Perioperative radiotherapy in rectal cancer

Local failure of rectal cancer is one of the principal causes of morbidity and mortality. In order to lower unacceptably high local failure rates, pre- or postoperative radiotherapy has been extensively investigated. The collected information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than half when radiotherapy up to moderately high doses is given preoperatively. This reduction is smaller after postoperative radiotherapy, even if higher doses are used. In addition, there is a positive influence on survival from preoperative radiotherapy. Improved survival has also been seen in trials using postoperative radiotherapy, but only when combined with chemotherapy. With proper radiation techniques, sufficiently high doses can be given preoperatively with little, if any, increase in postoperative mortality and morbidity. Furthermore, late toxicity can be anticipated to be low provided the technique is optimal. The beneficial effects noted so far have been achieved in trials where 'standard' surgery has been used, followed by a local recurrence rate of more than 20% (average 29%, range 23-46%) of the patients. It is, however, possible that the reduction in local failure rates is proportionally even greater added to 'optimal' surgery, although the absolute number of failures prevented is lower.     

A Systematic Overview of Radiation Therapy Effects in Rectal Cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for rectal cancer is based on data from 42 randomized trials and 3 meta-analyses. Moreover, data from 36 prospective studies, 7 retrospective studies and 17 other articles were used. A total of 131 scientific articles are included, involving 25 351 patients. The results were compared with those of a similar overview from 1996 including 15 042 patients. The conclusions reached can be summarized thus: The results after rectal cancer surgery have improved during the past decade. It is likely that local failure rates after 5 years of follow-up at hospitals adopting the TME-concept (TME=total mesorectal excision) have decreased from about 28% to 10-15%.Preoperative radiotherapy at biological effective doses above 30 Gy decreases the relative risk of a local failure by more than half (50-70%). Postoperative radiotherapy decreases the risk by 30-40% at doses that generally are higher than those used preoperatively.There is strong evidence that preoperative radiotherapy is more effective than postoperative.There is moderate evidence that preoperative radiotherapy significantly decreases the local failure rate (from 8% to 2% after 2 years) also with TME.There is strong evidence that preoperative radiotherapy improves survival (by about 10%).There is no evidence that postoperative radiotherapy improves survival.There is some indication that survival is prolonged when postoperative radiotherapy is combined with concomitant chemotherapy.Preoperative radiotherapy at adequate doses can be given with low acute toxicity. Higher, and unacceptable acute toxicity has been seen in some preoperative radiotherapy trials using suboptimal techniques. Postoperative radiotherapy can also be given with acceptable acute toxicity.The long-term consequences of radiotherapy appear to be limited with adequate radiation techniques, although they have been less extensively studied. Longer follow-up periods are needed before firm conclusions can be drawn.Peroperative radiotherapy, preferably preoperative since it is more effective, is routinely recommended for most patients with rectal cancer since it can substantially decrease the risk of a local failure and increases survival.In a primarily non-resectable tumour, preoperative radiotherapy can cause tumour regression allowing subsequent radical surgery. This therapy is routinely indicated. Whether radiochemotherapy is more efficient than radiotherapy alone is not clear, since the results of four small randomized trials are partly conflicting.Preoperative radiotherapy, frequently combined with chemotherapy, has been used to increase the chances of sphincter-preserving surgery in low-lying tumours. The literature is inconclusive with respect to how frequently this occurs.Radiotherapy frequently produces symptom relief in patients with rectal cancer not amendable to surgery.     

