Head and neck cancer: guidelines for chemotherapy

Head and neck cancer is estimated to be one of the most prevalent cancers in the world. This tumour type accounts for 5% of all new cancer cases in the US and Europe each year. Patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck have a poor prognosis, with a median duration of survival between 4 and 6 months. During the past few years, screening for potentially active new compounds, new associations and new modalities of chemotherapy administration have had some degree of success. Clinical investigations have also focused on the addition of chemotherapy to locoregional treatment for patients with locally advanced disease. Induction chemotherapy or concomitant chemo- and radiation therapy can result in high response rates, and reduced incidence of distant metastases. However, there is no clear demonstration of any benefit from the addition of chemotherapy to locoregional therapy on overall survival in patients with resectable disease. In patients with resectable laryngeal or hypopharyngeal cancer, chemotherapy combined with radiotherapy can be considered as a standard treatment option for larynx preservation, keeping total laryngectomy reserved for salvage therapy. In patients with unresectable head and neck cancer, simultaneous chemoradiotherapy has been shown to improve locoregional control and survival, at the cost of greater toxicity. Outside clinical trials, this approach can also be considered as a standard therapy for unresectable disease.     

Structure and differential target sensitivity of the stimulable cytotoxic complex from hemolymph of the Mediterranean mussel Mytilus galloprovincialis

Radiation therapy has been for years the treatment of choice of locally advanced non small cell lung cancer. Improvement due to the combination of radiation and chemotherapy has been shown recently through several randomized trials and a recent meta-analysis. These results may be explained by biological mechanisms, yet uncompletely explored, which are detailed in this review and applied to lung cancer. The optimal combination scheme is not yet defined, even though the concurrent approach is promising, at the expense of an increased toxicity which is the limiting factor of treatment escalation doses. Biological findings and future results of randomized trials will hopefully open new avenues in the therapeutic strategy of this poor prognosis disease.     

Complex and controversial issues in locally advanced non-small cell lung carcinoma

Locally advanced non-small cell lung carcinoma (NSCLC) presents enormous challenges to clinicians and researchers. Because of the absence of metastatic disease, it is a potentially curable condition, greatly differentiating it from stage IV NSCLC. The median and actuarial survival rates are poor, though clearly improved in the past decade, and clearly better than several other types of locally advanced malignancies (e.g., pancreatic cancer, glioblastoma). As demonstrated in Table I, the combination of chemotherapy and radiotherapy has earned the designation of "standard of care" for most good-performance-status patients with locally advanced NSCLC. It is likely that improvements in radiotherapy have also contributed to the enhanced survival and local control rates in this disease. With concurrent chemoradiotherapy, the majority of patients can receive a substantial local response (Fig. 1). Many achieve durable local control, only to succumb to eventual distant metastatic failure. There remains much room for improvement, and there are several avenues for clinical and translational research that offer promise. These include new systemic chemotherapy options (and newer ways of combining these drugs with radiotherapy), improvements in radiotherapy fractionation and dose intensity, methods of protection from chemoradiotherapy toxicity, specific therapies to prevent brain metastatic failure, and the integration of biologically targeted molecules into chemoradiation programs. This article summarizes the advances in the treatment of locally advanced NSCLC over the past several decades and explores some of the many remaining controversies and areas for future investigation.     

Is preoperative chemotherapy in locally advanced non-small-cell bronchial carcinoma of value?

Although surgeons are able to resect completely locally advanced non-small cell lung cancer with mediastinal lymph node involvement (stage IIIA), the majority of patients succumb from metastatic disease. Therefore, neoadjuvant therapy was introduced in the management of this disease in order to eradicate distant metastases at an early stage. Phase II trials with preoperative chemotherapy in stage IIIA patients have shown that the pathological response (amount of tumour necrosis) and the clearance of mediastinal lymph node correlate with a better survival and is the best predictor for eradication of distant metastases. Indeed, three small randomised phase III studies have demonstrated a survival advantage for preoperative chemotherapy compared to surgery alone. Further studies are required to determine the best neoadjuvant regimen inducing the largest amount of tumour necrosis.     

