Even a small percent increase in survival rates after treatment for lung cancer can produce a large benefit in terms of absolute numbers of lives saved, due to the very high incidence of the disease. Clinical results after surgery alone or radiotherapy alone are far from being satisfactory. Therefore, the integration of surgery with radiotherapy (both in the preoperative and in the postoperative setting) has been increasingly tested in the clinic. Radio-chemotherapeutic approaches progressively more effective have been developed for patients with inoperable disease, but also in combination with surgery. This review focuses on the current practice and on the ongoing clinical research in this field. The important issue of the short- and long-term toxicity of combined modality treatments in these patients is also emphasized, along with the research efforts for minimizing toxicity, especially as far as radiotherapy is concerned.
In consideration of the complexity of tumours, the modern and also the best approach to treat the neoplastic diseases is multi-modality therapy. Evidence suggests that this approach to cancer offers a patient the greatest change of survival. Actually, the involvement of a team of specialists warrants different expertise for the formulation of an appropriate treatment plan individualized for each patient, based upon tumour stage, medical conditions and patient preferences. Treatments are continually being updated and improved and the new treatment options provide fresh opportunities for controlling tumours and reducing morbidity and mortality. New developments in molecular biology and drug discovery are continually moving from the laboratory to clinical practice. This article reviews the role of integrated treatments in breast cancer, a common malignancy in women, and in head and neck cancers, that encompass a diverse group of uncommon tumours and frequently are aggressive in their biological behaviour. Careful evaluation of biological prognostic factors, performance status along with determination of life expectancy and preferences, represent the relevant information on which the oncologists should ground their decision for integrated treatments or attenuated or palliative measures, in order to maximize the balance of benefits and toxicities. Improving quality of life for patients with incurable disease remains an important goal for oncologists and is equally important as cure.
High-grade malignant gliomas (HGG) are the most common and malignant primary central nervous system tumors. Despite therapeutic efforts and advances in biologic knowledge, these diseases remain lethal. Standard treatment of HGG is based on surgery and radiotherapy, usually followed by adjuvant chemotherapy. Many randomized trials addressing the role of post-radiation or "adjuvant" chemotherapy have been conducted in the last three decades, yielding inconclusive results. However, a statistically significant survival benefit with adjuvant chemotherapy has been demonstrated in two meta-analyses with nitrosourea-based adjuvant chemotherapy and a recent phase III trial has demonstrated a survival advantage for radiotherapy with concomitant and adjuvant temozolomide (TMZ) in patients with newly diagnosed glioblastoma. Since high-grade malignant gliomas can seldom be cured, the primary aim of treatments for recurrent disease is to improve progression-free survival (PFS), and to improve or preserve neurological functions. TMZ showed activity even in the treatment of recurrent HGG with a good toxicity profile, whether few data are available for effective treatments in patients treated with adjuvant TMZ. As a result, new agents and novel approaches are required. Furthermore, molecular studies to evaluate chemosensitivity predictors are necessary for patients' selection. Brain metastases are estimated to occur in 20% to 40% of cancer patients, with a higher risk in lung cancer, breast cancer and melanoma. The incidence of brain metastases is rising as results of better imaging procedures and improvements in treatments which leave more cancer patients at risk as survival increases. The prognosis is dependent on a number of factors such as histology of primary tumor, performance status, localization number and size of brain metastases and status of extra cranial disease. Surgery and radiotherapy are indicated in controlled disease with isolated brain metastases. Systemic chemotherapy represents he optimal treatment in chemosensitive tumors with multiple or isolated brain metastases.
Metastatic spread of tumour cells detached from melanoma into the central nervous system (CNS) occurs haematogenously since lymphatic drainage is absent in the brain. CNS metastases occur in 10 to 40% of melanoma patients in clinical studies and up to 90% in autopsy studies. Headache is the most common presenting symptom, but brain metastases should be suspected in all melanoma patients with new neurologic findings. Magnetic resonance imaging is the best diagnostic technique for detecting CNS metastases. Median survival of melanoma patients with CNS metastases ranges between 2 and 8 months. The optimal treatment of melanoma patients with CNS metastases depends on the objective situation, often surgery, radiosurgery, whole brain radiotherapy and chemotherapy are used in combination to obtain longer remissions and optimal symptom relieve.
