Chemoradiotherapy for Non-small Cell Lung Cancer

For many years, radiotherapy has been the standard of care for inoperable stage III  non-small cell lung cancer (NSCLC). These patients, however, show a poor outcome with long-term survival rates of 5–10%. Therefore, many groups have explored the possibility to improve these results by adding chemotherapy to the radiation treatment. The EORTC (European Organisation for Research and Treatment of Cancer) was the first in 1992 to report the results of a randomized phase III study of concomitant  cisplatin (weekly or daily) and radiotherapy versus radiotherapy alone in patients with inoperable NSCLC. This combination of cisplatin with radiotherapy resulted in improved survival and control of local disease. The largest and significant benefit was seen in the treatment arm with radiotherapy and daily cisplatin. Two meta-analyses confirmed the benefit of concurrent cisplatin-based chemoradiotherapy compared with radiation alone and consolidated this regimen as standard treatment for stage III NSCLC. Whether chemoradiotherapy should be given sequentially or concurrently has also been the topic of several studies. Several randomized trials and  meta-analyses have demonstrated that concurrent is superior over sequential chemoradiotherapy in terms of local control and survival, but is also associated with more, yet manageable acute toxicity, mainly esophageal. So far, no significant increase in late toxicity has been reported.

Chemoradiotherapy for Small Cell Lung Cancer

In the treatment of limited stage SCLC, the central role of chemotherapy has been widely recognized. To define an additional role of thoracic irradiation, several large phase III studies have been performed. These, together with subsequent meta-analyses, established the positive impact of thoracic irradiation in combination with chemotherapy in terms of local tumor control and survival. Regarding the timing of both treatment modalities, it has been shown that early thoracic irradiation during chemotherapy is superior to its late scheduling.

Chemoradiotherapy for Cervical Cancer

The introduction of chemoradiotherapy in the treatment of  cervical cancer shows many similarities with that in NSCLC: until the 1980s, radiotherapy was the standard therapy for patients with locally advanced tumors. Despite modifications of the total radiation dose and overall treatment time, more than 70% of these patients developed a local regional recurrence. Therefore, improvements of these results were sought into the addition of chemotherapy to radiotherapy. In 1999, three articles were published reporting on studies comparing chemoradiotherapy with conventional radiotherapy for locally advanced cervical cancer. In all three studies, the combination of radiotherapy with cisplatin was significantly better than the control arms. An interesting observation came from Rose and colleagues, demonstrating that the single use of cisplatin was as effective as a combination of three drugs, the latter scheme being much more toxic. In the meantime, three additional trials on the concomitant use of cisplatin in cervical cancer have been published, demonstrating now in five out of six trials a significant improvement of local control and survival when concomitant cisplatin and irradiation was used. This is in contrast with eight out of nine phase III studies of neoadjuvant chemotherapy prior to radiotherapy, showing no benefit. Based on these results, concurrent chemoradiotherapy is nowadays the standard of care for cervical cancer. Several open questions persist, however. For example, it is unclear whether patients with very large tumors benefit as much from chemoradiotherapy as those with smaller tumors. Also, it remains to be established what the optimal chemotherapy or combination of cytostatic drug is for combined use with radiation and what role immunotherapy will play in combined modality strategies.

Chemo-Bioradiotherapy for Head and Neck Cancer

Several chemoradiation trials have been conducted in patients with previously untreated head and neck cancer using cisplatin alone, cisplatin and 6,4-photoproducts ( 5-FU), and other combinations. In eight single institutional studies, the average complete response to concomitant therapy was 67.5%. A  meta-analysis performed by the MACH-NC group concerning the updated results of 63 randomized trials including 10,717 patients demonstrated a clear benefit of 8% (p = 0.0001) improved disease-free survival for the concomitant chemotherapy treatment. In the same analysis adjuvant and neoadjuvant chemotherapy showed no improvement. Subsequent trials confirmed that the concomitant use of  cisplatin or carboplatin and irradiation leads to improved local cure and survival when compared with radiotherapy alone, including in the postoperative setting. The 3-arm GORTEC 99-02 randomized trial further showed that acceleration of radiotherapy cannot compensate for the absence of chemotherapy.

Despite these encouraging results, cisplatin-based chemoradiation protocols for advanced head and neck cancer are still associated with too many locoregional recurrences. Besides dose-escalation strategies, molecular targeted drugs represent a new and promising approach to further improve treatment results. One of these is the humanized monoclonal antibody directed against the  EGFR which is frequently overexpressed in head and neck cancer and associated with chemo-/radioresistance and poor outcome. In 2006, a large multicenter randomized phase III study was published comparing radiotherapy alone with radiotherapy plus  cetuximab in patients with locally advanced head and neck cancer. The results were very encouraging and demonstrated that the addition of cetuximab to radiotherapy significantly improved locoregional control and survival. Whether cetuximab (or other EGFR-blocking strategies) can further improve the results when added to standard chemoradiotherapy has been investigated in the RTOG 0522 randomized trial. Adding cetuximab to cisplatin-based chemoradiotherapy did not improve outcome, but was associated with significantly more acute toxicity. Whether HPV-positive head and neck cancer represents a separate disease entity requiring a differential approach is subject of ongoing trials.

