Relation between pO2, 31P magnetic resonance spectroscopy parameters and treatment outcome in patients with high-grade soft tissue sarcomas treated with thermoradiotherapy

PURPOSE: In a prior study, the combination of (31)P magnetic resonance spectroscopy (MRS)-based intracellular pH (pHi) and T2 relaxation time was highly predictive of the pathologic complete response (pCR) rate in a small series of patients with soft tissue sarcomas (STSs) treated with thermoradiotherapy. Changes in the magnetic resonance metabolite ratios and pO(2) were related to the pCR rate. Hypoxia also correlated with a greater likelihood for the development of metastases. Because of the limited number of patients in the prior series, we initiated this study to determine whether the prior observations were repeatable and whether (31)P MRS lipid-related resonances were related to a propensity for metastasis. METHODS AND MATERIALS: Patients with high-grade STSs were enrolled in an institutional review board-approved Phase II thermoradiotherapy trial. All tumors received daily external beam radiotherapy (1.8-2.0 Gy, five times weekly) to a total dose of 30-50 Gy. Hyperthermia followed radiotherapy by <1 h and was given two times weekly. Tumors were resected 4-6 weeks after radiotherapy completion. The MRS/MRI parameters included (31)P metabolite ratios, pHi, and T2 relaxation time. The median pO(2) and hypoxic fraction were determined using pO(2) histography. Comparisons between experimental endpoints and the pCR rate and metastasis-free and overall survival were made. RESULTS: Of 35 patients, 21 and 28 had reportable pretreatment MRS/MRI and pO(2) data, respectively. The cutpoints for a previously tested receiver operating curve for a pCR were T2 = 100 and pHi = 7.3. In the current series, few tumors fell below the cutpoints so validation was not possible. The phosphodiester (PDE)/inorganic phosphate (Pi) ratio and hypoxic fraction correlated inversely with the pCR rate in the current series (Spearman correlation coefficient -0.51, p = 0.017; odds ratio of percentage of necrosis > or =95% = 0.01 for a 1% increase in the hypoxic fraction; Wald p = 0.036). The pretreatment phosphomonoester (PME)/Pi ratio also correlated inversely with the pCR rate (odds ratio of percentage of necrosis > or =95% = 0.06 for pretreatment PME/Pi ratio >0.8 vs. < or =0.8, Wald p = 0.023). The pretreatment PME/PDE ratio correlated strongly with metastasis-free survival and overall survival (p = 0.012 and hazard ratio = 5.8, and p = 0.038 and hazard ratio = 6.75, respectively). CONCLUSION: The dual parameter model containing pHi and T2 to predict the pCR in STSs treated with thermoradiotherapy was not verified. However, other parameters were statistically significant, including the PDE/Pi ratio and hypoxic fraction. These relationships may have interfered with our ability to obtain the pCR rate predicted by thermal doses achieved in these patients. The relationship between the PME/PDE ratio and metastasis-free and overall survival was provocative, but requires additional study to verify its predictive capability. Currently, 50% of all STS patients with high-grade tumors develop distant metastasis even when excellent local control is achieved. Parameters that could help select for patients who need adjuvant chemotherapy could have significant clinical benefit.     

A retrospective statistical analysis of high-grade soft tissue sarcomas

Soft-tissue sarcomas have a mortality rate ranging from 40–60% for high-grade lesions. Prior identified risk factors for post-surgical mortality include tumor size, lesion histology, and margin status at resection. A better understanding of prognostic factors is needed to guide patient counseling and treatment. Data were collected from 129 patients surgically treated for high-grade extremity soft tissue sarcomas during 2002–2010. The primary endpoint was death related to high-grade soft tissue sarcoma. Thirteen variables were investigated: age, gender, race, tumor size, margin status, location, estimated blood loss, operative blood transfusions, pre-operative metastatic disease, pre-operative radiation, post-operative radiation, pre-operative chemotherapy, and post-operative chemotherapy. A Cox Survival Analysis model was created to determine the best predictors of survival time. Tumor size and the presence of pre-surgical metastasis were statistically significant predictors of overall survival. Patients with a tumor greater than 8 cm in any cross section had a 3.15 times greater chance of death. Presence of pre-surgical metastasis carried a 3.47 greater chance of death. The remaining variables did not predict patient outcomes in a statistically significant manner. The hazard ratios calculated add new data and can be used to more effectively guide patients in prognosis and treatment regimens.     

