Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-α be better?

BACKGROUND: The optimal dose of TNF-alpha delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown. PATIENTS AND METHODS: Randomised phase II trial comparing hyperthermic ILP (38-40 degrees ) with melphalan and one of the four assigned doses of TNF-alpha: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2-3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group. RESULTS: One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-alpha. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively. CONCLUSION: At the range of TNF-alpha doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-alpha doses. Efficacy and safety of low-dose TNF-alpha could greatly facilitate ILP procedures in the near future.     

Health-related quality of life after isolated limb perfusion compared to extended resection,or amputation for locally advanced extremity sarcoma: Is a limb salvage strategy worth the effort?

IntroductionThe aim of this study was to compare long-term patient reported outcomes (PROs) in patients with locally advanced extremity soft tissue sarcoma (eSTS) after isolated limb perfusion followed by resection (IR), compared to extended resection (ER), primary amputation (A) or secondary amputation after IR (IR-A).MethodsPatients were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted among sarcoma survivors registered in the Netherlands Cancer Registry (NCR), 2–10 years after diagnosis. Used PROs were the EORTC QLQ-C30, the Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS).ResultsWe identified 97 eSTS survivors: IR = 20, ER = 49, A = 20, IR-A = 8. While there were no differences in PROs between IR and ER, results showed better functioning and functionality in both groups versus the amputation groups. The amputation groups scored significantly lower on physical functioning (A = 62.7, IR-A = 65.7 versus IR = 78.0, ER = 82.7, p = 0.001) and role functioning (A = 67.5, IR-A = 52.8 versus IR = 79.2, ER = 80.6, p = 0.039), both EORTC QLQ-C30 scales. Also for the TESS, the scores were significantly lower for the amputation groups compared to the limb sparing groups (upper extremity p = 0.007 with A = 68.9, IR-A = 71.6 versus IR = 93.3, ER = 91.1; lower extremity p < 0.001 with A = 72.2, IR-A50.9 versus IR = 84.5 and ER = 85.5). There were no significant differences between the groups on cancer worry, anxiety and depression.ConclusionHRQoL in eSTS survivors treated with IR or ER is equal; for maintenance of physical functioning and functionality IR and ER outperform an amputation.     

First Eastern European experience of isolated limb infusion for in-transit metastatic melanoma confined to the limb: Is it still an effective treatment option in the modern era?

BackgroundIsolated limb infusion (ILI) with cytotoxic agents is a simple and effective treatment option for patients with melanoma in-transit metastases (ITMs) confined to an extremity. Data for ILIs performed in Europe are sparse and to date no Eastern European ILI experience has been reported. The aim of the current study was to evaluate the efficacy of ILI in Estonia.Patients and methodsData for twenty-one patients were collected and analysed. All patients had melanoma ITMs and underwent an ILI between January 2012 and May 2018. The cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation times were 20–30 min under mildly hyperthermic conditions (38–39 °C). Primary outcome measures were treatment response and overall survival.ResultsNineteen lower limb and two upper limb ILIs were performed. The female to male ratio was 18:3. The overall response rate (complete + partial response) was 76% (n = 16), with a complete response in 38% (n = 8). The overall long-term limb salvage rate was 90% (n = 19). During follow-up, eight patients (38%) died, two due to metastatic melanoma. Five-year overall survival was 57%.ConclusionThis first Eastern European report of ILI for melanoma ITMs shows results comparable to those from other parts of the world. In this era of effective targeted and immune therapies, ILI remains a useful treatment option, with a high overall response rate and durable responses in patients with melanoma ITMs confined to a limb.     

Can the probability for obliteration after radiosurgery for arteriovenous malformations be accurately predicted?

