Radiotherapy and chemotherapy in invasive bladder cancer with potential bladder sparing.

The standard treatment in the United States for patients with muscle infiltrating tumors is radical cystectomy with or without radiation treatment. The results of such treatment have been generally unsatisfactory, with 40% or more patients developing systemic disease with a 5-year survival rate of less than 50%. Combination chemotherapy employing both cisplatin and methotrexate can produce a 30% to 50% clinical complete response rate (negative biopsy, negative urinary cytology) of the primary tumor. Although the optimal combination of chemotherapeutic agents has not yet been determined, it is unlikely that combination chemotherapy alone, even in completely responding patients, will be adequate to rid the bladder of a primary invasive transitional cell carcinoma. Additional therapy by either surgery or external beam radiotherapy seems warranted owing to the high likelihood that there will be residual microscopic tumor in the bladder. Concomitant systemic chemotherapy and external beam radiotherapy produces complete remissions in 65% to 90% of patients. Follow-up of from 3 to 5 years following full chemoradiotherapy will be necessary to be certain that the bladder has been sterilized of cancer. Combined cisplatin and external beam radiation (using a boost technique that spares the section of the bladder uninvolved with tumor) does not seem to enhance local soft-tissue toxicity (relative to the radiotherapy alone) with the exception of the neurotoxicity seen with intra-arterial cisplatin. Debulking TURB tumor appears to improve the local success rate for patients being considered for bladder preservation with the use of the combination of systemic chemotherapy and/or radiotherapy. Not all patients respond to concomitant chemotherapy and radiation therapy. Our current approach is that the selection process must be carried on at several points during the treatment. Only patients who respond completely to the initial courses of chemotherapy and radiation should be carried to a full radiation dose. In the absence of a complete response following upfront chemotherapy and 4000 cGy in combination with additional cisplatin courses, cystectomy at that point is the recommended treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neoadjuvant chemotherapy in ovarian cancer

Primary radical tumor debulking followed by platinum/taxane-based chemotherapy is considered standard for advanced stage ovarian carcinomas. The extent of postoperative residual disease is the most important prognostic factor. However, complete tumor resection is achieved in only 40-50% of advanced ovarian cancers. For the remaining patients, who have an unfavorable prognosis, the concept of neoadjuvant or primary chemotherapy followed by interval laparotomy has emerged. Two different strategies are pursued. One is to administer several courses of neoadjuvant chemotherapy in order to downstage the tumor prior to primary debulking surgery. The other is to administer chemotherapy after suboptimal debulking surgery to optimize cytoreduction during interval laparotomy. Numerous retrospective studies demonstrated that neoadjuvant chemotherapy followed by primary debulking surgery is a feasible and safe approach. It is becoming increasingly evident that the selection of appropriate patients is crucial. Some studies demonstrated that the volume of ascites proved to be an easily measurable biomarker that allowed prediction of tumor resectability. However, further investigations are needed to better define patients who will benefit from neoadjuvant chemotherapy. Despite promising results, neoadjuvant chemotherapy must still be considered experimental. Therefore, the potential advantages of neoadjuvant chemotherapy need to be confirmed in prospective randomized studies.     

Neoadjuvant chemotherapy in ovarian cancer

Primary radical tumor debulking followed by platinum/taxane-based chemotherapy is considered standard for advanced stage ovarian carcinomas. The extent of postoperative residual disease is the most important prognostic factor. However, complete tumor resection is achieved in only 40–50% of advanced ovarian cancers. For the remaining patients, who have an unfavorable prognosis, the concept of neoadjuvant or primary chemotherapy followed by interval laparotomy has emerged. Two different strategies are pursued. One is to administer several courses of neoadjuvant chemotherapy in order to downstage the tumor prior to primary debulking surgery. The other is to administer chemotherapy after suboptimal debulking surgery to optimize cytoreduction during interval laparotomy. Numerous retrospective studies demonstrated that neoadjuvant chemotherapy followed by primary debulking surgery is a feasible and safe approach. It is becoming increasingly evident that the selection of appropriate patients is crucial. Some studies demonstrated that the volume of ascites proved to be an easily measurable biomarker that allowed prediction of tumor resectability. However, further investigations are needed to better define patients who will benefit from neoadjuvant chemotherapy. Despite promising results, neoadjuvant chemotherapy must still be considered experimental. Therefore, the potential advantages of neoadjuvant chemotherapy need to be confirmed in prospective randomized studies.     

