Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma
Retrospective analysis and identification of prognostic factors in 488 patients†
Presented at the ASCO 2006 Annual Meeting Proceedings, Part I, Vol. 24, No. 18S (June 20 Suppl) J Clin Oncol, 2006, Abstract 9520.
Abstract
BACKGROUND.
The efficacy of palliative chemotherapy was investigated in a large group of patients with advanced soft-tissue sarcomas (STS) treated on routine palliative protocols.
METHODS.
Patients with STS who had first-line chemotherapy for advanced and/or metastatic disease between 1991 and 2005 were identified from the Royal Marsden Hospital's sarcoma database. Patients with Ewing sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumor, and gastrointestinal stromal tumors were excluded from the study.
RESULTS.
In all, 488 patients (242 male, 246 female) fulfilled the study criteria. The median age was 49 years and the majority (83%) received chemotherapy for metastatic disease. The most common histologic subtypes were leiomyosarcoma (35%) synovial sarcoma (13%), liposarcoma (10%), and malignant fibrous histiocytoma (10%). In all, 61% received single-agent chemotherapy, usually doxorubicin. An objective response was reported in 33% of patients (53% in those with synovial sarcoma); 22% had stable disease and 45% derived ‘clinical benefit’ (objective responses + stable disease for ≥6 months). Median duration of response was 9 months and median posttreatment overall survival (OS) was 12 months. In multivariate analysis, age <40 years, liposarcoma, and synovial histology were found to be positive, and bone involvement to be negative, independent prognostic factors. Patients treated with combination chemotherapy experienced longer OS than those treated with a single agent.
CONCLUSIONS.
Palliative chemotherapy may be beneficial in approximately half of patients with advanced STS. Synovial sarcoma and liposarcoma subtypes have a better prognosis. However, the overall poor outcome of these patients indicates the need to continue the search for more effective agents. Cancer 2008. © 2008 American Cancer Society.
Soft-tissue sarcomas (STS) are malignant tumors of connective tissue, accounting for approximately 1% of all human cancers.1 They exhibit a wide range of clinical behavior depending on the histologic subtype, tumor site, grade, and site of disease. In particular, different histologic subtypes demonstrate various responsiveness to systemic therapy as defined by objective remission and subsequent survival. Systemic chemotherapy given with palliative intent is the only available treatment option for many patients with advanced STS, yet the results are generally unsatisfactory.2 Favorable prognostic factors for response to chemotherapy have been variously reported as young age, good performance status (PS), absence of liver metastases, and liposarcoma or synovial histology.3 Surgery offers the only reliable chance of cure, but locally advanced unresectable and metastatic disease are considered generally incurable, with few patients experiencing long-term survival.4 Single-agent doxorubicin is the most widely accepted treatment option for these tumors.5 Whereas combination chemotherapy has been reported to produce higher tumor response rates, mainly in single-center studies of selected patients, randomized trials have failed to detect a survival benefit for chemotherapy combinations6-8 or intensified chemotherapy regimens.9, 10
We conducted this retrospective study with the aim of investigating the role of routine palliative chemotherapy in an unselected cohort of patients with advanced STS treated at a single institution, and to identify the prognostic factors that will predict which patients are most likely to derive benefit from this treatment.
MATERIALS AND METHODS
Before the study, local research ethics committee approval was obtained. The Royal Marsden Hospital's prospective sarcoma database was used to identify patients treated for advanced STS. The patient population included patients registered between 1991 and 2005. Data regarding each patient were gathered retrospectively from patients' clinical notes and the Royal Marsden Hospital's electronic patient record. Patients' general practitioners were contacted where necessary to obtain follow-up information. In all cases histology was reviewed by a specialist soft tissue pathologist on referral to the Royal Marsden Hospital. Patients with the chemosensitive subtypes Ewing sarcoma, rhabdomyosarcoma, and desmoplastic small round cell tumor, as well as those with gastrointestinal stromal tumors (GIST), were excluded from the study. In the pre-GIST era, however, where these cases were mainly termed gastrointestinal leiomyosarcomas, cases with questionable histology were not excluded, as histology review was not feasible. Only patients who received chemotherapy in our institution were included in the analysis.
