Use Of Combined Modality Therapy Research Articles

Primary bone lymphoma: Treatment results and prognostic factors with long‐term follow‐up of 82 patients

To the authors' knowledge, there is limited information on the preferred treatment and long-term prognosis of primary bone lymphomas (PBLs). All PBL cases treated at the study center between 1963 and 2003 were analyzed to determine patient, disease, and treatment factors that could affect outcome measured by overall survival (OS), cause-specific survival (CSS), and freedom-from-treatment failure (FFTF). A total of 101 patients with PBL diagnosed at the study institution were identified. Nineteen patients were excluded because they transferred their treatment or follow-up to another center. Disease control, survival, and prognostic factors were analyzed for all 82 remaining patients. The median age of the patients was 48 years (range, 11-83 years). Approximately 80% presented with diffuse large-cell lymphoma (DLCL), and 81% presented with Ann Arbor Stage I or II disease. Approximately 57% were treated with combined modality therapy, 14% were treated with radiation therapy alone, and 30% were treated with chemotherapy alone. The median follow-up was 67 months (range, 2-280 months). The 5-year OS, CSS, and FFTF were 88%, 96%, and 81%, respectively. The 5-year OS for patients treated with combined modality versus single-modality therapy was 95% versus 78% (P = .013), and the 5-year FFTF for patients treated with combined modality versus single-modality therapy was 90% versus 67% (P = .025). The 5-year CSS for patients treated with combined modality versus single-modality therapy was 95% versus 83% (P = .065). Using a Cox regression for multivariate analysis, age < 40 years and use of combined modality therapy were found to be favorable prognostic factors for OS, CSS, and FFTF. To the authors' knowledge, the current study is the largest series of patients with PBL treated with modern curative modalities. The data demonstrate that primary lymphoma involving the bone has an excellent prognosis. Patients with PBL treated with combined modality versus single modality therapy were found to have a superior outcome, with a significantly better survival.

The Management of Patients with Limited-Stage Classical Hodgkin Lymphoma

The term limited-stage Hodgkin lymphoma refers to those patients with stage I-II disease and an absence of bulky disease. Among those patients with classical Hodgkin lymphoma, approximately one-third of patients will fall into this category. As long-term disease control can now be anticipated in more than 90% of these patients, management strategies must increasingly address the need to reduce the long-term treatment-related risks. Current treatment options include use of combined modality therapy that includes an abbreviated course of chemotherapy and involved-field radiation or treatment with chemotherapy, currently consisting of ABVD, as a single modality. The choice of treatment between these two options involves specific trade-offs that must balance issues of disease control against long-term risk of late effects.

Anal Cancer: Current and Future Methodology

Despite the small number of patients affected by carcinoma of the anal canal it remains one of the most challenging cancers to treat. For although it is one of the few malignancies that may be cured with chemoradiation alone, the use of combined modality therapy may result in significant treatment-related morbidity. Novel approaches currently are underway in this select patient population and will be addressed for the purposes of this manuscript.

EGFR Related Signaling Pathway Has Prognostic Significance in Cholangiocarcinoma

Purpose: Overexpression of signaling proteins including EGFR, Akt, MAPK and COX-2 was reported in cholangiocarcinoma cell lines. However, clinical 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 is undefined. Co-expression may reflect cross-talk between signaling pathways. In this clinicopathologic study, we report the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma describe their relationship to clinical outcome. Methods: Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 – 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 (JG, TK) independently scored the protein expression and there was full concordance. Clinical data were obtained in accordance with IRB approved protocol. Results: COX-2, Akt, and p- MAPK were commonly expressed in biliary cancers (91%, 88% and 74% of malignant cells respectively). EGFR (50%) and p- EGFR overexpression (13%) was also detected. There was a significant association between EGFR and p EGFR (p = 0.027) as well as Akt and p-Akt (p = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK (ERK) and p-Akt (p = 0.054). Multivariate analysis using the Cox-proportional hazard model identified use of combined modality therapy [Hazard ratio (HR) = 0.185, p = 0.0008] and p-AKT [HR = 0.238, p = 0.0373] as the best predictors of overall prognosis. Conclusions: Activation of EGFR signaling pathway is commonly seen in cholangiocarcinoma. Expression of p-Akt and use of combined modality therapy may predict favorable prognosis.