PURPOSE: To investigate how accurate different models predict the probability for obliteration following radiosurgery for an arteriovenous malformation (AVM). METHODS AND MATERIALS: The probability for obliteration was calculated for all 838 AVMs with a known treatment outcome and treated at the Karolinska Hospital with Gamma Knife surgery 1970-1993. Four different models were used for the calculation, resulting in four different values of the probability for obliteration. The calculated prediction values were added for each model, and the total number of predicted obliteration compared to that observed in the whole patient material as well as in different subgroups. RESULTS: Three of the four models predicted the total number of obliterations accurately. In two of those three models, the accuracy of the prediction was dependent on AVM volume and treatment dose. In one model only, the prediction was accurate and independent of all investigated parameters. CONCLUSIONS: The probability for obliteration was accurately predicted by one of the models analyzed. In this model, the probability for obliteration was related to the dose to the AVM periphery only. The AVM volume had no independent impact on the probability for obliteration. There was a trend that AVMs with a central location had a better obliteration rate than predicted.     

Isolated hepatic perfusion for the treatment of liver tumors: sunset or sunrise?

Experience with isolated hepatic perfusion (IHP) is limited to a few centers in the world because of the technical difficulties, surgery-related morbidity, and unproved efficacy in randomized trials. Experimental animal IHP models have led to exploring new ways of improving efficacy, reducing technical difficulties, and minimizing regional and systemic toxicity. Future research should be directed to the identification of suitable biologic or chemotherapeutic agents, defining clinical indications, and development of technical modifications to make it more generally applicable and even repeatable.     

Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?

A number of trials have studied the value of aromatase inhibitors (AIs) for the adjuvant treatment of early hormone-responsive postmenopausal breast cancer. Three different AIs have been used and they have been compared as initial treatment (two trials) or after 2–3 years of tamoxifen (four trials), in both cases against a standard arm of 5 years of tamoxifen. In addition, two trials have evaluated AIs against no treatment after 5 years of tamoxifen. In all circumstances, the AIs have demonstrated superior efficacy. However, no results are currently available for the key question, that is – is it better to start initially with an AI or use it sequentially after 2 years of tamoxifen? Here, we review the trial results and present two models, which address this issue. The models clearly show that early treatment with an AI is superior to using it after 5 years of tamoxifen. They also favour an upfront strategy to sequencing after 2 years of tamoxifen, but in this case the differences are small and model-dependent. A key question is whether AIs have substantially better efficacy than tamoxifen for ER-positive–PgR-negative tumours, where the data are currently contradictory. A mechanism explaining why greater efficacy might be so is proposed. Further results from ongoing trials will be needed to resolve this issue.     

Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic melanoma?

For more than 20 years interleukin-2 (IL2) was the preferred treatment for medically fit metastatic melanoma patients, but recently two new agents, ipilimumab and vemurafenib, were approved for stage IV disease. Single-institution data were used to determine the long-term survival rate for IL2-treated melanoma patients, and whether use of inpatient IL2 had declined recently. Between May 1987 and April 2010, 150 patients were hospitalized for high-dose, intravenous (i.v.) IL2. The average number of IL2 patients increased from 5.4 per year during 1987-1991 to 5.8 during 1992-1997 after regulatory approval of IL2, to 8.3 during 1998-2006 after a marketing indication in metastatic melanoma was granted, but dropped to 3.0 during 2007-2010. At the time of treatment, median age was 52 years; 27% were 60 years of age or older. At the time of analysis 122 patients were deceased. Median survival from the start date of IL2 treatment was 15.6 months, with a 20% 5-year survival. Among patients enrolled in clinical trials, there were as many nonresponders who survived 5 years as responders, which is consistent with a delayed immunotherapy benefit. In the absence of long-term survival data for these newer agents, IL2 probably should still be the preferred initial treatment for most patients with metastatic melanoma who are medically fit.     

Tonsillary carcinoma after temozolomide treatment for glioblastoma multiforme: treatment-related or dual-pathology?

