J.M. Thomas

A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection

BACKGROUND Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. PATIENTS AND METHODS Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). RESULTS Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. CONCLUSION Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.

Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children?

PURPOSE To determine whether age at diagnosis influences the behavior of Ewings sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewings sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION The behavior of Ewings sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewings sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.

Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling

In this study, we have used genome-wide expression profiling to categorise synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas (MFHs). Following hierarchical clustering analysis of the expression data, the best match between tumour clusters and conventional diagnosis was observed for synovial sarcomas. Eight of nine synovial sarcomas examined formed a cluster that was characterised by higher expression of a set of 48 genes. In contrast, sarcomas conventionally classified as leiomyosarcomas and MFHs did not match the clusters defined by hierarchical clustering analysis. One major cluster contained a mixture of both leiomyosarcomas and MFHs and was defined by the lower expression of a set of 202 genes. A cluster containing a subgroup of MFHs was also detected. These results may have implications for the classification of soft tissue sarcomas, and are consistent with the view that sarcomas conventionally defined as MFHs do not represent a separate diagnostic category.

The Role of Ultrasound-guided Cytology of Groin Lymph Nodes in the Management of Squamous Cell Carcinoma of the Vulva: 5-Year Experience in 44 Patients

AIM To assess the accuracy of ultrasound combined with fine-needle aspiration cytology (FNAC) in the detection of lymph node metastasis in patients with squamous cell carcinoma of the vulva. MATERIALS AND METHODS The groin nodes of 44 consecutive patients with primary squamous cell carcinoma of the vulva undergoing groin node dissection were assessed with ultrasound and FNAC. The results were compared with histology from subsequent inguinofemoral lymph node dissection. Twenty-nine patients underwent bilateral groin node dissections and 15 unilateral providing comparable data for 73 groins. RESULTS Histology demonstrated metastatic disease in 28 groins and no evidence of metastatic disease in 45. Ultrasound agreed with the histology in 67 of the 73 groins (92%), with two false-positives, four false-negatives and two indeterminate appearances. Cytology agreed with the histology in 65 of 72 FNAC samples obtained (90%), with six false-negatives, and one indeterminate result. No false-positive cytology results were seen. Ultrasound and FNAC together failed to detect metastatic disease in four groins, one with an indeterminate ultrasound appearance, another with indeterminate cytology, the two others each having a single positive inguinal node despite a negative ultrasound and FNAC. CONCLUSION The combination of ultrasound and FNAC provides a sensitive and specific tool for pre-operative assessment and may prevent unnecessary groin dissection and the attendant morbidity in selected patients with vulval cancer.

The natural history and management of Merkel cell carcinoma of the skin: A review of 22 patients treated at the Royal Marsden Hospital

Merkel cell carcinoma is a rare skin malignancy, which primarily affects the elderly. Currently, there is only limited data on the natural history of this condition and no consensus on its optimum management. We have reviewed the natural history and management of 22 patients with Merkel cell carcinoma, who were treated at the Royal Marsden Hospital between 1985 and 1994. The median age at diagnosis was 75 years (range 55-96), with the head and neck region being the most common site of disease (nine patients: 41%). Seventeen patients (77%) presented with skin disease, three (14%) with regional lymphadenopathy and two (9%) with metastatic disease. Of the Stage I patients, 41% developed local recurrence postoperatively at a median time to relapse of 12 months. Those with head and neck disease had the highest risk of local recurrence, which occurred in 62.5% of this group. Stage I patients also had a high risk of disease progression, with 53% developing regional lymphadenopathy or visceral metastases. The median survival for all disease stages was 47 months. The treatment of unresectable primary or recurrent disease with radiotherapy led to valuable long term control in four of nine patients treated. Six courses of chemotherapy were administered; one brief complete response was observed, occurring in a patient treated with cyclophosphamide, vincristine and doxorubicin. The data in this study confirms the predilection for the elderly and the aggressive nature of Merkel cell carcinoma, with only four of 17 Stage I patients remaining disease free. To clarify the role of adjuvant postoperative radiotherapy and to establish the appropriate use of chemotherapy in metastatic spread of this rare malignancy will require further studies with multicentre cooperation.