Sinonasal malignancies with neuroendocrine differentiation

Sinonasal neuroendocrine tumors are rare malignancies that are represented by a spectrum of histologies, including esthesioneuroblastoma (ENB), sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and small cell carcinoma (SmCC). The authors reviewed their institutional experience to determine whether sinonasal neuroendocrine tumors of different histologies have distinct clinical characteristics that warrant individualized treatment approaches. The authors treated 72 adults with pathologically proven, nonmetastatic, primary sinonasal neuroendocrine tumors from 1982 to 2002. There were 31 patients with ENB, 16 patients with SNUC, 18 patients with NEC, and 7 patients with SmCC. Patients with ENB usually were treated with local therapy alone (surgery and/or radiotherapy); only 3 of 31 patients (9.7%) received treatment (radiation) to regional lymphatics, and only 5 of 31 patients (16.1%) received chemotherapy. In contrast, patients with non-ENB histologies usually received chemotherapy (10 of 16 patients with SNUC, 12 of 18 patients with NEC, and 5 of 7 patients with SmCC), and nonsurgical locoregional therapy was used more frequently (6 of 16 patients with SNUC, 4 of 18 patients with NEC, and 5 of 7 patients with SmCC). The median follow-up for surviving patients was 81.5 months (range, 6-266 months). The Kaplan-Meier estimate of overall survival at 5 years was 93.1% for patients with ENB, 62.5% for patients with SNUC, 64.2% for patients with NEC, and 28.6% for patients with SmCC (P = 0.0029; log-rank test). The local control rate at 5 years also was superior for patients who had ENB (96.2%) compared with patients who had SNUC (78.6%), NEC (72.6%), or SmCC (66.7%) (P = 0.04). The regional failure (RF) rate at 5 years was 8.7% for patients with ENB, 15.6% for patients with SNUC, 12.9% for patients with NEC, and 44.4% for patients with SmCC. Additional late events increased the RF rate for patients with ENB to 31.9% at 10 years. The distant metastasis rate at 5 years was 0.0% for patients with ENB, 25.4% for patients with SNUC, 14.1% for patients with NEC, and 75.0% for patients with SmCC. This spectrum of malignancies with neuroendocrine features shares a common site of origin within the head and neck, but their natural histories appear to diverge into two main groups: ENB and non-ENB. Patients with ENB had excellent local and distant control rates with local therapy alone. Given the higher rates of systemic failure for patients with SNUC, NEC, and SmCC, the authors favor the use of combined-modality therapy for these patients.

Nuclear survivin expression correlates with poor prognosis in cholangiocarcinoma

4092 Background: Survivin is a unique anti apoptotic protein expressed in many human cancers. It is absent in non-proliferating adult tissues. Its expression and prognostic value in biliary tumors is yet to be elucidated. Methods: Twenty-four consecutive surgical cases of cholangiocarcinoma treated from 1996–2002 at Roswell Park Cancer Institute were studied. Immunohistochemistry was performed on paraffin embedded blocks using mouse monoclonal IgG2a antibody to survivin (Santa Cruz Biotechnology). DAKO high pressure antigen retrieval and mouse envision plus detection systems were used to detect survivin expression. Two pathologists (DT, CL) independently examined survivin expression and scored (0, 1+, 2+, 3+), based on presence and intensity of immunoreactivity in nucleus and cytoplasm. Clinical data were obtained in accordance with IRB approved protocol. Results: Median patient (pt) age was 68 (range 40 to 77). Sixteen pts were female, and 8 male. SEER staging was local in 2, regional in 15 and distant in 7 pts. Treatments included chemotherapy (2 pts), surgery (10), combined modality (10) or no therapy (2). Strong cytoplasmic survivin expression (3+) was seen in 6 cases and strong nuclear survivin (3+) in 4. One case had strong co-expression at both locations. There was no statistical correlation between expression of either cytoplasmic or nuclear survivin with sex, SEER staging or tumor grade. Statistically, cytoplasmic survivin expression did not have prognostic significance. However, 4 pts with strong nuclear survivin had a median survival of 11 months, significantly less than those with weak nuclear survivin expression (20 months, p=0.033). Multivariate analysis using the Cox- proportional hazards model identified the following 4 as best predictors of patient mortality: nuclear survivin (P=0.022), presence of metastasis (P=0.025), age (P=0.019), and use of combined modality therapy (P=0.006). Estimated hazard ratios (HR) suggested pts likely to survive longer were weak nuclear survivin expressers (HR = 3.1) and had non- metastatic disease (HR = 1.5). Conclusions: Nuclear survivin expression in cholangiocarcinoma may identify those with a poor prognosis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MGI Eli Lilly; Genentech; MGI Phama Eli Lily; Pfizer; Roche

