Use Of Systemic Chemotherapy Research Articles

To Resect or not the Primary Tumor in Metastatic Colorectal Cancer: Letter to the Editor

Colorectal cancer (CRC) is one of the most common tumors in the US, Europe, and worldwide but with a relatively good prognosis. In the adjuvant setting, high long-term survival rates have been reported, and even in the metastatic setting, with the use of systemic chemotherapy the median survival time has been improved to roughly 20 months. The addition of biologic agents such as cetuximab or panitumab has raised expectation for further survival improvement. With these developments, an old problem in surgical oncology has now been updated. Is the decision to resect the primary tumor, when it is locally completely resectable, correct, or will resection harm patients with a stage IV disease? To highlight this critical question in day-to-day clinical practice, Stillwell et al. [1] performed a meta-analysis and reported the results in the April 2010 issue of this journal. The authors concluded that palliative primary tumor resection in metastatic CRC (mCRC) prolongs survival and benefits patients. Can this report be considered a practicechanging study? Multiple variables complicate robust conclusions and correct decisions about surgery for an individual patient with mCRC. These factors include the extent of metastatic disease, namely, unresectable liver metastasis and/or minimal or extensive peritoneal carcinomatosis and/or other distant metastases; locally advanced or potentially complete removal of the primary tumor; tumor responsiveness or resistance to chemotherapy; general status of the patient; and risk of surgery-related complications that may delay recovery from surgery. For example, a safe performance of a laparoscopic colectomy without morbidity allows rapid recovery and may overcome the problem of surgerydelaying chemotherapy. In the absence of randomized controlled trials (RCTs), Stillwell et al. identified eight retrospective studies, including one with 1062 patients with asymptomatic and minimally symptomatic mCRC. Median overall survival was 6.0 months longer in the primary tumor resection group compared with that in chemotherapy-alone group (RR = 0.55; 95% CI = 0.29– 0.82; p\0.001). Patients managed with chemotherapy alone were seven times more likely to have a complication from the primary tumor. The authors concluded that palliative resection of the primary tumor prolongs survival and reduces the risk of primary tumor-related complications. Although it is thought that meta-analyses provide the highest level of evidence, this study was limited by the inclusion of retrospective studies and their heterogeneity given that several confounding variables reported above were not considered. Moreover, four studies within this series found that there was no significant difference in survival with resection of the primary tumor. For improving overall survival in the metastatic setting, there is much hope with the advent of next-generation DNA sequencing technologies and their promise for completing the somatic mutations of major cancer types such as colorectal cancer and helping us understand how an individual tumor functions as a complete biological and molecular system. These advances may allow identification of novel biomarkers for tailoring new biologic therapies along with standard chemotherapy [2–14].

Superselective Ophthalmic Artery Chemotherapy as Primary Treatment for Retinoblastoma (Chemosurgery)

To report on our 3-year experience with the use of superselective ophthalmic artery infusion of chemotherapy as initial, primary treatment for intraocular retinoblastoma. Prospective, institutional review board-approved clinical trial. Twenty-eight eyes of 23 newly diagnosed retinoblastoma patients (Reese-Ellsworth [RE] group V, 25 eyes; RE IV, 1 eye; RE III, 1 eye; RE II, 1 eye), ages 3-88 months (mean, 22; median, 11) followed for 3-37 months (mean, 15; median, 14). Cannulation of 1 or both ophthalmic arteries in young children with retinoblastoma was performed via the femoral artery under general anesthesia on an outpatient basis and chemotherapy (melphalan [n = 12], melphalan plus topotecan [n = 7], melphalan plus topotecan and carboplatin [n = 3], or melphalan plus carboplatin [n = 1]) infused. Patient survival, eye survival, systemic toxicity, complete blood counts, ophthalmic examination, retinal photography, and electroretinograms. We treated 23 newly diagnosed retinoblastoma patients initially with 75 separate intra-arterial chemotherapy infusions (range, 1-6 treatments; mean, 3.2) over a 3-year period. All children survived. Only 1 of the 28 eyes came to enucleation (for progressive disease). No eye was enucleated for ocular complications of the procedure and the only adverse ophthalmic findings were occasional transient lid edema, forehead hyperemia, and loss of nasal lashes. Kaplan-Meier enucleation free was 100% at 12 months and 89% at 2 years (95% confidence interval, 43%-98%). There were no deaths, strokes, or transfusions of any blood products; no effect on red cell count; 9 cycles of grade 3 and 1 cycle of grade 4 neutropenia; and no hospitalizations, episodes of fever/neutropenia, or complications at the site of femoral artery puncture. The ophthalmic artery(s) of children can safely be repeatedly canulated in very young children and high concentrations (but low doses) of chemotherapy infused on an outpatient basis. When used as initial therapy superselective chemotherapy delivered through the ophthalmic artery prevented enucleation, primary radiation or the use of systemic chemotherapy in 27 of 28 eyes.

