Complete clinical response after preoperative chemoradiation in rectal cancer: is a "wait and see" policy justified?

PURPOSE: A proportion of patients, who receive preoperative chemoradiation for locally advanced (T3, T4, NX) rectal cancer achieve a complete clinical response and a pathologic complete response in the region of 15 to 30 percent. Support is growing in the United Kingdom for the concept of "waiting to see" and not proceeding to radical surgery when a complete clinical response is observed. The purpose of this review was to use a literature search to assess how often complete clinical response is achieved after neoadjuvant chemoradiation, the concordance of this finding with pathologic complete response, and to determine whether it is feasible to observe patients who achieve complete clinical response rather than proceed to surgery. RESULTS: In total, 218 Phase I/II or retrospective studies and 28 Phase III trials of preoperative radiotherapy or chemoradiation were identified: 96 percent of trials documented the pathologic complete response, but only 38 trials presented data on the achievement of a complete clinical response/partial clinical response. Only five studies were found in which patients with clinically staged T2/T3 tumors were treated with radiotherapy/chemoradiation and did not routinely proceed to surgery and also reported on the long-term outcome of a "wait and see" policy. DISCUSSION: It remains uncertain whether the degree of response to chemoradiation in terms of complete clinical response or pathologic complete response is a useful clinical end point. Studies that include T3 rectal cancer are associated with high local recurrence rates after nonsurgical treatment. Few studies report long-term outcome after achievement of a complete clinical response. CONCLUSIONS: The end point of complete clinical response is inconsistently defined and seems insufficiently robust with only partial concordance with pathologic complete response. The rationale of a "wait and see" policy when complete clinical response status is achieved relies on retrospective observations, which are currently insufficient to support this policy except in patients who are recognized to be unfit for or refuse radical surgery.

Fluorine-18 fluorodeoxyglucose positron emission tomography in the preoperative staging of thoracic oesophageal and gastro-oesophageal junction cancer: a prospective study.

BACKGROUND: The pre-operative staging in oesophageal cancer is often challenging and underestimation of the extent of the disease may lead to unnecessary surgery. AIM: To audit the use and assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) as a staging tool for thoracic oesophageal and gastro-oesophageal junction (GOJ) cancers in our oncological surgical practice. PATIENTS AND METHODS: Over a 3 year period, between 2002 and 2004, 134 patients with thoracic oesophageal or GOJ cancer were referred to our unit for treatment. The standard preoperative staging investigation in all cases was CT (thorax, abdomen and pelvis). A preoperative FDG-PET scan was further requested in 22 patients. The case notes of all the patients that underwent a FDG-PET scan were reviewed and compared with the preoperative imaging, the operative findings and the histopathology of the resected tumours. RESULTS: Eighteen men and 4 women with a median age of 65 (range 43-79) years were studied. After FDG-PET, 13 out of 22 patients (59%) were deemed suitable for tumour resection. Twelve of the 13 patients were fit to undergo surgery. At laparotomy, 2 of those (17%) were found inoperable due to widespread disease. The sensitivity of CT versus FDG-PET to detect infiltrated lymph nodes was 29% (95% CI: 3-70) versus 71% (95% CI: 29-96) (P=0.0412), whereas both tests had 67% specificity (95% CI: 9-99) in detecting lymph nodes. The sensitivity and the specificity of CT versus FDG-PET to detect distant organ metastases (M1b) were 33% (95% CI: 4-77) and 88% (95% CI: 47-99) versus 50% (95% CI: 6-93) and 100% (95% CI: 69-100), respectively (P>0.05). The FDG-PET regarding the N and M status differed from the CT in 11 patients and led to modification of the planned management in 5 of them. CONCLUSIONS: FDG-PET is more accurate than CT in defining N and M status. It can result in a reduction of unnecessary surgery in a significant number of patients. The combined PET-CT scan as a single imaging modality is expected to further improve diagnostic accuracy of FDG-PET.

Tube pharyngostomy: a simple method for prolonged intubation of the foregut following oesophagogastric surgery.

Tube pharyngostomy involves the percutaneous passage of a tube through the pharynx as an alternative to nasogastric intubation. We use this method for upper gastrointestinal decompression after oesophagectomies and total gastrectomies where prolonged intubation of the foregut is anticipated. It is simple to perform and very well tolerated as compared to a nasogastric tube. The pharyngostomy tube can also be used for enteral feeding. We present here the technique in detail and our experience with 67 procedures over the last 6 years where only few minor complications were encountered. We also review the literature for previous reports of pharyngostomy.

Endoscopic palliation of malignant dysphagia: a challenging task in inoperable oesophageal cancer.