A systematic overview of radiation therapy effects in rectal cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for rectal cancer is based on data from 42 randomized trials and 3 meta-analyses. Moreover, data from 36 prospective studies, 7 retrospective studies and 17 other articles were used. A total of 131 scientific articles are included, involving 25 351 patients. The results were compared with those of a similar overview from 1996 including 15 042 patients. The conclusions reached can be summarized thus: The results after rectal cancer surgery have improved during the past decade. It is likely that local failure rates after 5 years of follow-up at hospitals adopting the TME-concept (TME = total mesorectal excision) have decreased from about 28% to 10-15%. Preoperative radiotherapy at biological effective doses above 30 Gy decreases the relative risk of a local failure by more than half (50-70%). Postoperative radiotherapy decreases the risk by 30-40% at doses that generally are higher than those used preoperatively. There is strong evidence that preoperative radiotherapy is more effective than postoperative. There is moderate evidence that preoperative radiotherapy significantly decreases the local failure rate (from 8% to 2% after 2 years) also with TME. There is strong evidence that preoperative radiotherapy improves survival (by about 10%). There is no evidence that postoperative radiotherapy improves survival. There is some indication that survival is prolonged when postoperative radiotherapy is combined with concomitant chemotherapy. Preoperative radiotherapy at adequate doses can be given with low acute toxicity. Higher, and unacceptable acute toxicity has been seen in some preoperative radiotherapy trials using suboptimal techniques. Postoperative radiotherapy can also be given with acceptable acute toxicity. The long-term consequences of radiotherapy appear to be limited with adequate radiation techniques, although they have been less extensively studied. Longer follow-up periods are needed before firm conclusions can be drawn. Peroperative radiotherapy, preferably preoperative since it is more effective, is routinely recommended for most patients with rectal cancer since it can substantially decrease the risk of a local failure and increases survival. In a primarily non-resectable tumour, preoperative radiotherapy can cause tumour regression allowing subsequent radical surgery. This therapy is routinely indicated. Whether radiochemotherapy is more efficient than radiotherapy alone is not clear, since the results of four small randomized trials are partly conflicting. Preoperative radiotherapy, frequently combined with chemotherapy, has been used to increase the chances of sphincter-preserving surgery in low-lying tumours. The literature is inconclusive with respect to how frequently this occurs. Radiotherapy frequently produces symptom relief in patients with rectal cancer not amendable to surgery.     

Chemoradiotherapy of esophageal cancer

Esophageal cancer is a disease with a poor prognosis and high biological aggressiveness. The disease used to be considered a mainly local problem, and palliative care with relief of dysphagia was the goal for most of those concerned with the disease. When surgical techniques were improved and parallel progress was made in intensive care and postoperative care, some patients could be cured of the disease. The development of pre- or postoperative radiotherapy also improved local control. Partly because of the interest that began to be focused on improving survival for this diagnostic group, chemotherapy combined with radiotherapy has been incorporated into the therapeutic arsenal. The aim of this review is to shed light on current treatment principles for esophageal cancer. However, treatment results from studies utilizing combination chemotherapy given concurrently with radiotherapy support the conclusion that well-designed randomized trials with long-term follow-ups should be performed.     

Postmastectomy radiotherapy: future directions.

With careful interpretation of existing studies of postmastectomy radiotherapy, much has been learned about the ability of radiotherapy to significantly reduce local failure and potentially impact on survival. With this knowledge, however, has come additional questions about the mechanisms by which radiotherapy could affect systemic control and the extent of that benefit. Therefore, these questions need to be investigated in well-designed, randomized trials that incorporate aggressive surgical techniques and contemporary chemotherapy regimens into the clinical plan. A trial that is currently in progress should give additional insight into whether regional irradiation in the modern era, which incorporates the internal mammary nodes in the radiotherapy field, impacts systemic control. An upcoming trial will investigate whether women at moderate risk for locoregional failure will benefit from comprehensive radiotherapy after aggressive surgery and chemotherapy. And, although no national studies are currently planned to test the optimal sequencing of radiotherapy and chemotherapy, consideration should be given to studying this issue in large, randomized trials.     

Postoperative radiotherapy in stage II or IIIA completely resected non-small cell lung cancer: a systematic review and practice guideline

The Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care conducted a systematic review of literature published between 1985 and July 2003 and developed an evidence-based clinical practice guideline on postoperative radiotherapy in patients with completely resected pathologic stage II or IIIA non-small cell lung cancer (NSCLC). Forty-four Ontario clinicians reviewed the draft guideline. Evidence included one meta-analysis of individual patient data (from nine randomized controlled trials) and three randomized controlled trials (two including data reported in the meta-analysis) that compared surgery with or without postoperative radiotherapy. The meta-analysis and one trial detected a significant detriment to survival with postoperative radiotherapy. Two trials detected no survival difference. The meta-analysis detected a significant advantage in local recurrence-free survival (time to local recurrence or death) with surgery alone, although two trials detected a significant advantage in rate of local recurrence with postoperative radiotherapy. Subset analyses from the meta-analysis and one trial suggested that postoperative radiotherapy was detrimental to survival mainly in stage II disease; no benefit or detriment was evident for stage III disease. Recommendations: Postoperative radiation therapy following complete resection of stage II non-small cell lung cancer is not recommended. No definitive recommendation can be made for stage IIIA disease.     

