赫赛汀在乳腺癌新辅助治疗与辅助治疗中的新进展

人源化单克隆抗体赫赛汀（herceptin）是第一个针对HER-2阳性乳腺癌的、以癌基因为靶的治疗药物。多项研究已证明,赫赛汀对治疗转移性乳腺癌有明显效果,单药治疗总有效率在25％左右。据Slamon等的Ⅲ期临床试验报道,将469例HER-2过度表达的女性转移性乳腺癌患者随机分为单用化疗组与化疗＋赫赛汀组,结果赫赛汀提高了肿瘤缓解率,延长了疾病进展时间（TTP））、中位缓解持续时间和整体生存时间。一组Ⅱ期随机对照研究（M77001）证明了赫赛汀联合泰索帝在一线治疗HER-2阳性转移性乳腺癌的地位。     

Liposomal anthracyclines: adjuvant and neoadjuvant therapy for breast cancer

Conventional anthracyclines, particularly doxorubicin, have played an important role in the treatment of patients with breast cancer for many decades. Conventional doxorubicin has shown excellent antitumor activity in the metastatic, neoadjuvant, and adjuvant settings. However, its clinical utility is limited due to acute and chronic toxicities, particularly cardiotoxicity, myelosuppression, nausea and vomiting, and alopecia. Liposomal doxorubicin formulations (liposomal doxorubicin [D-99] and pegylated liposomal doxorubicin) currently under investigation for the treatment of breast cancer have demonstrated similar efficacies and favorable toxicity profiles compared with conventional doxorubicin in patients with metastatic breast cancer. These agents have also shown efficacy and tolerability in several small studies as neoadjuvant therapy in patients with locally advanced breast cancer. While there are currently no studies with liposomal doxorubicin or pegylated liposomal doxorubicin as adjuvant therapy, their demonstrated activities and tolerabilities in the metastatic and neoadjuvant settings provide the rationale for the future study of these agents in adjuvant therapy for patients with early-stage breast cancer.     

The role of neoadjuvant and adjuvant chemotherapy regimens consisting of different combinations of drugs in the treatment of advanced oral cancer

We performed a retrospective analysis on the effect of neoadjuvant chemotherapy with three cycles of methotrexate (100 mg/m2 on day 1), cisplatin (90 mg/m2 on day 1) and bleomycin (20mg/m2 on day 1-5) with 21 d gap between each cycle in 44 patients with advanced squamous cell carcinoma of the cheek, lip and tongue followed by surgery and adjuvant chemotherapy consisting of cisplatin (90 mg/m2 on day 1), Mitomycin C (6 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 120 h continuous infusion from day 1) repeated every 3 weeks for three cycles. Following induction chemotherapy, complete response was observed in 11 out of 44 patients (25%), and a partial response in a further 28 patients (64%). The overall median survival of all patients was 29 months and those in stage III and stage IV were 30 and 15 months respectively (P< 0.001). The median duration of the time to relapse in patients who responded to adjuvant chemotherapy was 28 months. The main toxic effect was vomiting followed by hematological toxicity. No treatment-related deaths occurred. The regimen showed a significant response, encouraging median survival and a good tolerability profile.     

The role of neoadjuvant chemotherapy for breast cancer treatment

Neoadjuvant chemotherapy is being used increasingly in the management of patients with breast cancer, especially locally advanced cases. Such treatment is administered with the aim of of reducing the size of the primary tumor to increase the possibility of breast-conserving treatment (BCT). In our series, during the period from May 1995 to December 2000, 86 patients with tumors between 3.1 and 6.0 cm in diameter received epirubicin-based neoadjuvant chemotherapy. There were 55 (64.0%) responders and ultimately 64 patients (74.4%) were treated with BCT. With a median follow-up time of 39 months, 9 patients in the BCT group had developed local recurrence. Long-term follow-up is required to establish whether this procedure is a safe alternative to mastectomy for patients with large breast cancers.     

The role of neoadjuvant chemotherapy for breast cancer treatment

Neoadjuvant chemotherapy has become popular, especially for patients with advanced breast cancer. The pros and cons of neoadjuvant chemotherapy for treating breast cancer patients are reviewed. The advantages of neoadjuvant chemotherapy are 1) overall survival and recurrence-free survival rate are the same as post-operative chemotherapy, 2) serves as an in vivo sensitivity test, 3) increases the rate of breast conserving therapy, 4) facilitates the study of cancer biology. On the other hand, the disadvantages of neoadjuvant chemotherapy are 1) it modifies the stage, 2) treatment delay of PD cases, 3) residual intraductal component may be left behind after breast conserving surgery, 4) there are some cases of over-treatment. Combination chemotherapy is one possible way to increase the pathological CR rate, although the optimal order and cycles have not been determined. To avoid residual cancer cells after breast conserving surgery, the shrinkage pattern should be evaluated by MRI. Core needle biopsy should be performed before neoadjuvant chemotherapy to avoid over-treatment. It is essential to develop more effective regimens and stratify patients based on predictive factors.     

