Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial.

PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still under debate. We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2) lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of relapse. We have reviewed the results of our trial after follow-up of more than 10 years. PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patients were followed for more than 10 years. RESULTS: A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with curative intent. Morbidity (25% v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P =.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years. CONCLUSION: Overall, extended lymph node dissection as defined in this study generated no long-term survival benefit. The associated higher postoperative mortality offsets its long-term effect in survival. For patients with N2 disease an extended lymph node dissection may offer cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.

Avoiding long-term disturbance to bladder and sexual function in pelvic surgery, particularly with rectal cancer.

Urinary and sexual dysfunction are common problems after rectal cancer surgery, and the likely cause is damage to the pelvic autonomic nerves during surgery. In recent years, attention has been focused on preserving the autonomic nerves through a technique which is usually combined with total mesorectal excision or radical pelvic lymphadenectomy. The autonomic nerves consist of the paired sympathetic hypogastric nerve, sacral splanchnic nerves, and the pelvic autonomic nerve plexus. We will demonstrate the anatomy of the pelvic autonomic nerves and the relation of these nerves to the mesorectal fascial planes, and review the medical literature on sexual and urinary dysfunction after rectal cancer surgery with and without autonomic nerve preservation.

Adenocarcinoma arising within a tailgut cyst: clinicopathological description and follow up of an unusual case.

Full clinicopathological details and clinical follow up of a case of malignant transformation within a tailgut cyst are presented. A 43 year old woman presented with signs and symptoms of an imminent threatened abortion. Routine examination identified a coincidental, asymptomatic retrorectal/presacral mass. Following imaging studies, surgical resection was carried out and an adenocarcinoma arising within a pre-existent tailgut cyst was identified by microscopy. Four years later the patient presented with neurological symptoms consistent with local recurrence of the tumour. Surgical biopsies confirmed this diagnosis and she was subsequently started on chemotherapy. She died soon after from a cause unrelated to the disease, after declining further active intervention. Differential diagnosis of such cases includes (cystic) teratoma, epidermal cyst, rectal duplication cyst, anal gland cyst and carcinoma, extension of local carcinoma, and metastatic disease. It is recommended that these lesions be completely excised when detected incidentally.

Extended lymph-node dissection for gastric cancer.

BACKGROUND: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. METHODS: Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS: Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent). CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

[Initial experiences with shorter hospital stays after primary surgery for breast carcinoma]. / Eerste ervaringen met opnameduurverkorting na primaire chirurgie wegens mammacarcinoom.

OBJECTIVE: To describe some personal, medical and financial consequences of moving up the discharge of patients from hospital after an operation because of breast carcinoma. DESIGN: Descriptive. SETTING: Department of Oncological Surgery, Medical Centre, Leiden University, Leiden, the Netherlands. METHOD: Thirty-five patients with breast cancer were operated during the period March to August 1997. Thirteen patients of this group were discharged sooner after operation, with the drain still in situ; the other 22 remained in hospital until after removal of the drain. Medical and financial consequences were investigated. RESULTS: The patient characteristics of the two groups were similar. In the group discharged earlier, the number of postoperative days in hospital on average was 4.5 days smaller. The number of postoperative complications in the two groups were similar; development of seroma after removal of the drain occurred less frequently in the group discharged earlier. The financial savings amounted to an average of Dfl. 2497.-per patient. The patients discharged earlier were very satisfied. CONCLUSION: The orientative study suggests that moving up discharge after a breast cancer operation is a policy that is safe, financially advantageous and satisfactory to the patients.

Local recurrence of a phyllodes tumour of the breast presenting with widespread differentiation to a telangiectatic osteosarcoma.

Osteogenic sarcomas of the breast are extremely rare and need to be distinguished from a variety of breast lesions producing metaplastic bone. A 50 year old patient presented with a painless lump in her right breast after twice previously having undergone local excision of a phyllodes tumour at this site. Following radiological and cytological investigation, excision was advised. Histology showed focal remnants of the previously excised phyllodes tumour in continuity with areas of widespread differentiation towards a telangiectatic osteosarcoma. So far this is a unique morphological endpoint.

[Suppurative hidradenitis]. / Hidradenitis suppurativa.

