Randomized clinical trials in soft tissue sarcoma

What has been learned thus far from the very best prospective randomized controlled clinical trials for soft tissue sarcoma that will guide physicians in the quest for evidence-based treatment decision making? Based on the evidence provided in the following articles, we have learned that limb-sparing surgery with adjuvant radiation is equivalent (and therefore preferable) to a radical amputation in controlling local disease. We also learned that adding radiation therapy (both external beam and brachytherapy) to a complete surgical resection of extremity soft tissue sarcoma significantly improves local control over surgery alone. This is true for high-grade lesions and may be true (external beam) for larger low-grade lesions also. Local control, however, does not govern overall survival as most patients who die from this disease do so from systemic (not local) manifestations. Finally, further studies are required to identify the role of adjuvant chemotherapy in the treatment of soft tissue sarcoma as no single study has demonstrated a consistent long-term survival benefit with the use of any chemotherapeutic regimen. Based on a recent large meta-analysis, however, if there is any benefit to adjuvant doxorubicin based chemotherapy, it must be a very small one.     

Trabectedin is a feasible treatment for soft tissue sarcoma patients regardless of patient age: a retrospective pooled analysis of five phase II trials

Background:

This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS).

Methods:

Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (⩾60 years; n=83).

Results:

The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ⩾70 years, no significant differences in efficacy or safety outcomes were found.

Conclusion:

This analysis demonstrated that trabectedin is a feasible treatment in young and elderly patients with STS, with meaningful clinical benefits and an acceptable safety profile, essential in palliative treatment of elderly patients.     

Evidence for using adjuvant chemotherapy as standard treatment of soft tissue sarcoma

The role of adjuvant chemotherapy in the treatment of patients with soft-tissue sarcomas remains controversial. The initial observation that extremity tumors might benefit more than tumors of other primary sites prompted careful review of published data. Eight of 9 studies showed improved disease-free and overall survival for the adjuvant chemotherapy group. A meta-analysis of published data showed statistically significant improvement in both disease-free survival and overall survival for adjuvant chemotherapy patients. This analysis prompted a more accurate meta-analysis of individual patient data, which confirmed the results of the meta-analysis of published data. These positive results reflect the efficacy of the chemotherapy of the 1970s and 1980s. The only study of contemporary adjuvant chemotherapy, reported by the Italian Cooperative Group, showed a statistically significant advantage in both disease-free survival and overall survival for patients treated with adjuvant chemotherapy. The studies, taken as a whole, serve as proof of principle that chemotherapy, given early to patients with primary soft-tissue sarcomas of the extremities who are at high risk of developing local recurrence or metastatic disease, can delay and/or prevent relapse and improve cure rate.     

Adjuvant chemotherapy in clinical stage M0 sarcoma of soft tissue

The clinical course of 117 patients who were treated for Stages IIB-IIIC sarcoma of soft tissues by the combined approach of radiation and surgery at MGH during the period 1971-1984 have been analyzed for an effect of adjuvant chemotherapy to improve clinical results. Thirty-two patients received adjuvant chemotherapy and 85 were treated by local methods alone. The chemotherapy protocols featured doxorubicin (25 patients) or VAC (seven patients). The no chemotherapy patients were controls matched for tumor grade and size and were treated over approximately the same period. The two groups were not well matched for age: median age of 38.5 and 54 years for the treated and control groups, respectively. There was no significant difference in survival. However, the time to first metastasis was longer in the treated group, P = 0.04. Furthermore, the local failure rate appeared to be lower in the treated group, P = 0.06.     

Adjuvant chemotherapy of soft tissue sarcoma

As the adjuvant chemotherapy of osteosarcoma has been proved highly effective, that of soft tissue sarcoma has been expecting. However, there is still some question as to its effectiveness. The indication and methods were studied on literatures and our own cases. A survey of the literature regarding to the chemotherapeutic effect upon advanced soft tissue sarcoma shows response rate ranging 20 to 50 per cent. On the other hand, soft tissue sarcoma has a variety of histological type and malignancy and the sensitivity to chemotherapy varies considerably according to each tissue type. The literatures and our results indicate that most effective sarcoma is rhabdomyosarcoma, which is absolutely advisable to apply adjuvant chemotherapy. The same is the sarcoma with similar histological pattern. As to other type sarcomas, the therapy has to be applied according to their grade, stage, age and the effect of chemotherapy evaluated by advanced tumor. Most prevalent agents used for soft tissue sarcoma are adriamycin, cyclophosphamide, actinomycin-D, vincristine and DTIC. These agents usually used as combination called VAC, CYVADACT, CYVADIC, BCD.     