Date of histologic confirmation of diagnosis and patient's age at the time of diagnosis were recorded. Advanced disease was defined as primary tumor or local recurrence not amenable to complete surgical resection, or the presence of metastatic disease. Additional information included: date of diagnosis and site of metastases or local recurrence; chemotherapy agents used, number of courses administered, and response to treatment; treatment with palliative radiotherapy; and metastasectomy. Patients who received adjuvant chemotherapy were only included in the analysis if they subsequently received chemotherapy for recurrent or metastatic disease. The clinical outcome for each patient was recorded as of August 2005. Last follow-up visit was recorded as alive with disease or alive with no evidence of disease.
Response to chemotherapy was analyzed as a binary variable: responders were those who were reported as having achieved a complete or partial response; all other patients were classified as nonresponders. Patients who achieved stable disease for 6 months or more and an improvement of symptoms were considered as having derived clinical benefit from chemotherapy. Patients were usually re-imaged after every 2 or 3 cycles of chemotherapy according to unit policy. Response to chemotherapy was recorded by retrospective reviewing of radiology reports (most recent reports used Response Evaluation Criteria in Solid Tumors [RECIST], and older reports used the WHO criteria).
Statistical Methods
The effect of age, histologic subtype, presence of symptoms, and site of metastatic disease on response to chemotherapy was investigated in a univariate analysis by means of the χ2 test, Fisher exact test, and the Mann-Whitney test. The independent significance of variables was assessed by means of a logistic regression analysis using a step-up procedure. Histologic subtype was treated as a categorical variable and a test for heterogeneity was used. Contrasts were used to select the significant subtypes. A test for trend was used to assess the significance of the ordered categorical variables (age group and extent of disease = locally advanced/single organ metastasis/multiple organ metastases).
Overall survival (OS) was measured from the start of chemotherapy for advanced disease until death from any cause or last follow-up. Time to progression (TTP) was defined as the time from the start of chemotherapy until radiologic documentation of disease progression or, in the absence of radiology, until death from disease. Survival curves were calculated by the Kaplan-Meier method.
Age, histology, symptoms, and the site of disease were investigated as potential prognostic factors for OS by means of a univariate log-rank analysis. The independent significance of variables was assessed in a multivariate Cox regression analyses. A step-up procedure was used and variables were entered at the 5% level of significance. Hazard ratios (HRs) were calculated together with their 95% confidence intervals (CIs).
RESULTS
Patient Characteristics
Between January 1991 and December 2005, 687 new patients with advanced STS were diagnosed and treated with chemotherapy. The patient population included patients who were referred to the Royal Marsden Hospital at initial diagnosis, and those who were referred at the point of development of advanced disease. From the total population of patients, 199 who had been treated elsewhere with chemotherapy for metastatic disease were excluded from analysis. A total of 488 patients (242 males and 246 females, median age of 49 years) who received first-line chemotherapy for advanced STS in our institution were considered eligible for analysis. Tumor resection with or without adjuvant radical radiotherapy was the standard treatment modality for primary tumors, the majority of which were located in the lower limbs. The most prevalent histologic subtype was leiomyosarcoma (35%), followed by synovial sarcoma (13%), liposarcoma (10%), and malignant fibrous histiocytoma (10%). At the start of palliative chemotherapy, 81 patients (17%) had locally advanced disease and the remainder had metastatic disease. Lung was the most common site of metastatic disease (56%), followed by soft tissue (35%), liver (10%), and bone (9%). The majority of patients (70%) had single-organ metastatic involvement. The demographic details are shown in Table 1.
| No. | % | |
|---|---|---|
| Patients | 488 | |
| Male | 242 | 49.5 |
| Female | 246 | 50.5 |
| Median age [range], y | 49 [16–79] | |
| Histology | ||
| Leiomyosarcoma | 171 | 35 |
| Synovial sarcoma | 63 | 13 |
| Liposarcoma | 49 | 10 |
| Malignant fibrous histiocytoma | 47 | 10 |
| Sarcoma (not otherwise specified) | 44 | 9 |
| Fibrosarcoma | 25 | 5 |
| Malignant peripheral nerve sheath tumor | 25 | 5 |
| Angiosarcoma | 20 | 4 |
| Others | 44 | 9 |
| Symptoms at metastatic disease | ||
| Absence | 250 | 51 |
| Presence | 238 | 49 |
| Disease status | ||
| Advanced | 81 | 17 |
| Metastatic | 407 | 83 |
| Single organ | 287 | 70 |
| Multiple organs | 120 | 30 |
| Sites of metastasis | ||
| Lung | 274 | 56 |
| Soft tissue | 53 | 35 |
| Liver | 172 | 10 |
| Bones | 42 | 9 |
| Other | 19 | 4 |
Response to Chemotherapy
The majority of patients (84%) were treated with standard palliative chemotherapy protocols. In all, 299 patients received single-agent (61%) and 189 (39%) combination chemotherapy. Ten patients who were treated with endocrine therapy were included in the single-agent population. Doxorubicin was the most common single agent used (75%), followed by ifosfamide (13%) and other cytotoxic agents (12%). With regard to combination chemotherapy, 80% of patients were treated with doxorubicin and ifosfamide and 20% had other combination regimens. A total of 1762 chemotherapy cycles were administered (median number per patient = 4; range, 1–8) (see Table 2).
