Small cell lung cancer: defining a role for emerging platinum drugs

Small cell lung cancer (SCLC) is characterized by early dissemination and a rapid, aggressive clinical course. It has, however, marked susceptibility to both chemotherapy and radiotherapy, although treatment is complicated by the fact that SCLC tumors invariably develop resistance to multiple chemotherapeutic agents. Local therapy is rarely of benefit in SCLC because three-quarters of patients present with metastatic disease and many of the remaining patients are thought to have micrometastatic disease. Chemotherapy is, therefore, the cornerstone of treatment. Of the many combination regimens used, etoposide/cisplatin or etoposide/carboplatin have emerged as the regimens of choice because they offer a good therapeutic index and can be combined with radiotherapy. Response to second-line therapy remains consistently poor. As the prototype platinum compound, cisplatin has played a major role in the management of SCLC. Although its exact contribution to the treatment of SCLC has been difficult to ascertain, a recent meta-analysis reported a significant 1-year survival advantage of approximately 4% with cisplatin-containing regimens versus regimens without. However, cisplatin is characterized by several serious adverse events and, like other chemotherapeutic agents, is eventually rendered ineffective against SCLC because of acquired resistance. Several new platinum formulations or compounds are showing promising activity in SCLC. The impetus for their development has been to circumvent cisplatin resistance or to improve upon the toxicity profile of cisplatin. If the early promise shown by these compounds is confirmed in the clinic, they may offer a new approach to the treatment of SCLC, including recurrent disease for which limited treatment options are currently available.     

High dose chemotherapy--results of American studies

The role of high dose chemotherapy in the treatment of solid tumors is a subject of robust debate. Opinions range from the adoption of high dose chemotherapy with hematopoietic progenitor support as standard therapy for a number of solid tumors to the view that the application of such expensive and potentially toxic therapy is always experimental and should be the subject of clinical trials to define the role, if any. In germ cell tumors, the role of high dose chemotherapy is somewhat less contentious. In the US, high dose carboplatin and etoposide-based chemotherapy is routinely accepted as standard therapy for those patients failing prior standard dose regimens. There is increasing acceptance of the role of similar high dose therapy as a component of aggressive second line therapy and some initial acceptance of a potential role in primary treatment of poor risk disease. Formal study of these questions has been hampered by the rarity of the illness, the success of standard therapy and the smaller number of patients presenting with far advanced disease. This review will highlight the scientific underpinning of the role of high dose chemotherapy in multiply relapsed patients, as a component of initial salvage therapy and, finally as an attempt to improve outcome in patients with poor risk presenting features. As well, an attempt will be made to highlight where new prognostic information has influenced the design of current studies.     

Therapeutic potential of PARP inhibitors for metastatic breast cancer

Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step towards individualization of breast cancer therapy. The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors, with their novel and selective mechanism of action, are an example of this strategy. PARP plays a key role in DNA repair mechanisms, particularly the base excision repair pathway. Initially developed as inhibitors able to enhance the cytotoxicity of radiation and certain DNA-damaging agents, they have more recently been shown to have single-agent activity in certain tumors. Inhibition of PARP in a DNA repair-defective tumor can lead to gross genomic instability and cell death by exploiting the paradigm of synthetic lethality. Several studies have evaluated the role of PARP inhibitors for treatment of breast cancer, particularly in the context of BRCA-mutated and triple-negative breast cancers. In addition, inhibition of PARPs repair functions for chemotherapy-induced DNA lesions has been shown to potentiate the effect of some chemotherapy regimens. This article discusses the current understanding of PARP inhibition as a treatment for metastatic breast cancer, evidence from clinical trials and addresses its future implications.     

Evolving strategies for management of desmoid tumor

Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracycline-based or methotrexate-based regimens). A newer class of agents, γ-secretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients.     

Paclitaxel in the treatment of advanced urothelial cancer

Median survival in patients with advanced urothelial carcinoma continues to be approximately 1 year following treatment with traditional cisplatin (Platinol)-based regimens, which have substantial toxicity. Thus, research is focusing on newer chemotherapeutic agents and novel combination regimens to improve outcomes and tolerability. Paclitaxel (Taxol) demonstrated one of the highest single-agent response rates (42%) in patients with advanced urothelial tumors, prompting extensive evaluation of combination regimens, including paclitaxel/platinum-based doublets or triplets. In many trials, carboplatin (Paraplatin) has been substituted for cisplatin to produce a more convenient, less toxic regimen. These trials have demonstrated that paclitaxel/platinum-based combinations are similar in efficacy to traditional cisplatin-based regimens and are generally better tolerated. Consequently, paclitaxel-based combinations (e.g., paclitaxel/carboplatin) are now considered alternative treatment options for patients with advanced disease, particularly those who are ineligible for clinical trials or are unable to tolerate standard cisplatin-based regimens. Paclitaxel/ifosfamide (Ifex)/cisplatin is another promising alternative regimen for patients who can tolerate cisplatin-based regimens. An ongoing phase III trial comparing paclitaxel/carboplatin and MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin) should clarify the role of paclitaxel-based combinations. Paclitaxel-based combinations are also under evaluation in the adjuvant setting, and future trials may assess their potential role as neoadjuvant therapy or in combination with radiation therapy.     