Advances in Chemotherapy and Targeted Systemic Therapies for Urothelial Cancer

Systemic chemotherapy for cancer of the urothelial tract is used according to two main strategies. Neoadjuvant or adjuvant treatment combined with surgery and/or radiotherapy is aimed at cure of localised disease whilst treatment for advanced incurable disease allows for improved survival and palliation of symptoms. Cisplatin based combination regimens represent the standard of care in both of these settings and incorporation of gemcitabine has allowed for improvements in tolerability over older drugs. However, despite high objective response rates, impact on survival is modest. Targeted agents are now being incorporated into early phase clinical trials. These exciting new strategies hold promise for improved efficacy but with new challenges regarding toxicity profiles. This review will describe current evidence for the use of systemic chemotherapy for urothelial cancer and the state of the research evidence for use of the newer targeted agents. Keywords: Urothelial cancer, bladder cancer, chemotherapy, systemic therapy

Effect of Race on Colon Cancer Treatment and Outcomes in the Department of Defense Healthcare System

The increase in mortality noted in African Americans with colon cancer is attributed to advanced stage at presentation and disparities in treatment received. The aim of this study was to assess the influence of race on the treatments and survival of colon cancer patients in an equal-access healthcare system. This retrospective cohort study included African American and white patients with colon cancer treated at Department of Defense facilities. Disease stage, surgery performed, chemotherapy used, and overall survival were evaluated. Of the 6958 colon cancer patients identified, 1115 were African American. African Americans presented more frequently with stage IV disease, 23% vs 17% for whites (P < .001). There was no difference in surgical resection rates for African American or whites (85.8% vs 85.5%, respectively; chi2, P > .05). There was no difference in the use of systemic chemotherapy for stage III colon cancer (73.5% for African Americans vs 72.2% for whites; chi2, P > .05) or stage IV colon cancer (56.3% for African Americans vs 54.4% for whites; chi2, P > .05). The overall 5-year survival rate was similar for African American and white patients (56.1% vs 58.5%, respectively; log-rank, P > .05). After adjusting for gender, age, tumor grade, and stage, African American race was not a risk factor for survival in Cox proportional hazard analysis (hazard ratio, 0.981; 95% confidence interval, 0.888-1.084). In an equal-access healthcare system, African American race is not associated with an increase in mortality. African American patients undergo surgery and chemotherapy is administered at rates equal to whites for all stages of colon cancer.

Histological Characterization of 47 Breast Cancers with Neoplastic Meningitis Evolution.

