Serial CEA levels in colorectal carcinoma on adjuvant immuno(chemo)therapy—further follow-up. Modulation of adjuvant treatment

Serial plasma CEA levels have been studied preoperativelyd (testing A); one day after surgery (B); 10–15 days after surgery (C); 4 (D), 8(E), 12 (F), 16–18 (G), and 22–24 (H) months after surgery in a series of 45 patients affected by colorectal carcinoma who started soon after surgery a protocol of adjuvant immuno(chemo)therapy with Levamisole and BCG. Postoperative follow-up was from one to 26 months, with 28 patients followed for at least one year. Fourteen patients had recurrences: two of these had false-negative CEA tests, three had persistent high CEA levels after surgery, nine had increasing levels 9 12 months before clinical recurrence; and nine of these 14 patients showed frankly pathologic preoperative plasma CEA levels. Six patients who did not have a recurrence but (both at clinical and instrumental evaluation) who had two consecutive high plasma CEA levels, were put on prophylactic polichemotherapy. The prognostic importance of CEA levels both pre-and postoperatively, the possibility of “modulating” postoperative adjuvant treatments on the basis of CEA levels, and the problem of unexplained fluctuations of plasma CEA levels with the putative metabolic linkages are discussed.     

Value of serial CEA determinations in a surgical adjuvant trial of colorectal and gastric carcinoma

At the Cross Cancer Institute in Edmonton, a concurrently controlled, randomized, prospective surgical adjuvant trial involving Dukes' B2 and C colorectal carcinoma and gastric carcinoma (T1-4, No-2, Mo) has been activated for the last two years. To date, a total of 150 patients have been entered into the three arms of the trial (namely control, immunotherapy, and chemoimmunotherapy). Of these, 127 cases are colorectal carcinoma and 28 are gastric cancer. As part of the protocol, serial CEA determinations are obtained in all patients on a regular three-monthly basis. So far, 28 patients have confirmed recurrence (colorectal 20, gastric 8) demonstrated clinically or radiologically. Out of these 28 patients, 25 (89.2%) had CEA greater than 2.5 ng/ml months before actual demonstration of recurrence. However, if one uses a cutoff of 5.0 ng/ml as significant, that is, one standard deviation from the usual accepted value, then 21 out of 28 (75%) had persistent, elevated CEA's months before the recurrence manifested itself clinically or radiologically. The CEA profiles of three representative cases from each arm of the adjuvant trial are included. It is suggested that serial CEA determinations will be an invaluable adjunctive test in following patients in an adjuvant trial setting.     

Radiation therapy (RT) after prostatectomy: The case for salvage therapy as opposed to adjuvant therapy

Patients with pathologic stage T3 or T4 prostate cancer who have undetectable PSA levels following radical retropubic prostatectomy (RRP) have a substantial risk of recurrence. Radiotherapy (RT) can be administered immediately following the RRP (immediate adjuvant RT) or may be postponed until the PSA level has risen to a level that is indicative of residual or recurrent prostate cancer (salvage RT). Immediate adjuvant RT can significantly reduce the risk of relapse, but does not appear to increase the rate of survival. Approximately two-thirds of patients with rising PSA levels after RRP can be salvaged with RT alone. This result was achieved in patients treated with an adequate dose of radiation before the PSA rose to > 1.1 ng/ml. While no one can be certain which approach (adjuvant or salvage RT) is better, future studies should examine this issue. Whether immediate postoperative adjuvant RT is of value to patients is the subject of two randomized prospective studies. The benefit of adjuvant RT is a matter of controversy. Salvage RT treats only those patients with proven residual prostate cancer. The salvage RT approach has several advantages. This approach spares approximately 40% of patients who have had an RRP for T3 or T4 prostate cancer and eliminates the risks and costs associated with adjuvant RT. Additionally, it appears that the results of immediate adjuvant RT are similar to those achieved with early salvage RT.     

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.     

Prognostic significance of CEA levels and detection of CEA mRNA in draining venous blood in patients with colorectal cancer

BACKGROUND AND OBJECTIVES: The aims of this study were to determine carcinoembryonic antigen (CEA) levels and incidence of tumor cells using the RT-PCR technique in draining venous blood of patients with colorectal cancer, correlate the results with various histopathologic factors and determine their significance as prognostic factors. METHODS: From 1995 to 2000, 108 patients with adenocarcinoma of the colon or rectum, underwent curative surgery and enrolled in this prospective study. RESULTS: The 5-year survival group had significantly lower portal CEA levels compared to the hepatic metastasis outcome group. CEA mRNA was positive in the draining venous blood from 12 (11.1%) out of 108 patients included in the study. The rate of positive tumor cell detection in portal blood was significantly higher in the hepatic metastasis outcome group than in the 5-year survival and recurrence group. The proportion of patients with portal CEA > or =5 ng/ml was greater in patients with higher stage than in patients with lower stage. CONCLUSIONS: Positive CEA mRNA in draining venous blood predicted hepatic metastases and local recurrence with accuracy over 80% but with low sensitivity of 30% and 9%, respectively. Moreover, CEA level was a sensitive indicator in hepatic metastases as sensitivity was 95% and a specific indicator in predicting 5-year survival with specificity 84%.     