BACKGROUND: The main goal when managing patients with inoperable oesophageal cancer is to restore and maintain their oral nutrition. The aim of the present study was to assess the value of endoscopic palliation of dysphagia in patients with oesophageal cancer, who either due to advanced stage of the disease or co-morbidity are not suitable for surgery. PATIENTS AND METHODS: All the endoscopic palliative procedures performed over a 5-year period in our unit were retrospectively reviewed. Dilatation and insertion of self-expandable metal stents (SEMS) were mainly used for tight circumferential strictures whilst ablation with Nd-YAG laser was used for exophytic lesions. All procedures were performed under sedation. RESULTS: Overall 249 palliative procedures were performed in 59 men and 40 women, with a median age of 73 years (range 35-93). The median number of sessions per patient was 2 (range 1-13 sessions). Palliation involved laser ablation alone in 24%, stent insertion alone in 22% and dilatation alone in 13% of the patients. In 41% of the patients, a combination of the above palliative techniques was applied. A total of 45 SEMS were inserted. One third of the patients did not receive any other palliative treatment, whilst the rest received chemotherapy, radiotherapy or chemoradiotherapy. Swallowing was maintained in all patients up to death. Four oesophageal perforations were encountered; two were fatal whilst the other two were successfully treated with covered stent insertion and conservative treatment. The median survival from diagnosis was 10.5 months (range 0.5-83 months) and the median survival from 1st palliation was 5 months (range 0.5-68.5 months). CONCLUSION: Endoscopic interventions are effective and relatively safe palliative modalities for patients with oesophageal cancer. It is possible to adequately palliate almost all cases of malignant dysphagia. This is achieved by expertise in combination treatment.

Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision?

INTRODUCTION: Local excision is considered inappropriate treatment for T3-T4 rectal adenocarcinomas, as it cannot provide prognostic information regarding lymph node involvement and has a high risk of pelvic recurrence. Preoperative chemoradiation (CRT) studies in rectal cancer suggest that a pathological complete response (pCR) in the primary tumour provides an excellent long-term outcome. If downstaging to stage pT0 predicts a tumour response within the perirectal and pelvic lymph nodes, this may allow local excision to be performed without increased risk of pelvic recurrence. This retrospective study aimed to determine the incidence of involved lymph nodes following pCR (ypT0) after preoperative CRT and total mesorectal excision. METHOD: The outcome and treatment details of 211 patients undergoing preoperative CRT for clinically staged T3-T4 unresectable rectal adenocarcinomas between 1993 and 2003 at Mount Vernon Hospital were reviewed. RESULTS: Data were recorded from the 143 patients who completed treatment with a median follow-up of 25 months. Twenty-three patients (18%) were found to have had a pCR. Four out of 23 patients (17%) had involved lymph nodes. No pelvic recurrences developed after a ypCR. Overall survival was similar for patients with ypT0 or residual tumour. CONCLUSION: Pathological complete response in the primary tumour failed to predict a response in the perirectal lymph nodes (p=0.08). The degree of response predicted a lymph node response (p=0.02). The detection of ypCR identified patients with a low rate of pelvic recurrence. This may in the future allow selection of patients for whom local excision can be performed without a higher risk of local relapse.

The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy.

AIMS: To determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer. MATERIALS AND METHODS: One hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6-12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m2 via a 60-min infusion on days 1-5 and 29-33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (< or = 1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40). RESULTS: After SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0-21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36-1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26-0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55-5.97). CONCLUSIONS: The number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.

Preoperative ECF chemotherapy in gastro-oesophageal adenocarcinoma.

Epirubicin, cisplatin and continuous 5-fluorouracil (5-FU) infusion (ECF) has been reported to result in high clinical response rates in advanced gastro-oesophageal adenocarcinoma and is currently the 'gold standard' chemotherapy regimen for this tumour site. Despite this, its role as preoperative (neoadjuvant) treatment is unproven and therefore remains under investigation. We report our experience using ECF (intravenous epirubicin 50 mg/m2 and cisplatin 60 mg/m2 every 3 weeks, with continuous infusion of 5-FU 200 mg/m2 per day) as preoperative treatment in locally advanced adenocarcinoma of the lower oesophagus, gastro-oesophageal junction and stomach. Of the 23 patients treated (median age 54 years), 19 had potentially resectable disease, four were unresectable and seven had radiological evidence of lymph node involvement. A median of four cycles of ECF was delivered (range 1-6). Ten of 12 patients (83%) with dysphagia reported improvement of symptoms. Clinical disease progression occurred in six patients (26%) during chemotherapy. WHO grade 3 or 4 toxicity occurred in six patients (26%): four haematological, one mucositis, one vomiting. Seventeen patients (74%) proceeded to surgery; 14 (61%) were resected and three were unresectable. There were two (12%) postoperative deaths from respiratory failure. Major pathological response was seen in three patients (13%): one pathological complete response, two microscopic residual disease. Two patients had Stage II (T2N(0-1)) disease and nine were Stage III (T(3-4)N(0-1)). None of the patients with initially unresectable disease was rendered resectable. After a median follow-up interval of 33 months (range 26-53), the overall median survival was 12 months and 2-year survival was 30%. All patients who were initially unresectable or had radiological evidence of lymph node involvement have died. Therefore, despite good symptomatic response rates, ECF chemotherapy given in the preoperative setting did not appear to improve the outcome of patients with unresectable or radiologically lymph node-positive gastro-oesophageal adenocarcinoma. The role of ECF chemotherapy in resectable tumours is unclear and is currently under investigation in the randomized MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) study.