An obese woman aged 18 years had been suffering for several years from axillary hidradenitis suppurativa. Repeated incision and drainage never gave lasting results and the patient became socially isolated. Hidradenitis suppurativa is a chronic suppurative inflammation of skin areas containing apocrine glands: the skin of the axillae, of the breasts and of the anogenital region. Treatment in the first instance consists of general hygienic measures. Pharmaceuticals used include antibiotics, antiandrogens and oestrogens. Surgery is performed when the condition is at an advanced stage, with cellulitis and scarring; ample excision is necessary to reduce the risk of recurrence. CO2 laser therapy is a new method of treatment that shows good results in incipient and advanced lesions.

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer.

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.

Aggressive versus conventional strategies in the treatment of rectal adenocarcinoma.

OBJECTIVE: Comparison of an aggressive approach (including total mesorectal excision and combined modality adjuvant therapy) with a conventional approach in the treatment of primary rectal cancer. DESIGN: Retrospective study. SETTING: Memorial Sloan-Kettering Cancer Centre, New York (MSKCC) and University Hospital Leiden, the Netherlands (UHL). SUBJECTS: One hundred and sixty-nine patients treated at MSKCC and 96 patients treated at UHL. INTERVENTIONS: Total mesorectal excision (MSKCC) and conventional resection (UHL). MAIN OUTCOME MEASURES: Overall survival and local recurrence-free survival. RESULTS: Five-year overall survival was 73% for MSKCC patients and 52% for UHL patients (P < 0.001). Five-year local recurrence-free survival was 83% for MSKCC patients and 72% for UHL patients (P=0.001). Relative risk of dying or developing a local recurrence was 3.37 and 2.61, respectively, for patients treated at UHL compared to patients treated at MSKCC (P<0.001 and P=0.008, respectively). CONCLUSIONS: These data suggest that an aggressive approach including total mesorectal excision and combined modality adjuvant therapy improves survival and local control compared to a conventional approach.

Anatomical basis of autonomic nerve-preserving total mesorectal excision for rectal cancer.

Total mesorectal excision with autonomic nerve preservation for rectal cancer is based on the anatomy of the mesorectum and of the pelvic autonomic nerves. Cadaver dissections were performed to describe the relationship between these structures. Between the rectum and the sacrum a retrorectal space can be developed, lined anteriorly by the visceral leaf and posteriorly by the parietal leaf of the pelvic fascia. The hypogastric nerve runs anterior to the visceral fascia, from the sacral promontory in a laterocaudad direction. The splanchnic sacral nerves originate from the sacral foramina, posterior to the parietal fascia, and run caudad, laterally and anteriorly. After piercing the parietal layer of the pelvic fascia, approximately 4 cm from the midline, the sacral nerves run between a double layer of the visceral part of the pelvic fascia. The relationship between the hypogastric nerves, the splanchnic nerves and the pelvic fascia was comparable in all six specimens examined.

Prognostic value of the plasminogen activation system in patients with gastric carcinoma.

BACKGROUND: Patients with gastric cancer have a poor prognosis and can be cured by surgery only if the cancer is detected in an early stage. Extended surgery, down staging with chemotherapy before operation, and new postoperative treatments are recent approaches to increase survival rates. Categorizing patients' prognoses as good or poor by pathophysiologic markers, however, may be of great help in selecting therapies for these patients. For example, plasminogen activation (PA) parameters, that play an important role in tumor invasion and metastasis, have prognostic value for several human malignancies. METHODS: We evaluated the relation between several PA parameters in tissue with standard clinicopathologic parameters and with the overall survival of 50 consecutive patients with gastric carcinoma. RESULTS: Univariate analysis showed that a low tissue-type plasminogen activator (t-PA) activity in normal mucosa and in carcinomas and a high antigen level of inhibitor type-1 (PAI-1), and, to a lesser extent, of urokinase-type plasminogen activator (u-PA) receptor, in carcinomas are associated with a poor overall survival of the patients. In contrast, of the 14 clinicopathological parameters only the number of eosinophils in the tumors was associated with survival. Multivariate analysis revealed that the t-PA and PAI-1 levels are independently associated with survival. CONCLUSIONS: Plasminogen activation parameters in both normal and carcinomatous tissue of the stomach of patients with gastric carcinoma are of particular clinical interest because of their prognostic impact on overall survival.