Identification of low-risk tumours in histological high-grade soft tissue sarcomas

In more than one-third of patients with a histological high-grade malignant soft tissue sarcoma metastasis develops despite local control of the primary tumour. Hence, adjuvant chemotherapy is increasingly used for these relatively chemoresistant tumours which requires improved prognostication to exclude low-risk patients from overtreatment. We assessed the value of stepwise prognostication in a series of 434 histological high-grade STS of the extremity and trunk wall. Vascular invasion was used as the first discriminator whereafter the risk factors tumour necrosis, size (>8cm) and infiltrating growth pattern were used to discriminate high- and low-risk tumours. We identified a high-risk group with a cumulative incidence of metastasis >0.4 at 5 years, and a low-risk group, comprising half of the tumours, with a cumulative incidence of metastasis <0.15. The model was validated in an independent material of 175 patients. This model improved prognostication in STS and is of value for identifying patients who probably should not receive adjuvant chemotherapy.     

Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas

BACKGROUND:

Metastatic propensity of soft tissue sarcoma (STS) is heterogeneous and may be determined by gene expression patterns that do not correlate well with morphology. The authors have reported gene expression patterns that distinguish 2 broad classes of clear cell renal carcinoma (ccRCC‐gene set), and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA‐gene set) and aggressive fibromatosis (AF‐gene set); however, clinical follow‐up data were not available for these samples.

METHODS:

In the current study, gene expression patterns in 73 samples of high‐grade STS were examined using spotted cDNA microarray slides that contained ～16,000 unique UniGene clusters. Approximately 50% of the genes present in the ccRCC‐, OVCA‐, and AF‐gene sets were also represented in the data from this chip set, and these were combined to form a composite gene set of 278 probes.

RESULTS:

Hierarchical clustering using this composite gene set suggested the existence of subsets of the STS samples. Analysis revealed differences in the time to development of metastatic disease between the clusters defined by the first branch point of the clustering dendrogram (P = .005), and also among the 4 different clusters defined by the second branch points (P = .001).

CONCLUSIONS:

This approach suggests the existence of >2 subsets of high‐grade pleomorphic STS, each with distinct clinical behavior. A composite gene set such as that described here may be useful to stratify STS in clinical trials, and may be of practical utility in patient management. Cancer 2012. © 2012 American Cancer Society.     

Hyperbaric oxygenation in the preoperative radiotherapy of soft tissue sarcomas]

Based on the study of clinical and morphological criteria for estimation of the efficacy of distance gammatherapy under hyperbaric oxygenation in the combined treatment of patients with soft tissue sarcomas, it was concluded that hyperbaric oxygenation employed in radiotherapy contributed to the increased rate of neoplasms damage. The latter resulted in a decreased percentage of the recurrence. The attenuation of local radiation and less number of postoperative complications indicate that healthy tissues surrounding the tumor are preserved. No rise in the percentage of distant metastases was noted in irradiation under hyperbaric oxygenation.     

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas

Introduction: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process.

Objectives: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS.

Materials and methods: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs.

Results: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness.

Conclusions: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.     

腺泡状软组织肉瘤的临床治疗分析

目的探讨腺泡状软组织肉瘤手术切除及辅助放、化疗的临床治疗效果。方法对1993～2006年间收治的腺泡状软组织肉瘤12例回顾性分析。男5例,女7例。年龄11～37岁。肿瘤直径平均5.5cm。结果12例手术后切除缘评价中,达到广泛切除缘者10例,边缘切除缘者2例,术后辅助放疗2例,全组均予辅助化疗。12例手术后复发3例,占25%。有7例发生转移,首诊时转移2例,其中肺转移瘤5例,脑转移瘤2例。转移率58.3%。转移瘤单纯化疗5例中PR3例,NC1例,PD1例,3例PR患者均采用MAI方案。随访时间10个月～10年6个月,12例中7例生存,5例死亡,经过Kaolan-Meire生存率计算,3年生存率81.2%,5年生存率52.8%。结论腺泡状软组织肉瘤外科治疗应以广泛切除术为基本原则,术后辅助放疗可以减少复发,辅助化疗是转移瘤的主要治疗方法。     