Abstract IntroductionAround 5% of patients with breast cancer develop neoplastic meningitis (NM). The prognosis of NM in this population is supposed to be better with a median survival time of 7 months if treated with intrathecal therapy, systemic treatment and adapted supportive care (versus 4-6 weeks if untreated). This evolution needs to be detected as early as possible and it is necessary to identify tumors with such a risk. We report histological characteristics in 47 breast cancers with leptomeningeal treated in our institution for the last 2 years.Aim of the studyTo identify histopathological characteristics of breast cancer predictive of leptomeningeal evolution.Patients and methods47 consecutive female breast cancer patients were diagnosed with neoplastic meningitis on the basis of cerebrospinal fluid (CSF) cytology and/or cerebrospinal MRI plus clinical symptoms. These patients were matched with 47 breast cancer's patients without leptomeningeal evolution, according to age at breast cancer diagnosis (+/- 2 years), year of breast cancer diagnosis (+/- 2 years) and use of systemic chemotherapy as initial treatment of breast cancer. Differences between the 2 groups of patients were analyzed using usual statistical methods (t-test, Chi square test).ResultsAt the time of NM diagnosis, the median (min-max) age of patients with NM was 51 (26-76) years. Median delay after breast cancer diagnosis was 33 months (0-193). Brain, hepatic, bone, lung metastases were present in respectively 47%, 43%, 47% and 19%. CSF cytology was positive in 72%, median proteinorachia was 0,75 g/l (0,17–16,12); cerebrospinal MRI was also positive in 87%. At the time of breast cancer, median age was 49 (25-70) years. Initial breast samples were tumor biopsy in 43%, partial mastectomy in 31% and total mastectomy in 27%. Breast tumors were invasive ductal carcinoma in 84% with histoprognostic grade II/III in 49/42%, MSBR grade I/II in 52/47%. Grade 3 of differentiation was observed in 68%, grade 3 of anisonucleosis in 59% and grade 1 of mitosis in 48%. In the tumors, estrogen/progesterone receptors (ER/PR) were detected in 67/48% and HER2 overexpression was observed in 24%. 19% of the tumors were triple negative. Vascular emboli were detected in 58% of the cases. Tumors were T2 in 43%, N+ in 66% and M+ in 14%. Significant differences between initial breast cancers with or without NM evolution concerned histological type (p = 0,043), ER (p = 0,004) and PR (p = 0,023), triple negative status (p = 0,009) and initial metastatic status (p &amp;lt; 0,007).ConclusionsCarcinomatous meningitis preferentially occurs in invasive lobular tumors without hormonal receptors, particularly in triple negative tumors and in tumors metastatic upfront. HER2 overexpression is not a risk factor of NM, as is observed with brain metastases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6013.

Lymph Node Evaluation of Colon Cancer and Its Association with Improved Staging and Survival in the Department of Defense Health Care System

Improved survival is associated with an increased number of lymph nodes (LNs) examined. The aim of this study was to assess whether the examination of >or=12 LNs is associated with more accurate colon cancer staging. We queried the Department of Defense Automated Central Tumor Registry database for stage I-III colon cancer patients. Logistic regression analysis was performed to determine whether the examination of >or=12 LNs is associated with increased rates of LN-positive colon cancer. Kaplan-Meier and Cox proportional hazard analysis was performed to evaluate the effect of number of LNs examined on survival. The rate of LN-positive colon cancer is significantly higher with increasing number of LNs examined (1-3 LNs examined: 31% vs. >12 LNs examined: 41%, P<.001). Logistic regression analysis adjusting for patients, tumor, and hospital characteristics showed that examination of >or=12 LNs is associated with a >30% increase in detecting a LN-positive colon cancer (odds ratio, 1.350; 95% confidence interval, 1.175-1.511). The evaluation of >or=12 LNs is associated with improved survival in LN-negative colon cancer patients (P<.001). Our study demonstrates that the proportion of LN-positive colon cancer is far higher when >or=12 LNs are examined. Examination of >or=12 LNs may improve staging accuracy and outcome with optimal use of systemic chemotherapy.

