the treatment of distant metastases in soft tissue sarcoma

The Treatment of Distant Metastases in Soft Tissue Sarcoma Michael Sawyer and Vivien Bramwell

This article reviews the current standard approaches to the treatment of metastatic soft tissue sarcoma (STS) and evaluates new chemotherapy agents and novel approaches. A computerized search strategy was used to identify articles examining the role of chemotherapy and surgery in metastatic STS, which were published between January 1992 and December 1998. This search was supplemented by key articles from our files published before 1992. In selecting articles for inclusion in this review, emphasis was placed on randomized data and novel approaches. Only three agents--doxorubicin, ifosfamide, a'nd dacarbazine--have shown significant activity in metastatic STS. Numerous studies have examined the efficacy and toxicity of combining the known active agents in standard doses or in high doses with cytokine support. Promising results, in terms of increased response rates, often have not been repro- duced in randomized trials, and there is no convincing

evidence of enhanced overall survival. New regimens should be evaluated in randomized trials incorporating qual!ty-of-life endpoints. High-dose chemotherapy with bone marrow/stem cell rescue remains an investigational procedure of uncertain efficacy. Pilot studies have established the feasibility of intraperitoneal chemotherapy, after cytoreductive surgery, in patients with peritoneal sarcomatosis. To date, the efficacy of this approach has not been validated in phase II or III trials. The role of surgery in the treatment of isolated pulmonary metastases is well established. Results of small series raise the possibility that resection of hepatic metastases is benefi- cial in selected patients. Current chemotherapy options for patients with STS are limited. There is reason to hope that the situation will change with the further development of new agents that have novel and specific mechanisms of action. Copyright �9 1999 by W.B. Saunders Company

A dult patients presenting with soft tissue sarcomas (STS) are at significant risk of metastatic

disease, as illustrated by a series from Memorial Sloan-Kettering Cancer Center reporting a 22.7% incidence of metastasis ~ and another series from Massachusetts General Hospital showing that 10% of patients had metastases at presentation. 2 Even when surgery with curative intent is performed, relapses are common..The American College of Surgeons Pattern of Care Survey, involving a series of 1,209 patients, revealed that 216 patients presented with distant disease, and 452 subsequently developed metastases. 3

Many studies have evaluated a variety of chemotherapy regimens in metastatic adult STS./Most of these have been phase I and II or feasibility studies, with a relative paucity of randomized trials, many of which have included only small numbers of patients. A further complicating factor is the histological heterogeneity of these tumors. Central review panels often disagree with the diagnoses of local patholo- gists, judging 5% to 10% of cases not to be sarcomas, and this disagreement increases to 30% in terms of ascertaining the exact histological subtype. 4 With a

From the Department of Medical Oneology, London Regional Cancer Centre, London, Ontario, Canada.

Address reprint requests to Vivien Bramwell, PhD, MB, FRCPC, Department of Medical Oneology, London Regional Cancer Cenlre, 790 Commissioners Road, Era't, London, Ontario, Canada N6A 4L6.

Copjmight �9 1999 by W.B. Saunders Company 1053-4296/99/0904-0009$10.00/0

few exceptions, chemotherapy regimens have not been evaluated in single histological subtypes, and the studies enrolling all histological types have not been sufficiently large to allow valid conclusions to be drawn from subgroup analysis. Some observations about particular histological subtypes have been noted across several different trials. Anecdotal re- ports suggest that synovial sarcomas have marked chemosensitivity. 5 Leiomyosarcomas of the gastrointestinal tract (gastrointestinal stromal sarcomas) seem poorly responsive, particularly to standard anthracycline-based chemotherapy. In contrast, leiomyosarcomas of the uterus are often more sensitive to chemotherapy. These differences in response rate may relate to the sites of metastases, which in the case of gastrointestinal stromal sarcomas is preferen- tially the liver and for uterine leiomyosarcomas is the lung. The European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group reported that, by multivariate analyses, liver metastases (P < .0001) and advanced age (P = .0006) were the only adverse prognostic factors in predicting response in their chemotherapy studies. For survival, the adverse prognostic factors were poor performance status (t~ < .0001), high grade (P < .0009), and recent diagnosis (P = .0023).6

Methods

Using the Medline database, a literature search was performed using the keywords S T S and chemotherapy,

Seminars in Radiation Oncology, Vol 9, No 4 (October), 1999.'pp 389-400 389

390 Sawyer and BrarnweU

limited to the English language literature, from January 1992 to December 1998. The papers identified by the Medline search were supplemented by papers in our files, which included key articles published before 1992, as well as relevant papers gleaned from the reference lists of articles identified in the Medline search. Because of the large number of references available, in selecting studies for inclusion in this review emphasis was placed on inclusion of data from randomized trials or meta-analyses. Al- though these data were not available, large phase II/pilot studies and high-quality retrospective studies were considered. In addition, small pilot studies of novel agents or approaches were mentioned. The broad mandate of this review and the limited randomized data available in many areas as well as time and space constraints precluded any quantitative analyses.