The effects of right-hemisphere brain damage on patients'' use of terms of personal reference

The majority of patients with lung cancer have disseminated disease at the time of presentation. For the minority of patients with disease localized to the chest, the concept of staging becomes particularly important because it has a major impact on the treatment plan. Guided by findings on the computed tomographic scan, mediastinoscopy remains the definitive invasive staging procedure to document unequivocally the involvement of the mediastinal lymph nodes. Equally as important is the documentation of absence of disease in contralateral lymph nodes. Patients with locally advanced non-small cell lung cancer, especially those with involvement of mediastinal lymph nodes (N2), are candidates for a multimodality approach to treatment involving either chemotherapy alone or in combination with radiation therapy. Surgical excision may be important in the management of these patients after an induction regimen. If surgical excision is performed, complete excision is the single most important factor. Postoperative adjuvant therapy may reduce the incidence of local recurrence but has not been shown to improve survival.     

Development of oriented ocular dominance bands as a consequence of areal geometry

BACKGROUND: Breast cancer has become a national health problem, affecting more than 180,000 women each year. Although advances in early detection and treatment have been made, it remains the second leading cause of cancer-related death in women. KEY POINTS: The treatment of breast cancer requires the careful integration of systemic and local methods. Although the application of hormonal therapy or chemotherapy is becoming less distinct, this discussion will review the important clinical trials and future directions of chemotherapy in the management of breast cancer. Data support the use of chemotherapy in the adjuvant setting, for preoperative tumor reduction of locally advanced disease, and as palliation in metastatic disease. The optimal chemotherapeutic regimen is not known; however, data support a role for adjuvant doxorubicin in node-positive disease, neoadjuvant therapy for high-risk disease, and high-dose chemotherapy to consolidate responding metastatic disease. CONCLUSIONS: The clinician must determine the risks and potential benefits of systemic chemotherapy before recommending treatment strategies. Although progress has been made, future advances can only occur through active participation in clinical trials.     

The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature

Carcinoma of the biliary tract is a rare tumour. To date, there is no therapeutic measure with curative potential apart from surgical intervention. Thus, patients with advanced, i.e. unresectable or metastatic disease, face a dismal prognosis. They present a difficult problem to clinicians as to whether to choose a strictly supportive approach or to expose patients to the side-effects of a potentially ineffective treatment. The objective of this article is to review briefly the clinical trials available in the current literature utilising non-surgical oncological treatment (radiotherapy and chemotherapy) either in patients with advanced, i.e. locally inoperable or metastatic cancer of the biliary tract or as an adjunct to surgery. From 65 studies identified, there seems to be no standard therapy for advanced biliary cancer. Despite anecdotal reports of symptomatic palliation and survival advantages, most studies involved only a small number of patients and were performed in a phase II approach. In addition, the benefit of adjuvant treatment remains largely unproven. No clear trend in favour of radiation therapy could be seen when the studies included a control group. In addition, the only randomised chemotherapeutic series seemed to suggest a benefit of treatment in advanced disease, but due to the small number of patients included, definitive evidence from large, randomised series concerning the benefit of non-surgical oncological intervention as compared with supportive care is still lacking. Patients with advanced biliary tract cancer should be offered the opportunity to participate in clinical trials.     

Multidisciplinary approach to potentially curable non-small cell carcinoma of the lung

The management of patients with non-small-cell lung cancer (NSCLC) is still evolving. Newer third-generation chemotherapy (paclitaxel [Taxol]-based; vinorelbine [Navelbine]/ cisplatin [Platinol]) is more effective than second-generation cisplatin-based chemotherapy for patients with stage IIIB and IV disease. The combined use of cisplatin-based chemotherapy with sequential or concurrent radiation therapy has improved the survival of patients with unresectable stage IIIA disease. Neoadjuvant cisplatin-based chemotherapy has improved the survival of patients with resectable stage IIIA disease compared to surgery alone. Combined-modality therapy is a fertile area of innovative clinical investigations for the majority of stage III resectable and potentially curable NSCLC patients, as well as those with locally advanced unresectable stage III disease. We expect therapy to substantially improve over the next few years. Cooperative groups should move quickly to incorporate third-generation chemotherapy into large randomized trials in order to redefine the standard of therapy for patients with this disease.     