Non-Hodgkin's lymphoma (NHL) patients at a VA medical center: Comorbidity and treatment

e19559 Background: We hypothesized that measures of comorbidity may help explain the number of treatments administered to patients with non-Hodgkin's lymphoma. Methods: We performed a retrospective, IRB approved protocol, using chart review of all patients diagnosed with non-Hodgkin's lymphoma at the VANJHCS from January 1, 1997 through December 31, 2008. Records were reviewed for demographic, clinical, pathological data, the number of chemotherapy regimens, radiation therapy, and total number of treatments and survival. We tabulated the Charlson Comorbidity Index (CMI), the Kaplan-Feinstein Comorbidity Index (KFI), the Cumulative Illness Rating Scale (CIRS), International Prognostic Index (IPI), and performance status (PS) were tabulated for 100 patients seen at a VA Medical Center. Results: There were 100 patients with median (M) age 62 years (27–89). There were 61 deaths (61%) with M survival(MS) 1068 days(13–3976). The M Stage was 1(0–4), M LDH was 204 IU/L (88–1905), M Hgb 12.3gm/dL (7.3–17.4), M Albumin was 3.8g/dl(1.2–5.4), M Zubrod Performance Status(PS) was 1(0–4) in 50 pts(50%). The M CMI was 6(1–12), M KFI was 3(1–3), M CIRS17 was 1.7(1–3.15). The M total number of systemic therapy regimens received was 1(0–4.5), M radiotherapy was 0(0–1) and the overall M total treatment regimens used was 1 (0–4.5). IPI was a significant predictor in the use of radiation therapy (p&lt;0.054) but did not correlate with the use systemic therapy. The CMI was a predictor of the use of systemic chemotherapy (p&lt;0.007), and the total number of treatments received (p&lt;0.011), but not the KFI or the CIRS 17. The performance status did not predict for the number of treatments. In a Cox regression analysis, the number of treatments did not affect survival. Conclusions: This data provides evidence that one measure of comorbidity, the CMI, may partially explain the number of systemic therapy treatments, and total treatments received by NHL patients. Further work in larger groups of pts is warranted. No significant financial relationships to disclose.

Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer

Objectives Examine the association between clinical, demographic, and socioeconomic factors and the receipt of systemic chemotherapy for bladder cancer. Examine factors influencing the use of combination chemotherapy plus cystectomy and use of specific chemotherapy drugs over time for bladder cancer. Materials and methods Data from the SEER-Medicare database were analyzed for patients diagnosed with urothelial carcinoma of the bladder between 1992 and 2002. Cox proportional hazards regression analyses were used to assess differences in use of systemic chemotherapy based on demographic and clinical factors, site of care, and year of diagnosis. We assessed the proportion of patients who received chemotherapy in the adjuvant and neoadjuvant settings as well as use of chemotherapy in the monotherapy setting. We estimated the proportion of claims made for several commonly used chemotherapy agents in the outpatient setting by year. Results During follow-up, 13%, 28%, 37%, and 57% of patients with stages 1 through 4, respectively, received systemic chemotherapy for bladder cancer. Chemotherapy use in the neoadjuvant or adjuvant settings within 6 months of diagnosis was not commonly found. Neoadjuvant chemotherapy was delivered to 1.4% of stage 2 patients and 11% of stage 4 patients. In 2003, the most frequent claims for intravenous chemotherapy were for gemcitabine, carboplatin, and placlitaxel. Conclusions Chemotherapy was not generally used as recommended for persons with invasive bladder cancer in this patient population. Studies to clarify potential underutilization and variation in patterns of administration are warranted.

