Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year survival rate. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. Several randomized trials now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year survival rate among patients with T1N0 disease after they had received adjuvant therapy with a combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11% rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0 disease. Two recently published meta-analyses have estimated a relative risk reduction in mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B 9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus, there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.     

Neoadjuvant therapy in early-stage breast cancer

Neoadjuvant (preoperative) chemotherapy is becoming a commonly used option for women with early-stage breast cancer, allowing a greater proportion of patients to undergo breast conservation surgery. Neoadjuvant chemotherapy also allows the early assessment of response or resistance to chemotherapy and facilitates chemotherapy delivery prior to any surgical alterations to the vasculature. Ongoing research is examining the potential benefits of neoadjuvant therapy with cytotoxic agents as well as other treatments, including endocrine therapies and biologic agents. Additionally, biomarkers are being intensively investigated as methods for identifying patients who will most likely benefit from neoadjuvant chemotherapy. As of yet, neoadjuvant chemotherapy has not demonstrated a definitive benefit over adjuvant (postoperative) chemotherapy with regard to prolonging survival. It remains to be seen whether novel cytotoxic agents used in the neoadjuvant setting will improve pathologic clinical response rates and ultimately improve long-term outcome in women with early-stage breast cancer.     

(Neo)adjuvant strategies of advanced gastric carcinoma: time for a change?

Despite surgical R0 resections, patients with gastric cancer stage UICC II-III have a high risk of recurrence and metachronic metastases. Preliminary evidence exists that adjuvant chemotherapy or neoadjuvant chemo(radio)therapy protocols may improve the prognosis of these patients undergoing surgery of gastric cancer with curative intention. As for palliative regimens, 5-fluorouracil and cisplatin are integral components of such (neo)adjuvant strategies. Upcoming cytostatic agents, i.e. irinotecan, docetaxel, oxaliplatin, and oral fluoropyridines are currently under investigation in new multimodality treatment regimens and may further increase R0 resection rates and may prolong disease-free and overall survival in the treatment of advanced localized gastric cancer.     

The position of neoadjuvant chemotherapy in the treatment of non-small-cell lung carcinoma

Surgical treatment of patients with non-small-cell lung carcinoma (NSCLC) offers greatest chances for long-term survival. However, the treatment is applicable only to patients diagnosed at an early stage of the disease, i.e. at stage I or II. The five year survival rate of patients operated at stage IIIA is as low as 23%. Hence there is a great need for improving survival results, especially in the sphere of systemic chemotherapy, as most tumour relapses involve the formation of metastases. Even though neoadjuvant chemotherapy in the operable stages of NSCLC still appeared very promising as a method of treatment a couple of years ago, recently published results have shown that its role has not yet been fully clarified and is still a subject of research. Additional results from randomised studies are necessary before neoadjuvant therapy may become a treatment standard. The dilemma as to whether or not to apply adjuvant, neoadjuvant or both types of chemotherapy in patients operated on for NSCLC therefore remains unsolved. On the whole, the positive role of neoadjuvant chemotherapy does not appear to be proven in the treatment of operable stage I and II NSCLS. In contrast, results of randomised studies first published in 2004 were in favour of post-surgical adjuvant chemotherapy as opposed to surgical treatment alone in NSCLC stage IB, II and IIIA. The question of whether it is better to apply chemotherapy prior to or after surgery can only be answered by the extensive randomised studies underway. The role of neoadjuvant chemotherapy in patients with NSCLC at clinical stage IIIA remains uncertain. The most rational approach to such patients appears to be neoadjuvant chemotherapy or chemotherapy with subsequent surgery.     

Advances in chemotherapy of non-small cell lung cancer

In the United States, lung cancer kills more men and woman than the next three most common cancers combined. Unfortunately, the long-term outcome of lung cancer is still dismal with a 5-year survival rate of 15%. However, significant improvements in median survival times and 1-year and 2-year survival rates have been achieved in the last decade. This progress has been accomplished not only because of better surgical techniques but also because of the use of platinum-based regimens with newer chemotherapy agents and, more recently, targeted therapy. The role of chemotherapy as an integral part of the treatment of lung cancer has expanded significantly, particularly in the last few years with the proven benefit of adjuvant chemotherapy. For advanced stage non-small cell lung cancer (NSCLC), chemotherapy prolongs survival and improves quality of life in patients with good performance status, and appears to provide symptomatic improvement in patients with decreased performance status. Platinum-based doublet chemotherapy regimens are now the standard of care in patients with advanced stage NSCLC, and non-platinum-based combination therapies are reasonable alternatives in certain populations. The combination of the vascular endothelial growth factor inhibitor bevacizumab and chemotherapy has proven to prolong survival. As agents such as monoclonal antibodies, small molecules inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and tested, we are optimistic that these agents will result in improvement in the survival and quality of life of lung cancer patients.     