The role of ovarian ablation in the adjuvant therapy of breast cancer

Increasing interest has emerged in the role of ovarian function suppression, which has shown equivalence to adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil), whether achieved by surgery or irradiation, in breast cancer patients. Studies have suggested temporary amenorrhea can confer benefit in early breast cancer, giving luteinizing hormone-releasing hormone (LH-RH) agonists an advantage over oophorectomy or radiation. Compared with no therapy, LH-RH agonists reduce risks of recurrence and death among women younger than 50 years of age who have hormone receptor-positive tumors. Trials are assessing the benefits of adding LH-RH agonists to aromatase inhibitors, tamoxifen, or after chemotherapy in women remaining premenopausal, and the necessity for adjuvant chemotherapy with combined ovarian ablation and antiestrogen therapy.     

The role of neoadjuvant chemotherapy in the treatment of advanced ovarian cancer

Primary cytoreductive surgery followed by chemotherapy represents the current standard treatment for patients with advanced ovarian cancer. Neoadjuvant chemotherapy followed by interval debulking surgery has been proposed as an alternative approach for the initial management of bulky ovarian cancer, aiming at the improvement of surgical efficiency and patients' quality of life. According to the hitherto published studies, consisting mainly of retrospective observations, neoadjuvant chemotherapy followed by interval cytoreduction appears to improve the prognosis and quality of life in selected groups of patients. The survival outcome in these patients is similar to that of the conventional approach, or even better in some of the cases. Moreover, patients undergoing debulking surgery after having received neoadjuvant chemotherapy had a reduced perioperative morbidity compared to patients undergoing primary cytoreduction. Concurrently, neoadjuvant chemotherapy provides preoperative knowledge of tumor chemosensitivity, hence allowing the surgeon to choose appropriately aggressive treatment. However, until the results of prospective randomized trials become available, neoadjuvant chemotherapy followed by interval surgery should be applied only to individual cases and primarily in the context of clinical trials.     

Emerging modalities for adjuvant therapy of breast cancer: neoadjuvant chemotherapy

There is evidence from theoretical models and experimental studies that indicates that preoperative timing of chemotherapy (neoadjuvant treatment) may be a superior treatment strategy than its use postoperatively. We have shown in our pilot study of 43 premenopausal patients with newly diagnosed cancer of the breast that administration of one cycle of CMF chemotherapy preoperatively was safe. Subsequently, a randomized study of preoperative against postoperative adjuvant chemotherapy has been started and to the present time, 98 patients have been randomized. Preliminary assessment of the randomized study confirmed the safety of the adjuvant chemotherapy with one course of cyclophosphamide, methotrexate, and 5-fluorouracil given preoperatively and also showed that the interval between diagnosis and the first course of chemotherapy can be substantially reduced. In addition to the preoperative timing, other aspects of the neoadjuvant approach are discussed. They include a more frequent utilization of fine needle aspiration so that the tissue diagnosis of breast cancer can be obtained and also refinement of diagnostic techniques, used before the preoperative treatment for the selection of high-risk patients (the neoadjuvant staging). The purpose of our presentation is not to recommend presently preoperative chemotherapy routinely but rather to indicate a need for well-controlled studies testing its appealing theoretical rationale. Its use in adjuvant therapy of breast cancer represents a major departure from the conventional management and, therefore, if the cooperation of practitioners and cooperative groups is to be secured, its rationale and safety must be well-defined.     

The evolving role of aromatase inhibitors in adjuvant breast cancer therapy

The development of third-generation aromatase inhibitors (AIs) has brought about a major change in the therapeutic approach to patients with hormone-sensitive breast cancer. In randomized clinical trials, each of the third-generation AIs has demonstrated efficacy in the adjuvant treatment of postmenopausal women with receptor-positive tumors. Anastrozole has been shown to improve disease-free survival when compared with standard first-line tamoxifen, letrozole has been shown to further reduce the rate of breast cancer events when given as extended adjuvant therapy in women completing between 4.5 and 6 years of tamoxifen, and exemestane has been shown to improve disease-free survival when substituted for tamoxifen after an initial 2-3 years of adjuvant therapy. Although long-term follow-up for safety and overall survival continues in each of these trials, currently available data suggest that an AI should now be included as part of adjuvant endocrine therapy for the great majority of receptor-positive postmenopausal patients. To address these rapidly evolving issues related to the endocrine adjuvant treatment of postmenopausal women, an expert panel met in March 2004 in Hamburg, Germany, the site of the Fourth European Breast Cancer Conference. The panel's overview of recent endocrine data is presented along with updated results where available. In addition, case-based discussions are included to provide direction on how to integrate recent endocrine adjuvant clinical trial findings into everyday practice.     