Gemcitabine in the treatment of soft tissue sarcomas

Soft tissue sarcomas (STS) are rare mesenchymal tumors with poor prognosis once they present as advanced or metastasized disease. Only few cytostatic drugs have been proven to be active in sarcoma patients and there is a clear need for further treatment options in patients with tumors refractory to standard chemotherapy. Gemcitabine, a nucleoside analogue, has shown activity in several epithelial tumors. Clinical data on the activity of gemcitabine in STS, however, are scarce and heterogeneous. In trials including all subtypes of sarcomas response rates observed with single and multiagent schedules are ranging from 3 to 53%. Histopathological subtypes which seem to exhibit an increased susceptibility to gemcitabine are uterine leiomyosarcomas and angiosarcomas. The synergistic role of other cytostatic drugs, e.g. the role of taxanes, still remains unclear and warrants further trials. We here review the available literature on gemcitabine in the treatment of STS.     

Centralised treatment of soft tissue sarcomas in adults

The clinical research developed in specialised centres and oncologic cooperative groups has permitted various scientific societies to collect recommendations used in the treatment of soft tissue sarcomas (STS) and incorporate them into clinical practice guidelines (CPG). Some studies have been conducted in diverse healthcare ambits to assess the influence of CPG. This revision of the medical literature analyses the impact that healthcare management -centralised or otherwise- and clinical practice in conformity with CPG have on the clinical outcome variables of STS. Eight CPG have been identified, as well as 12 conformity studies or audits. These conformity studies and audits demonstrate that the grade of adaptation of medical interventions with CPG, medical healthcare in reference centres and procedures of referrals to these centres, as well as the process of organising healthcare teams into Sarcoma Committees, have a significant influence on clinical outcome. We can conclude that excellent healthcare of STS implies the adaptation of healthcare practice to CPG, the existence of Reference Centres guided by Sarcoma Committees, and the observance of strict referral procedures within the Healthcare Area.     

Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection

From 1970-1984, 114 patients with soft-tissue sarcomas received preoperative irradiation at U.T.M.D. Anderson Hospital. Two patients refused surgery and two had progressing disease and therefore did not proceed to surgery; in the remaining 110 patients, conservative surgical resections were performed 3-6 weeks following irradiation. Analysis of survival by histologic type, age, primary size, and histologic grade revealed a significant negative correlation with grade 3 and to a lesser extent to primary size greater than 15 cm. Eleven patients failed within the radiation portal for the primary, four in conjunction with distant metastases. Of the remaining seven, four were salvaged by further surgery for an ultimate primary-only failure rate of three. Distant metastasis occurred in 35 patients and was the major mechanism of treatment failure in this experience. Adjunctive chemotherapy was not used for the majority of patients and it remains to be seen if its routine employment in large, high-grade, lesions will diminish the deaths caused by distant metastases.     

The treatment of soft tissue sarcomas with focus on chemotherapy: a review

Radical surgery remains the most effective treatment of soft tissue sarcomas. The postoperative addition of radiotherapy appears to reduce local recurrence in extremity lesions. To date, there are still only two drugs with major activity as a single agent in the treatment of soft tissue sarcomas: doxorubicin (DX) and ifosfamide (IFX). Doxorubicin should be administered preferably as 3-weekly bolus injections at doses higher than 60 mg/m2 because of its dose-response relationship. In combination chemotherapy ADIC and CYVADIC are probably the best choice. Although there are no definite data on increased activity with the addition of cyclophosphamide (CTX) and vincristine (VCR) to ADIC, we prefer CYVADIC because of the higher reported complete response rate. A limited number of patients with soft tissue sarcomas achieving a complete response with chemotherapy, will probably be cured, and for this reason it is important to aim at achieving a complete response. Preoperative intraarterial chemotherapy in locally advanced soft tissue sarcomas may further improve survival results, but before definite conclusions can be drawn, this technique should be investigated in randomized studies. Postoperative adjuvant chemotherapy should still be considered investigational, as no advantage has been observed in head, neck and trunk lesions, while data on extremity lesions are still conflicting.     