节拍化疗在实体肿瘤治疗中的作用

肿瘤血管形成对于实体肿瘤的生长和转移起着至关重要的作用,建立于抗肿瘤血管新生理论之上的节拍化疗为实体肿瘤的治疗带来了曙光。在国内外的相关研究中,人们发现小剂量节拍性给予某些化疗药物可以抑制肿瘤血管的新生,而且效果要好于传统的最大耐受剂量（maximum tolerated dose,MTD）化疗方法。本文就节拍化疗在实体肿瘤治疗中的作用做一综述。     

Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy

Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4-16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. All patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, HDMTX with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin in addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%) have remained continuously free of recurrent or metastatic disease from 6-34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6-35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival in responding patients and in helping identify patients whose disease-free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease-free survival rate reported to date for osteogenic sarcoma.     

Scientific basis for adjuvant and primary (neoadjuvant) chemotherapy

It can be stated as a general biological principle that there are many compelling reasons why chemotherapy should be directed at minimal tumor burdens. This is true whatever the nature of the tumor and becomes especially valid when one is dealing with tumors that are not curable when treated at the advanced stage. The patients who are likely to have the greatest benefit from adjuvant chemotherapy are, somewhat paradoxically, those who are at the least risk for recurrence following primary treatment. This is because, on the average, these patients will have the least tumor burdens. Patients who are at very high risk for relapse in breast cancer, (stage II patients with four plus positive nodes) will be the ones with the greatest subclinical burdens and may well have already crossed the threshold of curability to incurability. Directing effective chemotherapy programs at patients with lesser risk of recurrence complicates the ethical problems associated with adjuvant chemotherapy. To some degree, these ethical concerns can be assuaged by the appreciation that it is likely that protracted programs of chemotherapy (1 to 2 years) may well not be necessary. In general, curative drug programs can generally accomplish objectives with 3 to 6 months of fairly intensive treatment. Reducing the duration of adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF) from 12 months to 6 months did not appear to have an adverse effect on long-term results. Factors such as dose intensity and early use of effective noncross-resistant agents may be much more important than the chronic administration of agents in suboptimal dosage. The narrower question as to whether advancing the time forward of adjuvant chemotherapy will make additional significant impact on survival cannot be answered yet but clearly is an important issue. There are several theoretical reasons why neoadjuvant treatment might be of particular benefit, and even if it ultimately transpires that breast cancer is not an ideal model disease for this approach, it does not preclude this particular technique for being effective in other types of malignancy.     

Preoperative chemotherapy of testicular cancer and Wilm's tumor

Of the various urogenital malignancies, preoperative chemotherapy is most effective for testicular cancer and Wilms' tumor. The most effective treatment regimens for advanced nonseminomatous testicular tumors employ vinblastine, CDDP and bleomycin and adjunctive surgery. Another effective chemotherapy regimen is combination of vinblastine, actinomycin D, bleomycin, cyclophosphamide and CDDP presented by MSKCC. Available pretreatment with 4 courses of platinum, vinblastine and bleomycin before any surgical treatment in those with massive bulk metastatic disease seems to provide the most effective cytoreduction and best survival. Donohue has shown that in a primary chemotherapy group, there is only 20% active carcinoma after primary chemotherapy, whereas in a salvage chemotherapy group there is approximately 50% active carcinoma at surgery. It must therefore be emphasized that complete remission should be obtained by primary chemotherapy and adjunctive surgery. In Wilms' tumor preoperative chemotherapy with vincristine and actinomycin D should be given.     