High-risk soft tissue sarcoma: clinical trial and hyperthermia combined chemotherapy.

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window.     

Neoadjuvant chemotherapy for soft tissue sarcoma

Soft tissue sarcoma is a rare and very heterogeneous disease. The prognosis of these cancers is mainly influenced by histological grading size location and type of histology. Many aspects argue in favor of neoadjuvant chemotherapy but no singular trial could unambiguously prove an advantage of neoadjuvant therapy. This short review has a focus on neoadjuvant chemotherapy as induction therapy prior to chemoradiation or neoadjuvant chemotherapy alone.     

Adjuvant chemotherapy for soft tissue sarcoma

PURPOSE OF REVIEW: To review current state-of-the-art knowledge about adjuvant medical therapy in adult soft tissue sarcomas. RECENT FINDINGS: Most recent contributions have added nonrandomized evidence to previously available controlled clinical trials, which were undertaken from the 1970s. Again, results are conflicting, with a limited benefit suggested by some retrospective analyses and denied by others. While a delay in relapse is likely to occur in a fraction of patients treated with adjuvant chemotherapy, a permanent benefit has been more difficult to prove. This result is consistent with findings from previous clinical trials, which pointed to a slight benefit from Doxorubicin-based adjuvant chemotherapy and a possibly higher, although less evidence-based, benefit from anthracycline plus Ifosfamide regimens. SUMMARY: Overall, adjuvant chemotherapy may give some benefit in soft tissue sarcoma. If any, it is likely to be of limited degree, confined to the highest-risk patients, and requiring a fully active chemotherapy regimen. This was mainly shown for extremity soft tissue sarcoma but may also apply to other primary sites. The value of molecular-targeted therapy as an adjuvant for high-risk gastrointestinal stromal tumor patients is a different subject awaiting long-term results of ongoing trials.     

Adjuvant chemotherapy in muscle-invasive bladder carcinoma: a pooled analysis from phase III studies

BACKGROUND: The treatment of muscle-invasive bladder carcinoma should include both the eradication of local disease and the elimination of potential micrometastases. To date, the 'gold standard' treatment for muscle invasive bladder carcinoma has been recognized to be radical cystectomy. Adjuvant chemotherapy (AC) has the advantage of being administered to patients with known prognostic factors of recurrence. A pooled analysis was used to verify whether AC is able to increase the disease-free survival (DFS) and overall survival (OS) of patients with muscle-invasive bladder carcinoma who had undergone radical cystectomy. METHODS: All published randomized Phase III studies were considered eligible and a literature-based pooled analysis was accomplished. DFS and OS were the endpoints. Event-based relative risk ratio (RR) and 95% confidence intervals (95% CI) were derived. Combined effect estimation was computed with a fixed- and a random-effect model. A heterogeneity test was applied as well. RESULTS: Five trials were collected. All were evaluable for OS (350 patients) and four of these also were evaluable for DFS (273 patients). A significant benefit from AC was noted both in OS (RR, 0.74; 95% CI, 0.62-0.88 [P = 0.001]) and DFS (RR, 0.65; CI 0.54-0.78, [P < 0.001]). No significant heterogeneity was found. CONCLUSIONS: Although the results of the analysis favor the use of AC, larger studies are needed to identify the role of AC in the treatment of muscle-invasive bladder carcinoma. Ongoing trials (European Organization for Research and Treatment of Cancer [EORTC]/Southwest Oncology Group [SWOG] and the Italian Multicentric Study) can help to better identify patients who can benefit from this approach.     