Prognostic index for extremity soft tissue sarcomas with isolated local recurrence.

Background: Local recurrence occurs in 10% to 20% of patients with extremity soft tissue sarcomas despite optimal treatment. The association of local recurrence with subsequent survival is controversial and conflicting. There is a need for a staging system to predict outcome in this subset of patients and also to plan optimal treatment, including adjuvant systemic therapy. Methods:Data collected from 110 patients with locally recurrent extremity soft tissue sarcomas were studied. The influence of clinical and pathologic factors on local recurrence, distant metastasis, and disease-specific survival were analyzed by univariate and multivariate techniques. Results: Of the 110 patients who presented with local recurrence, 92 had an isolated local recurrence and 18 had prior or concomitant distant metastases. The 5-year disease-specific survival for all patients was 63% and for those with isolated local recurrence, it was 69%. Histologic grade, malignant fibrous histiocytoma histology, pathologic margins, previous local recurrence, and prior radiotherapy were independent prognostic factors for subsequent local recurrence. Tumor size, histologic grade, and time to local recurrence were independent prognostic factors for distant metastasis and disease-specific survival. A prognostic index was calculated by assigning a score of 1 to 3 for each of the three independent prognostic factors for survival and added to give the prognostic index for each patient. As the prognostic index increased from 3 to 9, there was a progressive increase in the hazard ratios and a corresponding deterioration in survival. The patients were then categorized into three prognostic groups based on the hazard ratios for disease specific survival. The differences in the survival curves were highly statistically significant (P < .0001). Conclusions: Tumor size, histologic grade, and time to local recurrence are the primary determinants of distant metastases and survival in locally recurrent extremity soft tissue sarcomas. The impact of local recurrence on survival varies considerably. The nature of the local recurrence, rather than its presence per se, is a more useful guide to prognosis. We propose a simple staging system based on size, grade, and time to recurrence that correlates extremely well with prognosis and may serve as a guide to make therapeutic decisions in patients with locally recurrent extremity soft tissue sarcomas.