Results and Discussion

Role of Chemotherapy in Metastatic Sarcoma

Single-Agent Chemotherapy During their development, most modern chemothera- peutic agents have been evaluated for activity in the setting of metastatic STS. Of the agents evaluated over the last 30 years, only a handful have shown definite activity. These include doxorubicin and its analogue epirubicin, ifosfamide, and dacarbazine; for cisplatin and etoposide, there is conflicting evidence as to their efficacy. Vinorelbine is under investigation, and its role in the treatment of STS has not been defined. The taxanes and edatrexate have not shown clinically useful activity.

Anthraeydines. Doxorubicin is considered one of the cornerstones of treatment of metastatic STS, either as a single agent or in combination. Response rates in single arm studies have ranged from 15% to 80%, but the most reliable evidence of its activity comes from an analysis of eight randomized studies ofdoxorubicin, given in doses of 60 to 80 mg/m ~ every 3 weeks, compared with various combination chemo- therapies. In these studies, the average response rate was 21% (range, 16% to 27%) in 761 patients]

Epirubicin was developed as a less cardiotoxic analogue of doxorubicin and has been extensively studied in adult STS. The EORTC has compared doxorubicin and epirubicin in two randomized trials. The first study showed that equimolar doses of epirubicin and doxorubicin, given as 75 mg/m 2 intravenous bolus every 3 weeks, produced response rates

of 18% and 25%, which were not significantly different (P = .33). Doxorubicin caused more myelotoxic- ity, alopecia, nausea, and vomiting. ~ It was antici- pated that higher doses of epirubicin might be tolerable and more active, but the second EORTC study did not confirm this hypothesis. Response rates (14% to 15%) and progression-free survival were similar for epirubicin at 150 mg/m 2, given by two different schedules, versus doxorubicin at 75 mg/m 2. There were no differences in grade 3 or greater cardiotoxicity (0 to 2%) across the arms, but there was increased myelosuppression and two toxic deaths in one of the epirubicin arms. 9

The most serious side effect associated with anthracyclines is the development of congestive heart failure, although this is of most concern in the adjuvant setting. Several strategies have been used to reduce cardiotoxicity. Lowering peak blood levels may reduce cardiotoxicity. In 82 patients, Caspar et all0 compared the cardiotoxic effects of adjuvant doxorubicin 60 mg/m 2 given as an intravenous bolus injection or as a 72-hour continuous infusion. The rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was lower in the continuous infusion arm (P = .0017). Two patients in each group developed congestive heart failure with one cardiac. death in each group. There seemed to be a reduction in efficacy with infusion therapy. 1~ An alternative to doxorubicin infusion is administration of the cardioprotective agent dexrazoxane. Dexrazoxane acts by binding to free iron and preventing free radical formation within myocytes. In patients with metastatic breast cancer and pediatric sarcomas, it has allowed anthracycline dose escalation beyond the doses at which cardiotoxicity is normally encoun- tered. H In a study that included 34 patients with adult STS as well as advanced breast cancer (95 patients), epirubicin 160 mg/m 2 every 3 weeks was administered with or without dexrazoxane 1,000 mg/m 2. The response rates for~sarcoma patients were 37.5% in the epirubicin-alone arm and 11% in the epirubicin-plus-dexrazoxane group, a difference that was not statistically significant. Corresponding overall survival figures were 15.5 and 15 months. Combin- ing data for breast and sarcoma pat!end, by all methods of cardiac evaluation, there was a clearly documented cardioprotective effect of dexrazoxane, with four cases of congestive failure in the epirubicin- alone arm compared with none in the dexrazoxane arm. Although this was a small study, dexrazoxane did not appear to have a negative impact on patient survival. 12 The most important problem in adult STS

Distant Metastases in Soft Tissue Sarcoma 391

is drug resistance, with many patients exhibiting primary resistance or subsequent progressive disease while receiving doxorubicin, and thus the addition of dexrazoxane does not add benefit to their therapy. In rare cases, use of dexrazoxane may allow retreat- ment with anthracyclines in patients who have a delayed relapse after adjuvant therapy or a previous good response in the metastatic setting.

One approach to improving the side-effect profile and possibly the efficacy of doxrubicin has been to encapsulate the drug in liposomes. Liposome-encapsulated doxorubicin (LED) has been shown to be equivalent to doxorubicin in experimental in vitro models. Data from in vivo models of liver metastases have shown LED to be superior to free doxorubicin in milligram equivalent doses, la,14 LED is less cardiotoxic in beagle and murine models of anthracycline cardiotoxicity. 15,16 In a disease-specific phase I trial, 29 patients with metastatic or locally advanced STS, who had not received prior anthracycline chemotherapy, received LED escalated from 75 mg 2 every 2 weeks with granulocyte-colony-stimulating factor (G- CSF) support. Eleven patients had received prior chemotherapy, and 7 of these had received radiation. There were 3 of 23 (13%) partial responses; 2 of the 3 responding patients had not received prior chemotherapy. The maximal tolerated dose was 105 mg/m 2 every 2 weeks. 17 In a phase II study of LED (55 mg/m 9 every 4 weeks) in 28 evaluable patients who had failed prior chemotherapy (including doxorubicin, dacarbazine, ifosfamide, and etoposide), there was only one partial response with, additionally, one mixed and two minor responses. The major toxicities were mucositis and hand-foot syndrome, is There were no responses reported in two other phase II studies &LED.19,2~ Both studies included a preponderance ofleiomyosarcomas, 7 of 13 and 7 of 15 patients, which may have contributed to the low response rate. If LED is to be useful in STS, it must have activity at least in the same range as unencapsulated doxorubicin with a reduction in important toxicifies, such as myelosuppression and cardiac damage. Based on preliminary data, itdoes not meet the first criterion, but more complete information is needed before LED is abandoned as an active agent.