Therapeutic potential of PARP inhibitors for metastatic breast cancer

Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step towards individualization of breast cancer therapy. The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors, with their novel and selective mechanism of action, are an example of this strategy. PARP plays a key role in DNA repair mechanisms, particularly the base excision repair pathway. Initially developed as inhibitors able to enhance the cytotoxicity of radiation and certain DNA-damaging agents, they have more recently been shown to have single-agent activity in certain tumors. Inhibition of PARP in a DNA repair-defective tumor can lead to gross genomic instability and cell death by exploiting the paradigm of synthetic lethality. Several studies have evaluated the role of PARP inhibitors for treatment of breast cancer, particularly in the context of BRCA-mutated and triple-negative breast cancers. In addition, inhibition of PARPs repair functions for chemotherapy-induced DNA lesions has been shown to potentiate the effect of some chemotherapy regimens. This article discusses the current understanding of PARP inhibition as a treatment for metastatic breast cancer, evidence from clinical trials and addresses its future implications.     

Intraperitoneal chemotherapy for ovarian cancer

Intraperitoneal chemotherapy provides a means by which high concentrations of drugs and long durations of tissue exposure can be attained at the peritoneal surface. It has been studied widely in ovarian cancer, a disease in which intra-abdominal progression remains the major source of morbidity and mortality. Three large randomized trials have shown improved survival in optimally debulked patients who were treated with intraperitoneal chemotherapy as part of a front-line regimen, yet it has not become part of usual therapy. Several factors have contributed to the reluctance to adopt intraperitoneal therapy, including technical issues related to drug delivery and the fact that all of the large randomized trials employed intraperitoneal cisplatin, which has more toxicity than intravenous carboplatin, the current standard of care. Future research is needed for further definition of the clinical benefit of intraperitoneal chemotherapy, modification of existing regimens to minimize side effects, and exploration of intraperitoneal biologic, immunologic, and gene therapy techniques.     

Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.     

Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.     

Actual chemotherapeutical possibilities in hormone-refractory prostate cancer (HRPC) patients

Androgen deprivation therapy still remains the gold standard in the treatment of advanced prostate cancer. Unfortunately, patients with metastatic prostate cancer treated with androgen deprivation therapy frequently develop androgen-independent prostate cancer. Cytotoxic chemotherapy has not been used routinely and the current standard regimens have not demonstrated any significant alteration in the development of hormone-refractory disease. Recent phase III randomized clinical trials have suggested that docetaxel-based therapy, demonstrating a real increase of survival in treated patients, could represent the new standard treatment for metastatic patients. There is also promising activity of new drug combinations, such as taxanes plus vinca alkaloids, and of classic chemotherapeutic agents plus biological drugs. This review focuses on the current therapies for the treatment of HRPC.     

Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer

Diphtheria toxin (DT) is a potent inhibitor of protein synthesis. As little asa single molecule of DT can result in cell-cycle independent cell death. This profound potency has led to difficulties in the development of DT as a suicide gene in cancer gene therapy, because toxicity appears to be related primarily to the fidelity of basal gene expression and the yield of viral titer. We evaluated the feasibility of prostate-specific DT gene therapy by cloning the catalytic domain (A chain) of DT under the control of the prostate-specific antigen (PSA) promoter, the PSA promoter and enhancer, or the cytomegalovirus promoter. The data on expression of DT from the plasmid constructs demonstrate that the basal level of DT gene expression determines the toxicity. To better test the potential therapeutic efficacy of DT suicide gene therapy, we first developed a DT-resistant adenoviral packaging line (293DTR). This allowed us to manufacture a relatively high titer adenoviral vector encoding the DT-A gene under the control of the PSA promoter and enhancer (Ad5PSE-DT-A) as well as an attenuated DT-A virus (Ad5PSE-tox176). In vitro studies showed that our viral constructs preferentially kill PSA-positive prostate cancer cells in the presence of exogenous androgen (R1881). In vivo studies showed that the nu/nu mice with PSA-positive cancer cell LNCaP xenograft treated with wild-type DT-A virus had a rapid regression of tumors and survived over a year without tumor progression, whereas the attenuated DT-A virus restricted tumor growth for only 1 month. The same constructs had no significant effect on the non-PSA-secreting cell line DU-145. These encouraging results suggest that DT-A viral gene transfer may ultimately have a therapeutic role in the treatment of advanced human prostate cancer.     