The treatment and outcome of patients with soft tissue sarcomas and synchronous metastases

Introduction: There is a strong association between poor overall survival and a short disease-free interval for patients with soft tissue sarcomas (STS) and metastatic disease. Patients with STS and synchronous metastases should have a very dismal prognosis.The role of surgery in this subgroup of patients with STS has not been defined.Patients and Methods: A single-institution retrospective review was performed of 48 patients with STS and synchronous metastases in regard to patient demographics, presentation, tumor characteristics, metastatic sites, treatment, follow-up, and survival over a 27-year period.Results: Most primary tumors were >/=10 cm (58%), high-grade histology (77%), and located on the extremity (60%).The most frequent site of metastatic disease was the lung (63%); 27% of patients had metastases to >/=2 organ sites. Surgery to the primary tumor was performed in 94% of patients (n = 45) and 68% had additional radiation therapy (n = 32). Thirty- five percent of patients underwent at least one metastastectomy (n = 17). Chemotherapy was administered to 90% of patients (n = 43); 31% received >/=3 different regimens (n = 15) and 25% were given intra-arterial or intracavitary therapy (n = 12). Median overall survival was 15 months with a 21% 2-year survival. Local control of the primary tumor was achieved in 54% (n = 26), and metastastectomy was performed in 35% (n = 17). No analyzed factors were associated with an improvement in overall survivalConclusions: Despite multiple poor prognostic factors, the survival of patients with STS and metastases is comparable to those who develop delayed metastatic disease. However, unlike patients who present with metachronous disease, there was no improved survival observed for patients treated with metastastectomy. Consequently, treatment for patients with STS and synchronous metastases should be approached with caution. Surgical management of STS with synchronous metastases must be considered palliative and should be reserved for patients requiring palliation of symptoms. Patients must also be well informed of the noncurative nature of the procedure.     

Pediatric soft tissue sarcomas

Many of the soft tissue sarcomas that occur in children are of the same histology as those in adults; however, the relative prevalence of these sarcomas is different between children and adults. In some cases, the biologic behavior of pediatric sarcomas is more benign than that in adults. Treatment for sarcomas in children is also different. Pediatric sarcomas are more commonly responsive to chemotherapy. Furthermore, in children who are still growing, surgery and radiation are associated with higher morbidity than in adults. This article discusses the diagnosis and treatment of rhabdomyosarcoma and undifferentiated sarcomas, with an emphasis on surgical considerations, and the diagnosis and treatment of nonrhabdomyosarcomatous soft tissue sarcomas in children.     

Clinical results of thermoradiotherapy for soft tissue tumours

Thirty-one unresectable and/or recurrent soft tissue tumours in 27 patients underwent hyperthermia in combination with radiation therapy. Locoregional hyperthermia was administered once or twice a week for 40–60 min to a total of 2–14 sessions using RF capacitive or microwave heating equipment. Radiation therapy was given 10–20 min before hyperthermia at doses of 20·8 to 70 Gy. The mean ± SD of the maximum, average, and minimum intratumour temperatures was 44·0 ± 2·9°C, 42·3 ± 1·6°C, 40·1 ± 1·1M°C respectively, and that of the percentage of the intratumour points that exceeded 41 and 43°C was 66·0 ± 33·6, and 31·0 ± 26·1 respectively. Of the 31 tumours treated, 13 (42%) showed CR (complete regression), 10 (32%) PR (> 50 and < 100% regression) and 8 (26%) NC (< 50% regression). Since intratumour low density areas on post-treatment CT scans have been demonstrated to be a useful parameter for assessing tumour response to thermoradiotherapy, the presence of low density areas was also assessed. Low density areas were classified into the following three categories according to the percent area occupied in the maximal cross-section of the tumour: type I, < 50%, type II, 50–80%; type III, < 80%. Of 20 tumours evaluable, 6 (30%) exhibited type III change, 11 (55%) type II and 3 (15%) type I. All of the type III tumours demonstrated a marked response on follow-up or histopathological examination. The major complication associated with treatment was skin ulcer in two patients. The five-year survival of the total 27 patients and 18 patients who had no distant metastases at the start of treatment was 32 and 48% respectively. These results indicate the clinical benefit of thermoradiotherapy using RF capacitive or microwave equipment for locally advanced and/or recurrent soft tissue tumours.     