Multimodality therapy in the treatment of lung cancer

Lung cancer is the leading cause of cancer death in the world, causing more than one million deaths each year. The incidence and mortality rates are highest in the United States and Europe and continue to increase in developing nations. Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all new cases of lung cancer. The majority of patients with NSCLC present with advanced disease at the time of diagnosis. Although the prognosis of advanced NSCLC is very poor, current chemotherapy combinations have been shown to improve 1-year survival and quality of life for these patients. Approximately one third of patients with NSCLC are diagnosed with locally advanced disease. Although cure rates are modest and variable in locally advanced NSCLC, multimodality therapy (chemotherapy in combination with surgery or radiotherapy) has resulted in statistically significant improvement in 5-year survival when compared with surgery or radiotherapy alone. Patients with early-stage NSCLC have the best long-term survival rates following surgical resection; however, systemic recurrences remain a problem in the majority of these patients. The rationale for treating patients with early-stage NSCLC with combined-modality therapy (chemotherapy and surgery) is compelling, and several randomized trials are currently in progress. Although progress has been slow, when we consider the recent advances in smoking prevention, smoking cessation, staging classification, imaging and diagnostic techniques, screening and therapeutic modalities, and multidisciplinary care, as well as in the understanding of the molecular pathogenesis of lung cancer, the future, in my opinion, is very promising.     

Women with pathologic stage I, II, and III non-small cell lung cancer have better survival than men

OBJECTIVE: Bronchogenic malignancy is the number one cause of cancer deaths in both men and women worldwide. National registry-based studies have shown gender disparity in clinicopathologic characteristics and in survival. This study evaluates the risk factors and trends of lung cancer between genders. METHODS: A prospective cohort of consecutive patients with non-small cell lung cancer (NSCLC) who were carefully clinically (all underwent dedicated positron emission tomography scans) and pathologically staged with stage I, II, or III disease underwent homogenous treatment algorithms and were followed up over a period of 7 years. Primary outcomes were 5-year survival and response to neoadjuvant therapy. RESULTS: There were 1,085 patients (671 men and 414 women). Groups were similar for race, pulmonary function, smoking history, comorbidities, neoadjuvant therapy, histology, and resection rates. Women were younger (p = 0.014), had a higher incidence of adenocarcinoma (p = 0.01), and presented at an earlier pathologic stage (p = 0.01) than men. The overall age-adjusted and stage-adjusted 5-year survival rate favored women (60% vs 50%, respectively; p < 0.001). Women had better stage-specific 5-year survival rates (stage I disease, 69% vs 64%, respectively [p = 0.034]; stage II disease, 60% vs 50%, respectively [p = 0.042]; and stage III disease, 46% vs 37%, respectively [p = 0.024]). Women who received neoadjuvant chemotherapy alone (n = 76) were more likely to be a complete or partial responder than men (n = 142; p = 0.025). CONCLUSIONS: Despite uniform staging and treatment, the 5-year survival rate of women with stage I to III NSCLC was better than men overall and at each stage. Women are more likely to have adenocarcinoma, to present with earlier stage disease, and to be younger. Interestingly, women respond better to neoadjuvant chemotherapy.     