| Patients | No. | % |
|---|---|---|
| Chemotherapy | 488 | 100 |
| Total cycles given | 1762 | |
| Median per patient | 4 | |
| Range | 1–8 | |
| Single agent | 299 | 61 |
| Doxorubicin | 224 | |
| Ifosfamide | 37 | |
| Taxanes | 18 | |
| Endocrine therapy | 10 | |
| Other | 10 | |
| Combination | 189 | 39 |
| Doxorubicin/ifosfamide | 151 | |
| Doxorubicin/cisplatin | 18 | |
| Gemcitabine/docetaxel | 12 | |
| Other | 8 | |
| Response | ||
| CR+PR | 161 | 33 |
| SD | 105 | 22 |
| PD | 222 | 45 |
| Survival, mo | ||
| Median [range] | 12 [3–173] | |
- CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease.
An objective response was defined as a complete or partial response, the duration being measured from the first radiologic documentation of the response. An objective response was reported in 161 patients (33%), which included 3% of patients who achieved a complete response, and 30% who achieved a partial response. In all, 105 patients (22%) achieved stable disease and 222 patients (45%) progressed while on treatment. The median time to progression was 3 months for all patients, whereas the duration of response for patients who responded to chemotherapy was 9 months (range, 4–175) (Table 2). The median duration of stable disease for those patients for whom this was the best response was 6 months (range, 2 months to 70 months). Stable disease lasting for ≥6 months was observed in 12% of patients. These patients have been included with those having achieved an objective response to give an overall number deriving clinical benefit from treatment of 45%.
The results of the univariate analysis of factors predictive of objective response demonstrated young age (<40 years) and synovial histology to be highly predictive for response to chemotherapy (48% and 52%, respectively). A lower response rate for malignant peripheral nerve sheath tumors was of borderline significance (18%; P = .08). After adjusting for age and histology, combination chemotherapy achieved a better response rate compared with single-agent chemotherapy (47% vs 25%; P < .001).
Survival Analysis
At the time of analysis 99 patients (20%) were alive. The median postchemotherapy OS was 12 months (95% CI, 9–13 months) (Fig. 1). The median progression-free survival was 3 months, and the median duration of response was 9 months. In all, 23% of patients were alive at 2 years and 9% were alive at 5 years from the beginning of chemotherapy.
Overall survival of all patients.
Univariate analysis of factors predictive of survival after commencement of chemotherapy for advanced disease is shown in Table 3. Patients aged younger than 40 years were more likely to survive longer compared with older patients (P = .002). Also, patients with synovial sarcoma and liposarcoma had superior survival compared with other histologic subtypes (P < .001). Conversely, the presence of bone metastases was found to be an adverse prognostic factor (P = .004). A nonsignificant trend for superior survival was found for patients who had locally advanced disease (15 months) compared with those who had metastatic disease either in a single organ (13 months) or in multiple sites (9 months) (P = .06). Patients who had combination chemotherapy lived longer compared with those who were treated with single-agent chemotherapy (16 vs 11 months, P = .003).
| Variable | Groups | Median survival, mo | Statistical significance, P |
|---|---|---|---|
| Sex | |||
| Men | 12 | ns | |
| Women | 13 | ||
| Age, y | |||
| <40 | 16 | ||
| 40–60 | 12 | .002 | |
| >60 | 8 | ||
| Histology | |||
| Synovial | 19 | ns | |
| Liposarcoma | 18 | <.001 | |
| Fibrosarcoma | 14 | <.001 | |
| Leiomyosarcoma | 11 | ns | |
| Malignant peripheral nerve sheath tumor | 11 | ns | |
| Other/sarcoma NOS | 10 | ns | |
| Malignant fibrous histiocytoma | 7 | ns | |
| Disease | |||
| Locally advanced | 15 | ||
| Metastatic single organ | 13 | .06 | |
| Metastatic multiple organ | 9 | ||
| Sites of metastases | |||
| Lung | 13 | ns | |
| Liver | 12 | ns | |
| Soft tissue | 13 | ns | |
| Bone | 11 | .004 | |
- ns indicates not significant; NOS, not otherwise specified.