Feasibility study of neoadjuvant chemotherapy followed by interval cytoreductive surgery for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0206

A feasibility study was started in January 2003 on neoadjuvant chemotherapy (NAC) followed by interval cytoreductive surgery (ICS) and postoperative chemotherapy for stage III/IV müllerian carcinomas such as ovarian, tubal and peritoneal carcinomas. The purpose is to assess the safety and efficacy of the treatment starting with NAC and also to know whether we can accurately diagnose these advanced carcinomas by imaging studies, cytologic findings and tumor markers without staging laparotomy or laparoscopy. Fifty-six patients with advanced müllerian carcinomas will be recruited to the study. After confirmation of diagnosis by laparoscopic inspection and biopsies, patients undergo four cycles of chemotherapy as NAC, followed by ICS and an additional four cycles of post-surgical chemotherapy. The primary endpoint is proportion of clinical complete remission after accomplishment of the protocol treatment, while the major secondary endpoint is positive predictive value of diagnosis before laparoscopy regarding tumor origin, histology and stage. Based on the results of this study, we will conduct a phase III study to compare the treatment starting with NAC and primary cytoreductive surgery followed by post-surgical chemotherapy.     

Changes in gene expression associated with response to neoadjuvant chemotherapy in breast cancer.

PURPOSE: At present, clinically useful markers predicting response of primary breast carcinomas to either doxorubicin-cyclophosphamide (AC) or doxorubicin-docetaxel (AD) are lacking. We investigated whether gene expression profiles of the primary tumor could be used to predict treatment response to either of those chemotherapy regimens. PATIENTS AND METHODS: Within a single-institution, randomized, phase II trial, patients with locally advanced breast cancer received six courses of either AC (n = 24) or AD (n = 24) neoadjuvant chemotherapy. Gene expression profiles were generated from core-needle biopsies obtained before treatment and correlated with the response of the primary tumor to the chemotherapy administered. Additionally, pretreatment gene expression profiles were compared with those in tumors remaining after chemotherapy. RESULTS: Ten (20%) of 48 patients showed a (near) pathologic complete remission of the primary tumor after treatment. No gene expression pattern correlating with response could be identified for all patients or for the AC or AD groups separately. The comparison of the pretreatment biopsy and the tumor excised after chemotherapy revealed differences in gene expression in tumors that showed a partial remission but not in tumors that did not respond to chemotherapy. CONCLUSION: No gene expression profile predicting the response of primary breast carcinomas to AC- or AD-based neoadjuvant chemotherapy could be detected in this interim analysis. More subtle differences in gene expression are likely to be present but can only be reliably identified by studying a larger group of patients. Response of a breast tumor to neoadjuvant chemotherapy results in alterations in gene expression.     

Neoadjuvant chemotherapy for ovarian cancer

Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer-Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.     

Arterial infusion chemotherapy for advanced gallbladder cancer and liver metastasis

Ten patients with advanced gallbladder cancer were treated by arterial infusion chemotherapy. Seven patients had unresected tumors, and three had liver metastasis after resection of primary tumor. The infusion catheter-port system was implanted via the femoral artery. 5-fluorouracil, mitomycin C and epirubicin were administered using implantable port. The response rate was 50% and the median survival time was 192 days. In one patient with good PR, a primary tumor was resected, and he survived for 2 years 7 months without recurrence. No severe side effect was found. Systemic chemotherapy using gemcitabine is well accepted, however arterial infusion chemotherapy will be one of the options when systemic chemotherapy is fails.     

Primary (neoadjuvant) chemotherapy with docetaxel in breast cancer

The use of primary or neoadjuvant chemotherapy for locally advanced breast cancer, including those patients with inflammatory breast cancer, is well established. The use of primary chemotherapy has also been investigated in patients with operable breast cancer. The potential benefit of using primary chemotherapy is the opportunity to administer systemic therapy at an earlier timepoint, where it may be more effective against microscopic disease. In addition, primary chemotherapy for patients with operable breast cancer may also result in higher rates of breast conservation, axillary nodal downstaging, and potential improvement in patient outcome. A variety of different chemotherapy drugs have been evaluated in the primary chemotherapy setting. One of the most common approaches is to use an anthracycline-based regimen for 4 or more cycles of treatment before considering definitive local therapy. Although high tumor response rates have been reported using anthracycline-based regimens, the fraction of patients actually attaining a pathologic complete response has remained small (less than 20%). With the introduction of new chemotherapy drugs, such as docetaxel, which is associated with a very high tumor response rate in metastatic disease, a natural evolution of clinical investigation is to use docetaxel in the neoadjuvant or primary chemotherapy setting. Some of the recent trials that have evaluated single-agent docetaxel, docetaxel-based chemotherapy combinations, and novel sequencing strategies that include docetaxel in the neoadjuvant setting are reviewed. The results from these trials clearly suggest that docetaxel-containing treatment strategies can be considered a standard in the primary chemotherapy setting     

