Current Drug Therapy - Volume 5, Issue 3, 2010

In recent years, a substantial proportion of patients with solid tumors has received concurrent treatment with radiation and systemic chemotherapy; the association of chemotherapy and radiation is becoming the best current standard therapy option for many patients with locoregionally advanced solid tumors. This issue of Current Drug Therapy reviews for several tumor types the clinical evidence and the state of the current practice in the concurrent use of radiation and drugs. The addition of concurrent chemotherapy to standard radiotherapy has been established to improve locoregional control and overall survival in a variety of solid tumors. Potential interaction between radiation and chemotherapy was described more than a quarter of century ago even though the mechanisms underlying the potentiation of radiation by drugs are still not fully understood. After an introductory paper of Tirindelli-Danesi on the rationale and the biological processes underlying the association, some important examples of tumors treated with radiotherapy and chemotherapy are reported and preclinical and clinical studies discussed. Radiation sensitization has been described for several agents, and many of them have been used even though the most frequently single agent used in clinical practice remains cisplatin. The advent of targeted therapies and the identification of specific molecular profiles associated with different tumor types, will provide to extend the spectrum of chemoradiation schemes available. In the coming years a series of new molecular cancer agents delivered concurrently with radiation will allow oncology practice to increase the options for concurrent treatment regimens. Efficacy and safety in the administration of chemoradiotherapy can be improved by the use of newer and sophisticated radiation delivery modalities that can reduce the amount of irradiated normal tissues and target the tumor more precisely further decreasing the risk of side effects.

The combination of radiation and chemotherapy, based on a demonstrated preclinical rationale, has involved in the last decades the use of cytotoxic agents as radiosensitizers. Classic chemotherapeutic agents, such as 5-fluouracil and cisplatin, and more recently gemcitabine and taxanes, have been employed in different sequences with radiation therapy, even though the optimal combinations and scheduling are still in evolution. During recent years, due to the highly improved molecular understanding of intrinsic radioresistance and the profiling of cellular response to irradiation, a big effort exists in basic and translational research to identify novel treatment modalities combining radiation therapy with molecules that target very specific molecular pathways.

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy (RT). Several randomized trials conducted over the past 30 years have failed to show a significant survival advantage for patients treated with BCNU or PCV chemotherapy. The randomized EORTC 26981/22981-NCIC trial has clearly demonstrated that the addition of the methylating agent temozolomide (TMZ) to RT followed by 6 monthly cycles of TMZ provides significant survival benefit with minimal additional toxicity in patients with GBM. A recent analysis of the trial revealed longer survival in patients with GBM which exhibited the methylation of the promoter region of the O (6)-methylguanine DNA methyltransferase (MGMT) gene. In patients with unfavourable prognostic factors, such as older age and poor performance status, abbreviated courses of RT in association with TMZ may be employed as an alternative to more aggressive treatments. Identification of many molecular genetic and signal transduction pathways involved in gliomatogenesis have yielded to the development of several targeted drugs, including epidermal growth factor receptor (EGFR) tyrosin kinase inhibitors, antiangiogenic agents, and integrin inhibitors, that are currently tested in combination with TMZ and RT. This review summarizes the results of chemoradiation for GBM and the development of new strategies under evaluation to increase the efficacy of treatments.

Recently new strategies such as the association of chemotherapy with radiotherapy have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: for patients with locally advanced HN-SCC, where outcome with radiotherapy alone is poor. More than one-hundred Phase III trials collected in large meta-analyses have showed that loco regional control and overall survival may be improved at high level of evidence by chemo-radiotherapy especially if delivered with synchronous approach. Sequential or synchronous chemo-radiotherapy regimens can also play a crucial role in larynx-function preservation programs without the risk of overall survival reduction for patients with larynx or hypo pharynx tumors who are candidates to radical surgery. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemoradiotherapy. Despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, awaiting for the results from ongoing trials where chemo-radiotherapy is explored in conjunction with new targeted therapies, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.

Over the past 30 years, significant advances have been made in the integration of radiation therapy and chemotherapy in the treatment of patients with esophageal malignancies. The therapeutic goal of chemoradiotherapy is to enhance local control resulting in improved loco-regional control and survival of these patients. To define the optimal sequence, the need of combination with surgery, and the efficacy of these modalities, several trials have been conducted, mainly as phase II studies and often underpowered or flawed phase III studies. The clinical evidence strongly suggests that preoperative chemoradiotherapy improves outcome. Therefore, this strategy has replaced single-modality approaches (surgery, radiotherapy) becoming a standard treatment option in patients with operable advanced disease. Moreover, recent published studies indicate that patients treated with 'definitive' chemoradiotherapy have similar survival to patients undergoing neoadjuvant chemoradiotherapy followed by surgery. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing radiation dose have not been successful. The use of other novel agents (camptothecin, taxane …) combined with radiation has altered the toxicity profile, but substantial prognostic improvement has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents and the use of molecular predictors of response as a strategy to select the treatment. Early identification of responders will also be required in order to guide and select the therapy. This overview highlights current results, controversies and potential future directions in the chemoradiotherapeutic treatment of selected esophageal cancer.

Radiochemotherapy represents the cornerstone of the treatment for patients affected by locally advanced non small cell lung cancer. Nevertheless, to date there is no agreement concerning how the standard therapy is and many questions are still open. Two timing modalities have been proposed to combine chemotherapy and radiotherapy: after many phase II/III have tested concurrent or sequential approach, concurrent radiochemotherapy is today considered as the treatment of choice, despite the role of induction or consolidation chemotherapy is still unclear. Cisplatin alone or in combination is considered as the reference drug in combination with chemotherapy, but in the last decades, many trials have demonstrated that new-generation drugs, which are routinely used in metastatic disease, may be used during radiotherapy and may enhance its tumor control rate, frequently having a radiosentizing power. Finally, in the era of molecular biomarkers and target therapies, new approaches could dramatically change the physicians' view about the drug choice giving the opportunity of a tailored therapy customized on the single patient also in the treatment of locally advanced non-small cell lung cancer.