Ifosfamide. The collected data from 300 patients enrolled in phase II studies of single-agent ifosfamide show a response rate of 26%. 21 In an EORTC trial, patients were randomized between ifosfamide 5 g/m2/24 h every 3 weeks and cyclophosphamide 1.5 g/mg/24 h every 3 weeks. Response rates were 18% for ifosfamide versus 8% for cyclophosphamide. A1-

though the difference was not statistically significant (P = . 13) the trend clearly favored ifosfamide, which at this dose was less myelosuppressive than cyclo- sphosphamide, thus suggesting that it could be combined more easily with other myelosuppressive drugs, such as doxorubicin. 22

There is evidence of a dose-response relationship for ifosfamide. This relationship was first noted in a phase I study of high-dose ifosfamide by Elias et al, 23 who observed three responses in patients previously treated with standard dose ifosfamide. Investigators at the Institut Gustave Roussy studied the effects of high-dose ifosfamide in 40 patients, all previously treated with doxorubicin or standard dose ifosfamide, 29 of whom had failed regimens that contained standard-dose ifosfamide. Ifosfamide 12 g/m 9 was given as a 72-hour continuous infusion every 4 weeks. There were 12 partial responses and 8 patients with stable disease in 36 evaluable patients. Five of the partial response occurred in patients previously treated with standard dose ifosfamide. The dose- limiting toxicity was neutropenia, with 100% of patients experiencing World Health Organization (WHO) grade 3 or 4 neutropenia, which occurred in 76% of cycles. Seven patients (17%) experienced neurotoxicity, and 4 patients developed irreversible acute renal failure. 24 Buesa et a195 published their results of high-dose ifosfamide as first-line therapy for metastatic STS. Forty-eight patients received ifosfamide 14 g/m 2 as a continuous infusion over 6 days every 4 weeks. Patients were supported with G-CSF if they developed febrile neutropenia or experienced delay in hematological recovery. The overall response rate was 37.7%, including 6 pathological complete responses and 11 partial response, and the toxicities described were similar to other studies with high-dose ifosfamide.

An EORTC randomized study, published in ab- stract form, supports the dose-response relationship suggested by the phase II studies. Patients were randomized between ifosfamide 5 g/m 2 as a 24-hour infusion or 3 g/m 2 over 4 hours day 1 to 3 every 3 weeks. Response rates of 3% and 17% were observed for the standard-dose ifosfamide and high-dose ifosfamide. 96 Althotigh these response rates are lower than previously reported for first-line chemotherapy with ifosfamide, the authors argue that this may be due to the high proportion of leiomyosarcomas (42%) included in the study. This was not a pure test of dose intensification because the schedules were different, and it has been suggested that intermittent bolus treatment is more effective than continuous infusion.

392 Sawyer and Brarnwell

Two consecutive phase II studies 27 by investigators at M.D. Anderson Cancer Center evaluated ifosfamide 14 g/m 2 over 3 days, given either as a 72-hour infusion or 2-hour daily infusions for 3 days. Seventy-four patients, who had received previous chemotherapy for soft tissue and bone sarcomas, were treated with the 72-hour infusion, and 15 patients received the 2-hour infusion regimen. For STS, response rates were 19% and 42%. Toxicities were similar for the two schedules. These were nonrandom comparisons, but they raise questions about the dose and schedule of ifosfamide, and further randomized studies are needed to address separately the efficacy of different doses and schedules of administration of ifosfamide. Studies evaluating high-dose versus low-dose regimens should carefully evaluate toxicity and quality of life for these palliative treatments.

Dacarbazine. Information on dacarbazine as a single agent is more limited. Collected data from phase II studies in 109 patients show a 16% response rate.13 The value of dacarbazine was further strength- ened by an Eastern Cooperative Oncology Group (ECOG) trial, which compared a regimen of doxorubicin and dacarbazine (92 patients) to doxorubicin (94 patients) alone and showed response rates of 30% versus 18% (P = .03). 28 Based on this study, the combination of doxornbicin and dacarbazine became a standard control arm for randomized studies in the United States, whereas in Europe the control arm remained doxorubicin alone.

Other drugs. Single-agent data suggest that the platinum analogues, cisplatin and carboplatin, have limited activity in metastatic STS, with an average response rate for cisplatin of 12% (range, 0 to 42%) and a tendency for higher response rates in the setting of gynecological sarcomas. 21 In a phase II study of 50 patients receiving carboplatin as a single agent, the response rate also was 12%. 29 Two randomized studies, however, seem to suggest benefit with the addition of cisplatin to anthracycline chemotherapy. One study of 106 patients showed a 54% response rate for patients randomized to epirubicin and cisplatin compared to 29% for epirubicin alone (P < .02).a~ An ECOG study showed a response rate of 20% for doxorubicin alone versus 32% for a regimen containing doxorubicin, cisplatin, and mitomycin C (P = . 0 3 ) . 31 More randomized studies, per- halos focusing on specific histological subtypes, are needed to evaluate the role of platinum analogues in STS.