Glioblastoma multiforme is a primary malignant brain tumor with a prognosis of typically less than 2 years. Standard treatment paradigms include surgery, radiation therapy and temozolomide. Little data exists for temozolomide recommendations after the first 6 months. We present a case of a patient with glioblastoma multiforme treated with surgery, radiation and chronic temozolomide for 6 years. He continues to survive glioblastoma-recurrence-free, but developed tonsillary carcinoma. This case raises the question of whether this secondary solid-organ malignancy is treatment-related or dual pathology.     

Do age and comorbidity impair recovery during two years after treatment for endometrial cancer?

BackgroundA better understanding of the impact of age and comorbidity on health-related quality of life (HRQoL) may improve treatment decision-making in patients with endometrial cancer. We investigated whether either age or comorbidity is more strongly associated with changes in HRQoL over time.MethodsEndometrial cancer patients (n = 296) were invited to complete questionnaires after initial treatment and after 6, 12 and 24 months follow-up. Patients were divided into subgroups according to age (<60, 60–75 and ≥75 years) and according to comorbidity (0, 1, 2 or ≥3). HRQoL was measured with the five EORTC QLQ-C30 functioning scales. Linear mixed models were performed for the different subgroups to assess changes in HRQoL over time. HRQoL was also compared to longitudinal outcomes from an age- and gender-matched normative population.ResultsThe first questionnaire was returned by 221 patients (75%) of whom six were excluded due to progressive disease. Changes in HRQoL were mainly associated with cumulative comorbidity burden and not with age. Patients with comorbidity reported deterioration of physical and role functioning between 12 and 24 months. Compared to the normative population, patients initially scored higher on physical and role functioning, but at 24 months outcomes were no longer different.ConclusionCumulative comorbidity burden was more strongly associated with deterioration of HRQoL than patient's age. Therefore, patients with endometrial cancer and multiple comorbid conditions require careful follow-up of HRQoL after treatment.     

Can a pathological complete response of breast cancer after neoadjuvant chemotherapy be diagnosed by minimal invasive biopsy?

BackgroundThis study aimed to explore the ability of a minimal invasive biopsy to diagnose a pathological complete response (pCR = ypT0) in the breast.MethodsUltrasound-guided, vacuum-assisted, minimal invasive biopsy (VAB) was performed in 50 patients after neoadjuvant chemotherapy and before breast surgery. Negative predictive values (NPV) and false negative rates (FNR) to predict a pCR in surgical specimen were the main outcome measures. To assess the possible sampling error, the representativeness of the sample was evaluated by the biopsy performing physician (subjectively based on the visibility in ultrasound), by radiography of the biopsy specimen, and by the pathologist (based on histopathology).ResultsThe cohort (n = 50) consisted of 15 (30%) triple negative breast cancers, 13 (26%) human epidermal growth factor receptor 2 (HER2) positive and 22 (44%) hormone receptor positive/HER2 negative cancers. ypT0 was diagnosed in 23 (46%) cases. In the overall cohort (n = 50), VAB yielded an NPV of 76.7% and an FNR of 25.9%. Given a representative VAB sample, according to the histopathological evaluation (n = 38), the NPV was 94.4% (95% CI 87.1–100.0) and the FNR 4.8% (95% CI 0.0–11.6). Non-representative VABs were mainly due to bad visibility of the target lesion in ultrasound.ConclusionA VAB can accurately diagnose a pCR, given a histopathologically representative sample.     

Should surgery followed by whole-brain radiation therapy be the standard treatment for single brain metastasis?