New antimetabolites in the treatment of human malignancies.

Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.     

Present state and future prospects: a review of cooperative groups' adjuvant and neoadjuvant trials in breast cancer

In patients with operable breast cancer, adjuvant hormonal therapy and adjuvant chemotherapy result in significant and long-term reductions in the rates of disease recurrence and death. These reductions are evident in both patients with node-negative as well as in those with node-positive disease. However, several issues in the adjuvant treatment of breast cancer still remain unresolved. These issues were recently considered at the 2000 National Institutes of Health (NIH) Consensus Development Conference, which reviewed the current state of knowledge on adjuvant therapy and outlined strategies for future research. In the area of adjuvant hormonal therapy, tamoxifen is still the gold standard, and present evidence supports the use of tamoxifen for patients with estrogen receptor (ER)-positive tumors irrespective of age, menopausal status, nodal status, or tumor size. Optimal duration of tamoxifen therapy is about 5 years. Future research directions include evaluating the benefit of extending tamoxifen beyond 5 years, the contribution of ovarian ablation, and the role of hormonal manipulations involving selective ER modulators and aromatase inhibitors instead of or in addition to tamoxifen. In the area of adjuvant chemotherapy, polychemotherapy regimens have been consistently found to be superior to single agents, and anthracycline-containing regimens produce a small but statistically significant improvement in survival when compared with regimens not containing an anthracycline. High-dose adjuvant chemotherapy with stem cell support has not been proven superior to standard regimens. Neoadjuvant therapy offers the possibility of testing in vivo the sensitivity of individual tumors to particular cytotoxic regimens and, hence, of improving ultimate disease control, as well as reducing the extent of local therapy. The contribution and optimal integration of taxanes in the adjuvant setting are yet to be established but are the subject of intense research effort. Similarly, novel targeted therapies such as trastuzumab and bisphosphonates are currently being evaluated in adjuvant studies     

家族性腺瘤性息肉病相关的硬纤维瘤

目的 总结家族性腺瘤性息肉病（familial adenomatous polyposis,FAP）相关的硬纤维瘤（desmoid tumours,DT）的临床病理特点,提高认识,探讨合理的治疗方法 .方法 回顾性分析总结了从1981年10月至2005年5月住院治疗的50例FAP发生的5例DT的临床病理资料,并结合文献分析.结果 男3例,女2例,年龄在31～47岁,平均36.6岁,4例在首次结直肠手术后出现,距离首次手术的时间间隔1～3年,平均2.3年,1例在FAP首次行结直肠手术时发现,4例无明显症状,1例反复发作肠梗阻及腹腔感染症状.腹壁DT 2例,腹腔DT 1例,同时腹壁和腹腔DT 2例.2例腹壁DT切除术后12年和11年分别出现残余结直肠腺瘤癌变,但未见DT复发.1例术中发现的肠系膜根部DT,仅行切取活检,但术后5年患者死于直肠癌转移时DT仍稳定.1例腹壁和腹腔DT,行腹壁DT切除,乙状结肠造口术,术后8年患者死亡,原因不明.另1例腹壁和腹腔DT患者仅行活检术,3年后患者死于DT所致的肠梗阻和败血症.结论 FAP相关的DT的治疗应个体化对待,腹壁DT应及时切除,治疗效果好,腹腔DT应根据分期选择合理的治疗方案.     

The role of ifosfamide in the treatment of lymphomas.

Over the last few decades, progress has been made in classification and treatment guidelines for patients with lymphoma with differing prognostic factors. As investigators look for alternatives to current standard therapy there has been a resurgence of interest in the alkylating agent ifosfamide. A basic tenet of lymphoma therapy has been to use combinations of non-cross resistant agents in an effort to avoid tumor resistance. Ifosfamide is at least partially non-cross resistant with cyclophosphamide, and because it is often only modestly myelosuppressive, it is useful in combination regimens. Other toxicities of ifosfamide, including urinary bladder toxicity and neurotoxicity, are generally predictive and seldom occur in clinical practice with standard ifosfamide doses and proper screening and preventive therapy. Several regimens incorporating ifosfamide in a variety of doses and schedules have demonstrated clinical efficacy in the treatment of lymphomas. Ifosfamide is most commonly used in regimens for patients with relapsed or refractory disease, although there has been interest in ifosfamide as part of initial therapy regimens. Ifosfamide is an active agent as part of combination therapy for patients with both indolent and aggressive relapsed lymphomas, and has also been used in high-dose therapy regimens followed by stem cell or bone marrow rescue. Future studies incorporating ifosfamide should be directed towards its use in outpatient regimens as initial therapy for patients with lymphoma and in regimens designed for patients with relapsed or refractory disease.     