Nuclear survivin expression correlates with poor prognosis in cholangiocarcinoma

4092 Background: Survivin is a unique anti apoptotic protein expressed in many human cancers. It is absent in non-proliferating adult tissues. Its expression and prognostic value in biliary tumors is yet to be elucidated. Methods: Twenty-four consecutive surgical cases of cholangiocarcinoma treated from 1996–2002 at Roswell Park Cancer Institute were studied. Immunohistochemistry was performed on paraffin embedded blocks using mouse monoclonal IgG2a antibody to survivin (Santa Cruz Biotechnology). DAKO high pressure antigen retrieval and mouse envision plus detection systems were used to detect survivin expression. Two pathologists (DT, CL) independently examined survivin expression and scored (0, 1+, 2+, 3+), based on presence and intensity of immunoreactivity in nucleus and cytoplasm. Clinical data were obtained in accordance with IRB approved protocol. Results: Median patient (pt) age was 68 (range 40 to 77). Sixteen pts were female, and 8 male. SEER staging was local in 2, regional in 15 and distant in 7 pts. Treatments included chemotherapy (2 pts), surgery (10), combined modality (10) or no therapy (2). Strong cytoplasmic survivin expression (3+) was seen in 6 cases and strong nuclear survivin (3+) in 4. One case had strong co-expression at both locations. There was no statistical correlation between expression of either cytoplasmic or nuclear survivin with sex, SEER staging or tumor grade. Statistically, cytoplasmic survivin expression did not have prognostic significance. However, 4 pts with strong nuclear survivin had a median survival of 11 months, significantly less than those with weak nuclear survivin expression (20 months, p=0.033). Multivariate analysis using the Cox- proportional hazards model identified the following 4 as best predictors of patient mortality: nuclear survivin (P=0.022), presence of metastasis (P=0.025), age (P=0.019), and use of combined modality therapy (P=0.006). Estimated hazard ratios (HR) suggested pts likely to survive longer were weak nuclear survivin expressers (HR = 3.1) and had non- metastatic disease (HR = 1.5). Conclusions: Nuclear survivin expression in cholangiocarcinoma may identify those with a poor prognosis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MGI Eli Lilly; Genentech; MGI Phama Eli Lily; Pfizer; Roche

An update on the management of relapsed and primary refractory Hodgkin’s disease

With the use of combined modality therapy for early stage disease and a risk-adapted approach for advanced stage disease, nearly 90% of patients with Hodgkin’s lymphoma are cured with initial therapy. However, in patients who have primary refractory or relapsed disease, high-dose therapy and autologous stem cell transplantation is the best curative option. The use of peripheral blood progenitor cells has decreased transplant related mortality to less than 3%; but long-term progression-free survival as increased minimally. Although prognostic factors have been used to tailor therapy in de novo Hodgkin’s lymphoma their utility in the relapsed-refractory setting has not been exploited. This update will discuss these important prognostic factors and try to guide oncologists in treatment decisions in this setting.

Adjuvant therapy for rectal cancer in the elderly.

