compared Liposarcoma, myxoid: trabectedin … three cycles of epidoxorubicin, Angiosarcoma/intimal sarcoma: taxanes, gemcitabine … followed by surgery with or without Synovial sarcoma: hd ifosfomide, trabectedin … radiotherapy, with the same regimen Solitary fibrous tumour: DTIC (& temozolamide) … followed by a further two cycles of epidoxorubicin in patients with high- MPNST: ci-hd ifosfomide, VP16 + … grade spindle-cell sarcoma. Results Pleomorphic rhabdomyosarcoma: gemcitabine … were the same, so we currently Epithelioid sarcoma: gemcitabine … propose three cycles of chemotherapy to patients at high risk, quite often DTIC dacarbazine, ci – continuous infusion, hd – high-dose, MPNST – malignant peripheral nerve sheath tumours before surgery. This is because surgery in patients with high-risk sarcomas Histology-driven can be quite challenging and may potentially involve reconstructive Dermatofibrosarcoma: imatinib surgery, so it may be better to give Leiomyosarcoma: pazopanib ... chemoradiotherapy before surgery and not after (see figure opposite,top ). Synovial sarcoma: pazopanib ... We developed an app (Sarculator, MPNST: pazopanib … see www.sarculator.com) to assess Desmoids: hormones, sorafenib, imatinib … prognosis in patients with soft tissue Alveolar soft part sarcoma: pazopanib, , cediranib … sarcoma, based on our series, which Solitary fibrous tumour: sunitinib, pazopanib, … may be helpful to make treatment decisions on chemotherapy. Extraskeletal myxoid chondrosarcoma: pazopanib, sunitinib … Inflammatory myofibroblastic tumour: crizotinib … Gastrointestinal stromal Lymphangioleiomyomatosis and PEComas: m-TOR inhibitors tumours (GIST) Epithelioidsarcoma: pazopanib … Clear cell sarcoma: pazopanib … Treatment of GIST is quite simple, Hemangioendothelioma: m-TOR inhibitors, interferon with standard treatment being surgery. Imatinib is used as adjuvant treatment Angiosarcoma: pazopanib, sorafenib … in high-risk GIST. For advanced Pigmented villonodular synovitis: imatinib … disease, imatinib, sunitinib and MPNST – malignant peripheral nerve sheath tumours regorafenib are the three molecularly targeted agents available as first-, of histology in treating soft tissue sarcomas together makes it difficult to second- and third-line treatment. sarcomas, with different histologies make sense of the findings. Surgery for is not standard, responding to different chemotherapies but can be used in some cases, even and targeted drugs (see tables above). though we do not have convincing The range of different histologies makes Adjuvant chemotherapy evidence for this in addition to medical it difficult to carry out randomised therapy. controlled trials in soft tissue sarcomas. A systematic meta-analysis This treatment approach is based Results from the trials that are carried suggested a 10% advantage with on the molecular biology of GIST, with out need to be interpreted cautiously, adjuvant chemotherapy in high- molecular analysis being essential to because putting different soft tissue risk, localised, resectable soft-tissue make decisions on medical therapy (see 36 September / October 2016 Grandround figure below). Not all GIST responds The case for neoadjuvant treatment to imatinib. Exon 11-mutated KIT, which is the most common mutation (60%), responds, but GISTs with the exon 9 mutation may require 800 mg or 400 mg doses of imatinib. The exon 18 D842V mutation is completely insensitive to imatinib. The 10% of GIST cases that are wild type have a completely different natural history and do not respond, in practice, to imatinib, although they may respond to sunitinib or regorafenib. These are divided into two main groups: Chemotherapy is sometimes used before surgery in patients with high- succinate dehydrogenase- (SDH-) risk sarcomas, as they can be quite challenging and may potentially involve negative and SDH-positive. reconstructive surgery In unresectable or metastatic GIST expressing KIT, imatinib gives Molecular biology of GIST a median progression-free survival of two years and a median overall survival of five years JCO( 2008, 26:626–32). Some patients show much longer