Adjuvant chemotherapy in the treatment of sarcomas

For many types of cancers, adjuvant chemotherapy showed a moderate but significant benefit in terms of survival improvement. In sarcomas, the situation is contrasted and depends on the histological, molecular sub-types, as well as the topography of the tumor. Soft tissue sarcomas are in general poorly chemosensitive tumors and while adjuvant chemotherapy was found effective to delay relapses or to decrease the local relapses, it failed to yield a significant benefit with regard to overall survival. Sub-groups analysis indicate a significant lengthening of survival for the soft tissues sarcomas of the extremities. Neoadjuvant chemotherapy of the soft tissues sarcomas starts should be reserved to rhabdomyosarcomas and the bone sarcomas like the osteosarcomas and the Ewing's sarcomas of bones are more susceptible to chemotherapy, which is an integral part of the treatment with a preoperative chemotherapy and, following surgery of the primary tumor, an adjuvant chemotherapy adapted to the histological response to the neoadjuvant treatment.     

Proliferating fraction during neoadjuvant chemotherapy of primary breast cancer in relation to objective local response and relapse-free survival.

In women with inoperable primary breast cancer or large T2 tumors, preoperative chemotherapy may induce tumor shrinkage, facilitate surgery and possibly improve survival. However, at present there are no reliable tumor cell parameters to predict which patients will benefit from preoperative chemotherapy. The aims of this study were to analyze the utility of tumor cell proliferation as assessed by Ki-67 staining in fine-needle aspirates from primary breast carcinomas to predict initial response to neoadjuvant chemotherapy as well as recurrence-free survival. The study comprised 51 women with primary breast cancer who received 3-4 courses of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) as neoadjuvant chemotherapy. Tumor cells were procured through fine-needle aspiration biopsy prior to treatment. A second biopsy was performed before the second course of therapy in 33 women. Twenty-nine women (56%) experienced an objective local response after neoadjuvant treatment. During a median follow-up period of 39 months, 21 women (41%) developed disease recurrence. A decrease of more than 25% in proliferating fraction after the first course of chemotherapy correlated significantly with a decreased risk of disease recurrence (p = 0.033) but showed no significant correlation with local objective response. A multivariate analysis revealed that the decrease in proliferating fraction significantly (p < 0.05) added prognostic information to that of involved lymph nodes. These results suggest that changes in proliferating fraction as assessed by Ki-67 staining in fine-needle aspirates during preoperative chemotherapy may be of value in selecting postoperative adjuvant systemic treatment.     

肿瘤化疗与免疫疗法联合应用新进展

目前应用于恶性肿瘤的治疗方法主要有手术治疗、放疗、化疗以及免疫治疗等.虽然这些方法对肿瘤有一定的治疗作用,但应用单一的治疗手段均有不同的局限性,因此人们不断寻求多种治疗方法的联合应用,以期达到更好地抑制肿瘤生长及改善患者预后的效果.在已探索的各种化疗和免疫治疗的组合中,化疗联合细胞因子、化疗联合肿瘤疫苗、化疗联合免疫佐剂等组合在各种试验及临床应用中均取得可喜效果,有望为人们攻克肿瘤这一难题提供新的途径.     

Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery.