Combined modality treatment of non-small-cell lung cancer

Among all nonmetastatic non-small-cell lung cancer (NSCLC) patients, the best survival rates are observed in patients who undergo surgery. Nevertheless, 5-year survival rates vary between 20% and 60% depending on the stage of the disease. Several combined modality treatments have been investigated to improve outcome in localized NSCLC. These include local treatment, systemic before local treatment, concomitant systemic and local treatments, and systemic after local treatment. Preoperative irradiation was shown to be of no benefit on local recurrence rates or overall survival. Even doses of radiation >/=40 grays (Gy) were associated with lower survival rates. Postoperative irradiation did not influence survival in stage III disease and seemed to be deleterious in stages I and II disease. Modern radiotherapy techniques might be of interest in this setting but have been insufficiently tested. The early phase III studies of preoperative chemotherapy versus primary surgery in stage III NSCLC showed a tremendous difference in favor of chemotherapy. A larger study did not confirm these results but suggested that preoperative chemotherapy might have a greater effect in stages I and II of the disease. In locally advanced disease, chemotherapy followed by radiotherapy was shown to increase survival when compared with radiotherapy alone. Studies comparing concurrent chemoradiation with radiotherapy only were in favor of the concomitant schedule, which improved local control. Promising results have been reported with chemoradiation followed by surgery in stage IIIa and even stage IIIb disease. Randomized studies of postoperative chemotherapy demonstrated a 5% improvement in 5-year survival over adjuvant-free treatment. Postoperative chemoradiation showed no advantage over postoperative radiotherapy. Several trials that are ongoing or whose accrual was recently completed should further define the role of perioperative chemotherapy in resectable NSCLC and of trimodality treatments in advanced disease. Targeted agents are being developed in the postoperative setting. New schedules of chemoradiation with higher therapeutic indexes are also being investigated in nonresectable stage III NSCLC.     

Lung cancer: A review of current therapeutic modalities

This article describes the current approach to the systematic management of both small cell and non-small cell lung cancer (NSCLC). The treatment of stages I, II, and IIIa NSCLC is surgical resection. Although adjuvant chemotherapy in stage I disease offers no survival benefit, the role of adjuvant chemotherapy in stage II and IIIa NSCLC remains controversial. Results of pilot studies using neoadjuvant chemotherapy in stage IIIa NSCLC are encouraging and data from ongoing randomized trials are awaited with interest. For locally advanced NSCLC, chest irradiation remains the standard of care. However, the addition of systemic chemotherapy holds promise. The impact of cisplatin-based regimens on overall survival in stage IV NSCLC remains disappointing. The introduction of newer agents, such as 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), a topoisomerase-I inhibitor, has shown early favorable results.Chemotherapy is the most important therapeutic modality in the management of small cell lung cancer because of this cancer's propensity for early dissemination. In limited stage small cell lung cancer, chest radiotherapy, particularly if used early and concurrently with chemotherapy, may improve survival, but at the expense of increased toxicity. The role of prophylactic brain irradiation remains controversial in limited-stage disease. Chemotherapy is also the most important treatment modality in extensive-stage disease, but its role is only palliative. Radiotherapy is reserved primarily for disease-related complications in patients in whom chemotherapy has failed.     

Ovarian cancer

Ovarian cancer accounts for 4% of all cancers in women and is the leading cause of death from gynaecologic malignancies. Because early-stage ovarian cancer is generally asymptomatic, approximately 75% of women present with advanced disease at diagnosis. Survival is highly dependent on stage of disease: 5-year survival in patients with early-stage is 80-90% compared to 25% for patients with advanced-stage disease. For all patients, a comprehensive surgical staging should be performed to obtain the histological confirmation of diagnosis and to evaluate the extent of disease. Patients with early-stage should both be optimally staged and be treated with adjuvant platinum-based chemotherapy if they have a medium or high-risk tumour. For advanced disease the currently recommended management is primary cytoreductive surgery followed by platinum-paclitaxel combination chemotherapy. Appropriate salvage therapy is based on the timing and nature of recurrence and the extent of prior chemotherapy. Surgical resection should be considered in patients with long-term remission, especially in those with isolated recurrences and good performance status. Platinum-based combination represents the standard second-line chemotherapy in patients with platinum-sensitive relapsed ovarian cancer. Salvage chemotherapy in platinum-refractory patients usually results in low response rates and short survival.     

Trends in endocrine therapy and chemotherapy for early breast cancer: a focus on the premenopausal patient

Purpose: The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. Conclusions: This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting.     

Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC)

NSCLC, a tobacco-caused disease which is therefore highly preventable, is responsible for about 30% of all cancer deaths. Improvements in terms of survival have been overall disappointing. A major advance has been the demonstration of the value of platinum-based chemotherapy, not only for advanced disease, but also in the adjuvant and neoadjuvant settings. The favorable impact of second line therapy has been established as well.The most exciting recent development consists in the effective use of biological targeted therapies, namely the EGFR inhibitors. In selected groups of patients, these agents can be used successfully for first line or second line therapy.It is likely that other biologically targeted therapies will be developed in a near future. These progresses will lead hopefully to a more personalized and effective treatment of NSCLC.     