Actinomycin-D is an important component of chemotherapy in the treatment of pediatric rhabdo-

myosarcema, but its place in adult STS is not as well defined. A Southwestern Oncology Group trial comparing doxorubicin/dacarbazine versus the same regimen with the addition of actinomycin-D at 1.2 mg/m 2 showed no added benefit from this drug. 32 Other studies have shown inferior results when actinomycin-D is substituted for doxorubicin in combination chemotherapy. 33

Etoposide in combination with ifosfamide is considered an acceptable salvage regimen in pediatric STS and has been used in adult STS. There have been no randomized studies in the adult setting ~omparing single-agent ifosfamide with etoposide/ifosfamide. Phase II studies of etoposide as a single agent, given by 72-hour continuous infusion 34 and also as oral therapy, 35 have shown no significant activity.

Agents recently investigated. Vinorelbine has been studied extensively in metastatic breast cancer and non-small cell lung cancer, in which it has demon- strated efficacy and a favorable side-effect profile. Fidias et a128 evaluated vinorelbine 30 mg/m 2 weekly in 37 patients with sarcoma who had failed doxorubicin-based chemotherapy. Four patients had osteosarcoma, whereas the remainder had STS. Two patients were not evaluable for response. The results were not encouraging, with one complete response (2.7%); three mixed responses (8.3%), and six patients (16.6%) who had stable disease. 36

Edatrexate is a relatively new antifolate. In a Canadian Sarcoma Group study, 31 evaluable patients received edatrexate 80 mg/m2/wk, resulting in only one complete response and one partial response (overall response rate 6.4%): Mucositis was the most common reason for dose modification but was unpre- dictable. 37 An ECOG study, using a similar dose and schedule, also showed disappointing results with three partial responses (12.5%) in 24 evaluable patients. 38

The Canadian Sarcoma Group evaluated topotecan 1.5 mg/m2/d for 5 dayg evmy 3 weeks in 32 patients who had not received prior chemotherapy and found limited activity with three partial responses (10.3%). 39 Investigators for Southwestern Oncology Group drew similar conclusions in their study of topotecan 0.5 mg/m2/24 h given as a 21-day infusion with 7 days offbefore the~next cycle, reporting no objective responses in 20 evaluable patients. 4~

The taxanes have come to the forefront in many malignancies, but these drugs are inactive in the setting of STS. Three studies of docetaxel and two of paclitaxel have been published. Despite initial promising results for docetaxel in an EORTC phase II

Distant Metastm'es in Soft Tissue Sarcoma 393

study, 41 in which a response rate of 17.2% was observed in patients who had received prior chemotherapy, this was not confirmed (response rate 10.7%) in a Canadian Sarcoma Group phase II study, using the same schedule 100 mg/m 2 every 3 weeks in chemotherapy-naive patients. 42 There were no responses to docetaxel in a follow-up EORTC study comparing it with doxorubicin. 43 For paclitaxel, two different doses and schedules have been evaluated. Researchers at M.D. Anderson Cancer Center administered paclitaxel at 200 mg/m 2 as a 24-hour infusion every 3 weeks. There were no objective responses in 19 patients. 44 Casper et aP 5 administered paclitaxel 250 mg/m 2 over 3 hours to 28 patients, 10 of whom had received previous treatment with doxorubicin. Only two partial responses were noted.

Combination Chemotherapy In many tumors, combination chemotherapy has improved response rates and survival. In STS, combination chemotherapy has produced modest improvements in response rate in some randomized studies but not in others and rarely leads to increased overall survival. The major concern for clinicians is whether the increased toxicity incurred with combination chemotherapy is compensated by clinically significant improvements in response rate and duration of response.

The Sarcoma Committee of Cancer Care Ontar- io's Practice Guideline Initiative has examined randomized studies comparing single-agent doxorubicin with doxorubicin-based combination chemotherapy. A meta-analysis was performed on the eight randomized trials, which, for tumor response rate, allowed 9 doxorubicin arms to be compared with 10 combination chemotherapy regimens in 2,281 patients. For overall survival at 2 years, six comparisons were performed involving 2,097 patients. In these eight trials, the 10 combination chemotherapy- regimens were two studies using dacarbazine, two adding ifosfamide, three adding cyclophosphamide alone or plus other drugs, and the remaining studies using various other agents. The meta-analyses were performed using a random effects model, and for response rate there was a trend favoring combination chemotherapy (odds ratio, 0.78; 95% confidence intervals, 0.60 to 1.05; P = .10). In terms of overall survival, the meta-analysis favored combination chemotherapy , but the difference was not significant (odds ratiO, 0.84; 95% confidence intervals, 0.67 to 1.06;P =.13). 7

One difficulty in interpreting the benefits of

combination versus single-agent chemotherapy is that many of these randomized studies induced cyclophosphamide, which now has been displaced by ifosfamide. Dacarbazine is often included in combination chemotherapy regimens, and a study by Craw- ford and Jerwood 4~ raised questions about the dose intensity of dacarbazine. They analyzed the importance of dose intensity of each component of the CYVADIC regimen (cyclophosphamide 500 mg/m 2 day 1, vincristine 1.4 mg/m 2, doxorubicin 50 mg/m 2 day I, dacarbazine 250 mg/m 2 days 1 through 5), repeated every 3 to 4 weeks, performing a regression analysis based on 2,092 patients receiving variants of this regimen. For dacarbazine, they showed a strong relationship between dose intensity and response. In contrast, they found a threshold dose intensity for doxorubicin but no added effect with dose escalation above this level.