Rectal cancer, like most malignancies, is a disease of older age. By the year 2030, nearly 70% of all cancer patients are expected to be over the age of 65 years. Adjuvant therapy for colorectal cancer has been one of the most important contributions of medical oncology to the health of the population, saving more lives annually than more effective therapy for less common cancers, such as Hodgkin's disease. Nonetheless, population-based studies have shown that less than half of those over the age of 65 years receive the standard adjuvant therapy for rectal cancer. In many instances, there may be legitimate reasons for this, but efforts must be made to overcome any age bias and nihilism in the use of adjuvant therapy in the treatment of rectal cancer in the elderly. Although the elderly have been under-represented in clinical trials, they have been shown to tolerate cancer treatment and derive benefit from the adjuvant therapies. Despite early reports to the contrary, older patients have been shown to tolerate surgical resections for rectal cancer as well as their younger counterparts. Studies have supported the use of combined modality therapy as standard adjuvant care for clinical T3 rectal cancer in the preoperative setting and for patients with T3 and/or N1/N2 disease in the postoperative setting, wtih improved rates of sphincter preservation, recurrence and overall survival.

A discourse: the 2002 Wataru W. Sutow lecture. Hodgkin disease in children--perspectives and progress.

THE PIONEER: Wataru W. Sutow, 1912-1981, was a remarkable and pivotal leader in pediatric oncology. Early in his medical career, he conducted important clinical and anthropometric studies among Japanese and Marshall Island children exposed to atomic radiation. These studies established standards for childhood growth and development still in use today. Dr. Sutow pioneered the multidisciplinary approach to childhood cancer by combining multidrug chemotherapy protocols with surgery and radiotherapy in the common childhood solid tumors. The textbook "Clinical Pediatric Oncology," of which he was the senior editor, served to define the discipline of pediatric oncology and educate a new era of oncologists in the curative treatment for childhood cancer. THE PAST AND PRESENT: The first edition of "Clinical Pediatric Oncology," published in 1973, demonstrated that only children with early-stage localized Hodgkin disease had a realistic opportunity for cure. Soon the use of combined-modality therapy consisting of low-dose, involved-field radiation plus multi-agent chemotherapy emerged, and made the goal of cure realistic for all patients. This approach is now universal. Today, the 5-year relative survival rate for American children with Hodgkin disease, who are under 14 years of age, is 94%, a dramatic and remarkable achievement. Management of children with Hodgkin disease now involves clinical staging and risk-adapted, combined-modality therapy. Clinical and translational research initiatives that hold promise for children with Hodgkin disease in the future include: use of the WHO Classification System combining morphologic and biologic criteria; noninvasive staging procedures with increased sensitivity and specificity; development of a useful prognostic index to define groups for risk-adapted therapy; high-dose therapy with stem cell transplantation; and novel therapies.

Management of localized (stage I and II) clinically aggressive lymphomas.

The treatment for non-Hodgkin's lymphomas is chiefly dependent on the histologic type and the anatomic extent of the disease, reflected by the stage. In the past 30 years, the treatment of localized large cell lymphomas has evolved from the use of radiotherapy (RT) alone to the routine use of combined modality therapy (CMT). Randomized controlled trials have shown superiority of the CMT approach as compared to RT alone, or chemotherapy alone. The data will be critically appraised in this review. Currently, approximately two-thirds of patients with stage I and II clinically-aggressive lymphomas will be cured with initial planned combined modality therapy. The clinical prognostic factors predicting refractory or relapse disease are now clearly recognized, and they are: older age, stage II disease, high lactate dehydrogenase (LDH), poor performance status, and bulky disease. Patients with poor-risk features are candidates for clinical trials to examine the potential benefits of initial treatment intensification programs. Elderly patients over the age of 60 years account for about half of the patients with lymphoma, and they may tolerate therapy less well. They are a special subgroup where prospective studies are required to determine the optimal management.

Is concurrent chemotherapy and radiotherapy the new standard of care for locally advanced cervical cancer?