Curative resection plus adjuvant chemotherapy for early stage primary gastric non-Hodgkin's lymphoma: a retrospective study with emphasis on prognostic factors and treatment outcome

BACKGROUND: There is controversy regarding the optimal therapy for primary non-Hodgkin gastric lymphoma with some authors defending surgical extirpation either alone or in association with radiotherapy and or chemotherapy, especially in relation to the earlier stages of the disease. AIM: To analyze the clinical-pathological features and the results of management approaches for patients with primary early-stage non-Hodgkin's lymphoma of the stomach operated in Surgical Gastroenterology Department, "Hospital do Servidor Público Estadual", S?o Paulo, SP, Brazil. The literature is reviewed to highlight the aspects of diagnosis, prognostic factors and role of the various treatment regimens. METHOD: Sixteen patients with primary early-stage gastric lymphoma underwent curative surgical treatment. The variables analyzed were age, sex, location, size, type of surgery, number of lesions, depth of invasion, histological type in accordance with Kiel's classification, involvement of lymph nodes, Ann Arbor stage classification modified by Musshoff and Schmidt-Vollmer, histological grade, margins, adjuvant therapy, clinical course and survival. RESULTS: Ten patients (62.5%) underwent subtotal gastrectomy and six (37.5%) underwent total gastrectomy. The majority (9/56.2%) of the lesions were located in the antrum. Single lesions (10/62.5%) were more frequent than multiple lesions (6/37.5%). Thirteen patients (81.2%) were classified as stage IE and three (18.7%) as stage IIE1. Primary gastric lymphoma classified histologically as low or high grade was presented by 10 (62.5%) and 6 (37.5%) patients, respectively. The most frequent histological types were the lymphoplasmocytic cytoid (4/25.0%) and centroblastic (4/25.0%). Ten patients (62.5%) received adjuvant treatment (chemotherapy and/or radiotherapy). Nine patients (56.2%), all in stage IE, reached a survival greater than 5 years and of these eight (50.0.%) had received adjuvant therapy. Two (12.5%) patients with stage IIE1 presented peritoneal relapse and died 3.0 years and 3.5 years after their respective operations. The mean overall survival was 42.5 months. CONCLUSIONS: Among the patients with primary early-stage gastric lymphoma (IE and IIE1), the gastric resection enabled an accurate clinicopathological staging, in addition to obtaining sufficient material for histopathological study and extirpation of the lesion. Furthermore, for patients with stage IE disease, the gastric resection combined with adjuvant therapy was associated with a greater than 5-year survival. Until prospective randomized studies are realized in order to evaluate the real efficacy of the different types of treatment for primary early-stage gastric lymphoma, management approaches should be individually tailored.     

Reevaluation of Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma: A Meta-Analysis of Randomized Controlled Trials Over the Past 20 Years

The effect of neoadjuvant chemotherapy on the survival of patients with thoracic esophageal squamous cell carcinomas (ESCCs) remains controversial. The optimal management strategy for resectable ESCCs varies regionally based on local randomized controlled trials. A systematic review and meta-analysis was conducted to re-evaluate this controversial issue.A systematic review of the Medline, Embase, and PubMed databases was carried out on data collected between August 1994 and August 2014 to evaluate the role of neoadjuvant chemotherapy. Only randomized controlled trials comparing the effects of neoadjuvant chemotherapy with that of surgery and surgery plus adjuvant chemotherapy were selected.Six studies with a total of 1202 patients were identified, consisting of a neoadjuvant chemotherapy arm (n = 597) and a surgery alone and surgery plus adjuvant chemotherapy arm (n = 605). The 5-year overall survival benefit for neoadjuvant chemotherapy was statistically significant at α = 0.1 (hazard ratio = 0.81, 95% confidence intervals, 0.65–1.00, P = 0.053). All 6 trials recruited patients for more than 5 years with undefined lymphadenectomies. Cisplatin and fluorouracil were adopted as neoadjuvant chemotherapy regimens.The role of neoadjuvant chemotherapy for ESCC is worth re-investigating. The design of randomized controlled trials should adopt new chemotherapy regimens as well as define the surgical procedure and the details of the lymphadenectomy.     