Primary central nervous system lymphoma in Japan: Changes in clinical features, treatment, and prognosis during 1985-2004

We have conducted nationwide surveys of primary central nervous system lymphoma (PCNSL) treated since 1985. In the present study, we newly collected data between 2000 and 2004 and investigated changes in clinical features and outcome over time. A total of 739 patients with histologically proven PCNSL under going radiotherapy were analyzed. Seventeen institutions were surveyed, and data on 131 patients were collected. These data were compared with updated data that were previously obtained for 466 patients treated during 1985-1994 and 142 patients treated during 1995-1999. Recent trends toward decrease in male/female ratio, increase in aged patients, and increase in patients with multiple lesions were seen. Regarding treatment, decrease in attempts at surgical tumor removal and increases in use of systemic chemotherapy and methotrexate (MTX)-containing regimens were observed. The median survival time was 18, 29, and 24 months for patients seen during 1985-1994, 1995-1999, and 2000-2004, respectively, and the respective 5-year survival rates were 15%, 30%, and 30%. In groups seen during 1995-1999 and during 2000-2004, patients who received systemic or MTX-containing chemotherapy had better prognosis than those who did not. Multivariate analysis of all patients seen during 1985-2004 suggested the usefulness of MTX-containing chemotherapy as well as the importance of age, lactate dehydrogenase level, and tumor multiplicity as prognostic factors. Thus, this study revealed several notable changes in clinical features of PCNSL patients. The prognosis improved during the last 10 years. Advantage of radiation plus chemotherapy, especially MTX-containing chemotherapy, over radiation alone was suggested.

Impact of intrathoracic (IT) metastases upon survival in stage IV non small cell lung cancer (NSCLC)

19051 Background: The current AJCC staging (6th Ed, 2002) for NSCLC defines stage IV by presence of distant metastases (any T, any N, M1). There is no subdivision for IT vs. extrathoracic (ET) metastases. Recent phase III trials in stage IV NSCLC (e.g. ECOG 1594, CALGB 9730, TAX 326 and ECOG 4599) have not stratified for this potential variable. We hypothesize that patients with stage IV NSCLC with IT disease have a longer overall survival. Methods: After IRB approval patient charts were reviewed to obtain data on: age, gender, dates of diagnosis and death, IT vs. ET disease, ECOG performance status (PS). chemotherapy use and smoking. IT disease included metastases to ipsilateral or contralateral lung parenchyma. Patients with metastatic disease outside of the lungs were considered to have ET metastases. Statistical analysis included estimation of overall survival by the Kaplan-Meier method using the log rank test. Cox regression model was used to determine simultaneously the associations between survival and potentially prognostic variables. Results: A total of 193 patients were diagnosed with stage IV NSCLC at VAMC, Syracuse between 1999–2006. The patients were predominantly males (98%) and smokers (98%) with median age of 69 years. A third recieved chemotherapy, 46% had PS of 0–1, and 50% had < 5% weight loss. A total of 159 patients had ET and 34 patients (18%) had IT metastases. On univariate analysis patients with IT metastases had a median survival of 7.3 months vs. 3.4 months for ET disease (p <.01). Other factors favoring survival included good PS (p<.001), weight loss < 5% (p=.02), and use of cytotoxic chemotherapy (p<.001). Among patient who received chemotherapy (n=63), those with IT metastases had a longer median survival (13.5 m vs. 9.5 m, p=.04). On multivariate analysis, site of metastases retained its significance (RR 1.59,C.I. 1.00–2.52) as well as use of systemic chemotherapy (RR for survival without chemotherapy is 0.42, C.I. .28-.64). Conclusions: In addition to use of systemic chemotherapy, the site of metastatic disease is a determinant for survival in our cohort of patients. These data if confirmed in large prospective series make case for modification of current TNM staging system to reflect the impact of IT and ET metastases upon survival. No significant financial relationships to disclose.

Systemic therapy for metastatic colorectal cancer

A proliferation of new cytotoxic and biologic agents has led to improved survival in patients with metastatic colorectal cancer (mCRC). The ability of surgery to increase long-term survival in patients with liver and/or lung metastases also has been firmly established. It has become increasingly difficult as the numbers and types of treatment options have expanded to identify optimal drug combinations, sequences, and duration and the best way to integrate systemic chemotherapy with potentially curative surgery for metastatic lesions. For this review, the authors examined how recent clinical trials have addressed some pertinent questions regarding the use of systemic chemotherapy and biologic agents in patients with mCRC.