The results of five multi-institutional randomized controlled trials demonstrating a survival advantage for the concurrent administration of chemotherapy and radiotherapy in the management of cervix cancer represented the first major advance in the management of this malignancy in many years and prompted many practitioners to alter their pattern of practice. More recently, the results of the National Cancer Institute of Canada (NCIC) trial demonstrating no survival benefit when combined modality therapy is compared with optimally delivered radiotherapy, has led many to question the strength of the evidence supporting the adoption of combined modality therapy as the standard therapy for cervix cancer and in particular the magnitude of the benefit derived from the addition of chemotherapy to an optimally delivered radiotherapy regimen. This review paper will critically examine the evidence presented in the literature indicating a benefit for the use of combined modality therapy, discuss possible reasons why the conclusions of negative trials such as the NCIC study differ from those of the other studies and highlight those aspects of the use of combined modality therapy that require further evaluation.

Is concurrent chemotherapy and radiotherapy the new standard of care for locally advanced cervical cancer?

Abstract. Lehman M, Thomas G. Is concurrent chemotherapy and radiotherapy the new standard of care for locally advanced cervix cancer? The results of five multi-institutional randomized controlled trials demonstrating a survival advantage for the concurrent administration of chemotherapy and radiotherapy in the management of cervix cancer represented the first major advance in the management of this malignancy in many years and prompted many practitioners to alter their pattern of practice. More recently, the results of the National Cancer Institute of Canada (NCIC) trial demonstrating no survival benefit when combined modality therapy is compared with optimally delivered radiotherapy, has led many to question the strength of the evidence supporting the adoption of combined modality therapy as the standard therapy for cervix cancer and in particular the magnitude of the benefit derived from the addition of chemotherapy to an optimally delivered radiotherapy regimen. This review paper will critically examine the evidence presented in the literature indicating a benefit for the use of combined modality therapy, discuss possible reasons why the conclusions of negative trials such as the NCIC study differ from those of the other studies and highlight those aspects of the use of combined modality therapy that require further evaluation.

Results of the 1988–1989 patterns of care study process survey for Hodgkin’s disease

Purpose: To document national standards of care for patients receiving radiotherapy as part of curative treatment for Hodgkin’s disease. Materials and Methods: A national survey was conducted of 61 institutions treating 275 patients with Stages I–III Hodgkin’s disease and representing six facility type strata. Pretreatment evaluation, radiotherapy treatment parameters, and use of combined modality therapy were assessed. Results: Ann Arbor stage for the 275 patients was as follows: IA, 69 (25%); IB, 7 (3%); IIA, 123 (45%); IIB, 36 (13%); IIIA 23 (8%), IIIB, 14 (5%); unknown, 3 (1%). Pretreatment evaluation included complete blood count for 93%, sedimentation rate in 29%, chest CT in 88%, abdominal CT scan in 87%, and bone marrow biopsy in 81%. Lymphangiograms were obtained in 50% of cases; laparotomy was performed in 46%. The yield of positive findings in the spleen at laparotomy was 6.5% overall. Facility differences with respect to staging were seen only for the use of gallium scans, which were more commonly used in academic centers (44% vs. 15–23% elsewhere, p < 0.001). Radiotherapy was delivered with a linear accelerator in 94% of cases. Treatment simulation was performed for 94% and individualized blocks constructed for 95% overall; however, freestanding facilities had a lower rate of performance of these procedures (78% vs. 98–99% for simulation and 88% vs. 96–99% for customized blocking, p < 0.001). The mean supradiaphragmatic dose was 36.74 Gy and the mean subdiaphragmatic dose was 33.81 Gy. Planned combined modality therapy was given in 36% of patients. The use of combined modality therapy by stage was as follows: IA, 11%; IB, 43%; IIA, 30%; IIB, 68%; IIIA, 57%; IIIB, 100%. Chemotherapy was completed prior to radiation in 80% of cases and generally consisted of ABVD (32%), an alternating regimen (25%), or MOPP (22%). Among Stage I/II patients, use of chemotherapy was associated with reduced radiation doses (mean supradiaphragmatic dose 34.53 Gy vs. 38.43 Gy and mean subdiaphragmatic dose 31.27 Gy vs. 34.51 Gy), and reduced volumes of treatment (87% vs. 28% treated to one side of the diaphragm only). Laparotomy was not associated with decreased supra- or subdiaphragmatic radiation doses or decreased volumes of treatment. Conclusions: With the exception of gallium scans, pretreatment evaluation is relatively uniform across facility strata. Increased understanding of prognostic factors in Hodgkin’s disease and greater use of planned combined modality therapy for higher risk patients appears to have contributed to a decreased use of and low yield of positive findings for laparotomy. Laparotomy was not associated with reduced radiation volumes or doses. Freestanding radiation facilities had a lower rate than other facility types for the performance of treatment simulation and customized patient blocking.