Since the identification of ifosfamide as an active agent, there have been many" studies evaluating ifosfamide in combination with doxorubicin. In phase II studies, response rates have ranged from 22% to 67%. There have been three randomized comparisons of combination chemotherapy including ifosfamide, the control arms being doxorubicin in two studies and doxorubin/dacarbazine in the other. An ECOG study, which enrolled 178 patients, showed a response rate of 34% for the combination and 20% for doxorubicin alone (P = .03). Despite the improved response rate, the increase in the median survival from 8.4 to 11.5 months was not statistically significant. 47 An EORTC study, in which 231 patients were randomized to doxorubicin/ifosfamide and 240 patients to doxorubicin alone, showed respective response rates of 28% and 23%, which did not reach statistical significance. Median survivals were similar at 12.7 months and 12 months. 4a Similarly an Inter- group study failed to show an improvement in overall survival for mesna, doxorubicin, ifosfamide, dacarbazine (MAID) versus doxorubicin and dacarbazine, despite response rates of 32% versus 17% (P < .002) and improved times to progression, 6 months versus 4 months (P < .02).49

Dose-Intensified Regimens Occasional long-term survivors were noted in early studies of the use of systemic chemotherapy for metastatic STS. The EORTC described 39 5-year survivors in a series of 1,308 patients treated with chemotherapy between 1976 and 1990.5~ Achieving a complete response was a major predictor of long- term survival. The hypothesis that the higher re-

394 Sawyer and Bramwell

sponse rates, particularly if complete, associated with multiagent chemotherapy regimens would translate into more long-term survivors has not been confirmed in randomized trials. Dose intensification of chemotherapy, using cytokine support, has a similar g o a l - t o increase the complete response rate, which might lead to more long-term survivors.

Combinations of high-dose ifosfamide and anthracycline with G-CSF support have been studied (Table 1). In a feasibility study, 14 patients with advanced STS and 9 patients treated in an adjuvant setting received ifosfamide 12.5 g/m 2 as an infusion over 120 hours, with doxorubicin 20 mg/m 2 on days 1 to 3, each cycle repeated every 3 weeks. The overall response rate was 50%, with two complete responses and 5 partial responses. Four patients were hospitalized with febrile neutropenia, and 87% of patients experienced grade 3 or 4 neutropenia. One patient experienced grade 4 neurotoxicity. 51 The Swiss Group for Clinical Research performed a dose escalation study of doxorubicin with two dose levels of ifosfamide. Ifosfamide was administered as a continuous infusion over 6 days and doxorubicin as divided doses over 3 days to 33 patients, escalating through five dose levels. Although the maximal tolerated dose was

reached for the combination ifosfamide 12 g/m 2 and doxorubicin 60 mg/m 2, it was not reached for ifosfamide 10 g/m 2 and doxrubicin 90 mg/m 9, and the investigators concluded that the latter regimen was acceptable in a multicenter study. This t reatment induced W H O grade 4 leukopenia in 58% and grade 3 or greater thrombocytopenia in 42% of patients as well as major mucositis in 50%. Central nervous system toxicity occurred in 4 of 33 patients but was grade 3 in only one case. Although this was a phase I study, and response as such was not the primary endpoint, there was a trend toward increased response rates at the higher dose levels. 52

Frustaci et a153 studied escalating doses of epirubicin in conjunction with fixed doses of ifosfamide. All patients received ifosfamide 1.8 g/m2/d for 5 days and received epirubicin 50 mg/m2/d, 60 mg/m2/d, or 70 mg/m2/d for days 1 and 2. All patients received G-CSF 5 /xg/kg/d days 6 to 19. Six, 18, and 13 evaluable patients were enrolled at each epirubicin level. The response rates for the three levels were 17%, 33%, and 100%. Increasing frequencies of hematological toxicities were noted with W H O grade 3 or 4 leukopenia and thrombocytopenia occurring in 90% and 17% of cycles at the highest dose level.

Table 1. Studies of High-Dose Ifgsfamide + Anthracycline With Granulocyte-Colony-Stimulating Factor Support

Patients Patients Response Median Febrile Author Chemotherapy Regimen Enrolled Evaluable Rate (%) Survival (too) Neutropenia (%)

DePas et al, 199851 Ifosfamide 12.5 g/m 2 23 14 50 NR 57 Doxorubicin 20 mg/m 2 days 1-3

Leyvraz et al, 199852 Ifosfamide 12 g/m 2 + 33 31 24 87 Doxorubicin 50 mg/m 2 7 43 60 mg/m 2 4 50

Ifosfamide 10 g/m 2 + Doxorubicin 60 mg/m 2 6 50 75 mg/m 2 6 83 90 mg/m 2 8 100

Frustaci et al, 199753 Ifosfamide 1-8 g/m 2 days 1-5 18 43 Epirubicin

50 mg/m ~ 6 17 60 mg/m 2 18 33 70 mg/m 2 13 100

Reichardt et al, 199854 Ifosfamide 2.5 g/m 2 days 1-5 46 46 52 24 54 Epirubicin 45 mg/m 2 day 2 + 3

Vadhan-Raj et al, 199655 Ifosfamide 6 g/m 2 34 31 52 N/A 62 Doxorubicin 60 mg/m 2 Dacarbazine 900 mg/m 2

Bui et al, 199856 Ifosfamide 7.5 g/m 2 80 76 37 N/A 43 Doxorubicin 60 mg/m 2 Dacarbazine 900 mg/m 2 Ifosfamide 9 g/m 2 82 72 43 N/A 53 Doxorubicin 75 mg/m ~ Dacarbazine 1,200 mg/m 2

Abbreviations: N/A, not available; NR, not reached with median follow-up of 9 months.