On multivariate analysis of factors predictive of overall survival, synovial sarcoma and liposarcoma histologic subtypes were found to be independent favorable prognostic factors, with relative risks (RRs) of 0.65 (95% CI: 0.48–0.89, P = .01) and 0.70 (95% CI: 0.50–0.98, P = .03), respectively (Table 4). Moreover, the presence of bone metastases was found to be an independent adverse prognostic factor (RR 1.60, 95% CI: 1.13–2.23, P = .009). After adjusting for age, bone involvement, and histologic subtype, combination chemotherapy had a significant positive impact on overall survival, with a median survival of 11 and 16 months for single agent and combination chemotherapy, respectively (RR = 1.40, 95% CI: 1.12–1.74, P = .003) (Fig. 2).
Overall survival according to treatment group (single-agent 11 months vs combination treatment 16 months, P = .003).
| Variable | Groups | Relative risk | 95% Confidence interval | Statistical significance, P |
|---|---|---|---|---|
| Age, y | ||||
| <40 | 1.0 | |||
| 40–60 | 1.21 | 1.05–1.38 | <.001 | |
| >60 | 1.46 | 1.10–1.92 | ||
| Bone | ||||
| Not involved | 1.0 | |||
| Involved | 1.60 | 1.13–2.23 | .009 | |
| Histology | ||||
| Synovial | 0.65 | 0.48–0.89 | .01 | |
| Liposarcoma | 0.70 | 0.50–0.98 | .03 | |
| Other histology | 1.0 | |||
| Chemotherapy | ||||
| Combination | 1.0 | |||
| Single agent | 1.40 | 1.12–1.74 | .003 | |
DISCUSSION
Adult STS, despite their heterogeneity and acknowledged clinical, pathologic, and molecular differences, are generally treated in a similar fashion. Exceptions to this include GISTs, Ewing family tumors, and other small round cell tumors. For patients with localized disease, optimal treatment consists of surgical resection followed by radical postoperative radiotherapy for those with intermediate and high-grade tumors, or close resection margins. However, despite some improvement in local control rates over the past decades, many patients subsequently recur with locally advanced or metastatic disease. Systemic chemotherapy is considered the only therapeutic option for patients presenting with widely metastatic disease or with locally advanced disease not amenable to surgery or radiotherapy.11 For the majority of these patients, cytotoxic chemotherapy should be regarded as palliative, although in a small subset of patients long-term survival may be achieved.12
In our cohort of 488 patients, the median survival from the start of chemotherapy was 12 months. This is in accordance with most published studies, which have demonstrated median survival ranging between 7 and 12 months.3, 13 It has been suggested that there is a potential advantage for combination chemotherapy in terms of superior response rates and overall survival. However, no phase 3 studies have demonstrated a progression-free or survival benefit of combination chemotherapy compared with single-agent doxorubicin, although higher response rates were documented with some combinations.6, 8 Furthermore, it is acknowledged that intensive combination chemotherapy regimens are associated with greater toxicity.9, 14
In this retrospective study, as per our unit policy, patients receiving doxorubicin and ifosfamide combination chemotherapy were generally selected on the basis of a younger age and good PS, frequently with the aim of downstaging disease to render it resectable. Given that age and PS have a major impact on the effect of chemotherapy in sarcoma this is a likely cause of bias in favor of combination therapy. However, combination chemotherapy produced a higher response rate even after adjusting for age and histology. Nevertheless, PS was not was not accurately documented in a fair number of cases and, thus, limited any statistical analysis. We therefore speculate that PS and the multiple regimens included in the combination treatment group might have led to the superior clinical outcome observed in this group of patients.
The use of combination chemotherapy in locally advanced or metastatic disease to improve survival remains unproven and needs to be confirmed in large phase 3 randomized trials. Indeed, the ongoing phase 3 EORTC 62,012 study, comparing single-agent doxorubicin with a GCSF-supported dose-intense combination of doxorubicin and ifosfamide, is designed to answer the question of whether combination chemotherapy results in improved survival of patients with advanced STS. For the majority of patients receiving chemotherapy for palliation of symptoms, this can often be achieved with less intensive, and hence less toxic, schedules.