Isolated lung perfusion and related techniques for the treatment of pulmonary metastases☆

Surgical resection is a widely accepted treatment for pulmonary metastases on the condition that a complete resection can be obtained. However, many patients will develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Similar to the basic principles of isolated limb and liver perfusion, isolated lung perfusion is an attractive and promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biological response modifiers, like tumour necrosis factor, is also feasible. Other related methods of delivering high-dose locoregional chemotherapy include embolic trapping (chemo-embolisation) and pulmonary artery infusion without control of the venous effluent. Isolated lung perfusion has proven to be highly effective in experimental models of pulmonary metastases with a clear survival advantage. Lung levels of cytostatic drugs are significantly higher after isolated lung perfusion compared to intravenous therapy without systemic exposure. Phase I human studies have shown that isolated lung perfusion is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function and survival.

Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

The prognosis of patients with bone metastasis from lung cancer has not been well documented. We assessed the survival rates after bone metastasis and prognostic factors in 118 patients with bone metastases from lung cancer. The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1-74.5 months). A favorable prognosis was more likely in women and patients with adenocarcinoma, solitary bone metastasis, no metastases to the appendicular bone, no pathologic fractures, performance status 1 or less, use of systemic chemotherapy, and use of an epithelial growth factor receptor inhibitor. Analyses of single and multiple variables indicated better prognoses for patients with adenocarcinoma, no evidence of appendicular bone metastases, and treatment with an epithelial growth factor receptor inhibitor. The mean survival period was longer in a small group treated with an epithelial growth factor receptor inhibitor than in the larger untreated group. The data preliminarily suggest treatment with an epithelial growth factor receptor inhibitor may improve survival after bone metastasis.

Have Changes in Systemic Treatment Improved Survival in Patients with Breast Cancer Metastatic to the Brain?

Newly developed systemic treatment regimens might lead to improved survival also in the subgroup of breast cancer patients that harbour brain metastases. In order to examine this hypothesis, a matched pairs analysis was performed that involved one group of patients, which were treated after these new drugs were introduced, and one group of patients, which were treated approximately 10 years earlier. The two groups were well balanced for the known prognostic factors age, KPS, extracranial disease status, and recursive partitioning analysis class, as well as for the extent of brain treatment. The results show that the use of systemic chemotherapy has increased over time, both before and after the diagnosis of brain metastases. However, such treatment was performed nearly exclusively in those patients with brain metastases that belonged to the prognostically more favourable groups. Survival after whole-brain radiotherapy has remained unchanged in patients without further active treatment. It has improved in prognostically better patients and especially patients that received active treatment, where the 1-year survival rates have almost doubled. As these patient groups were small, confirmation of the results in other series should be attempted. Nevertheless, the present results are compatible with the hypothesis that improved systemic therapy might contribute to prolonged survival in patients with brain metastases from breast cancer.

In Brief

Primary vitreoretinal lymphoma (PVRL) was previously termed primary intraocular lymphoma. PVRL is a potentially fatal intraocular malignancy, and 65–90% of PVRL cases eventually involve the central nervous system (CNS). The incidence of PVRL has been rising in both immunocompromised and immunocompetent populations worldwide. PVRL frequently masquerades as chronic uveitis. Advanced auxiliary examinations, such as optical coherence tomography and fundus autofluorescence have been applied in the diagnosis of PVRL. Histology and immunohistochemistry in combination with molecular tests and interleukin-10 analysis have been demonstrated as reliable in diagnosing PVRL. Despite early initiation of treatment, mortality is high with PVRL associated with CNS involvement and relapses are common. The use of systemic chemotherapy has not been proven to prevent CNS involvement; however, local therapies including intravitreal injections of methotrexate and/or rituximab and low-dose radiotherapy to the eye, has shown to be extremely effective in controlling intraocular lymphoma with encouraging results.