淋巴结阴性乳腺癌患者辅助治疗的研究进展

淋巴结阴性乳腺癌患者中有20%～30%经手术治疗后复发和转移.本文综述了如何选择需要内分泌治疗和/或化疗的淋巴结阴性乳腺癌患者,以及如何选择正确的治疗模式.     

Usefulness of preoperative CEA levels in the assessment of colorectal cancer patient stage

In order to demonstrate a prognostic value of preoperative CEA levels, we have tried to define a correlation between CEA and histologic stage of tumor in 124 patients with colorectal carcinoma. CEA concentration has been evaluated by radioimmunologic assay and the histologic stage following Dukes' classification. The results show a 25.0% positivity rate for patients in stage A, 48.2% for stage B, 61.1% for stage C, and 85.7% for stage D. The mean CEA values are 7.8 ng/ml in the first group, 30.3 ng/ml in the second, 58.1 ng/ml in the third, and 134.3 ng/ml in the last group. Furthermore, we have tried to relate the histopathologic grade of the tumor (G) with CEA levels in 54 patients of the 124. We conclude that preoperative CEA has a prognostic value, and it is useful in the staging of colorectal cancer patients. A low concentration indicates an early stage of the tumor, while a high concentration indicates a wide spread of disease; on the other hand, there are not significant correlations with cancer grading.     

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke''s stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.     

乳腺癌术后系统性辅助治疗的现状和进展

辅助治疗是可手术乳腺癌综合治疗的重要组成部分，了解乳腺癌辅助治疗的进展，选择合理的辅助治疗方案，对提高乳腺癌患者术后的长期生存率有重要的意义。     

Involvement of circulating CEA in liver metastases from colorectal cancers re-examined in a new experimental model.

Both experimental and clinical data show evidence of a correlation between elevated blood levels of carcinoembryonic antigen (CEA) and the development of liver metastases from colorectal carcinomas. However, a cause-effect relationship between these two observations has not been demonstrated. For this reason, we developed a new experimental model to evaluate the possible role of circulating CEA in the facilitation of liver metastases. A CEA-negative subclone from the human colon carcinoma cell line CO115 was transfected either with CEA-cDNA truncated at its 3' end by the deletion of 78 base pairs leading to the synthesis of a secreted form of CEA or with a full-length CEA-cDNA leading to the synthesis of the entire CEA molecule linked to the cell surface by a GPI anchor. Transfectants were selected either for their high CEA secretion (clone CO115-2C2 secreting up to 13 microg CEA per 10(6) cells within 72 h) or for their high CEA membrane expression (clone CO115-5F12 expressing up to 1 x 10(6) CEA molecules per cell). When grafted subcutaneously, CO115-2C2 cells gave rise to circulating CEA levels that were directly related to the tumour volume (from 100 to 1000 ng ml(-1) for tumours ranging from 100 to 1000 mm3), whereas no circulating CEA was detectable in CO115 and CO115-5F12 tumour-bearing mice. Three series of nude mice bearing a subcutaneous xenograft from either clone CO115-2C2 or the CO115-5F12 transfectant, or an untransfected CO115 xenograft, were further challenged for induction of experimental liver metastases by intrasplenic injection of three different CEA-expressing human colorectal carcinoma cell lines (LoVo, LS174T or CO112). The number and size of the liver metastases were shown to be independent of the circulating CEA levels induced by the subcutaneous CEA secreting clone (CO115-2C2), but they were directly related to the metastatic properties of the intrasplenically injected tumour cells.     

Targeted adjuvant therapy in breast cancer

Introduction: The potential of molecular targeted therapy to improve the clinical outcomes of patients with early-stage breast cancer (BC) as adjuvant therapy has been first demonstrated through endocrine treatment. The introduction of HER2 blockade, through the successful clinical development of trastuzumab, changed the natural history of HER2-positive BC subtype.

Areas covered: There are ongoing efforts to augment further the use of targeted agents as adjuvant treatment in BC, hoping that early introduction of targeted therapy blocking key oncogenic drivers of micro-residual disease, will significantly improve clinical outcomes. In the present Review, we present data through extensive search of PubMed about the following targeted adjuvant therapeutic strategies in BC: i) HER2 blockade and ongoing efforts to further augment its efficacy for patients with HER2-positive disease, ii) angiogenesis inhibition, iii) PI3K-mTOR- AKT pathway inhibition, iv) CDK4/6 inhibition, v) PARP inhibition.