Radiotherapy in Addition to Radical Surgery in Rectal Cancer

In order to lower unacceptably high local failure rates after surgery reported as curative for rectal cancer, perioperative radiotherapy has been extensively investigated. The collected information from a number of controlled trials indicates that the proportion of local recurrences is reduced to less than half when radiotherapy at moderately high doses is given preoperatively. This reduction in local failure rates is not seen after postoperative radiotherapy, even if higher doses have been used. Possibly, there is also a slight positive influence on survival from preoperative radiotherapy. Improved survival has been seen also in trials using postoperative radiotherapy, but then only when combined with chemotherapy. With proper dose planning, sufficiently high doses can be given preoperatively with little if any increase in postoperative mortality. Thus, although published knowledge is still rather limited, a properly planned preoperative radiotherapy seems to inflict small bowel and other complication rates, that are less than when radiotherapy of similar efficacy against the tumour is given postoperatively.     

A Systematic Overview of Radiation Therapy Effects in Oesophageal Cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for oesophageal cancer is based on data from 42 randomized trials and 2 meta-analyses. A total of 44 scientific articles are included, involving 5 772 patients. The conclusions reached can be summarized as follows: There is fairly strong evidence that preoperative radiotherapy does not improve the survival in patients with potentially resectable oesophageal cancer.There is moderate evidence that preoperative chemo-radiotherapy has no beneficial impact on the survival of patients with potentially resectable oesophageal cancer.There is no scientific evidence that postoperative radiotherapy improves survival in patients with resectable oesophageal cancer. The documentation is, however, poor, consisting of only three randomized trials.There is fairly strong evidence that concomitant (but not sequential) chemo-radiotherapy gives significantly better survival rate than radiotherapy alone in inoperable oesophageal cancer. The results of the reported clinical trials are, however, conflicting, and no solid conclusion can be drawn.Hyperfractionated radiotherapy has been compared with conventionally fractionated radiotherapy in two randomized studies with conflicting results and no firm conclusion can be drawn.     

A systematic overview of radiation therapy effects in oesophageal cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for oesophageal cancer is based on data from 42 randomized trials and 2 meta-analyses. A total of 44 scientific articles are included, involving 5 772 patients. The conclusions reached can be summarized as follows: There is fairly strong evidence that preoperative radiotherapy does not improve the survival in patients with potentially resectable oesophageal cancer. There is moderate evidence that preoperative chemo-radiotherapy has no beneficial impact on the survival of patients with potentially resectable oesophageal cancer. There is no scientific evidence that postoperative radiotherapy improves survival in patients with resectable oesophageal cancer. The documentation is, however, poor, consisting of only three randomized trials. There is fairly strong evidence that concomitant (but not sequential) chemo-radiotherapy gives significantly better survival rate than radiotherapy alone in inoperable oesophageal cancer. The results of the reported clinical trials are, however, conflicting, and no solid conclusion can be drawn. Hyperfractionated radiotherapy has been compared with conventionally fractionated radiotherapy in two randomized studies with conflicting results and no firm conclusion can be drawn.     

Les carcinomes du nasopharynx Les modalités de la radiothérapie et les associations de la radiothérapie et de la chimiothérapie: état actuel et perspectives

Nasopharyngeal carcinoma (NPC) is a highly radiosensitive and chemosensitive. In the patient with locally advanced Humours, the results of conventional radiotherapy are unsatisfactory with significant rates of both local recurrences and distant metastases. The aim of this review is to report the innovative strategies for treatment of the nasopharyngeal carcinoma. Altered fractionation techniques can improve local control. The impact of the innovative techniques, including conformai radiation, stereotactic radiation and IMRT, on survival, must be evaluated in randomised trials. The encouraging early results obtained with concurrent (more than sequential) chemotherapy and radiotherapy must be confirmed in prospective randomized trial in endemic areas.     

The influence on treatment outcome of structuring rectal cancer care.

Clinical trials and registers data for quality assurance have been mandatory to achieve the good results and the enormous evolution which has been involved in rectal cancer surgery during the past 20 years. The whole business came into focus when local recurrences were considered as a matter of tumour biology and radiotherapy was introduced in many countries as a standard treatment in rectal cancer patients to reduce the local recurrence rate and to improve survival. During the last 30 years more than 8000 patients have been randomized in trials using pre- or post-operative radiotherapy. Those data are summarized in two good meta-analyses. In short, a summary of those meta-analyses has shown that radiotherapy reduces the local recurrence rate with 50%. Moreover, it has been revealed that pre-operative radiotherapy is better than post-operative radiotherapy in attempt to reduce the local recurrence rate and finally that there is a survival benefit with this reduction of the local recurrence rate.     