There were no toxic deaths. The authors found epirubicin 70 mg/m2/d was the maximal tolerated dose level, although, because of dose reductions, the received dose of epirubicin was not different from that at the 60 mg/m2/d dose level.

Reichardt's group 54 explored 45 mg/m2/d epirubicin given as a continuous infusion for 2 days with ifosfamide 2.5 g/m2/d for 5 days with G-CSF. Forty- six patients with locally advanced or metastatic STS were enrolled from January 1993 to November 1996. All patients experienced NCI grade 3 or 4 hematological toxicity, but there were no toxic deaths. The overall response rate was 52% with 22% complete responses.

MAID is a commonly used combination regimen, but dose modification is frequently necessary because of myelosuppression. In a study at M.D. Anderson Cancer Center, MAID doxorubicin 60 mg/m 2, ifosfamide 6g/m 2, dacarbazine 900 mg/m 2 (MAID) was given with PIXY321 (a fusion protein of GM-CSF and interleukin-3), or G-CSF. Thirty-four previously untreated sarcoma patients were treated, and 31 were evaluable for response. Overall response rate was 52%, with 15 partial responses and 1 complete response. Despite the use of cytokines, 21 patients experienced febrile neutropenia. The cytokines per- mitted maintenance of the planned dose intensity, but the authors concluded that response rates were not significantly different from historical experience with MAID. 55 Bui et a156 randomized 162 chemotherapy-naive patients with metastatic sarcoma to MAID or MAID intensified by 25% (doxorubicin 75 mg/m 2, ifosfamide 9 g/m 2, dacarbazine 1200 mg/m 2 [i- MAID]). Response rates were 37% and 43%. There were five toxic deaths in the i-MAID arm versus none on standard MAID, and nine patients stopped i-MAIl) prematurely versus three on MAID. 56

Most studies of dose intensification with cytokine support have been small phase I studies or nonran- domized phase II studies. These studies have demon- strated high response rates at the cost of consider- able myelosuppression and other toxicities. In the one randomized study, there was no improvement in response rate for intensified MAID, but there were five toxic deaths in the intensified arm. It is possible that attempting to intensify all three drugs was ambitious because there were no unavoidable toxic deaths in the other studies. These dose-intensified regimens of, ifosfamide with doxorubicin or epirubicin have tr be assessed in randomized trials before their place in the treatment of STS can be defined. A series of articles published under the title Current

Controversies in Cancer addresses the question, "should high dose chemotherapy be used in the treatment of soft tissue sarcomas?" and provides arguments for and against. 57

High-Dose Chemotherapy With Bone Marrow or Stem Cell Rescue

The role of high-dose chemotherapy and autologous bone marrow transplant in the treatment of various malignancies, such as lymphoma and leukemia, has been better defined, but there are limited data in adult STS. Several investigators 5a-61 have reported small studies in which 8 to 22 patients received myeloablative chemotherapy and autologous bone marrow or stem cell transplant. Conditioning regimens generally included a variety of alkylating agents, sometimes with platinum analogues, radiation, or both. Most patients received this treatment after a response to conventional chemotherapy. A series collected by the European Bone Marrow Transplant Registry is typical.62 A total of 95 patients with STS were identified, and 64 were transplanted in complete response or partial response. Five-year overall survival was 20% for the entire series, but there were no survivors in patients transplanted in partial response or progressive disease. The ages of the patients were not provided, but most transplants -were in patients with rhabdomyosarcoma, which is usually a chemoresponsive pediatric tumor.

These studies and reviews describe small numbers of patients and include many pediatric patients with soft tissue and bone tumors (eg, Ewing's sarcoma, osteosarcoma) that are more chemosensitive than typical adult patients with STS. It is difficult to draw any definite conclusions from the literature except that only patients with chemosensitive tumors should be considered for this treatment, which should be performed in a trial setting.

Intraperitoneal Chemotherapy Intraperitoneal dissemination is a frequent occur- rence from ~isceral and retroperitoneal STS. In visceral sarcomas, intraperitoneal seeding is thought to occur by the tumor invading through the bowel wall. Positive margins are common after resection of retroperitoneal sarcomas and may lead eventually to intraperitoneal seeding. 63 Intraperitoneal chemotherapy has been used in the treatment of other malignancies, especially ovarian cancer, and in a randomized trial of cisplatin given either intravenously or intraper- itoneally with cyclophosphamide, improved median


survival with reduced toxicity was seen with the intraperitoneal route. ~4 This trial has raised interest in exploring this approach for localized intraperitoneal sarcomatosis. It has the theoretical advantage of attainment of high chemotherapy concentrations in the peritoneal cavity, while avoiding high systemic concentrations with the associated generalized side effects. The potential drawbacks to this approach are the development of adhesions and data showing that chemotherapy penetrates only a few millimetres into tissue. 65