Surgical management of primary colorectal cancer

Surgery for potentially curable colorectal cancer most commonly involves resection of the primary tumor and regional lymph nodes. However, the site, extent and presentation of disease have an impact on surgical strategy and the use of combined modality therapy. For colon cancer, complex presentations such as obstructing or perforated colon cancer may influence surgical therapy, and issues pertaining to en bloc resection and oophorectomy remain unresolved. For rectal cancer, surgical management may range from local excision to radical resection. Extent of resection and relatively new operative techniques such as coloanal anastomosis with or without a colonic pouch reservoir are directed towards optimizing both oncologic and functional results.

Neoadjuvant therapy for upper gastrointestinal tract cancers.

Esophageal, gastric, and pancreatic cancers frequently present with extensive local regional disease, which can be difficult to resect or to definitively control with radiation therapy given as a single modality. In addition, these patients are at high risk for the development of distant metastasis. Neoadjuvant chemotherapy is a promising experimental approach for the use of combined modality treatments that involve a systemic component. The theoretical background for the use of chemotherapy followed by an operation or chemotherapy plus radiation in these tumors has been extensively described. For esophageal cancer, many phase II trials have demonstrated tolerance to systemic chemotherapy; chemotherapy plus radiation prior to operation has more toxicity. Definitive phase III studies testing the hypothesis that this approach is superior to operation alone have recently been performed in the United States and Europe. These data are currently being analyzed. For the use of combined modality therapy of chemoradiation, random assignment trials have demonstrated an improvement in cure rate for patients with squamous cell carcinomas of the esophagus. Preliminary data suggest a similar outcome for adenocarcinoma, but the number of patients who have been studied is smaller. Newer phase III studies involve the use of new systemic agents that have demonstrated activity in metastatic disease (such as paclitaxel) or the use of higher doses of radiation therapy. For gastric cancer, a substantial number of phase II trials have again demonstrated tolerance to preoperative chemotherapy with no increase in operative morbidity or mortality. Small-scale phase III trials have been performed that suggest an improvement in outcome. Definitive studies are in the planning stage. Finally, for pancreatic carcinoma, in which local control is an even more difficult issue, a major stumbling block remains the development of newer systemic therapies that have activity in this disease. The recent identification of gemcitabine as having modest activity as a single agent and its potential use with radiation therapy is being explored in the neoadjuvant setting.

The role of adjuvant radiation therapy for stages III and IV Hodgkin's disease

The treatment for advanced stage Hodgkin's disease was revolutionized approximately 30 years ago with the introduction of combination chemotherapy. This approach has resulted in the cure of approximately 50% of patients with advanced disease. In an effort to improve these results, consolidation radiotherapy (RT) was introduced approximately 25 years ago. The rationale for adjuvant RT comes from several observations: significant numbers of patients relapse following combination chemotherapy alone, these relapses occur predominantly at initially involved sites, and successful salvage following relapse can be quite difficult to achieve. Data from numerous phase II trials have demonstrated that adjuvant RT significantly reduces the relapse rate compared with what is seen following chemotherapy alone and appears to increase survival as well. Phase III trials have confirmed the reduction in relapse but, as yet, have failed to demonstrate survival benefits. Because definitive phase III trials are lacking, the use of consolidation radiotherapy has gained only partial acceptance and remains controlversial. There have been numerous methodological difficulties with the execution of the reported phase III trials, most notably the failure of a substantial portion of patients randomly allocated to the radiotherapy group to actually receive radiation. This review presents updated results of studies using chemotherapy alone including patterns of failure analyses, summarizes the available literature pertaining to both retrospective and prospective trials of combined modality therapy, discusses toxicity issues, and attempts to provide guidelines regarding patient selection, sequencing of chemotherapy and radiotherapy, and radiation dose and field size. It is our conclusion that the available evidence supports the routine use of combined modality therapy for patients with advanced stage Hodgkin's disease.