Treating soft tissue sarcomas with adjuvant chemotherapy

Surgery remains the cornerstone of treatment and the only curative loco-regional approach of localized resectable soft tissue sarcoma (STS) in 2011: the usual first-line treatment is wide margin surgery plus radiotherapy, especially in the case of primary tumors arising in the limbs. An optimal initial R0 resection is one of the most reproducible and reliable prognostic factors for survival in resectable STS. Nevertheless, despite improved local control rates, more than half of the patients still develop and die from unresectable, locally advanced, and/or metastatic disease. Unfortunately, very few cytotoxic drugs have shown activity in this clinical setting with the exception of doxorubicin, ifosfamide, and to a lesser extent, dacarbazine. A conventional-dose, single-agent chemotherapy is still considered to be the standard treatment for metastatic disease. The impact of adjuvant chemotherapy after resection of a high-grade STS remains controversial due to the lack of reproducible impact on survival. Because STS is a rare disease, most trials have involved a relatively small number of patients, with heterogeneous groups of histological/molecular subtypes of sarcomas, initial sites of the disease, and patient’s characteristics. In a few trials, a lower risk for local recurrence was observed among patients receiving adjuvant chemotherapy but without any significant gain in overall survival. A meta-analysis based on individual data of these randomized studies has confirmed a significant impact of adjuvant chemotherapy on relapse, either local or metastatic, but without any significant benefit on survival. It should be of importance to include the last recent large trials in a new meta-analysis of source data in order to more carefully analyze a possible benefit of systemic adjuvant chemotherapy in localized sarcoma. Until this study is performed, it is an obvious conclusion that adjuvant chemotherapy has not reproducibly demonstrated its capacity to improve overall survival and relapse-free survival in an unselected population of patients. In 2011, there is therefore an urgent need to determine whether or not there are small subpopulations of patients truly benefiting from adjuvant chemotherapy (with conventional agents), and to identify prospectively these populations. With the exception of male, older than 40 years, with a non-optimal resection of their primary (R1 resection) or in the subgroup of grade 3 STS, no other relevant clinical prognostic/predictive factors have been highlighted. The take home messages in 2011 could be as follows: (1) adjuvant chemotherapy is not recommended routinely in high-grade STS; (2) adjuvant chemotherapy is recommended in patients underwent a R1 resection and with a grade 3 STS; (3) adjuvant chemotherapy cannot rescue an inadequate initial surgery; (4) if selected, chemotherapy has to be contain anthracycline and fractionated adequate dose of ifosfamide (around 9 g/m² per cycle); (5) the era of adjuvant chemotherapy trials with the same chemotherapy regimen in all histological subtype of sarcoma is ended; and (6) prognosis of patients with a localized STS starts at diagnosis. The dramatic activity of imatinib in GIST, the heterogeneous outcome of each histological subtype of sarcomas akin to being different diseases, and the high sensitivity of some histological subtypes of sarcoma to specific agents clearly open a new era in the management and the evaluation of new agents in the field of STS. The design of the future adjuvant trials has to incorporate these new findings and new prognostic/predictive biomarkers in order to improve the as yet dismal prognosis of patients developing high-grade localized STS.     

Dose-intensive chemotherapy in advanced adult soft tissue sarcoma

The treatment of metastatic soft tissue sarcomas in adults is one of the most challenging areas in oncology. While multidisciplinary management of early-stage, localized disease has led to a number of improved outcomes, therapy of unresectable or advanced disease remains problematic. Virtually every conventional cytotoxic agent has been systematically assessed in this malignancy, yet only a handful have demonstrated significant activity. Adriamycin and ifosfamide are the only chemotherapeutic drugs to have consistently produced response rates of over 20% when given as single agents and these two drugs have been exhaustively studied alone or in combination. Recent efforts to improve response rates and by inference, disease-free survival and overall survival, have involved exploration of high-dose regime incorporating growth factors and/or autologous cellular support. In this article, the status of dose-intensive chemotherapy in advanced adult soft tissue sarcomas (excluding pediatric histologies, such as Ewing’s sarcoma and rhabdomyosarcoma) will be discussed. Emphasis will be placed on data from randomized Phase III trials but information from Phase I/II studies will also be reviewed and recommendations will be made on a systematic analysis of the data.     

The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma

For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5–14·III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2–22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS.     