The role of neutrons in the treatment of soft tissue sarcomas

Two-hundred twenty-one patients with soft tissue sarcoma were treated from 1978 to 1983. Treatment was nonrandomized and consisted of neutron irradiation in 94 cases with gross tumor. Treatment was nonrandomized and consisted of neutron boost irradiation after photon-irradiation or electron-irradiation in 127 cases with no gross tumor after surgery. Patient distribution according to UICC (1978) criteria was 15, 100, and 106 of T1, T2, and T3 respectively. Distribution by pathologic grade was 54, 107, and 60 for Grade 1, Grade 2, and Grade 3 tumors. Distribution by tumor residuum after surgery was 23 cases without microscopic disease (R0), 104 with microscopic disease (R1), and 94 with gross residuum (R2) or nonoperative disease. Five-year follow-up reveals a significant difference (P = 0.024) in disease-free survival (DFS) for T1 (60%), T2 (71%), and T3 (29%, P = 0.016) tumors. Similarly, there are significant DFS differences among G 1 (74%), G 2 (48%, P = 0.035), and G 3 lesions (22%, P = 0.024). The impact of tumor bulk or residuum on DFS after operation is significant when comparing R0 (87%) and R1 (65%) disease (P = 0.042). The 5-year survival of patients who had gross residuum (R2) after surgery was significantly worse (26%, P = 0.003). Ninety percent of patients failed treatment locally and distally within 2 years. The late morbidity rate was 27% for neutron and 7% for neutron-boost irradiation. In our series and reported photon data, local control rates for tumors 5 to 10 cm with neutrons were 76% and 53%, respectively. Low energy (d(14) + Be) neutrons are considered beneficial in the postoperative treatment of well-differentiated soft tissue sarcomas where gross tumor remains. Neutron-boost irradiation is of potential benefit in the treatment after operation of T2-3, and G 1-2 tumors if there is microscopic residual tumor.     

A combination of intraarterial chemotherapy, preoperative and postoperative radiotherapy, and surgery as limb-saving treatment of primarily unresectable high-grade soft tissue sarcomas of the extremities

The localization and size of a high-grade soft tissue sarcoma of an extremity are generally the limiting factor in limb-saving surgery. Since 1982 nine patients with a high-grade soft tissue sarcoma of an extremity, which usually requires amputation, have been treated by intraarterial chemotherapy, preoperative and postoperative radiotherapy, and surgery. The limb was saved in eight patients (89%). During a median follow-up of 24 months (mean follow-up 32 months, range 12 to 64 months) one local recurrence and four distant metastases were diagnosed. Three patients developed complications due to the intraarterial chemotherapy, a motor and sensory neuropathy of the sciatic nerve was diagnosed in one patient, and two patients developed a flexion contracture of the knee. The results obtained in this small series show that the combination of intraarterial doxorubicin, preoperative and postoperative radiotherapy, and surgery is feasible in limb-saving treatment of primarily "unresectable" high-grade soft tissue sarcomas of the extremities without increasing the risk of a local recurrence.     

Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy

One hundred eighty-three patients with malignant skeletal (83) or soft tissue sarcoma (100) were entered into the multimodality preoperative limb salvage protocol. Local recurrences were observed in 5 of 183 (2.7%). Six patients required amputation because of complications, and 13 patients died within 1 year from metastatic disease. There was no statistical difference in survival rates between a series of patients who had amputation and adjuvant therapy and patients treated by limb salvage and adjuvant therapy. Overall survival rates for patients with soft tissue sarcoma were 76%. Although the exact reason for the improved local control is not known, it is our belief that it is the result of the multidisciplinary therapy that destroys microscopic disease at the periphery of the primary tumor.