Invasive cutaneous melanoma in The Netherlands, 1989-1990.

The Breslow or tumour thickness is the most important prognostic factor for survival from cutaneous melanoma. We studied the occurrence of melanoma in relation to tumour thickness and subsite in The Netherlands. Data on all newly diagnosed invasive cutaneous melanomas in the Netherlands Cancer Registry in 1989 and 1990 were used to estimate age and sex-specific incidence rates according to site and depth of tumour invasion. The incidence among women (9.5 per 100,000 person-years) was relatively high compared with other European countries. The predominant site was the trunk among men and the leg among women. After age 70, one-third of the melanomas were observed in the head and neck region. According to data from PALGA, the national computerized archive of Dutch pathology laboratories, 37% of the men and 29% of the women had a melanoma > 1.5 mm thick. Among persons younger than age 60, 26% had a melanoma > 1.5 mm thick, compared with 44% among those 60 years and over. In both registries the absolute and relative risks for a thicker melanoma increased with age, particularly for men. In The Netherlands, preventive measures for population groups with thicker melanomas should be targeted towards men and elderly persons.

Adjuvant chemotherapy for premenopausal breast cancer: a meta-analysis using quality-adjusted survival.

PURPOSE: Adjuvant chemotherapy for early breast cancer has been shown to offer an improvement in recurrence-free and overall survival, especially for younger women, but the acute toxic effects of this treatment discourage some physicians from prescribing it. The purpose of this analysis was to determine whether the benefit of 6 months of adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) treatment outweighs its costs in terms of toxic effects. METHODS: A meta-analysis of quality-adjusted survival was performed based on data from 1229 patients, aged 49 years or younger, randomized in eight trials comparing CMF versus no adjuvant systemic therapy. The eight trials were included in the worldwide overview conducted by the Early Breast Cancer Trialists' Collaborative Group. The Q-TWiST method was used in a meta-analysis that provided treatment comparisons incorporating differences in quality of life associated with the amount of time patients spend with subjective toxic effects, after relapse, and without symptoms of relapse. RESULTS: Within 6 years of follow-up evaluation for patients with node-positive disease, the benefit in terms of increased relapse-free and overall survival balanced the costs in terms of acute toxic side effects. This was true even for the extreme case in which a zero value was assigned to all 6 months during which patients might receive adjuvant CMF chemotherapy. Within 10 years of follow-up evaluation, treated patients gained an average of 1.5 years of relapse-free survival time, almost 1 year of overall survival time, and 1 year of time without symptoms and toxicity. CONCLUSIONS: Adjuvant chemotherapy for younger women with node-positive breast cancer provided substantial amounts of quality-adjusted survival time, even after accounting for costs associated with toxic effects of the treatment. The Q-TWiST method represents a valuable tool for comparing treatments because it incorporates patients' perceptions of their quality of life for therapeutic decision-making.

Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients.

For patients with gastric cancer deemed curable the only treatment option is surgery, but there is disagreement about whether accompanying lymph-node dissection should be limited to the perigastric nodes (D1) or should extend to regional lymph nodes outside the perigastric area (D2). We carried out a multicentre randomised comparison of D1 and D2 dissection. 1078 patients were randomised (539 to each group). 26 allocated D1 and 56 allocated D2 were found not to satisfy eligibility criteria (histologically confirmed adenocarcinoma of the stomach without clinical evidence of distant metastasis). Each of the remainder was attended by one of eleven supervising surgeons who decided whether curative resection was possible and, if so, assisted with the allocated procedure. Among the 711 patients (380 D1, 331 D2) judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (10 vs 4%, p = 0.004) and experienced more complications (43 vs 25%, p < 0.001). They also needed longer postoperative hospital stays (median 25 [range 7-277] vs 18 [7-143] days, p < 0.001). Morbidity and mortality differences persisted in almost all subgroup analyses. While we await survival results, D2 dissection should not be used as standard treatment for western patients.

Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. Cooperating Investigators.