Akt expression may predict favorable prognosis in cholangiocarcinoma

Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins has not been reported. Co-expression may reflect cross-talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome. Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 to 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists independently scored the protein expression. Cyclooxygenase-2, Akt, and p-MAPK were commonly expressed in biliary cancers (100%, 96% and 87% of malignant cells, respectively). EGFR (60%) and p-EGFR (22%) overexpression was also detected. There was a significant association between EGFR and p-EGFR (P = 0.027) and between Akt and p-Akt (P = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK and p-Akt (P = 0.054). Multivariate analysis using the Cox proportional hazard model identified the use of chemotherapy (hazard ratio [HR] = 0.039, P = 0.0002), radiation (HR = 0.176, P = 0.0441) and Akt expression (HR = 0.139, P = 0.006) as the best predictors of overall prognosis. Epidermal growth factor receptor signaling intermediates are commonly expressed in cholangiocarcinoma. Expression of Akt and use of systemic chemotherapy or radiation may correlate with improved survival.

Does Induction Chemotherapy Have a Role in the Management of Locoregionally Advanced Squamous Cell Head and Neck Cancer?

The use of systemic chemotherapy before definitive locoregional management, or induction chemotherapy, has been a theoretically attractive and well-studied approach in the management of squamous cell head and neck cancer. Although a decrease in distant metastases has frequently been observed, an improvement in survival from induction has been difficult to demonstrate. When chemotherapy and radiation are used concomitantly, however, an improvement in both survival and locoregional control can be identified, and this has led to the adoption of concurrent chemoradiotherapy as a standard of care for these patients. With this improvement in locoregional control, distant metastases have become a more frequently recognized cause of treatment failure, suggesting that an intervention, such as induction chemotherapy, directed at improving distant control might now be of some importance in improving overall treatment success. The recent development of taxane-containing, three-drug induction regimens that are capable of producing significantly better response rates than the older cisplatin and fluorouracil combination has also raised the possibility of a new and more important role for induction. The results of phase II investigations using this kind of a sequential schedule of induction chemotherapy followed by concurrent chemoradiotherapy have been encouraging, and phase III trials are now underway. This treatment approach remains investigational however, and these phase III studies are critical. The current randomized trials are reviewed and discussed.

Role of Non-Taxane-Containing Chemotherapy in Advanced Non-Small Cell Lung Cancer

Treatment for advanced-stage NSCLC generally includes the use of systemic chemotherapy as well as biologic therapies (targeted therapy) at later stages of the disease. However, in general, NSCLC is moderately sensitive to the currently available cytotoxic drugs, so the intention of chemotherapeutic treatment in the advanced setting is mainly palliative. Several treatment regimens are available, but in the first-line setting, treatment traditions differ both within countries and between various parts of the world. The role of taxane-platinum chemotherapeutic combinations (mainly used in North America) has been questioned in the palliative setting since these combinations are known to cause neutropenia, skin and nail problems, as well as neurological toxicity.

Chemotherapy in Brain Metastases

The use OF chemotherapy to treat patients with brain metastases has been viewed historically with skepticism. To date, a survival benefit has not been demonstrated with the use of systemic chemotherapy in patients with brain metastases. However, the introduction of novel agents and delivery techniques warrants a reexamination of the role of systemic chemotherapy in the management of brain metastases. Temozolomide has shown encouraging results in patients with nonsmall cell lung cancer, and implanted carmustine wafers have demonstrated excellent local tumor control rates. This review discusses clinical data from the past decade with emphasis on trial design, tumor histology, available agents, and multimodality strategies. In addition, delivery techniques that circumvent the blood-brain barrier are reviewed. Although chemotherapy is usually used as a salvage therapy, it may be considered for use in selected patients with newly diagnosed brain metastases. To better evaluate chemotherapy in brain metastases, future trials should evaluate novel agents in the preirradiation setting. Enhanced regional delivery methods warrant further investigation, and Phase III trials of current regimens stratified by histology and by prognostic factors will establish the role of specific chemotherapy regimens in the treatment of patients with brain metastases.