Appraising the current role of chemotherapy for the treatment of sarcoma

Sarcomas are a heterogeneous group of relatively rare mesenchymal neoplasms. They can be grouped into two general categories: soft tissue sarcoma (STS) and primary bone sarcoma, which are treated differently. Because sarcomas are relatively rare and complex with a wide variety of different histopathologic subtypes, evaluation by multidisciplinary teams who have expertise in the field is recommended. Treatment guidelines for the use of chemotherapy in patients with STS and bone sarcoma have been published by the National Comprehensive Cancer Network. The role of adjuvant chemotherapy in resected STS remains controversial. Although chemotherapy improves disease-free survival, the long-term overall survival benefit remains unproven. Chemotherapy is typically used as palliative treatment for most subtypes of metastatic STS. In contrast, chemotherapy has a proven role in the treatment of primary bone tumors and Ewing sarcoma, but it has not demonstrated efficacy in the treatment of chondrosarcoma. The standard chemotherapy regimens used in sarcoma are associated with significant toxicity, including long-term complications. Less intense and less toxic regimens are the focus of ongoing clinical research. Newer cytotoxic agents with an improved safety profile, such as trabectedin and palifosfamide, are currently in development. Future research needs to focus on identification of subpopulations of patients that are most likely to benefit from chemotherapy.     

Epidermal growth factor receptor tyrosine kinase inhibitors: present and future role in gastrointestinal cancer treatment: a review

BACKGROUND: Despite advances in conventional and targeted anticancer therapy, the prognosis remains poor for many patients with solid tumors. Ongoing research into the molecular basis of malignant disease, however, has yielded many novel agents with potential activity, including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). DESIGN: This review summarizes current clinical data for EGFR-TKIs as monotherapy or in combination with 5-fluorouracil/leucovorin, irinotecan, or oxaliplatin, focusing on the rapidly developing area of colorectal, gastroesophageal, and pancreatic cancers. RESULTS: EGFR-TKIs have limited but valuable activity as monotherapy in non-small cell lung cancer patients who have received prior anticancer treatment. The potential for application as a single agent in colorectal, gastroesophageal, and pancreatic cancers has yet to be demonstrated conclusively and deserves further investigation, especially as second- or third-line therapy. In combination with oxaliplatin-based regimens and 5-fluorouracil/leucovorin-based regimens, TKIs have shown benefits, suggesting that there may be a synergistic effect with chemotherapy. However, combinations with irinotecan-based regimens have been limited by toxicities. CONCLUSIONS: EGFR-TKIs show benefits when used in combination with chemotherapy, and the favorable toxicity profiles observed suggest that these may be of value in frail or elderly patients.     

Preoperative chemotherapy treatment of breast cancer--a review

Despite proven benefits of neoadjuvant chemotherapy in patients with locally advanced, invasive breast cancer, no regimen is recommended as the treatment of choice. Neoadjuvant chemotherapy regimens encompass single-agent and combination therapy and sequential treatment. For this report, the author reviewed the literature to determine which regimen, if any, was most beneficial. The results indicated that studies have yielded a wide range of response rates, but no single regimen has emerged as a clear leader. The literature is compounded further by lack of standardized criteria to determine pathologic complete response (which is predictive of survival benefits) and between-study variation in the stringency by which this endpoint is defined. Given the lack of a preferred treatment regimen in the neoadjuvant setting, identifying patients who are likely to respond to specific agents could inform treatment decisions, improve treatment outcomes, and aid in avoiding unnecessary exposure to potential toxicities. The development of novel agents for use alone or in combination with existing agents may improve response rates further in the neoadjuvant setting, especially because a significant proportion of breast tumors can be resistant to many current antineoplastic agents. Particularly noteworthy are the epothilones and their analogs because of their low susceptibility to common tumor-resistance mechanisms. Initial data have indicated that ixabepilone, which is an epothilone analog, has activity in the neoadjuvant setting, and predictive factors for response have been identified. The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors and developing novel agents. This ultimately may lead to improved outcomes for women with breast cancer.