Three feasibility studies have been reported--two studies used intraperitoneal cisplatin 66,67 and doxorubicin, and the other used mitoxantrone alone. 6a All patients underwent cytoreductive surgery before start- ing intraperitoneal chemotherapy. The studies were small, the largest recruiting 53 patients 68 and the other two 11 and 4 patients. 66,67 The most common histological subtype was leiomyosarcoma, comprising 83% in one study and 50% in the other two. In the largest series, 40% of patients had relapsed, and 28% remained alive with a median follow-up of 30 months (range, 12 to 84 months). There was no mortality associated with the procedure, and a 6% incidence of adhesions was reported in the largest study. This approach remains investigational, but these studies show that intraperitoneal chemotherapywith doxorubicin and cisplatin or mitoxantrone is feasible. With- out a control group, it is difficult to predict the outcomes without intraperitoneal chemotherapy, because even metastatic gastrointestinal stromal sarcomas and retroperitoneal sarcomas can have a slow natural evolution.

Role of Surgery in Metastatic Sarcoma

Soft tissue sarcoma have a strong predisposition to metastasize to the lungs, which may be the only site of distant dissemination. Although resection of pulmonary metastases has the potential to be curative, there have been no prospective, randomized studies addressing this question. Frost 69 reviewed the literature dating from 1978 to 1994 and found 12 case series comprising 697 patients. Because of differences in reporting results and the lack of complete raw data for the studies, a meta-analysis could not be performed. All 12 studies were retrospective, and only 1 had a matched historical control group. A qualitative analysis revealed that 5-year survival rates ranged from 15% to 35% for initial pulmonary metastectomy and 12% to 52% for repeat metastectomy. Features having an adverse effect on outcome were,

in order of significance, (1) incomplete resection, (2) tumor doubling time less than 40 days, (3) more than four nodules, and (4) a disease-free interval less than 12 months. Less significant adverse prognostic indica- tors were a grade III primary tumor, local recurrence at the primary site, and hilar lymphadenopathy or extrapleural nodules. 69

The EORTC performed a multiinstitutional retrospective review of patients treated by resection of pulmonary metastases with curative intent. A total of 255 patients were reviewed, but patients with chon- drosarcoma and small round cell tumors" were ex- cluded. The 3- and 5-year overall and disease-free survival rates were 54% and 38%, and 42% and 35%. Several factors predicted a favorable outcome, including a disease-free interval 2.5 years or longer, micro- scopically clear margins, age younger than 40 years, and grade I/II tumors. 7~

A question that arises after the resection of pulmonary metastases is the role of chemotherapy to eradicate occult microscopic disease. Currently, evidence is anecdotal only because there have been no randomized studies reported. The EORTC, in collabo- ration with ECOG and the Scandinavian Sarcoma Group, is conducting a trial to answer this question. Patients with potentially resectable metastases ar~ randomized either to no chemotherapy or to receive doxorubicin/ifosfamide for three cycles preoperatively, with two additional cycles given postopera- tively if there has been objective response with the preoperative treatment.

Investigators from Memorial Sloan-Kettering Can- cer Center reviewed their experience of surgery for noncolorectal, nonneuroendocrine hepatic metastases. Between 1980 and 1995, hepatic metastases were resected in 96 patients, of whom 27 patients had metastatic sarcoma. Two patients had osteosarco- mas, and the rest had STS. Of these STS, 66% were leiomyosarcomas and 70% were high-grade tumors. The primary tumor locations were visceral (52%), retroperitoneal (22%), uterine (4%), extremity (11%), and other (11%). The preponderance of visceral and retroperitoneal primaries is not surprising, because sarcomas arising in these locations frequently ini- tially metastasize to the liver. The median smMval for patients with sarcoma was 31 months, and there was one 5-year survivor. Two adverse prognostic factors were noted: an incomplete resection and a disease-free interval from treatment of the primary tumor of less than 36 months: Tumor type influenced outcome, with survival for sarcomas being intermedi-


ate between genitourinary and noncolorectal gastrointestinal tumors (P < .05). 71

Based on a 12-year experience of resection of noncolorectal hepatic metastases, investigators at the Institute Gustave Roussy reported on 147 patients, 13 with metastatic sarcoma, all of whom received chemotherapy preoperatively or postopera- tively. There was residual microscopic or macroscopic disease after surgery in 5 of 13 patients. Five sarcoma patients underwent extrahepatic metastectomy, but the authors did not state whether these were the same patients who were considered to have residual disease. For sarcomas, the 5-year survival rate was 18%. 72 !

In contrast with colorectal cancer, the literature describing hepatic metastectomy in sarcomas is limited. Although resection of hepatic metastases can- not be considered standard therapy, there are inter- esting points raised by these two series. These retrospective reviews included only patients with hepatic metastases who were fit for surgery and had disease considered operable with the potential for cure. The size of the total denominator in each case is unknown. Hepatic metastases, however, particularly those from leiomyosarcomas (or gastrointestinal stro- real sarcoma) respond poorly to chemotherapy, and patients generally fare badly, so that alternative treatments are needed. The limited data, with 5-year survival figures at approximately 20%, suggest benefit only slightly less than that for pulmonary metastectomy. Thus, in exceptional circumstances, it is worth referring young, fit patients with disease localized to the liver to an experienced hepatobiliary surgeon, realizing that the chance for cure is remote. This approach should be more thoroughly studied in a prospective, randomized manner.