Cancer of the esophagus: outcome of neoadjuvant therapy on surgical morbidity and mortality

Prognosis of oesophageal cancer is poor. There have been phase II-III trials of postoperative chemotherapy with the aim of improving survival. Chemoradiotherapy seems more promising than both chemotherapy and radiotherapy alone. In contrast, better results obtained with chemoradiotherapy were associated with an increase in morbidity and mortality, and finally overall survival was uncommonly improved. It is necessary to implement new multidisciplinary randomised trial.     

Tissue preparation for immunocytochemistry

The results in 9 patients with unresectable recurrent squamous cell cancer of the head and neck who were treated with aggressive concurrent chemoradiotherapy are reported. Treatment consisted of one or two courses of chemotherapy with 5-fluorouracil 1000 mg/m2/day and cisplatin 20 mg/m2/day, both given as 4-day continuous intravenous infusions, concurrent with radiation therapy. Salvage radiation doses between 30 and 70 Gy were administered. Seven patients had previously undergone an attempt at curative surgery, and 7 had been treated with radiation doses between 52 and 72 Gy. The recurrent disease was locally confined in 3, locoregional in 5, and locoregional with metastases in 1 of the 9 patients. Treatment toxicity was significant and included mucositis, nausea/vomiting, and granulocytopenia, but there were no toxic deaths. Complete tumor clearance was possible in 6 of these 9 patients, and 5 patients remain disease-free at 41+, 43+, 45+, 47+, and 50+ months. Of these 5 patients, 4 had previously been treated with both surgery and radiation, while 1 had only undergone surgery. We conclude that aggressive chemotherapy and concurrent (re)irradiation can be given to patients with unresectable, recurrent, squamous cell cancer of the head and neck. Treatment is tolerable, and disease-free long-term survival is possible. Careful patient selection, however, is required.     

A novel zinc finger cDNA with a polymorphic pentanucleotide repeat (ATTTT)n maps on human chromosome 19p

PURPOSE: To evaluate the therapeutic effectiveness of a combined chemoradiotherapy program, followed by surgery in selected cases, in Stage III non-small cell lung cancer. METHODS AND MATERIALS: Between August 1988 and February 1990, 43 patients Staged IIIa-b (UICC 1987, 58% IIIb) have been treated with concomitant chemotherapy (cisplatin 15 mg/m2 and VP16 75 mg/m2, 5 days a week on week 1 and 5) and radiotherapy (40 Gy split course, 2 Gy/day on week 1, 2, 5, and 6), followed by attempted curative thoracotomy or more cycles of full dose chemotherapy with the same two drugs. RESULTS: Planned chemoradiotherapy has been given to 91% of patients; 13/43 patients have been operated, with 12 complete resections and three (7%) pathological complete responses. Toxicity was significant, with two postoperative deaths and two fatal radiation pneumonitis. Crude progression-free survival rate is 21% at 30 months, with nine patients (21%) alive and free from progression at follow-up times ranging from 31 to 49 months. Subset survival analysis showed a possibly greater therapeutic effect for non-squamous histology as compared to squamous carcinoma. CONCLUSION: These results are encouraging in a cohort of patients with quite advanced disease (58% Stage IIIb).     

The lateralizing value of ictal clinical symptoms in uniregional temporal lobe epilepsy

Since 1984, the Cancer and Leukemia Group B (CALGB) has focused its clinical research in stage IV non-small cell lung cancer (NSCLC) on investigations of new agents and combinations. Currently, efforts are aimed at identifying non-cisplatin-based combinations with an increased therapeutic index. In stage III disease multimodality therapies have been pursued. Dillman et al. reported a study comparing standard radiotherapy versus induction chemotherapy followed by radiotherapy in patients with unresectable stage III NSCLC. The chemotherapy-treated patients were found to benefit with a 4-month increase in median survival time compared with patients receiving radiotherapy alone (13.8 vs. 9.7 months) and an increased 3-year survival rate of 23% versus 11%. This was the first randomized cooperative group study demonstrating a survival advantage resulting from the use of induction chemotherapy in locoregionally advanced NSCLC. In a subsequent study, the administration of additional "posterior" chemotherapy was not found to be feasible because of early disease progression and toxicity, while the administration of induction chemotherapy followed by concomitant chemoradiotherapy was feasible; therefore, the latter approach was studied further in a randomized phase III setting. This study compared a standard of two cycles of cisplatin and vinblastine followed by radiotherapy with an experimental arm of cisplatin and vinblastine followed by radiotherapy and concomitant carboplatin. Accrual to this study has been completed and results are expected in the near future. In resectable stage III disease, studies have focused on the optimal sequencing of multimodality therapy. A randomized study comparing standard regional therapy with radiotherapy and surgery versus a previously piloted approach combining chemotherapy, surgery, and radiotherapy was closed prematurely due to poor accrual. The next generation of studies in stage III NSCLC will focus on the integration of new chemotherapy agents into the treatment armamentarium for NSCLC. A randomized phase II study investigating paclitaxel, gemcitabine, and vinorelbine in combination with cisplatin in the induction setting and as concomitant chemoradiotherapy has recently been activated.     