PURPOSE: To investigate whether treatment with prolonged low-dose adjuvant chemotherapy could improve survival of patients with axillary node-positive breast cancer. PATIENTS AND METHODS: Four hundred fifty-two patients with axillary node-positive breast cancer who received postoperative irradiation were prospectively randomized in a trial (European Organization for Research and Treatment of Cancer [EORTC] 09771) that compared surgery followed by prolonged low-dose chemotherapy versus surgery alone. Chemotherapy was given for a period of 2 years and consisted of monthly courses of cyclophosphamide 50 mg/m2 orally on days 1 to 14, methotrexate 15 mg/m2 intravenously on days 1 and 8, and fluorouracil 350 mg/m2 intravenously on days 1 and 8 (CMF). RESULTS: At a median follow-up time of 10 years, the overall survival duration was significantly prolonged in the chemotherapy arm (hazards ratio, 0.75; 95% confidence interval, 0.56 to 0.99; P = .04). Ten-year overall survival rates (+/- SE) were 59% (+/- 3.6%) for the chemotherapy arm and 50% (+/- 3.7%) for the control arm. Time to local relapse was significantly prolonged in the chemotherapy arm (hazards ratio, 0.63; 95% confidence interval, 0.42 to 0.94; P = .02). Patients with one to three positive axillary nodes and patients with estrogen receptor-negative tumors especially benefited from chemotherapy. Toxicity was observed in 93% of patients. CONCLUSION: We conclude that prolonged low-dose adjuvant CMF can significantly prolong overall survival in patients with node-positive breast cancer. However, considering the fact that toxicity was still considerable despite reducing the dose of chemotherapy by 50%, we believe that conventionally dosed short-term regimens are preferable in the treatment of node-positive breast cancer.

Ifosfamide treatment as a 10-day continuous intravenous infusion.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis.

BACKGROUND/AIMS: Human colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activator expression, both in antigen and activity, accompanied by simultaneously enhanced levels of plasminogen activator inhibitors type 1 and type 2. This increased proteolytic activity may contribute to invasive growth and metastasis of the tumors. METHODS: In the present study, homogenates of liver metastases, primary colorectal carcinomas, and adjacent normal tissues were evaluated regarding the level and composition of urokinase, tissue-type plasminogen activator, and plasminogen activator inhibitors. RESULTS: Concentrations of urokinase were significantly increased in primary carcinomas and liver metastases compared with normal tissues, whereas tissue-type plasminogen activator levels were significantly decreased. Liver metastases showed, in contrast to the carcinomas, hardly any activity of plasminogen activators, which could be attributed to the enhanced presence of the inactive proenzyme form of urokinase in combination with more complexes of plasminogen activators with inhibitors. Furthermore, liver metastases had an eightfold higher content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen activators to metastasis homogenates, which resulted in increased complex formation. CONCLUSIONS: Colorectal cancer metastasis in the liver is associated with an inactivation of the enhanced urokinase cascade, which might allow tumor cells to settle in the liver.

Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer.

Human colorectal carcinogenesis has been shown previously to be associated with impressive changes in the tissue levels of plasminogen activators and their inhibitors, exemplified by an increase in the urokinase-type plasminogen activator (u-PA) and the inhibitors PAI-1 and PAI-2, and a decrease in tissue-type plasminogen activator (t-PA). In the present study we evaluated the prognostic significance of these parameters to the overall survival of patients with colorectal cancer, in conjunction with several major clinicopathological parameters like age, gender, differentiation grade, and Dukes' stage. Univariate analyses revealed that a low t-PA antigen level, low t-PA activity, and high u-PA/t-PA antigen ratio in normal mucosa and a high u-PA and PAI-2 antigen level in carcinomas are prognostic for a poor overall survival of patients with colorectal cancer. The prognostic value of t-PA antigen and activity in normal mucosa, the antigen ratio of u-PA in carcinoma (C) and t-PA in corresponding normal (N) mucosa [u-PA(C)/t-PA(N) antigen ratio], and PAI-2 antigen in carcinomas was found to be independent from clinicopathological parameters by multivariate analyses. These observations illustrate the clinical importance of the plasminogen activation cascade at the tissue level in colorectal cancer invasion, metastasis, and survival.