This Practice Point commentary discusses the results of a retrospective analysis conducted by Rades et al. that examined surgical intervention followed by whole-brain radiation therapy (WBRT) and WBRT alone in patients with a single brain metastasis. Although three trials have already provided level 1 data regarding the treatment of such patients, there is a disparity in the conclusions of these studies, with two trials favoring surgery before WBRT and the third not finding a benefit with surgery. The number of patients enrolled in each prospective randomized study was, however, small. The retrospective analysis by Rades et al. simply confirms and reinforces the standard practice of surgical resection before WBRT. There are fine distinctions between patients with this malignancy that were not discussed and deserve mention. Not all patients with a single brain metastasis have a surgically resectable lesion, notably individuals who have a tumor in an eloquent region of brain, the deep gray matter, or the brainstem. Other treatments are more appropriate for tumors in these locations and, therefore, the results of the Rades et al. analysis pertain only to patients with resectable tumors.     

Can concomitant-boost accelerated radiotherapy be adopted as routine treatment for head-and-neck cancers? A 10-year single-institution experience

PURPOSE: Accelerated schedules are effective in overcoming repopulation during radiotherapy (RT) for head-and-neck cancers, but their feasibility is compromised by increased toxicity. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the 10-year experience of a single institution in the routine use of concomitant boost RT as standard radical treatment in all but the most favorable stage patients. METHODS AND MATERIALS: Between February 1991 and June 2001, 296 patients (mean age, 59 years) were treated with concomitant boost RT either alone (67%) or combined with cisplatin-based chemotherapy (33%), with a median tumor dose of 69.9 Gy. Tumors were located in the oropharynx in 52%, hypopharynx in 20%, larynx in 15%, nasopharynx in 7%, and oral cavity in 6%. International Union Against Cancer Stage III-IV disease represented 77% of tumors. The median follow-up for surviving patients was 55 months (range, 10-138 months). RESULTS: The RT schedule was completed to the prescribed dose in all but 1 patient. Twenty patients (7%) had a treatment interruption (median, 5 days; range, 2-35 days). Grade 3-4 Radiation Therapy Oncology Group acute toxicity was observed in 77% of patients, and nutritional support was required in 110 patients (37%). For all patients, the 5-year actuarial locoregional control and disease-free survival rate was 72% and 61%, respectively. In a multivariate analysis, only T and N stage was significantly associated with locoregional control and disease-free survival. Grade 3-4 late toxicity occurred in 14%, mostly bone and cartilage necrosis. CONCLUSIONS: The present, moderately accelerated, concomitant boost regimen is logistically feasible, causing minimal inconvenience to the technical staff and yielding a high rate of patient compliance. Concomitant chemotherapy administration is feasible provided that patients are carefully selected and supportive care is introduced in a timely fashion. Considering the manageable toxicity and the satisfactory tumor control obtained, this regimen represents a good choice when considering implementation of an altered RT fractionation schedule as standard treatment for head-and-neck cancers.     

Can a genetic signature for metastatic head and neck squamous cell carcinoma be characterised by comparative genomic hybridisation?

Survival from head and neck squamous cell carcinoma (HNSCC) has remained static for the last 20 years. The development of lymph node metastasis (LNM) significantly reduces the 5-year survival rate, thus the ability to identify tumours with the potential to metastasise would allow more aggressive treatment regimes to be directed at these patients regardless of negative clinical and radiological findings at the time of presentation. Comparative genomic hybridisation (CGH) can identify chromosomal aberrations that may lead to metastasis. DNA from 23-paired specimens of primary tumour (PT) and LNM were analysed. Nonrandom copy number changes were identified in all paired samples. Similar numbers of aberrations were identified on PT and LNM samples. The most common aberrations were 3q (90%), 8q (65%), 1q (50%), 5p (43%), 2q (41%) and 11q (41%) and deletions 3p (57%), 1p (54%), 4p (48%), 13q (48%), 11q (41%) and 10q (37%). A number of differences were also detected. No aberration was found to be preferentially associated with the LNM, although gains on 6q (48 vs 22%) and 22q (26 vs 9%) were found at higher frequencies. Clonality studies demonstrated that LNM develop from the dominant population of cells in the PT. These results were compared with two similar publications. No combination of chromosomal aberrations, as detected by CGH, was associated with metastatic progression in HNSCC.