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

Within the past 10 years, the role of chemotherapy in the treatment of patients with non-small cell lung cancer has expanded greatly. Previously chemotherapy was used only for patients with disseminated disease and, despite advances in combination therapy with new agents, response rates remained low, response duration was short, and cures were rare. Performance status is an important prognostic indicator both from the standpoint of response and duration of survival. Patients with locally advanced disease who are otherwise candidates for operation have a significantly higher response rate to chemotherapy and tolerate the treatment reasonably well. Combination chemotherapy given preoperatively seems to be associated with improved survival, especially in those patients able to undergo complete resection. Radiation therapy and chemotherapy given preoperatively may be even more efficacious than either modality alone. The question as to whether surgical resection improves on what can be accomplished with radiation therapy and chemotherapy in patients with mediastinal lymph node involvement remains an open one and is currently being evaluated.     

A case of liver metastasis from so-called hepatoid adenocarcinoma of stomach with lipiodol accumulation]

Although the overall survival rates for patients with metastatic non-small cell lung cancer have not changed in the past two decades, meta-analytic studies have confirmed that a modest increase in mean survival time can be gained with platinum-based combination chemotherapy. With appropriate selection of patients, chemotherapy will have symptomatic benefits in more than 60% of patients, and concerns regarding the costs of chemotherapy will be lessened by the observation that in some instances chemotherapy is less costly than best supportive care. Until the end of the 1980s, apart from the few active agents and their analogues no new drugs became available, but in the past 5 years several new agents have shown promising results and are now being included in combination programs. Large-scale comparative studies, looking for the combination with the best therapeutic index, are awaited with great interest. The number of patients with non-small cell lung cancer is so great that even modest improvements in therapy will have a great impact on survival rates.     

Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer

We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. Weekly i.v. paclitaxel (60 mg/m2; 3-h infusion) plus concurrent chest RT (60 Gy over 6 weeks) was delivered for 6 weeks. Twenty-nine patients were evaluable for response. Three patients achieved a complete response (10%), and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68-96%). One patient progressed during the therapy, and three patients had stable disease. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (37%). One patient died of pneumonia after completion of therapy. Additional grade > or =3 toxicities included pneumonitis (12%) and neutropenia (6%). One patient had a grade 3 hypersensitivity reaction. The median overall survival duration for all 33 patients who entered the study was 20 months, and 1-, 2-, and 3-year overall survival rates were 60.6%, 33.3%, and 18.2%, respectively. The median progression-free survival duration for all 33 patients was 10.7 months, and 1-, 2-, and 3-year progression-free survival rates were 39.4%, 12.1%, and 6.1%, respectively. Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.     

Diet supplemented with yoghurt or milk fermented by Lactobacillus casei DN-114 001 stimulates growth and brush-border enzyme activities in mouse small intestine

Adjuvant and neoadjuvant therapeutic principles have in recent years received increasing attention in the management of patients with carcinoma of the upper gastrointestinal tract. A series of randomized prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in gastric or esophageal cancer. The available data on the role of neoadjuvant preoperative therapy in these patients as yet permit no conclusion. While neoadjuvant therapy may reduce the tumor mass in a substantial portion of patients, a series of randomized controlled trials has shown that, compared to primary resection, a multimodal approach does not result in a survival benefit in patients with loco-regional, i.e. potentially resectable, tumors. In contrast, in patients with locally advanced tumors, i.e. tumors for which complete removal with primary surgery appears unlikely, neoadjuvant therapy increases the chance for complete tumor resection on subsequent surgery. However, only patients with objective histopathologic response to preoperative therapy appear to benefit from this approach. Compared to preoperative chemotherapy alone, combined radio-chemotherapy increases the rate of response, particularly in squamous cell esophageal cancer, but may also increase postoperative morbidity and mortality. Neoadjuvant therapy should therefore currently only be performed in experienced centers within the context of prospective clinical trials. The identification of factors that would allow prediction of response to neoadjuvant or adjuvant therapy is the focus of ongoing studies.     

