Jo Hermans

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.

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation

Summary Background Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. Methods Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range Findings At the time of analysis, 1922 (61%) of the 3142 patients were alive—1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA—identical sibling transplants and unrelated transplants for transplants done in 1989–93 and 1994–96. Interpretation Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.

Micrometastases and Survival in Stage II Colorectal Cancer

BACKGROUND Standard treatment of colorectal cancer includes adjuvant chemotherapy for patients with stage III disease (defined by the presence of lymph-node metastases), but not for patients with stage II tumors (who have no lymph-node metastases). However, 20 percent of patients with stage II tumors die of recurrent disease. We investigated whether the detection of micrometastases can be used to identify patients with stage II disease who are at high risk for recurrence. METHODS We analyzed 192 lymph nodes from 26 consecutive patients with stage II colorectal cancer, using a carcinoembryonic antigen-specific nested reverse-transcriptase polymerase chain reaction. Five-year follow-up information was obtained on all patients. Observed and adjusted survival rates were assessed in the patients with and the patients without micrometastases. RESULTS Micrometastases were detected in one or more lymph nodes from 14 of 26 patients (54 percent). The adjusted five-year survival rate (for which only cancer-related deaths were considered) was 50 percent in this group, whereas in the 12 patients without micrometastases, the survival rate was 91 percent (P=0.02 by the log-rank test). The observed five-year survival rates were 36 percent and 75 percent, respectively (P=0.03). The groups were similar with respect to age, sex, tumor side (location in relation to the flexura lienalis), degree of tumor differentiation (grade), and diameter of the primary tumor. CONCLUSIONS Molecular detection of micrometastases is a prognostic tool in stage II colorectal cancer.

The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age

PURPOSE To determine if in patients with single brain metastasis the addition of neurosurgery to radiotherapy leads to lengthening of survival or to better quality of life. METHODS AND MATERIALS From 1985 to 1990, 66 patients with single brain metastasis from a solid tumor were entered in a randomized trial of neurosurgery plus radiotherapy vs. radiotherapy alone. Patients were stratified for lung cancer vs. other sites of cancer and for progressive vs. stable systemic cancer. Radiotherapy was given to the whole brain by a novel scheme of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks, to obtain a relatively high total dose and short overall time, with minimal risk of late damage to normal tissue in long-term survivors. RESULTS In the whole group of 63 evaluable patients, both with lung cancer as with other tumors, the combined treatment led to a better duration of survival (median 10 vs. 6 months; p = 0.04). The largest difference between both treatment arms was observed in patients with inactive extracranial disease (median 12 vs. 7 months; p = 0.02). Patients with active extracranial disease had an equal median survival of only 5 months, irrespective of given treatment. Age proved to be a strong and independent prognostic factor: patients older than 60 years had a hazard ratio of dying of 2.74 (p = 0.003) compared with younger patients. Following treatment, most patients remained functionally independent until a few weeks before death. In the majority of patients the cause of death was systemic tumor progression. CONCLUSION Patients with single brain metastasis and with controlled or absent extracranial tumor activity should be treated with surgery and radiotherapy, especially when they are younger than 60 years. For patients with progressive extracranial disease, radiotherapy alone seems to be sufficient. The accelerated radiotherapy scheme of 40 Gy in 2 weeks to the whole brain is tolerated well and should also be considered for patients in a good performance status with surgically unaccessible single metastasis or even with multiple brain metastases.

Beneficial Effects of Leukocyte Depletion of Transfused Blood on Postoperative Complications in Patients Undergoing Cardiac Surgery A Randomized Clinical Trial