The role of bisphosphonates as adjuvant therapy for breast cancer

Bone is the most common site of distant recurrence in breast cancer. The development of skeletal metastases involves complex interactions between the cancer cells and the bone microenvironment. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption. Bisphosphonates are potent inhibitors of osteoclastic bone resorption with proven efficacy in reducing tumor-associated skeletal complications. Several studies have investigated the adjuvant, or preventive, use of these drugs in breast cancer. Laboratory experiments have shown that the development of bone metastases can be inhibited by bisphosphonates. Three randomized clinical trials of bisphosphonates in nonmetastatic breast cancer patients have yielded conflicting results with respect to development of osseous and visceral metastases and survival. Defining the potential role of these agents in adjuvant breast cancer treatment requires further investigation in randomized, large-scale, multicenter clinical trials. The data available to date provide a strong impetus for continued clinical and laboratory work with bisphosphonates in breast cancer.     

The role of 5-fluorouracil dose in the adjuvant therapy of colorectal cancer

BACKGROUND: In many centres, the use of 5-fluorouracil (5-FU) combined withlevamisole has become standard ther apy for the treatment ofpatients with Dukes' C colon cancer. However, the role of levarnisoleremains unclear. MATERIALS AND METHODS: All of the published adjuvant studies for colorectal cancerin which 5-FU (either as a single agent or in combination withother cytotoxics or levamisole) was compared to a no-treatmentcontrol group were ranked according to the total planned doseof 5-FU (assuming a body weight of 70 kg or a body surface areaof 1.7 m over a three-month time frame. The effect of plannedtotal dose of adjuvant therapy on the reduction of mortalitywas analysed using indirect comparisons of dose on the log oddsratio of death in a linear regression analysis. RESULTS: Overall, this analysis demonstrated a significant reductionin the odds of death for those receiving 5-VU regi mens comparedto untreated controls (estimate 0.82, 95% CI 0.74 to 0.91, p< 0.001). This effect was larger in those re ceiving a largerplanned dose; for a total dose of 5-VU in the first three monthsof greater than 10 grams, 8 to 10 grains, less than 8 gramsor oral 5-PU, estimates were 0.71, 0.79, 0.93 and 1.04, respectively(p=0.02 for trend). Similar results were observed when the plannedtotal dose of 5-VU received over 12 months was analysed. Theanalysis was then repeated by separating those studies in which5-PU and leva misole were compared to a no-treatment control.A larger effect was seen in the 5-FU/levamisole trials (oddsratio, 0.64) compared to the other 5-Hi regimens (odds ratio0.86, p=0.04). However, when adjusted for dose, the effect oflevamisole was no longer significant (p=0.09). CONCLUSION: These data suggest two separate hypotheses. The first is thatthe benefit associated with the use of 5-FU and levamisole givenas adjuvant therapy in Dukes' C colon cancer is directly relatedto the planned total dose of 5-FU administered. Alternatively,in view of the fact that levami sole was part of the treatmentregimens in two of the three studies in which the total planneddose of 5-FU exceeded 10 grams in three months (or 40 grainsin 12 months), levamisole may be critical to outcome and the5-FU total dose or dose intensity less relevant. colorectal carcinoma, dose intensity, 5-fluorouracil, levamisole, total dose     

The role of adjuvant endocrine therapy in the management of operable breast cancer

Since June, 1982, a chemoendocrine adjuvant clinical trial has been conducted at the Aichi Cancer Center Hospital. Women with operable breast cancer were stratified on the basis of the number of positive axillary nodes. Node negative patients received tamoxifen (TAM) for 6 months (Trial I), patients with 1-7 positive nodes received either cyclophosphamide (CPA) for 4 weeks and TAM for one year (Trial II), and patients with 8 or more positive nodes received either CPA for 8 weeks and TAM for 3 years (Trial III). Numbers of evaluable cases are 449 for Trial I, 228 for Trial II and 84 for Trial III. This is an interim report, and the median follow-up time is 3 years and 5 months. This is a prospective non-randomized trial, and control groups (observation group and chemotherapy group) are historical. Results: 1. Premenopausal patients in Trial I yielded intermediate outcome between those of observation and chemotherapy groups. Thus, for this subgroup, adjuvant chemotherapy can be considered as a standard, and addition of TAM is recommended. 2. The benefit of TAM is apparent for postmenopausal patients in Trial I. 3. TAM is effective for both pre- and postmenopausal patients in Trial II. Addition of more aggressive chemotherapy should be considered. 4. Premenopausal patients in Trial III had a better disease-free survival compared with those of control groups. More effective combined chemotherapy may yield longer overall survival. 5. Postmenopausal patients in Trial III had a better disease-free and overall survival rate. Adjuvant TAM and combined chemotherapy can be considered as standard care for this subgroup.     

The evolution of adjuvant therapy in the treatment of early-stage colon cancer

Adjuvant treatment of colon cancer, one of the most common malignancies, is an important issue in oncology. This article describes the development of adjuvant therapy and how the 2 major evolution steps, the successes of fluoropyrimidines, and then of oxaliplatin, have been achieved, Problems and failures, such as those of targeted therapies, also are addressed to help us to overcome their limitations. Special situations, such as stage II disease and an elderly population in which adjuvant chemotherapy is still controversial, are reviewed from the clinician perspective. The synthesis of these data allows us to conceive a future development focused on translational research.