Evidence-based outcomes for patients with advanced non-small cell lung cancer

A majority of patients diagnosed with non-small cell lung cancer (NSCLC) will have advanced disease at diagnosis. In the past, systemic therapy (chemotherapy) has demonstrated only slight improvement in survival, hence, practitioners were reluctant to refer patients for cytotoxic therapy. In the past few years, newer chemotherapeutic agents, with increased activity against NSCLC, have been shown to significantly improve median and 1-year survival rates and improve quality of life. Although advanced NSCLC is considered incurable disease, it is, however, potentially treatable disease. This chapter will address the evidence regarding currently available therapies for patients with advanced stage NSCLC.     

Neoadjuvant vindesine, etoposide, and cisplatin for locally advanced non-small cell lung cancer. Final report of a phase 2 study

We treated 27 patients with regionally advanced non-small-cell lung cancer (NSCLC) with two cycles of neoadjuvant chemotherapy with etoposide, vindesine, and cisplatin. Twenty-three patients were evaluable for response; 13 had a partial response while ten patients had stable disease or disease progression. Subsequent local therapy consisted of surgery followed by radiotherapy in four patients and of radiotherapy alone in 14 patients. Five patients did not receive local therapy. At completion of local therapy, seven patients were considered free of disease including all four who had undergone surgery. Median time to disease progression for the 13 patients who had a partial response to neoadjuvant chemotherapy was eight months (three to 51+ months). The median survival for all patients registered on study was eight months (three days to 53+ months). Chemotherapy induced toxicities included moderate myelosuppression, nausea and vomiting in all patients, and occasional ototoxicity, neurotoxicity, and wasting syndrome. One patient died of intracerebral hemorrhage due to thrombocytopenia. This trial shows that administration of neoadjuvant chemotherapy to patients with locoregionally advanced NSCLC is feasible and may yield an increased response rate compared to patients with stage IV disease. While no clearly beneficial effect of the use of chemotherapy on patient survival is apparent in this study, further studies utilizing neoadjuvant chemotherapy in patients with NSCLC are warranted and should attempt to identify more active combinations of drugs.     

Beliefs among pulmonologists and thoracic surgeons in the therapeutic approach to non-small cell lung cancer

STUDY OBJECTIVES: The physicians who initially evaluate patients with non-small cell lung cancer (NSCLC) strongly impact the course of therapy. Their beliefs in treatment and prognosis may contribute to practices of variable quality and appropriateness. We sought to better describe beliefs among pulmonologists and thoracic surgeons who were selected for guiding early therapy and referrals in patients with NSCLC. DESIGN: Mail questionnaire focusing on survival estimates, treatment perceptions, and referral patterns. PARTICIPANTS: Twelve hundred pulmonologists and 800 thoracic surgeons who were clinically active members of the American College of Chest Physicians. MEASUREMENTS AND RESULTS: Response rates of 50% for pulmonologists and 52% for thoracic surgeons were obtained after two mailings. Five-year survival estimates for patients with resected stage I NSCLC revealed that 30% of respondents overestimated survival rates and 18% underestimated survival rates. The underestimation of survival rate was found among more respondents who are practicing pulmonology than thoracic surgery (22% vs 10% [corrected], respectively), who were trained before 1980 than after 1980 (29% vs 10% [corrected], respectively), and who were seeing < 10 lung cancer patients annually than those who were seeing > 25 (31% vs 0.14%, respectively). Beliefs in the survival benefit of adjuvant chemotherapy or of radiation in stage I-IIIA disease divided respondents within both specialties. Chemotherapy plus radiation vs radiation alone in unresectable stage IIIA-B NSCLC was viewed as benefiting survival less often by physicians seeing < 10 lung cancer patients annually rather than > 25 (57% vs 77% [corrected], respectively) and by physicians underestimating rather than correctly estimating survival in early-stage disease (58% vs 72% [corrected], respectively). Chemotherapy was believed to confer survival benefits in patients with stage IV disease by one third of respondents. CONCLUSIONS: Certain physician characteristics, particularly the length of time since training and NSCLC patient volume, are associated with beliefs not conclusively supported in the medical literature or with opinions inconsistent within and between specialties.     