Comparison of diclofenac sodium and morphine sulphate for postoperative analgesia after day case inguinal hernia surgery.

Postoperative pain may be a significant reason for delayed discharge from hospital, increased morbidity and reduced patient satisfaction with ambulatory hernia surgery. This study compared two postoperative oral analgesic protocols after day case inguinal hernia repair; 30 mg morphine sulphate (MST) and 10 mg metoclopramide every 8 h for 48 h or 75 mg diclofenac twice daily for 48 h. The pain reported in the MST group was significantly greater on both the day of operation and the first postoperative day (P < 0.05, Mann-Whitney U test). A significantly higher proportion of patients taking MST complained of nausea on the day of operation and on the 1st postoperative day (P < 0.05, chi 2). The time taken to walk, dress and leave home alone were achieved in a significantly shorter duration in patients taking diclofenac. We conclude that diclofenac provides effective analgesia, has a more acceptable side-effect profile than morphine sulphate and is the treatment of choice after ambulatory hernia surgery.

Are Japanese and European gastric cancer the same biological entity? An immunohistochemical study.

To examine the suggested biological difference between Japanese and British gastric cancers, immunohistochemistry was used to demonstrate eight markers of biological activity in a matched series of 40 Japanese and 33 British cases. There were no differences in the proportions of Japanese and British tumours positive to epidermal growth factor, epidermal growth factor receptor, transforming growth factor alpha, cripto or p53. A significantly greater proportion of British tumours were positive to c-erbB-2 whilst a significantly greater proportion of Japanese tumours were positive to nm23. British tumours had a significantly greater mean proliferating cell nuclear antigen proliferation index than Japanese tumours. These differences could be clinically significant.

Duodenal plasmacytoma: a rare extramedullary localization simulating carcinoma of the head of the pancreas.

Plasmacytomas occurring in extramedullary sites are rare tumours, particularly so when located in the gastrointestinal tract. We report the case of a solitary extramedullary plasmacytoma arising in the duodenum and simulating a carcinoma of the head of the pancreas. Diagnostic and treatment options are discussed.

Expression of transforming growth factor alpha in experimental gastric carcinogenesis.

The induction of adenocarcinomas in the glandular stomach of the adult male Wistar rat by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used as a model to study the expression of the growth promoting peptide, transforming growth factor alpha (TGF alpha), during experimental gastric carcinogenesis. TGF alpha was identified using the monoclonal antibody Ab-2 and standard immunohistochemistry, together with a semiquantitative assessment of the intensity of expression. Immunoreactivity was confined to the differentiated compartment of the mucosa while the carcinogen MNNG caused a significant increase in the intensity of TGF alpha expression (p < 0.01), after as little as 16 weeks' exposure. In experimental adenocarcinomas, a change to a previously undescribed pattern of perinuclear TGF alpha expression was found, which may represent the site of intense TGF alpha production in the Golgi apparatus after malignant transformation.

Role of pre-admission clinics in a general surgical unit: a 6-month audit.

We report a 6-month audit of the running of a pre-admission assessment clinic for routine general surgical admissions. An attendance rate of 91.4% of fit patients ready for surgery on the day of admission was achieved. Of all patients attending the pre-admission clinics, 79.5% underwent surgery as planned. Pre-admission clinics are recommended as a method of improving the efficiency of elective surgical admissions.

Laparoscopic varicocele repair.

Varicocele is a common condition for which currently accepted methods of treatment are less than satisfactory. Reported herein is a successful laparoscopic technique of repair.

A five year audit of the role of parathyroid hormone assays and thallium-technetium isotope subtraction scanning in the preoperative investigation of primary hyperparathyroidism.

An audit has been performed of the value of parathyroid hormone assays and thallium-technetium isotope scanning in the pre-operative investigation of 67 hypercalcaemic patients referred for surgery over a 5 year period. Parathyroid hormone assay by region-specific technique was found to have a diagnostic sensitivity of 75% (n = 52) whilst the more recent assay for the intact molecule was 97% sensitive (n = 34). Thallium-technetium isotope scanning was only 64% sensitive overall (n = 59), due in part to the small size of adenomata now being referred for surgery. This study confirms the role of the intact parathyroid hormone assay but questions that of thallium-technetium isotope scanning in standard protocols of investigation for hypercalcaemia.