There is little evidence in the literature to support the resection of metastases outside the lungs or liver. In younger patients with good performance status, metastases may he resected, but these 'procedures rarely are curative. Similarly, radical radiation therapy may occasionally be warranted if disease at other sites has been controlled. Enthusiasm for surgery combined with c~emotherapy is tempered by the reported experience of the Scandinavian Sarcoma Group. This group reviewed outcome for 38 patients achieving a complete response on multiple sequential chemotherapy protocols and found that patients who achieved this response with chemotherapy alone did better than those who required surgery after chemotherapy to achieve a complete response. 73

Evidence Applied to Individual Patients

Many factors are important in determining the approach for an individual patient, including the patient's age, performance status, location of metastases, status of the primary tumor, tumor burden, rate of tumor growth, and most importantly the wishes of the patient. Pulmonary metastases are the most common initial site of spread, and the first consideration is whether they can be resected. A patient who does not have evidence of extrapul- monary disease, in whom local control has been achieved, should be evaluated for pulmonary reserve and fitness for surgery. Patients who present with early relapse, especially less than 1 year, and with multiple pulmonary nodules are probably not candi- dates for pulmonary resection. These patients should be observed for 2 to 3 months because it is possible that they will develop miliary spread or other sites of metastasis. A malignant pleural effusion is an abso- lute contraindication to surgery. Chemotherapy could be administered before pulmonary resection to evaluate chemosensitivity, but ideally these patients should be enrolled in clinical trials.

Gastrointestinal stromal sarcomas are problem- atic to treat because usually they metastasize to the liver and show poor response to chemotherapy. There is limited experience with metastectomy, but it may be appropriate for highly selected patients. Patients with metastases from gastrointestinal stromal sarcomas who are asymptomatic should be followed expect- antly to assess the rate of tumor growth before committing to a course of chemotherapy. Because palliation is the goal in patients with metastatic disease, therapy should be initiated when the patient is mildly symptomatic and still has a good performance status. Patients should receive two to three cycles of chemotherapy, and their tumors should be assessed for response. Patients who show progression of disease at this point are unlikely to respond. Patients with stabilization of disease should continue to receive chemotherapy with a maximum of six cycles, unless there is clear-cut response or disease progression.

The selection of single-agent chemotherapy versus combination chemotherapy depends on many factors, such as the patient's wishes, performance status, and age. Patients who are older, with im- paired performance status, may be best served by sequential single-agent chemotherapy. This approach minimizes toxicity and improves patient toler- ance but may produce lower response rates and


durations of response. For young patients with good performance status who wish to optimize their chance for response and for long-term control and remotely for cure, an aggressive approach using combination chemotherapy with or without growth factors may be reasonable. The limited efficacy of dacarbazine is outweighed by its toxicity, and it should not be used at the expense of reduced dose intensity of doxorubicin or ifosfamide.

Patients who present with tumors that are inoperable because of their location, such as retroperito- neum or mediastinum, or because of extensive disease pose difficult clinical problems. The principles that guide therapy in the metastatic setting, such as the presence of symptoms, patient preference, age, rate of tumor growth, and performance status, apply to the situation of inoperable local disease. Patients

who respond to chemotherapy can be considered for resection of tumor or for radiation therapy to consoli- date the response to therapy. Doxorubicin combined with cisplatin is the preferred regimen for uterine mixed mesodermal sarcomas in young, fit patients. For other histologies, the standard practice is to treat with doxorubicin with or without ifosfamide. Adults with a good performance status who present with sarcomas more commonly seen in the pediatric age group, such as embryonal rhabdomyosarcoma or soft tissue Ewing's sarcoma, should be treated with aggressive mult iagent regimens of the type used to treat these tumors in the pediatric setting.

Conclusions and Future Directions

At present, only three agents--doxorubicin, ifosfamide, and dacarbazine--have significant activity against STS. Most new agents during phase I testing have been evaluated in adult STS, but none have proven active. Even those with novel mechanisms of action and major activity in other tumor types, such as the taxanes, have shown disappointing activity.

The next decade will see the evaluation of several new classes of agents, such as cyclin inhibitors, antiangiogenesis agents, matrix metalloproteinase inhibitors, and protein kinase C inhibitors. Many of these agents are currently under investigation in National Cancer Insti tute-sponsored or pharmaceu- tical company-sponsored trials. Flavopiridol has shown activity in solid tumors, particularly against renal cell cancer. Other agents under investigation in trials registered in the Physician Data Query database include UNC-01 (a protein kinase C inhibitor) and marimastat (a matrix metalloproteinase inhibi-

tot). Because STS are often highly vascular tumors, agents such as angiostatin and endostatin are of particular interest. Many of these agents have new mechanisms of action and different toxicities from current drugs. A major task for oncologists specializ- ing in the management of STS will be to measure accurately the single-agent activity of these drugs and to integrate promising agents into mult iagent regimens. This approach may allow significant

progress to occur in the management of STS, after a decade of relative stagnation.

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the treatment of distant metastases in soft tissue sarcoma

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