Combined modality therapy of early stage nonsmall cell lung cancer

Therapy for locally advanced NSCLC has evolved into a multidisciplinary effort. Patients who are considered for this approach should undergo rigorous testing to accurately stage their disease. Patients with pleural effusions (with rare exception) are not candidates for intensive combined modality therapy. Appropriate patients for combined modality therapy should have a good performance status (generally Zubrod 0 or 1), adequate pulmonary function, absence of significant heart, lung, or other medical diseases, and be appropriate candidates for combination chemotherapy and thoracic surgery or thoracic radiotherapy. Several lessons can be learned from looking broadly at the phase II and phase III combined modality experience. The available data do not support the routine use of postoperative therapy in patients with completely resected disease. Treatment with chemotherapy before surgery or radiation has demonstrated survival benefit in patients with stage III disease. The French phase III trial of induction chemotherapy in patients with early stage disease found an 11-month improvement in overall survival (P = 0.15) and a significant increase in the risk of death for patients with stage I and II disease. The ongoing U.S. intergroup trial (SWOG 9900) and European trials will help to further define the role of chemotherapy in patients with clinical stage IB, II and IIIA NSCLC. Clinical trials should be conducted to compare preoperative chemoradiotherapy with preoperative chemotherapy. The recently completed intergroup 0139 trial (chemoradiation followed by surgery or not) should help to define whether surgery and radiation are required in the management of stage IIIA NSCLC. Finally, further improvement in survival with the use of "newer" cytotoxic agents seems unlikely as phase III trials in metastatic NSCLC have not demonstrated marked superiority over cispiatin-based regimens. Ongoing trials are assessing the incorporation of newer, biologic-based "targeted" therapies. Despite the dismal findings of trials of postoperative therapy, many patients continue to have surgery as their initial treatment followed by postoperative therapy. In contrast, trials with induction treatment seem to offer improved survival. It is time for a true multidisciplinary approach to the treatment of locally advanced NSCLC. Pulmonary physicians, thoracic surgeons, medical oncologists, and radiation oncologists should meet before the initiation of treatment to plan the most appropriate therapy for the individual patient.     

Liver transplantation for non-hepatocellular carcinoma malignancy

Liver transplantation (LT) for hepatocellular carcinoma is effective for selected patients. LT for other malignancies like cholangiocarcinoma (CCA), hepatoblastoma (HB), hepatic epithelioid hemangioepithelioma (HEHE), angiosarcoma (AS), and neuroendocrine tumors (NET) is being defined. For CCA, series that did not emphasize highly selected early stage disease and neoadjuvant or adjuvant chemoradiation had an average 5-year survival of 10%. However, emphasizing neoadjuvant radiation and chemosensitization in operatively confirmed stage I or II hilar CCA has led to improved 5-year survival, up to 82%. LT is indicated under strict research protocols at selected centers, for patients with early stage CCA and anatomically unresectable (Bismuth type IV) lesions. HB is typically sensitive to cisplatin-based chemotherapy. LT plays a role as primary surgical therapy for those individuals in whom tumors remain unresectable after chemotherapy or as rescue therapy for those who are incompletely resected, recur after resection, or develop hepatic insufficiency after chemotherapy and/or resection. Long-term survival is reported at 58-88%. HEHE is a multifocal tumor that lies somewhere between benign hemangiomas and malignant AS. The extensive multifocal nature makes resection difficult and LT an attractive option. Series on LT for HEHE report overall survival of 71-78% at 5 years. However, AS is an aggressive tumor and LT is contraindicated. For NET, resection of the primary tumor and all gross metastatic disease is reported to provide 5-year survival of 70-85%. LT has been employed for some patients for unresectable tumors or for palliation of medically uncontrollable symptoms with 5-year survival reported between 36% and 80%.     

Accelerated dose escalation with proton beam therapy for non-small cell lung cancer

Local tumor control remains challenging in many cases of non-small cell lung cancer (NSCLC), particularly those that involve large or centrally located tumors. Concurrent chemotherapy and radiation can maximize tumor control and survival for patients with locally advanced disease, but a substantial proportion of such patients cannot tolerate this therapy, and sequential chemoradiation regimens or radiation given alone at conventionally fractionated doses produces suboptimal results. An alternative approach is the use of hypofractionated proton beam therapy (PBT). The energy distribution of protons can be exploited to reduce involuntary irradiation of normal tissues, particularly the low-dose irradiation problematic in intensity-modulated (photon) radiation therapy (IMRT). Here we summarize current evidence on the use of hypofractionated PBT for both early-stage and locally advanced NSCLC, and the possibility of using hypofractionated regimens for patients who are not candidates for concurrent chemotherapy.KEYWORDS : Hypofractionation, early-stage disease, locally advanced disease, proton beam therapy (PBT), stereotactic ablative body radiation (SABR), intensity-modulated proton therapy (IMPT), passive scattering, dosimetric comparisons, clinical studies