The sensitivity to chemotherapy of oligodendroglioma (OD) is the major clinical distinction between oligodendroglial and astrocytic tumours. In particular, chemotherapy with alkylating agents (PCV chemotherapy, temozolomide) in recurrent OD is of proven efficacy, with 50 to 70% of patients responding. The value of adjuvant chemotherapy in newly diagnosed tumours still remains to be proven. The efficacy of radiotherapy (RT) has never been proven in a phase III trial on OD, but based on historical phase III trials on anaplastic glioma this generally considered part of standard treatment of these tumours. Recent molecular biological studies show that OD are characterised by a combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19 q). This combined loss of 1p and 19 q also identifies a group of tumours with a better response to chemotherapy and a longer survival after RT. It is expected that this knowledge will change the diagnostic criteria for OD and will help to select patients for specific treatments. However, improvement of the currently available treatments is needed, as the outcome of these patients remains dismal.
Both genetic and environmental factors confer a significantly increased risk for cutaneous melanoma. This review discusses hereditary predisposition to the disease, focusing on the high-penetrance candidate genes INK4A/ARF and CDK4, and on pathogenetic mechanisms of mutations in those genes. As known mutations account for approximately 25 to 40% of melanoma families reported to date, it is clear that other melanoma genes and other mechanisms underlying predisposition remain to be discovered. Low penetrance susceptibility genes such as melanocortin 1 receptor and their modifying effect, also in concert with UV radiation, are likely to be implicated. Recent reports on a new candidate locus on chromosome 1p22 and somatic mutations in genes of the RAS-RAF-ERK signalling pathway raise interesting questions for further investigation.
Intra-cranial ependymal tumours are very rare in the adult population, so most of reported series are retrospective, include also paediatric patients and have limited statistical power due to the small number of cases. As a consequence, universally accepted prognostic factors and therapeutic guidelines are lacking. The addition of postoperative chemotherapy with lomustine, vincristine and prednisone to cranio-spinal irradiation did not improve survival with respect to RT alone in a randomised phase III trial of children with infratentorial ependymoma. Different chemotherapy regimens have been tested in children with ependymoma or anaplastic ependymoma yielding comparable results to those reported for patients receiving RT alone. No data is available for adult population. Thus far, there is no proof that the addition of chemotherapy to RT improves the outcome and adjuvant chemotherapy should be confined to investigational controlled clinical trials.
More than 80% of intracranial tumours in the elderly are malignant gliomas with aggressive behaviour. Older patients have been frequently excluded from clinical trials in view of their dismal prognosis and low tolerability of chemo-radiotherapy treatments, therefore they were underrepresented in the past oncological literature. Controversies in the use and dose of RT and in the administration of chemotherapeutic agents have not been solved by the small retrospective studies conducted so far. It appears reasonable that an aggressive treatment with surgery, full dose RT and, possibly, chemotherapy should be applied to patients with good performance status, preserved cognitive functions and no relevant comorbidities, although in the absence of randomised studies the balance of benefits and side effects of integrated treatments remains controversial. Patients with low performance status and/or serious comorbidities, unable to undergo surgery, may receive a shorter RT plan, or even no treatment at all, in consideration of the rapid course of their disease which may be shorter than the hypothetical benefit of any specific treatment. Further studies should be designed to perform a reliable analysis of prognostic factors of malignant gliomas in the elderly in order to tailor treatments to each patient to obtain the best feasible benefit without compromising their quality of life.
The best therapeutic management in primary central nervous system lymphomas remains to be defined because of current knowledge on these malignancies results from small retrospective series with a short follow-up, a limited number of prospective studies with some methodological pitfalls and a single published randomised trial. This review focuses on the current therapeutic approaches, most commonly used drugs, role of intrathecal chemotherapy, and indications for consolidation radiotherapy, providing recommendations for ordinary clinical practice. Some important therapeutic issues, such as the management of meningeal and intraocular lymphomas, as well as the relevance of salvage therapy as a playground for evaluation of new drugs are also analysed. Finally, the main open questions, as well as current and expected investigation trends are discussed.