In this analysis we also found a trend for better OS in patients with locally advanced disease or metastases in a single organ compared with those who had multiple organ involvement. Chemotherapy may contribute to cure in these patients if tumor shrinkage facilitates subsequent optimal local treatment.12 In such cases it is logical to use chemotherapeutic regimens that yield the highest response rates achievable. Nevertheless, only 10 patients from our cohort went on to have their residual disease treated with radiotherapy and/or surgery, suggesting that careful selection of patients for such ‘neoadjuvant’ combination chemotherapy is essential.
Objective responses were observed in about a third of patients in our cohort. These findings are in agreement with previously published studies. However, if we also include those patients who had radiologically stable disease lasting for at least 6 months, 45% of patients derived clinical benefit from chemotherapy.
Several studies have examined whether specific factors influence outcome of chemotherapy in adult patients with STS. The largest report was an analysis of 2185 patients participating in EORTC studies.3
On multivariate analysis, absence of liver metastases, young age, and high histopathologic grade were identified as favorable factors for response to chemotherapy. In the same cohort, good performance status, young age, no liver involvement, a low histopathologic grade, and a long time period between primary diagnosis and initiation of chemotherapy were independently associated with a better OS. It must be noted that all patients in the EORTC analysis were included because of their eligibility for clinical trials, including good PS. Our patients, on the other hand, were treated on the basis of clinical need, and may not be directly comparable. Complete data on PS in our dataset are lacking. In our analysis, young age was also found to favor response to chemotherapy and prognosis of patients with advanced STS. The presence of bone metastases was found to be an independent adverse prognostic factor. In the EORTC study the presence of bone metastases was also an adverse prognostic factor on univariate, although not on multivariate, analysis. A possible explanation for the adverse impact of skeletal metastases could be that the development of bone metastases is often a relatively late feature of the natural history of the disease. A further adverse prognostic factor was the presence of liver metastases. It is likely that in the era before the accurate diagnosis of GIST, many patients with GIST were treated on STS chemotherapy trial protocols. This would have adversely influenced the results, given the chemoinsensitivity of GIST. However, the presence of liver disease remained an independent adverse prognostic factor in the EORTC analysis, even after removing all cases of GIST.3
The EORTC group also analyzed the characteristics of long-term survivors after initial systemic treatment of advanced STS in the same cohort of patients analyzed for the identification of prognostic factors associated with response and OS.12 Survival for more than 5 years was observed in 66 of 1888 patients (8%). On multivariate analysis, good PS, female sex, low tumor grade, and complete response after first-line treatment were identified as predictive of superior 5-year survival. Consistent with these findings, 9% of cases in our cohort survived for more than 5 years. However, because of the small number of cases a separate statistical analysis is not feasible.
We identified liposarcoma histology to be a favorable prognostic factor for survival, although not for response to chemotherapy. In contrast, the EORTC cohort discussed previously did not find liposarcoma to be predictive of survival, although it was a favorable prognostic factor for response to chemotherapy. This may be explained by the finding that in our cohort the majority of liposarcoma patients who received chemotherapy were the myxoid subtype, which has been recently shown to display a superior response to chemotherapy as compared with other liposarcoma subtypes.15
Synovial sarcoma histology has also been found to be an independent favorable prognostic factor for survival and predictive of response to chemotherapy.16 More than half of the patients with synovial sarcoma in our cohort had an objective response to palliative chemotherapy. Hence, synovial sarcoma could be considered as the most chemosensitive sarcoma subtype after Ewing family tumors and rhabdomyosarcomas. The higher response rate achieved with chemotherapy might contribute to the more favorable outcome and the better survival of patients with these tumors.
We postulate that combination chemotherapy might benefit younger patients with more chemosensitive tumor types so as to achieve the maximum response and possibly improved survival. In addition, combination chemotherapy could be considered the standard option for downstaging patients to render disease resectable, an approach that is important and potentially curative for a small subgroup of patients.12, 17
We conclude that palliative chemotherapy in advanced STS should be regarded as a standard treatment option in the management of these aggressive tumors, with approximately half of patients deriving clinical benefit. Our study suggests that doxorubicin-based combination regimens may be associated with superior survival to that achieved with single-agent doxorubicin, although this has yet to be confirmed in prospective randomized trials. Other factors predictive of superior survival in our cohort of patients included younger age, absence of bone metastases, and synovial or liposarcoma histology. Nevertheless, despite the short-term benefits of chemotherapy for certain patient subgroups, continuing research into new therapeutic agents for STS is required to improve the treatment of patients with locally advanced and metastatic disease, whose long-term outlook remains bleak.