Dose-intensive chemotherapy in advanced adult soft tissue sarcoma

The treatment of metastatic soft tissue sarcomas in adults is one of the most challenging areas in oncology. While multidisciplinary management of early-stage, localized disease has led to a number of improved outcomes, therapy of unresectable or advanced disease remains problematic. Virtually every conventional cytotoxic agent has been systematically assessed in this malignancy, yet only a handful have demonstrated significant activity. Adriamycin and ifosfamide are the only chemotherapeutic drugs to have consistently produced response rates of over 20% when given as single agents and these two drugs have been exhaustively studied alone or in combination. Recent efforts to improve response rates and, by inference, disease-free survival and overall survival, have involved exploration of high-dose regimen incorporating growth factors and/or autologous cellular support. In this article, the status of dose-intensive chemotherapy in advanced adult soft tissue sarcomas (excluding pediatric histologies, such as Ewing's sarcoma and rhabdomyosarcoma) will be discussed. Emphasis will be placed on data from randomized Phase III trials but information from Phase I/II studies will also be reviewed and recommendations will be made on a systematic analysis of the data.     

Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review

The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings.     

Adriamycin-ifosfamide induction chemotherapy for extremity soft tissue sarcoma: comparison of two non-randomized protocols.

Chemotherapeutic cytoreduction of soft tissue sarcomas may permit less radical operation. In cases of large or multi-compartmental masses, deeply seated tumors or involvement of a neurovascular bundle, down-sizing of the mass is required before limb sparing surgery can be considered. We have applied a combination chemotherapy consisting of intravenous adriamycin and ifosfamide with intra-arterial cisplatin for patients with soft tissue sarcomas of the extremity as induction treatment, and switched to an intravenous-only protocol due to toxicity and management difficulties. Adjuvant chemotherapy and radiation therapy were given after limb-sparing surgery in both regimens. Fresh tumor specimens were obtained and were examined for tumor size, surgical margins, percent of necrosis, evidence of vascular or perineural invasion, and the presence of Pgp, Ki-67, p53, PCNA and bcl-2-oncoprotein. Our results in terms of percentage of tumor necrosis were comparable and even better in favor of the second regimen [38% good histological response with intravenous (i.v.)-only versus 12.5% for combined i.v. + intra-arterial (i.a.]. The clinical and radiological responses were also better for the second (i.v. only) regimen (45%) than for the first (i.v. + i.a.) regimen (12.5%). The toxicity and the inconvenience to the patients and to the treating staff were greater in the first regimen that combined intra-arterial and intravenous infusions. In the first group the failure rate is 75% within 32 months of follow-up, while it is 33% within 12 months follow-up in the second group. The immunohistochemical markers did not correlate with disease control nor with the patient outcome. Intravenous administration of ADR-IFX induction chemotherapy was more feasible than combined i.v. ADR-IFX plus i.a. cisplatin and achieved better results.     

Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study

Purpose: To assess the efficacy of gemcitabine in patients with a variety of sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based chemotherapy. Patients and methods: A group of 18 symptomatic heavily pretreated patients with sarcomas of bone or soft tissue received one induction course of gemcitabine at a dose of 1000 mg/m² per week for 7 consecutive weeks, followed by 1 week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m² per week for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Results: A total of 51 cycles of gemcitabine were given including 18 cycles of induction. A mean of 3.6 postinduction cycles were given to nine patients. The treatment was well tolerated by the patients. One partial response (leiomyosarcoma) and one minimal response (angiosarcoma) were observed, yielding a true objective response rate of 5.5%. An additional six patients achieved stabilization of disease (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Clinical benefit response was observed only in those who also achieved a progression-free state. Conclusion: Gemcitabine was found to be effective in achieving stabilization and even a minimal response of soft tissue or bone sarcoma refractory to standard chemotherapy. Received: 10 June 1999 / Accepted: 7 September 1999     

The reason for confining the use of adjuvant chemotherapy in soft tissue sarcoma to the investigational setting

Adjuvant chemotherapy for soft tissue sarcoma has been the subject of many studies. Most studies have been nonrandomized and therefore by definition inconclusive. In addition, most of the 14 performed randomized studies have had small sample sizes. A meta-analysis on the data of these 14 studies suggested a possible survival improvement, albeit not significant. The outcome of the meta-analysis should be interpreted with caution in view of the fact that in 18% of patients, histology data were lacking; ineligibility rates in included studies were high; central pathology was not uniformly performed; and in 6% of patients, sarcomas other than soft tissue sarcomas were included. Because it is generally recommended that meta-analyses of small randomized trials are used only to generate hypotheses for more reliable randomized trials, it is argued that adjuvant chemotherapy in soft tissue sarcomas should remain confined to the investigational setting.