From 1973--1975, 31 patients with biopsied primary osteogenic sarcoma were treated with preoperative chemotherapy followed by surgical ablation of the primary tumor. Surgery was delayed in order to obtain a custom-fitted prosthetic bone implant in an attempt to avoid amputation. Preoperative chemotherapy included high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (T-5 protocol) and was administered for 3 months preoperatively and continued with the inclusion of cyclophosphamide for approximately 5 months postoperatively. At a follow-up period of 30--52 months, 23 of 31 patients (75%) are surviving (21 of 23 with no evidence of disease). Histologic examination of primary tumor removed at surgery revealed varying degrees of tumor destruction (from very little effect to no evidence of viable tumor) attributable to the effect of chemotherapy. The 21 patients that are disease-free survivors had a more complete effect of preoperative chemotherapy on the primary tumor. Some patients achieving favorable effects upon the primary tumor did so only after the dose of HDMTX was escalated to greater than the starting dose of 8 g/m2. Preoperative chemotherapy for all patients with osteogenic sarcoma would seem to offer the following advantages: 1) Evaluation of the effect of HDMTX with CFR on the primary tumor with escalation of the dose of HDMTX until a clinical response is observed, thus defining the dose of HDMTX effective in that patient, to be continued postoperatively as adjuvant therapy; 2) The early use of systemic therapy to eradicate distant microfoci of disease that will eventually kill the patient if not adequately treated by effective chemotherapy; 3) Allow more time for postoperative healing without the need to start adjuvant chemotherapy immediately; and 4) Provide the surgeon time to plan resection surgery. To date, 20 additional patients with biopsy proven osteogenic sarcoma have been treated with more aggressive preoperative chemotherapy (T-7) for approximately 2 1/2 months prior to definitive surgery (resection or amputation). Doses of HDMTX were escalated where necessary and good clinical responses were obtained in 19 of 20 patients. In the majority of patients, no evidence of viable tumor was found on histologic examination of the surgically removed primary tumor. All 20 patients are surviving free of active disease at this brief follow-up period of 4--20 months.     

Preoperative chemotherapy and endocrine therapy in patients with breast cancer

This review focuses on the aims, results, advantages, and possible disadvantages of preoperative chemotherapy and endocrine therapy. We present the recent improvements in terms of pathologic response rates that have resulted from new combinations of drugs. The change of established prognostic factors during neoadjuvant treatment, the need for new markers, and the consequences in terms of clinical decision-making are demonstrated. We discuss the risk of local relapse after breast-conserving surgery, which was made feasible by preoperative chemotherapy. A short overview of current neoadjuvant cytostatic, endocrine, and immunotherapy trials is provided. Future opportunities for tailoring therapy to each individual patient based on early information from the primary tumor are discussed. Important considerations and results of recent endocrine trials that analyzed possible tamoxifen-resistance in subgroups are reported. New opportunities exist to evaluate the efficacy of new cancer drugs more rapidly in the neoadjuvant setting than in the metastatic and adjuvant setting. This approach offers the possibility of monitoring prognostic markers in the primary tumor before, during, and after treatment with specific chemotherapeutic agents. With respect to recent findings of gene-array techniques, it is likely that the advances in this technology will lead to improved prognostic statements. It will show the influence of therapy on gene expression profiles in the course of treatment and might enable us to identify chemoresistance of specific tumors rather early. This could potentially lead to a new direction of cancer therapy.     

The impact of chemotherapy on cognitive outcomes in adults with primary brain tumors

There is growing recognition that chemotherapy may have short and long term impact on cognitive function of cancer patients. However, the impact of chemotherapy on the cognition of adult patients with primary brain tumor has not been extensively studied. This article will review the evidence for both positive and negative impact of chemotherapy on cognitive function of adult brain tumor patients as well as potential confounding factors.     

Use of gene-expression profiling to recommend adjuvant chemotherapy for breast cancer

One of the primary challenges in the treatment of patients with early-stage breast cancer is determining which patients will benefit from adjuvant chemotherapy. Traditionally, treatment decisions have been made based on a combination of tumor characteristics and patient and physician perspectives regarding risks and benefits. Recent technologic advances, including the development of gene-expression arrays, have led to the identification of molecular signatures that provide prognostic information in addition to the basic clinicopathologic features of individual tumors. While these new methods allow for more refined determination of prognosis for an individual patient, few data are available to support use of these new technologies in the clinic for treatment decision-making. At present, data from a single retrospective study are available to support the use of one assay, the 21-gene recurrence score, for decision-making regarding adjuvant chemotherapy. Large, multinational clinical trials are currently ongoing to evaluate the use of two of the multiparameter assays, although it will be many years before oncologists can apply the results of these trials in the clinic.     

化疗对肿瘤免疫功能影响的研究进展

肿瘤的发生、发展及转归与机体免疫功能密切相关。化疗是肿瘤常规治疗手段,其在杀伤肿瘤细胞的同时,对机体免疫系统也有不同程度的杀伤和抑制作用。近年来研究发现,化疗对机体免疫格局的调整可能具有双向作用。因此,依据化疗后机体免疫功能的不同变化,调整相应的治疗方案,将化疗和机体免疫功能有机结合,将最终提高肿瘤的治疗效果。