Caution with sentinel node biopsy in cutaneous melanoma

Sentinel lymph node biopsy (SNB) in cutaneous melanoma has been adopted as the standard of care in the USA and some other countries. Patients who are sentinel node (SN) negative have a better prognosis than those who are positive, and SN status is claimed to be the best single staging and prognostic indicator1. However, algorithms that incorporate certain histological features of the primary tumour2, together with ultrasonography of the nodal basin at risk3, may provide prognostic information that is just as powerful. Two other important advantages of SNB were anticipated: first, that completion lymphadenectomy in SN-positive patients would provide a survival advantage and, second, that SN status would identify patients for effective adjuvant therapy. Unfortunately the latter is not currently available. The prognostic distinction between SNBdetected micrometastatic and palpable macrometastatic nodal disease has been incorporated into the most recent American Joint Committee on Cancer melanoma staging system4. The hope of a survival advantage as a result of early lymph node dissection has existed for over a century. In 1892, Dr Herbert Snow observed that patients with palpable regional node metastases usually died from their disease and so advised ‘anticipatory lymphadenectomy’ before the nodes became palpable. However, this operation, now known as elective lymph node dissection, has failed to show any overall survival advantage in four randomized controlled trials. Furthermore, the operation was unnecessary in 80 per cent of patients, in whom the dissected specimen contained no melanoma. In 1992 Dr Donald Morton described SNB with or without completion lymphadenectomy, a procedure that was claimed to identify the 20 per cent or so of patients with spread to the sentinel node basin(s). The Multicentre Selective Lymphadenectomy Trial (MSLT-1) was designed to investigate any possible survival advantage. Patients with cutaneous melanoma over 1 mm thick were randomized to either wide local excision (WLE) alone (with delayed nodal dissection if metastases became palpable), or to WLE plus SNB with or without completion lymphadenectomy (depending on SN status). This trial randomized 2001 patients and the results were presented at the May 2005 meeting of the American Society of Clinical Oncology (http://www.asco.org). There was no significant difference in overall survival (87 and 86 per cent respectively at 5 years). Furthermore, any advantage in terms of disease-free survival (DFS) was most probably an artefact of the trial design. The commonest site of first recurrence was the regional lymph nodes and in the test group all SN-positive patients had completion lymphadenectomy at the outset. It is therefore inevitable that there would be more and earlier nodal recurrences in the control group. The only reliable way to calculate DFS in the MSLT-1 is to exclude all regional nodal recurrences and to compare the incidence of regional non-nodal and systemic recurrences only. If SNB with completion lymphadenectomy does not confer a survival advantage, how valuable is this technique as a prognostic tool? A common argument cited is that SNB is patient driven because patients want to know their individual prognostic status. Unfortunately, being SN negative is no guarantee of freedom from recurrence and it is known that 13 per cent of such patients will develop recurrence somewhere by 3 years1. The technique has a failure rate of about 4 per cent when the metastatic melanoma in the nodal basin is not detected in the lymph node(s) sampled. Furthermore, some melanomas spread by the haematogenous rather than the lymphatic route, in which case a truly negative SN is prognostically inaccurate. It is for these reasons that SN-negative patients whose primary tumour shows adverse prognostic factors are still advised to have careful follow-up. In the context of this discussion, it must be remembered that therapeutic node dissection for palpable nodal disease may be curative, depending on the number and bulk of metastatic nodes, and that ultrasonographic surveillance can identify nodal metastases before they become palpable5. SNB in the head and neck (repeatedly described in the literature as a ‘unique surgical challenge’) deserves special mention because of the rich and complex lymphatic and vascular drainage at this site. Melanomas of the head and neck are associated with an increased recurrence rate and reduced survival compared with those of the trunk or extremities, but they carry the lowest incidence of SN positivity and the highest rate of false negativity, raising questions about the efficiency and value of SNB in this region6. Furthermore,

The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing's family tumours

BACKGROUND Ewings sarcoma and primitive neuroectodermal tumour (ES/PNET) are rare, limiting opportunities for therapy studies in adults. Chemotherapy regimens adapted from paediatric studies are often used for adults but concerns about poor outcome and treatment toxicity may adversely affect drug dose intensity. We present our experience using a paediatric protocol at full dose. PATIENTS AND METHODS Records of 34 patients with ES/PNET who received the IVAD chemotherapy regimens were reviewed. Received drug dose intensity, toxicity and survival data were collected. RESULTS Received dose intensity in 30 evaluable patients was 0.92 compared to the standard IVAD schedule. Myelosuppression was the major toxicity, 83% of patients experienced grade 4 neutropenia. There was no major renal or cardiac toxicity. In patients without metastases at presentation, five-year overall survival was 63% and progression free survival was 39%. Tumour burden at presentation was statistically significantly associated with survival (P = 0.002). The five-year survival rate of 80% in patients presenting with low volume non metastatic disease was equivalent to published paediatric series. CONCLUSIONS Although the IVAD chemotherapy regimens are myelotoxic in adults, they can be given safely. We recommend that adults with ES/PNET should be included in current multicentre, multidisciplinary treatment studies directed at children.

Major amputation for soft-tissue sarcoma†

Advances in oncological practice have reduced the number of major amputations performed for soft‐tissue sarcoma, but this remains a valuable, if infrequent, option for both curative and palliative indications.

The management of retroperitoneal soft tissue sarcomas

Over a 5-year period, all retroperitoneal soft tissue sarcomas (119) referred to the Royal Marsden Hospital, London, U.K., were recorded prospectively on a database and managed with a consistent treatment policy. On multivariate analysis, the significant factors responsible for determining prognosis were grade and completeness of excision. Despite improvements in surgical clearance rates (nearly 50% completely excised in this series), the prognosis was poor with 2- and 5-year survival rates of 53 and 20%, respectively. Further improvements in survival rates will depend on better adjuvant treatment.