The economics of lung cancer

Lung cancer remains the leading cause of cancer death in most Western countries. Despite several decades of clinical trials, the introduction of new approaches to management, and improvements in supportive care, the outlook for most patients diagnosed with carcinoma of the lung remains poor. Small improvements in outcome have been achieved, in particular by the reduction of surgical morbidity and mortality, in those patients with operable non-small cell lung cancer (NSCLC). Furthermore, the use of combined modality therapy in locally advanced NSCLC offers the promise of better results [8,9], as does the combination of radiotherapy and chemotherapy in limited stage small cell lung cancer [6]. The rising demand for health care services coupled with static or decreasing resources with which to pay for them has resulted in increasing interest in the economic analysis of medical interventions. Research into the economic aspects of health care is now carried out or supported by health care professionals, government, the insurance industry and the pharmaceutical industry. Each of these groups brings to the field their own particular biases and vested interests, and the interpretation of studies needs to be carried out with recognition of this fact. Both the pharmaceutical industry [4], and governments [l] have recognised the potential importance of economic analysis in health care, the former to aid in the promotion of new and expensive products, and the latter to limit the costs of the very same interventions. In common with other areas of medical practice, the economic aspects of caring for patients with lung cancer has also attracted growing interest in recent years. The

18 Novel radiation modifiers

The clinical approaches toward radiosensitization have utilized a number of different concepts including hypoxic cell sensitization, halopyrimidine-based radiosensitization and the use of combined modality therapy with chemotherapy plus irradiation. There are currently a new set of agents undergoing clinical trials called radiation enhancers or hypoxic-cytotoxic agents. These agents are designed to kill poorly perfused cells, which might limit the success of both radiation therapy and chemotherapy. Unlike the hypoxic sensitizers or oxygen modifiers, these agents can produce sensitization when given either before or after radiation. Based on the emerging knowledge of the cellular and molecular responses to ionizing radiation, novel agents are being conceptualized that may alter both tumor and normal tissue response. Supported in part by CA 42391, NIH, DHHS, Bethesda, MD. The clinical approaches toward radiosensitization have utilized a number of different concepts including hypoxic cell sensitization, halopyrimidine-based radiosensitization and the use of combined modality therapy with chemotherapy plus irradiation. There are currently a new set of agents undergoing clinical trials called radiation enhancers or hypoxic-cytotoxic agents. These agents are designed to kill poorly perfused cells, which might limit the success of both radiation therapy and chemotherapy. Unlike the hypoxic sensitizers or oxygen modifiers, these agents can produce sensitization when given either before or after radiation. Based on the emerging knowledge of the cellular and molecular responses to ionizing radiation, novel agents are being conceptualized that may alter both tumor and normal tissue response. Supported in part by CA 42391, NIH, DHHS, Bethesda, MD.

Combined modality therapy for gynecologic cancer

The use of combined modality therapy in the primary management of gynecologic cancer continues to be explored. Although early ovarian cancer is treated with postoperative adjuvant treatment, the data to support its value is lacking. In advanced disease, paclitaxel has emerged as the most optimal treatment after maximal cytoreduction. Although studies on consolidative therapy using radiotherapy, intraperitoneal therapy, or further chemotherapy are reported, there are no comparative data against a control arm. In those subsets of endometrial cancer patients who have a poor survival, adjuvant treatment strategies using chemotherapy or wide-field whole-abdominal therapy is being evaluated to improve outcome. Small phase II studies of either sequential or concurrent chemotherapy with radiation continue to be reported in advanced cervix cancer, yet large prospective randomized trials comparing standard radiotherapy to combined chemotherapy and radiotherapy are scarce. Alternative strategies to standard surgery to limit morbidity is being explored in the management of vulvar cancer with encouraging results. More properly conducted phase III trials are necessary to evaluate the efficacy of these newer treatment strategies.