Dose and fractionation concepts in the primary radiotherapy of non-small cell lung cancer

At present, radiotherapy alone or in combination with chemotherapy offers the only chance of cure of medically inoperable or locally advanced unresectable non-small cell lung cancer. The radiobiological basis and clinical results of current dose and fractionation concepts in the primary radiotherapy of NSCLC are briefly reviewed. Whenever possible, focus is given to the results of randomized phase III trials. With the exception of early disease treated to doses higher than 60 Gy, the prognosis of inoperable localized NSCLC is very poor. Local recurrence is the major cause of failure after radiation therapy calling for intensified local treatment. Dose-escalation using conventional fractionation or moderate hypofractionation is promising but randomized trials are presently not available. Dose-escalated hyperfractionation theoretically offers advantages, however, there appears currently no strong evidence from randomized trials supporting this approach in NSCLC. The highly accelerated CHART regimen significantly improved survival by 9% compared to standard radiotherapy. Nevertheless, even when treated with CHART, about 80% of all patients will eventually develop local recurrence and 60% distant metastases. Many trials on combined radiochemotherapy have used radiotherapy regimens that are not optimal from a current perspective. Because of the high rate of both, local recurrence and distant metastases, future research should be directed to further intensify radiotherapy as well as to integrate such protocols with systemic treatment in carefully selected patients. Since toxicity is expected to increase, state-of-the-art 3D conformal radiation techniques need to be part of clinical trials testing such strategies.     

Radiothérapie et sarcomes des tissus mous

Since the Rosenberg studies of 1982, soft tissue sarcoma in the extremities has been treated with conservative surgery and postoperative radiotherapy. Two randomized trials highlight the benefit of postoperative radiotherapy to local control. No advantage in survival after radiotherapy has been established. For retroperitoneal, head and neck, breast and trunk sarcoma, the effectiveness of radiotherapy has not been demonstrated, although a number of retrospective studies have indicated the beneficial aspects of this treatment modality. Radiation therapy will never replace surgery. After complete surgery, the dose of radiation is usually 50 Gy, but, in the case of residual disease, doses greater than 64 Gy are appropriate. New radiation technologies have become very useful in treating soft tissue sarcoma.     

Chimioradiothérapie des carcinomes des voies aérodigestives supérieures

The objective of this study was to review randomized trials which evaluated the effect of the radio-chemotherapy in head and neck carcinoma, and which compared radiotherapy alone vs the same local treatment plus chemotherapy. Over 40 such randomized trials have been performed, which generally showed no statistical difference between both arms. However few trials showed a benefit which is almost always in favor of the CT arm. Indeed, some trials of concomitant chemoradiotherapy have shown a statistically significant benefit in favor of the combined treatment. On the contrary, neoadjuvant chemotherapy generally leads to no detectable benefit compared to radiotherapy alone. These results have been reinforced by those of four randomized trials comparing neoadjuvant chemoradiotherapy and the same chemotherapy but given concomitantly with radiotherapy. The global effect of chemotherapy on survival of patients with head & neck sqamous cell carcinoma has been recently evaluated by a meta-analysis based on individual patient data which included more than 10,000 patients from 63 randomized trials. The absolute survival rate benefit at 5 years is 4%, but is more pronounced in the concomitant combinations (8% at 5 years). In tumors classified as “T3” of the pharyngo-larynx, neoadjuvant chemotherapy followed by radiotherapy in good responders can avoid a total laryngectomy without significantly compromised survival. In the nasopharynx carcinoma, a few randomized studies have been performed, suggesting a benefit in favor of chemoradiotherapy. Finally, future randomized trials will determine what are the optimal chemoradiotherapy schedules, as well as determining what is the best radiotherapy (accelerated, hyperfractionated) to use in combination with chemotherapy.     

Radiothérapie des cancers du sein en 2012 : quelles stratégies ?

Postoperative radiotherapy remains essential in breast cancer in 2012. After conserving surgery, it reduces local recurrence risks from 50 to 70%, both for ductal carcinoma in situ and invasive cancers. This was confirmed in several randomized trials and three meta-analyses. The boost increases local control in invasive cancers, but its role should be better defined in ductal carcinoma in situ. Among the latter, there is no clearly identified subgroup for which radiotherapy could be avoided. Local recurrence risk factors are now well-identified both for ductal carcinoma in situ and invasive cancers, with an inclusion, for the latter, of new molecular subgroups. After mastectomy, radiotherapy reduces local recurrence rates from 60 to 70%, especially among patients with axillary nodal involvement, with, in parallel, a 7 to 9% increased survival rate. In order to reduce the waiting list and to avoid under treatment, especially in the elderly, several hypofractionated radiotherapy schemes have been developed for several years. Three randomized trials confirmed similar results to classical radiotherapy. For ten years, several techniques of partial breast irradiation have been developed, with various doses and treated volumes. The optimal indications should be defined according to the new international guidelines.     