Expert commentary: we provide insights about challenges and potential ways to overcome them, in terms of successful clinical development of targeted agents as adjuvant therapy for patients with BC. In particular, we emphasize the need to systematically assess minimal residual cancer burden as a way to increase the rates of successful clinical development of targeted agents in the adjuvant setting.     

Cognitive impairment associated with adjuvant therapy in breast cancer

The purpose of this study was to determine whether cognitive function changes over time in women with breast cancer who received adjuvant therapy as compared to women with breast cancer who received no adjuvant therapy. Three groups of women (n = 46) were studied; groups 1 and 2 consisted of women with stage I or II breast cancer. Group 1 received chemotherapy and group 2 received chemotherapy plus tamoxifen. Group 3 consisted of women with ductal carcinoma in situ who received no chemotherapy or tamoxifen. Cognitive function was evaluated at three timepoints. Time 1 occurred after surgery and before chemotherapy initiation in groups 1 and 2. Time 1 for group 3 occurred post-surgery. Time 2 occurred within 1 week after the conclusion of chemotherapy for groups 1 and 2 and at a comparable time for group 3. Time 3 occurred 1 year after Time 2. Women who received chemotherapy plus tamoxifen exhibited deterioration on measures of visual memory and verbal working memory and reported more memory complaints. Women who received chemotherapy alone also exhibited deteriorations in verbal working memory. Conversely, cognitive function scores improved in women who received no therapy, indicating practice effects. In conclusion, adjuvant chemotherapy in women with breast cancer can be associated with deteriorations in memory and this may persist over time. The addition of tamoxifen may lead to more widespread memory deficits.     

序贯化疗在乳腺癌辅助治疗中的研究进展

随着新的活性药物的出现和细胞生长动力学模型概念应用于临床,乳腺癌辅助化疗的疗效得到了一定的提高.序贯化疗的治疗方式在一定程度上改善了辅助治疗的疗效和治疗指数.本文对近年来序贯化疗在乳腺癌辅助治疗中临床研究进展进行了回顾.     

Lymphadenectomy and adjuvant therapy in endometrial carcinoma: role of adjuvant chemotherapy

To evaluate the therapeutic benefit of lymphadenectomy and adjuvant therapy, in particular chemotherapy, we retrospectively analysed survival rates and patterns of recurrence of endometrioid adenocarcinoma in 106 patients who underwent surgery including retroperitoneal lymphadenectomy. Adjuvant chemotherapy was administered to 46 patients (42 received a platinum-based regimen) and pelvic irradiation to 12. The 5-year survival rate of 23 patients with lymph node metastasis was worse than that of patients without lymph node metastasis (60% vs 96%, P<0.0001). Recurrence was observed in 14 patients (10 patients with chemotherapy, two with irradiation, and two without adjuvant therapy); the first site of recurrence was in distant sites in 12 patients; recurrence in the pelvic sidewall or exclusively in lymph nodes was not observed. The 5-year survival rate of 18 patients with lymph node metastasis treated with chemotherapy, was 61% including all 14 with macroscopically positive nodes and all nine with paraaortic metastasis. Of seven patients with bulky positives nodes, three patients with bulky paraaortic nodes died of the disease, three of the four patients with bulky pelvic but without bulky paraaortic nodes had no recurrence. In summary, lymphadenectomy may afford a survival benefit via the debulking of macroscopically positive nodes, and the predominance of distant recurrences suggests that chemotherapy is a suitable choice as an adjuvant therapy in endometrial carcinoma after lymphadenectomy.     

The case for routine use of adjuvant therapy in pancreatic cancer

Pancreatic cancer is a devastating disease with a poor prognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope of long-term survival. Even with optimal surgical management, 5-year survival averages 15% to 20% for resectable disease. Progress is being made, however. Currently, the benefits of postoperative therapy for resected pancreatic ductal adenocarcinoma appear clear, and recommendations for such therapy appear to us to be well justified. Additional benefit to patients awaits the development of new agents, molecular targeted drugs, and novel approaches such as immunotherapy.     

A panel discussion of controversies and challenges in the adjuvant treatment of colon cancer

Current issues of adjuvant therapy for colon cancer concern the introduction of drugs other than fluorouracil-5/leucovorin (5-FU/LV), the benefits for stage II patients, the use of new primary endpoints and the influence of age on treatment benefits. These issues were addressed in a panel discussion and the conclusions were the following: FOLFOX4 is the first regimen that shows superiority over 5-FU/LV. The use of 3-year disease-free survival as primary endoint could encourage the quicker adoption of improved therapeutic strategies into clinical practice. Available data suggest that there are some benefits for stage II patients, and the decision needs to be individualised for each patient. Further, therapeutic decisions based solely on the patient's age are inappropriate, and geriatric assessment tools will help in making this decision. This information would improve patient and physician understanding of the recent data regarding the potential benefits of adjuvant therapy.