A new chemotherapy agent and a method for local delivery of carmustine have recently been approved for the treatment of malignant glioma. However, the increase in survival remains modest at best with only a very select patients currently benefiting truly of these treatments. Combination regimen of different alkylating agents or prior O6-alkyltransferase depletion by O6-benzylguanine or continuous temozolomide administration schedules have shown some indication for increased activity. There is preclinical rational for combining temozolomide with radiotherapy and the initial results of a phase II clinical trial were promising. Several new cytotoxic agents are currently in clinical trials in patients with recurrent glioma. More importantly, targeted therapy and antiangiogenic agents have entered the clinical development phase also for patients with glioblastoma and anaplastic astrocytoma. The optimal timing of administration of non-cytotoxic substances and their integration into the currently available treatments remains a challenge. Novel study designs and identification of surrogate markers are necessary in order to make rapid and clinically meaningful progress. This review summarises the currently available evidence of activity of the recently approved drugs against malignant glioma and mentions also agents which have failed to demonstrate a significant antitumour activity. Study endpoints are critically discussed. Combination regimens with other agents and radiation therapy are reviewed. The rational for using antiangiogenic drugs in selected ongoing trials is discussed.
Treatment options for low-grade gliomas are a challenging dilemma in neuro-oncology. Young age at onset, low rate of growth and long-term treatment sequelae, indicate that minimally invasive treatments are required. However, local recurrence and conversion to malignant glioma occur within 4 to 8 yrs after diagnosis, calling for adjuvant treatment strategies, such as RT and chemotherapy with the aim of improving the disease-free interval. As glioma has a low incidence, and few randomised trials are available in literature, there is little consensus on the correct timing and dosage for RT, or on indications for timing and choice of cytotoxic drugs administration. The present paper therefore focuses on current concepts and future perspectives in the treatment options for low-grade gliomas.
In the past decade, the characterisation of tumour antigens recognised by T cells has revolutionised the cancer-vaccine approach, providing for the first time the opportunity to immunise patients against cancer by using well-defined antigens. Because melanoma is one of the prototypic immunogenic tumours, a number of early-phase clinical trials have been conducted on melanoma. Some tumour regressions have been documented, mainly for patients with metastatic disease. Recent advances include new tools for monitoring the anti-cancer immune response and the development of adjuvants aimed at inducing a robust anti-melanoma immune response. Together, these developments should allow an optimal vaccination modality to be selected within the next few years.
Medulloblastoma in adults are rare and differ from their childhood counterparts in terms of tumor site (hemispheric location), histological subtype (desmoplastic variant), lower incidence of metastatic spread and frequent late relapses. As in children the presence of metastatic disease is of major prognostic significance. The role of different histological subtypes and molecular genetic/biological markers is unknown and deserves further investigations. The therapeutic strategies are essentially based on experiences in childhood medulloblastomas. Surgery followed by irradiation of the entire central nervous system followed by a boost to the posterior fossa is the cornerstones of treatment. A sufficient dose prescription and a high quality of treatment are a prerequisite for an optimal tumor control. Unlike in children the role of chemotherapy is an open question and requires prospective investigations. The forthcoming EORTC-study is addressing this issue.
Based on the observation of a small proportion of long-term responses the use of biotherapy or biochemotherapy is currently preferred in many institutions as first line treatment in stage IV melanoma, but still the outcome for patients with stage IV melanoma is unsatisfactory. Various interleukin 2 (IL-2) dosing schedules and combinations with interferon alpha (IFN-alpha) have been tested in patients with advanced melanoma in phase I and II studies. The response rate reported with cytokines alone (IL-2 as a single agent or in combination with IFN-alpha) varies from 10-41%. Subsequently, biochemotherapy regimens combining IL-2, IFN-alpha and chemotherapy have been evaluated in phase II trials suggesting improved response rates. Recent randomised trials have investigated the role of biochemotherapy as compared to biotherapy alone or as compared to chemotherapy for the treatment of advanced melanoma. So far, none of the approaches has been proven to confer a survival benefit and thus the uniform desire is to include as many patients as possible into controlled clinical trials. Therefore current trials are under way trying to improve the efficacy of immunotherapy alone by adding histamine or vaccines to IL-2.