Just When You Thought the Fluorouracil Debate Was Over: S-1 and Gastric Cancer

Despite a decline in incidence in the United States and Western Europe, gastric cancer is common worldwide and remains the second leading cause of cancer-related death. In a shift in the epidemiology of gastric cancer, adenocarcinomas of the esophagus and gastroesophageal junction are increasing at a dramatic rate in the United States and Western Europe, and represent an even more virulent disease entity. The pattern of more distal gastric cancer elsewhere in the world may be a function of rates of infection by Helicobacter pylori, dietary practices, and potential dietary deficiency in micronutrients such as selenium and vitamin C. The predominance of adenocarcinoma of the esophagus and gastroesophageal junction in the West may reflect population trends in obesity and tobacco abuse, and paradoxically, a decrease in Helicobacter infection that may increase the risk of esophageal reflux disease. Because of the absence of effective screening, patients with gastric cancer in the United States usually present with symptomatic and either locally advanced or metastatic disease. High rates of recurrence after surgery have engendered decades of clinical trials evaluating the use of adjuvant chemotherapy, with or without radiation. Fortunately, recent clinical trials have made advances with the validation of the use of systemic chemotherapy to improve survival. Intergroup trial 116 showed that postoperative bolus fluorouracil (FU), leucovorin, and radiation therapy improved survival compared with surgery alone, despite the relative inactivity for FU and leucovorin in metastatic disease. Although postoperative adjuvant chemotherapy alone has failed to affect survival in gastric cancer, preand postoperative chemotherapy with epirubicin, cisplatin, and protracted-infusion FU (ECF) without the use of radiation, as recently reported in the MAGIC trial from the United Kingdom, significantly improved survival compared with surgery alone. The improvement in survival in recent adjuvant trials, however, is marginal, and the key to further progress is the identification of more active systemic agents in gastric cancer. The evaluation of a novel combination chemotherapy regimen, S-1 and cisplatin, is the focus of the phase I trial reported by Ajani et al in the current issue of the Journal of Clinical Oncology. This trial raises important issues about the pace of progress of chemotherapy development in gastric cancer, including the role of oral agents as a replacement for intravenous drugs. The trial also, for better or for worse, rekindles the time-worn debate of how best to administer fluoropyrimidines as part of combination chemotherapy. Conventional chemotherapy used in the treatment of gastric cancer has limited effectiveness and significant toxicity, depending on the dose and schedule of agents used. If we are searching for direction in gastric cancer drug development, colorectal cancer should clearly serve as a model. Progress has been made in colorectal cancer in the identification of new chemotherapy agents, optimal dosing and scheduling of agents, and the incorporation of targeted therapies. Colorectal cancer trials have firmly established that, in comparison with bolus FU, the use of continuous-infusion FU administered as a biweekly 48-hour infusion results in superior antitumor efficacy, longer patient survival, and improved therapy tolerance. The debate about the optimal schedule of FU has largely been replaced by discussion of the best sequencing of available therapies and the addition of targeted agents. The substitution of oral agents for continuous-infusion FU is a topic of more secondary interest given the accumulating data from phase III trials that show equivalence, but not necessarily superiority, of oral drugs. Whereas response, survival, and toxicity benefits have all been accomplished in colorectal cancer trials, such advances have eluded gastric cancer investigators. In gastric cancer, there has been a seeming reluctance to incorporate lessons learned from the trial experience in colorectal cancer. There is continued acceptance of the combination of a 5-day infusion of FU in combination with every 3to 4-week dosing of relatively high doses of cisplatin. The toxicity and limited efficacy of this regimen was underscored in a phase III JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 28 OCTOBER 1 2005