BACKGROUND Leukocytes in transfused blood are associated with several posttransfusion immunomodulatory effects. Although leukocytes play an important role in reperfusion injury, the contribution of leukocytes in transfused blood products has not been investigated. To estimate the role and the timing of leukocyte filtration of red cells in cardiac surgery, we performed a randomized study. METHODS AND RESULTS Patients scheduled for cardiac surgery were randomly allocated to receive either packed cells without buffy coat (PC, n = 306), fresh-filtered units (FF, n = 305), or stored-filtered units (SF, n = 303) when transfusion was indicated. We evaluated the periods of hospitalization and stay at the intensive care unit, and the occurrences of postoperative complications up to 60 days after surgery. The average hospital stay was 10.7 days, of which 3.2 days were in the intensive care unit, without significant differences between the groups. In the PC trial arm, 23.0% of the patients had infections versus 16.9% and 17.9% of the patients in the leukocyte-depleted trial arms (P=.13). Within 60 days, 45 patients had died, 24 patients in the PC trial arm (7.8%), versus 11 (3.6%) and 10 (3.3%) patients in the FF and SF trial arms, respectively (P=.015). CONCLUSIONS In cardiac surgery patients, especially when more than three blood transfusions are required, leukocyte depletion by filtration results in a significant reduction of the postoperative mortality that can only partially be explained by the higher incidence of postoperative infections in the PC group.

Randomised controlled trial comparing transfusion of leucocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer

In retrospective studies, perioperative blood transfusions were associated with poor prognosis after surgery for cancer and were a major independent risk factor for postoperative bacterial infection. Leucocyte-depleted, in contrast to buffy-coat-depleted, blood has no immunosuppressive effects in transplantation and so might lack detrimental effects on cancer prognosis and postoperative infections. We studied this hypothesis in a controlled trial by randomly allocating patients to receive either leucocyte-depleted red cells or packed cells without buffy coat when blood was needed. Between 1987 and 1990, 871 eligible patients with colorectal cancer, including 697 patients operated upon with curative intent, were randomised in the 16 participating hospitals. Neither the eligible group nor the curative group showed significant differences between the two trial transfusions in survival, disease-free survival, cancer recurrence rates, or overall infection rates after an average follow-up of 36 months. Patients who had a curative resection and who received blood of any sort had a lower 3-year survival than non-transfused patients (69% vs 81%, p = 0.001) and a higher infection rate (39% vs 24%, p < 0.001). Colorectal cancer recurrence rates, however, were not influenced by blood transfusion (30% vs 26%, p = 0.22). These combined observations confirm the association between blood transfusion and poor patient survival but indicate that the relation is not due to promotion of cancer.

The value of morphometry to classic prognosticators in breast cancer

In 271 breast cancer patients with adequate follow‐up for at least 5.5 and maximally 12 years, the value of morphometry to classic prognosticators of breast cancer (tumor size and axillary lymph node status) was assessed. Previous studies had indicated the value of this quantitative microscopic technique. Apart from quantitative microscopic features, subjective qualitative features such as nuclear and histologic grade were assessed as well. Univariate life‐table analysis showed the significance (p <0.001) of several features such as lymph node status, tumor size, nuclear and histologic grade, and several morphometric variables (mitotic activity index, mean and standard deviation of nuclear area). Cellularity index was also significant (p = 0.02). Survival analysis with Coxs regression model, using a stepwise selection as well as backwards elimination, pointed to three features: mitotic activity index, tumor size, and lymph node status. Mitotic activity was the most important prognostic feature, but the combination of these three features in a multivariate prognostic index had even more prognostic significance. Kaplan‐Meier curves showed that the 5‐year survival of lymph node‐negative patients (n = 146) is 85%, versus 93% in patients with a “good prognosis index” (n 150). For lymph nodepositive patients (n = 125), 5‐year survival was 55%, compared with 47% in the “high index” (poor prognosis) patients (n = 121). Logistic discriminant analysis with 5.5‐year follow‐up as a fixed endpoint (191 survivors and 80 nonsurvivors) essentially gave the same results. Application of two instead of one decision threshold (e.g., numerical classification probability 0.60 and 0.40) decreased the number of false‐negative and false‐positive outcomes, however, with a number of patients falling in the class “uncertain.” Thus, in agreement with other studies, morphometry significantly adds to the prognosis prediction of lymph node status and tumor size. Mitotic activity index is the best single predictor of the prognosis. An additional index advantage is that the multivariate model results in a continuous index variable that can be subdivided in many classes with an increasing risk of recurrence, so that more refined clinical therapeutic decision making is possible in individual patient care. The morphometric techniques are inexpensive and fairly simple and therefore can be applied in most pathology laboratories.

Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study

BACKGROUND Intraoperative hyperfibrinolysis contributes to bleeding during adult orthotopic liver transplantation. We aimed to find out whether aprotinin, a potent antifibrinolytic agent, reduces blood loss and transfusion requirements. METHODS We did a randomised, double-blind, placebo-controlled trial in which six liver-transplant centres participated. Patients undergoing primary liver transplantation were randomly assigned intraoperative high-dose aprotinin, regular-dose aprotinin, or placebo. Primary endpoints were intraoperative blood loss and transfusion requirements. Secondary endpoints were perioperative fluid requirements, postoperative blood transfusions, complications, and mortality. FINDINGS 137 patients received high-dose aprotinin (n=46), regular-dose aprotinin (n=43), or placebo (n=48). Intraoperative blood loss was significantly lower in the aprotinin-treated patients, with a reduction of 60% in the high-dose group and 44% in the regular-dose group, compared with the placebo group (p=0.03). Total amount of red blood cell (homologous and autologous) transfusion requirements was 37% lower in the high-dose group and 20% lower in the regular-dose group, than in the placebo group (p=0.02). Thromboembolic events occurred in two patients in the high-dose group, none in the regular-dose group, and in two patients in the placebo group (p=0.39). Mortality at 30 days did not differ between the three groups (6.5%, 4.7%, and 8.3%; p=0.79). INTERPRETATION Intraoperative use of aprotinin in adult patients undergoing orthotopic liver transplantation significantly reduces blood-transfusion requirements and should be routinely used in patients without contraindications.

Prevention of relapses in systemic lupus erythematosus

Many relapses of systemic lupus erythematosus (SLE) are preceded by a rise in antibodies against double-stranded DNA (anti-dsDNA). We investigated whether these relapses can be prevented by giving prednisone when a rise in anti-dsDNA occurs. 156 patients with SLE were studied. Anti-dsDNA was measured by Farr assay monthly. When a rise in anti-dsDNA was found, patients were randomly assigned either conventional treatment or 30 mg prednisone added to the current daily dose and tapering off to baseline over 18 weeks. A rise in anti-dsDNA was detected in 46 patients (24 assigned conventional treatment and 22 prednisolone). The relapse rate was higher in the conventional group than in the prednisolone group (20 vs 2, p < 0.001). Although rises in anti-dsDNA in the prednisone group were treated with additional prednisone, the cumulative oral doses of prednisone in the two groups did not differ significantly (p = 0.025). 7 major relapses requiring additional cytotoxic immunosuppressive treatment occurred in the conventional group versus 2 in the prednisone group. Treatment with prednisone as soon as a significant rise in anti-dsDNA occurs prevents relapse in most cases, without increasing the cumulative dose of prednisdone given.

Local Recurrence After Breast-Conserving Therapy for Invasive Breast Cancer: High Incidence in Young Patients and Association with Poor Survival

PURPOSE To study risk factors for local recurrence (LR) after breast-conserving therapy (BCT) for invasive breast cancer and, for patients with an LR, the mode of detection, location, treatment, influence of radiation therapy, and impact on survival. METHODS AND MATERIALS 1360 patients (median age 52 years; range 24-88) with a total of 1393 pT1-2 N0-1 tumors treated with BCT between 1980-1994 were studied (median follow-up 52 months). The adequacy of radiation treatment of the patients developing LR was studied in a quality control study. The impact of LR on overall survival and distant metastasis was studied in a Cox regression model with LR as a time-dependent covariate. RESULTS A total of 88 LR occurred with a 5- and 10-year LR risk of 8 and 12%. Age was the only significant risk factor. Compared to patients > 65 years old, patients < 45 years old and patients 45-65 years old had a relative risk (RR) of 4.09 and 2.41, respectively, of developing LR. Risk on LR was found to increase gradually with younger age. Radiation therapy was considered adequate and did not play a role in influencing the LR rate. Almost 65% of the LR were true or marginal recurrences. Of all LR, 80% appeared during the first 5 years and were detected with equal frequency by the patient herself, the physician, and annual mammography. LR was a major predictor for distant metastasis (RR: 4.90; 3.15-7.62) and death (RR: 4.29; 2.93-6.28). CONCLUSION Young age is a major risk factor for LR and there is a significant gradual increase in LR with decreasing age. LR is associated with a higher risk of distant metastasis and death. Whether LR is the cause of or a marker for distant metastasis remains unresolved.