EPIDEMIOLOGY:Meningiomas constitute the largest subgroup of all intracranial tumours. Their incidence is about 2-3/100,000/yr, with a 3:2 to 2:1 female:male ratio, with a peak incidence in the sixth and the seventh decade of life. Meningiomas are usually slow growing, benign neoplasms, causing symptoms by compression of adjacent structures or by increased cranial pressure, the specific symptoms depending on the location of the tumour.RISK FACTORS:Meningiomas can be induced by radiation to the head, even by low dose radiation as used for dental radiographic examination after up to 35 yrs interval. The female preponderance in meningioma patients as well as the expression of progesterone receptor on the cell membranes of more than 50% of meningiomas is argument for an influence of gestagene in meningioma proliferation. The most frequent genetic predisposition of meningiomas is associated with neurofibromatosis 2 (NF-2); at least 40% of meningiomas show a deletion in the NF-2 gene.TREATMENT:To date, surgical resection is the mainstay of meningioma therapy. The completeness of the resection is the single most important prognostic factor for recurrence. In case of incomplete resection or recurrence, radiation therapy with 54 Gy (1.8 to 2 Gy/fraction) yields comparable results to total resection. Radiosurgery is a valuable alternative to radiotherapy (RT), maybe in the future also for surgery, as recently demonstrated. In the rare meningioma patients, that have exhausted the possibilities of surgery and RT, there have been some successful small series using hydroxyurea or interferon alpha. Future therapeutic options might consist in octreotide isotopic therapy or targeted therapy directed against tumour neo-angiogenesis or other proliferation associated markers in meningiomas.
The incidence of melanoma continues to rise at a rate greater than all other cancers. Survival in melanoma varies widely by stage, and is affected by a number of prognostic factors including tumour thickness, ulceration and lymph node involvement. New AJCC staging criteria adopted in the 6(th) edition reflect the prognostic value of tumour ulceration, the number of positive lymph nodes as a better prognostic indicator than the size of nodal metastasis, and the similar prognostic value provided by nodal, in-transit and local recurrences. It also recognises the pathologic information about staging provided by lymphatic mapping and sentinel lymphadenectomy. High-risk resected melanoma is defined as disease that after surgery is at higher than 40 to 50% risk of recurrence and death. The urgency to the effort to develop effective therapy for melanoma has led to a wide variety of approaches that have been tested over the years in the high-risk adjuvant setting. Among the many therapeutic modalities tested, the only agent that has shown a significant and reproducible benefit in terms of survival and relapse-free interval has been high-dose interferon-alpha2b. We here review the evidence that has led to the regulatory approval of this regimen, as well as ongoing studies using high-dose interferon-alpha in the high-risk adjuvant setting. We also present selected ongoing trials testing potential future therapies that may prove effective for patients with high-risk resected melanoma.
The number of elderly women diagnosed with breast cancer by 2025, will increase by 72%. These elderly women do not yet participate in most screening programmes. One notes more favourable biological characteristics of the tumour, including more expression of steroid receptors (oestrogen receptor, progesterone receptor), low proliferative rate, good differentiation, normal p53 and low expression of epidermal growth factor. Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy and chemotherapy. There is a paucity of data to substantiate that such an approach is better than a more radical one. The efficacy of chemotherapy and guidelines for its use vary by tumour stage and patient age. Drugs like modified anthracyclines, vinorelbine, the taxanes and capecitabine may be changing the paradigm of combination therapy superiority.
The most appropriate systemic therapy for a population of patients with breast cancer is determined from clinical trial data. However, the heterogeneity of breast cancer is such that within a population individual patients derive variable benefit. There is therefore a need for predictive molecular factors in order that treatment can be individualised. This review describes the roles of HER-2, epidermal growth factor receptor (EGFR), oestrogen receptor (ER)/progesterone receptor (PgR), Ki67, Bcl-2, p53 and gene expression profiling in predicting responses to endocrine, cytotoxic and biological therapies. ER and PgR remain the only well-established predictive markers of responses to endocrine therapy, although HER-2/neu has an emerging role in this area and in choice of adjuvant chemotherapy. There are considerable methodological difficulties in identifying useful predictive factors but on the basis of current evidence other biomarkers add little additional information. The development of targeted therapies means that the molecular targets themselves may become useful predictive factors for directing use of these therapies. HER-2 already has an established role in this area, but the role of EGFR requires further elaboration. The use of DNA microarrays to assess gene expression profiles may revolutionise our ability to predict responses to therapy.
To date, seven randomised trials of high-dose chemotherapy for high-risk breast cancer have been published, both in Europe and in the US. We will not comment on the discredited Bezwoda trials. The main inclusion criteria for entry into these trials was an involvement of 4 or more axillary lymph nodes. Only two of these trials showed a trend in event-free survival favouring the high-dose arm. However, many differences in the designs of the trials were observed and general conclusions cannot be drawn as yet. The number of randomised patients spanned from 78 to 885, the scheduling and the drug combination of high-dose regimens varied notably and finally the issue of the contamination of the grafts by tumour cells still needs to be correctly addressed. We certainly are only at the end of the beginning.