Progress of postoperative adjuvant therapies for esophageal cancer

Among the gastrointestinal cancers, esophageal cancer is supposed to be relatively sensitive to both radiotherapy and chemotherapy. The efficacy of combined chemo-radiotherapy in unresectable patients has been confirmed by several investigators. However, no prospective randomized controlled trials with surgery alone as a control had demonstrated significant survival benefit by postoperative adjuvant radiotherapy or chemotherapy in resectable patients. Only a slight prolongation of disease-free survival has been demonstrated with postoperative CDDP + 5-FU therapy. Thus, at present time, postoperative adjuvant therapy is not considered to be a standard therapy for resectable esophageal cancer. Clinical trials with more active combination chemotherapy including new anticancer drugs and new therapeutic strategies such as specific cancer immunotherapy and molecular targeting agents are hoped for in the future.     

Radiation therapy as an adjunct to primary surgery in early stage breast cancer: biological and clinical rationale.

In spite of the widespread use of adjuvant endocrine and cytotoxic chemotherapy, a substantial proportion of patients with early-stage breast cancer eventually develop a distant disease recurrence. Local control also remains a clinically significant problem in subsets of patients. Whether improved local control through the use of postoperative radiation therapy would prevent distant dissemination has been much debated for several decades. Studies on the long-term outcome of systemically untreated breast cancer patients indicate that breast cancer in many patients is a local disease that can be cured by surgery or radiotherapy. Randomized trials of breast screening have also shown that a delay in effective local treatment is associated with an increased incidence of distant dissemination and death from to the disease. Data from individual randomized trials and overviews of postoperative radiation therapy have indicated that radiation therapy as an adjunct to primary surgery is associated with a decrease in distant dissemination and breast cancer death. This benefit may be translated into a substantial overall survival benefit, provided that the treatment technique avoids long-term cardiac side effects. In many of the older radiation therapy trials, such effects appear to have balanced the benefit in terms of a reduced incidence of distant disease among the patients allocated to radiotherapy.     

ACR Appropriateness Criteria® postoperative adjuvant therapy in non-small cell lung cancer

Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.     

Adjuvant versus salvage radiotherapy following radical prostatectomy: do the AUA/ASTRO guidelines have all the answers?

Debate continues surrounding the indications for adjuvant and salvage radiotherapy as the published randomized trials have only addressed adjuvant treatment. Salvage radiotherapy has been advocated to limit significant toxicity to patients that would not have benefited from immediate adjuvant radiotherapy. The American Urological Association and American Society for Radiation Oncology guideline released in 2013 has since recommended offering adjuvant therapy to all patients with any adverse features and salvage to those with prostate-specific antigen or local recurrence. The suggested criteria is limited in its application as it potentially subjects patients with few adverse features to adjuvant therapy despite not qualifying as high risk according to established postoperative predictive tools such as the Kattan nomogram. This article reviews the indications for postoperative radiotherapy, limitations of the guideline and alternative prognostication tools for clinicians faced with biochemical or locally recurrent post-prostatectomy prostate cancer.     

Postmastectomy radiotherapy in women with breast cancer metastatic to one to three axillary lymph nodes

The influence of postmastectomy radiotherapy on survival has long been debated. Early randomized trials established a clear role for adjuvant postmastectomy chest wall radiotherapy (PMCWRT) in reducing locoregional recurrence (LRR), and PMCWRT became standard therapy for patients at high risk of LRR: those with T3 or T4 tumors and four or more involved lymph nodes. However, without effective systemic therapy, distant metastases limited any effect of improved local control on overall outcome, and radiotherapy showed no benefit in survival. In fact, early meta-analyses showed a negative impact of radiotherapy on survival. As data and techniques matured, a favorable influence of PMCWRT on breast cancer-specific mortality emerged but was offset by a radiotherapy-related increase in vascular mortality. Improvements in radiotherapy delivery to increase efficacy and reduce toxicity, restriction of PMCWRT to patients at intermediate or high risk of LRR after mastectomy, and improved distant control of disease with systemic therapy are expected to bring the greatest likelihood of a survival advantage from locoregional control. Three randomized trials with sufficient follow-up meet these criteria. All demonstrate significant improvement in overall survival with PMCWRT. However, the trials were not designed to specifically address the benefit of PMCWRT in patients at intermediate risk of LRR (those with T1 or T2 tumors and one to three involved lymph nodes). These findings have been discussed in a host of publications and conferences in light of historical negative results. This review focuses on the recent data on PMCWRT in patients with one to three involved nodes.