Postoperative treatment of early-stage breast cancer often includes radio- and chemo- therapy and, more recently, trastuzumab. Optimal timing, i.e. sequential or concomitant, of radiotherapy and systemic therapies to maximize efficacy and cosmetic outcome and minimize toxicity, is still controversial. This review analyzes the effects of different sequences after surgery as reported in phase III randomized studies and the most significant retrospective studies. Few randomized clinical trials investigated the optimal therapeutic sequence as most were designed to evaluate the efficacy of different chemotherapy schemes and schedules. Since end-points did not usually include the optimal timing of the two modalities, single participant centers were often free to decide whether radiotherapy should be administered or not, and what fields and schedules to use. Concomitant or sequential chemo- and radio-therapy were not associated with major differences in outcome. Concurrent administration is reserved for patients treated with CMF; it is not recommended when antracycline or taxanes are used, because of the increased risk of cutaneous, esophageal, cardiac and pulmonary toxicity. Although concurrent trastuzumab and radiotherapy seem feasible, trastuzumab induces cardiac damage. Even though it seems reversible, follow-ups in diverse studies were too short to assess the late side effects of concomitant trastuzumab and radiotherapy.

Invasive transitional cell carcinoma of the urinary bladder is traditionally treated with radical cystectomy (RC), which remains the “gold standard” of therapy, providing a 5-year survival rate of about 75% in organ confined disease. However, approximatively half of the patients (pts) treated in this way experienced distant recurrence besides great morbidity and lifestyle changes. Although radiation has been the mainstay of nonsurgical treatments, with a 5- year survival rate ranging from 30% to 50%, its use has declined in many parts of the world because of: 1) the perception that radical cystectomy is more effective in controlling the primary tumor and preventing the development of new bladder tumors; 2) improvements in surgical techniques for radical cystectomy, and 3) the availability of more acceptable alternatives for urinary diversion, including stomal and orthotopic neobladders. However, parallel advances in high precision radiation treatment planning and delivery, along with an improved understanding of radiobiology, have reinforced the important role that radiotherapy (RT) plays in the treatment of pts. RT is now frequently combined with chemotherapy (CT) to treat muscle invasive bladder cancer, with the aim of improving local effectiveness and preventing the development of distant metastases. Over the past 20 years, bladder preservation techniques, incorporating maximal transurethral resection of tumor (TURBT), RT and CT in different timing (neoadjuvant CT, concomitant CT-RT, adjuvant CT) and selection by initial response, have demonstrated equivalent disease control rates when compared to radical surgery. The goals of selective bladder preservation are first of all the cure of the patient, and then, the mantainance of a tumor free bladder without compromising survival. From 1985, the Radiation Therapy Oncology Group (RTOG) in North America has completed six prospective protocols of combined modality therapy. A total of 415 pts. entered these trials: the 5-year overall survival rate was approximately 50%, with 75% of those pts. who completed the full course of RT-CT mantaining a functional bladder. Concurrently a number of European groups (University of Paris, Erlangen in Germany, Genova, Trento and Roma in Italy) published their experience with bladder sparing approaches including aggressive TURBT, RT and CT. Various agents have been used in combination with RT (cisplatin alone or with 5-Fluorouracil, mitomycin C, gemcitabine and, more recently paclitaxel). Complete response (CR) rates ranging between 47% and 90%, 5 years bladder preservation and overall survival rates between 25-40% and 40-52% respectively have been reported.The highest success rates are for early T2 tumors, without associated hydronephrosis or extensive carcinoma in situ and with adeguate renal function to allow cisplatin concurrent with RT. Using immunohistochemical staining, the RTOG Genitourinary Translational Research Group has evaluated the significance of the abnormal expression of Erb-1 (EGFR) and Erb-2 (HER-2) on RTOG protocols: overexpression of HER-2 is significantly associated with a reduced complete response rate ( 50% vs. 81% ), while EGFR positivity is associated with improved disease specific survival. Up to 1/3 of pts. may require a cystectomy for tumor persistence or invasive recurrence: 5 and 10 year disease specific survival rates following salvage cystectomy are 45% and 40%. Although radical cystectomy remains the standard therapy for invasive bladder cancer, the overall survival is comparable with conservative approaches. Acceptance of chemoradiation used in modern bladder sparing therapy should not be limited by either concerns of high rates of late pelvic toxicity or concerns of a significantly lower chance of patient cure compared to immediate cystectomy.

Significant advances have been made in the treatment of rectal cancer. Multidisciplinary management is the preferred approach and offers the best clinical outcome. In locally advanced disease, surgery with total mesorectal excision remains the leading option, but adjuvant treatments are necessary due to local and systemic failure. Even if the preoperative approach is the treatment of choice, chemoradiotherapy may be considered both in preoperative or postoperative setting as it significantly improves local control with lower toxicity rates. Nevertheless, additional drugs are to be incorporated in the combined treatment programs mainly aiming to reduce metastases at distant sites.

Squamous cell carcinoma of anal canal (SCCA) and its precursor lesions are increasing in prevalence for the diffusion of human papillomavirus infection. The treatment of the cancer of the anal canal represents a model for the application of organ sparing, combined modality therapy for curative treatment. Squamous cell carcinoma of anal canal was originally a surgically treated disease that required Abdominoperineal Resection (APR), approximately two thirds of patients are now cured with a combination of chemotherapy and radiation with sphincter preservation. This article reviews randomized trials and recent studies on chemoradiation for anal cancer.