Long-term survival of experimental calves with a left ventricular assist impeller pump

Screening with mammography in order to detect early curable breast cancer has been widely used during the last 2-3 decades. Especially an overview of 4 randomised trials in Sweden has shown a convincing short-term relative reduction of the breast cancer mortality while the long-term absolute effect on this mortality has been impossible to study due to screening of the control groups after some years. There is, however, rather general consensus about the value of screening in women above 50 years of age whereas screening in the age group 40-49 is still controversial due to the low rate of mammographically demonstrable cancers and the high rate of recalls for supplementary mammography, clinical examinations and biopsies in relation to cancers found. Recent follow-up of the pooled Swedish randomised trials have shown an about 20% almost significant reduction of the breast cancer mortality in women aged 40-49 at randomisation but the design of these trials does not allow an adequate estimation of the extra benefit obtained by starting periodical screening at age 40 instead of at age 50. The author proposes that screening in the age group 40-49 should be regarded as experimental and subject to proper randomised trials of a type on-going in UK and planned within UICC.     

High-dose therapy with cytostatic agents as primary treatment of advanced breast cancer

Thousands of women with breast cancer have received high dose chemotherapy prior to the results from controlled clinical trials being known. As one of these patients the author reviews and discusses the results of the first randomised study from South Africa. High dose therapy with autologous stem cell support was compared with conventional chemotherapy in 90 young women with metastatic aggressive breast cancer. Though survival was short in both groups the disease free survival was doubled in the high dose group. A significant increase was found in response rate, duration of response and survival. Data from America show the cost effectiveness of this treatment to be comparable to that of other life-saving therapies. A comparison is made with the absolute and relative survival benefit of simvastatin treatment. A Norwegian White Paper on high dose therapy does not include advanced breast cancer in the planned trial protocols. It is argued that future health planning should give high priority to the treatment of advanced breast cancer in young women.     

Cancer of the oesophagus

Oesophageal cancer is the fourth most common tumour in developing countries, comprising mainly squamous cell tumours, although the incidence of adenocarcinoma has increased enormously over the last decades. Surgical resection has long been acknowledged as the mainstay of treatment, and developments in surgical technique are reviewed. The roles of radiotherapy and chemotherapy in the management of oesophageal cancer remain unclear, especially as the majority of studies to date have been uncontrolled trials. We present an analysis of 601 patients who underwent resection for carcinoma of the oesophagus between 1970 and 1994 in the Department of Clinical Surgery, St James's Hospital, Dublin. The analysis shows clearly that, while peri-operative mortality continues to improve, conventional surgery offers little prospect of cure in the majority of cases. We have therefore embarked upon a prospective controlled trial of neoadjuvant chemoradiotherapy followed by surgery versus surgery alone in patients with adenocarcinoma or squamous cell tumours of the oesophagus. Preliminary results indicate that multi-modality treatment may have a valuable role to play in the treatment of carcinoma of the oesophagus.     

Vitamin therapy in cystic fibrosis--a review and rationale

An emphasis on careful surgical staging of adenocarcinoma of the colon has improved the predictive value of tumor staging systems. As a result of improved staging and carefully conducted randomized clinical trials, adjuvant therapy of locally advanced colon cancer, based on 5-fluorouracil chemotherapy, has been proven to substantially reduce recurrence rates and significantly increase overall survival for selected patients. Improved treatments and schedules are currently being studied in randomized trials and may increase the efficacy of this adjuvant therapy. Radiation therapy has not as yet been integrated into the adjuvant treatment of colon carcinoma. The application of a combined approach of surgery and chemotherapy in selected patients with liver metastases may also improve cure rates and long-term survival. The developing understanding of molecular determinants for the biological behavior of these cancers will increase the opportunities to identify, on the one hand, those patients who will benefit from specific therapies, and, on the other hand, new therapeutic strategies and treatments.