progression-free survival; however, we do not know who they are, whether they are just the tail of the curve, or whether there are specific reasons why they survive for so long. There are speculations that some kind of immune response may play a role in these patients, with imatinib potentiating antitumour responses through the inhibition of IDO (Nature Med 2011, 17:1094). Sunitinib demonstrates prolonged progression-free survival and overall survival in patients with advanced GIST after failure of imatinib (Lancet 2006, 368:1329), and regorafenib is also active as third-line therapy, with a benefit of some months compared to placebo (Lancet 2013, 381:295). Medical therapy with these agents Source: Republished from H Joensuu et al (2013) Lancet 382:973, © 2013, with should be continued long term, permission from Elsevier otherwise patients lose response. It may be assumed there is not complete Secondary resistance is the limiting Although available drugs show activity pathologic response to imatinib. factor, with the main mechanism being against different secondary mutations, Radiologically, the response pattern molecular heterogeneity. Biopsies this is not helpful in predicting shows typical hypodensity, although show different secondary mutations, response, because of the heterogeneity. there may not be tumour shrinkage. in a similar way to other tumour types. Focal progression can occur in GIST, September / October 2016 37 Grandround

Radiological response of GIST to imatinib Forthcoming educational events Update on rare adult solid cancers, 25–27 November 2016, Milan This is the first of an annual event organised by the European School of Oncology (ESO), in association with the European so surgery may be an option in patients Adjuvant imatinib is effective after Society for Medical Oncology who progress on imatinib, essentially resection of localised GIST (Lancet (ESMO) and Rare Cancers Europe. to prolong survival, as it will not cure 2009, 374:1097). Longer duration metastatic GIST. treatment improves survival, with one Postgraduate Master’s degree Surgery of widely progressing year better than no adjuvant imatinib, in rare cancers disease is not effective, but surgery two years better than one, and three ESO is planning to provide for focal progression may provide years better than two. However, the an individualised educational some benefit. Restarting imatinib can cure rate is not increased. The benefit pathway for young oncologists to prolong progression-free survival in of longer-term imatinib is currently develop their careers in rare adult cases where there are no other drug unclear, but results from the PERSIST solid cancers in collaboration options to use after failure of imatinib study, which investigated five years of with the Università Degli Studi and sunitinib (Lancet Oncol 2013, treatment, are awaited. di Milano and the Fondazione 14:1175). The decision to use adjuvant IRCCS Istituto Nazionale dei Tumori. For more information Risk stratification in GIST contact: [email protected]

Size Mitotic rate Gastric Jejunal/ Duodenal Rectal imatinib should be made jointly with (cm) M/50HPF ileal the patient, depending on their risk 1 ≤2 ≤5 0 0 0 0 and the molecular biology of their GIST. The risk assessment should none none none none be based on the tumour size, mitotic 2 >2≤5 ≤5 1.9% 4.3% 8.3% 8.5% rate and tumour site (see Table 3). very low low low low An additional factor to take into 3a >5≤10 ≤5 3.6% 24% 3a >5<10 account is whether tumour rupture low moderate has occurred, because this is a very 3b >10 ≤5 12% 52% 34% 57% adverse prognostic factor. moderate high high high 4 ≤2 >5 0 50% 54% 4 Revising the guidelines high 5 >2≤5 >5 16% 73% 50% 52% We are currently updating the moderate high high high European Society for Medical 6a >5≤10 >5 55% 85% 6a >5<10 Oncology’s Clinical Practice high high Guidelines for the diagnosis, treatment and follow-up of GIST 6b >10 >5 86% 90% 86% 71% and soft tissue sarcomas, which will high high high high incorporate the research reviewed in Source: M Miettinen (2006) Semin Diagn Pathol 23:70 this grandround. 38 September / October 2016