Chemoradiotherapy for Esophageal Cancer

Surgical resection is currently the preferred treatment for  esophageal cancer. Neoadjuvant chemotherapy may improve the results of surgery and may prevent patients from recurrent disease. However, a Cochrane meta-analysis based on seven phase III randomized trials with neoadjuvant chemotherapy failed to demonstrate such a beneficial effect. In a number of studies, sequential chemoradiotherapy or concurrent chemoradiotherapy was compared with radiotherapy alone. The RTOG 85-01 phase III study comparing radiotherapy alone with 5-FU/cisplatin-based chemoradiotherapy showed a statistically significant survival difference in favor of the chemoradiotherapy arm. Treatment-related toxicity was increased in the chemoradiotherapy arm, 44% severe and 20% life-threatening side effects versus 25% and 3% in the radiotherapy alone arm. Late toxicity was not increased as has been reported in other studies with concomitant chemoradiotherapy. Al-Sarraf reported on an additional group of patients treated with the same chemoradiotherapy regime. The 5-year survival was 26% versus 0% in the chemoradiotherapy arm and radiotherapy alone arm, respectively. These studies show that concurrent chemoradiation is recommended compared with radiotherapy alone. In most concurrent chemoradiotherapy studies, the classic 5-FU/cisplatin regimen has been used. Studies with taxanes as concurrently administered cytotoxic drugs showed promising results. In the Dutch randomized phase III CROSS trial, preoperative chemoradiotherapy with a weekly schedule of  paclitaxel and carboplatin was shown to result in significant tumor downstaging, high microscopically complete resection rate, and improved survival as compared to surgery only, with acceptable toxicity.

Chemoradiotherapy for Gastric Cancer

Surgical resection remains the cornerstone of curative treatment of  gastric cancer. However, the long-term prognosis remains poor for patients with locally advanced disease. Therefore, different (neo-)adjuvant strategies have been evaluated in the past decades to improve these results. Adjuvant chemotherapy only resulted in a small survival benefit of 3–5% in Western populations as shown in multiple meta-analyses. Preoperative radiotherapy also showed a small, but significant improvement in survival. MacDonald et al. performed a randomized phase III study comparing surgery alone with surgery and postoperative adjuvant therapy, combining radiotherapy with 5-FU-leucovorin. In this study of 556 patients, a statistically and clinically significant reduced risk of relapse and improved survival were observed. Median overall survival in the surgery alone group was 27 months, compared with 36 months in the chemoradiation group. The 3-year survival rate was 41% versus 50% (p = 0.005), respectively. An update of the 10-year follow-up results in 2012 showed a strong persistent benefit from adjuvant chemoradiotherapy. In 2005, final results of the MAGIC study on perioperative chemotherapy have been presented. In this large multicenter study, patients were randomized between surgery only and three cycles of preoperative ECF (epirubicin,  cisplatin,  5-FU) followed by surgery and then another three cycles of ECF chemotherapy. This regimen resulted in a 10% higher resectability rate and a significant survival benefit of 13% (23% vs. 36% at 5 years). Which of both strategies – postoperative chemoradiotherapy and perioperative chemotherapy – is superior remains to be determined. Since preoperative-combined chemoradiotherapy has shown a beneficial impact on surgical outcome in esophageal and rectal cancer, this is considered an attractive approach to explore in operable gastric cancer as well. Indeed, several phase I–II studies showed significant tumor downsizing, high R0, and pathological complete response rates by neoadjuvant chemoradiotherapy in locally advanced gastric cancer.

Chemoradiotherapy for Rectal Cancer

Surgical resection is the only curative treatment for  colorectal cancer. However, following resection, local recurrence rate varies between 5% and 40%. Total mesorectal excision (TME), the standard surgical technique for primary resectable rectal cancer, has significantly improved the outcome of this disease, in particular, through the realization of free circumferential margins. The Dutch TME trial demonstrated that short-term preoperative radiotherapy is effective in preventing local recurrences, but not in patients with a positive resection margin. Although positive margins can be partly due to poor surgical techniques, they occur more often in locally advanced tumors. For these stages, a more aggressive (neo-)adjuvant approach is required. Postoperative chemoradiation has been mainly evaluated in the United States. The Gastrointestinal Tumor Study Group conducted a four-arm study: surgery only, postoperative chemotherapy, postoperative radiotherapy, and postoperative chemoradiotherapy (GITSG 71-75). Pairwise comparisons showed superior survival and local recurrence rates in the chemoradiation arm versus the surgery-only arm. The North Central Cancer Treatment Group compared radiotherapy with postoperative chemoradiation and demonstrated lower local and distant recurrence rates in the combined treatment arm. Survival was significantly increased (NCCTG 794751). The evidence that the addition of chemotherapy to preoperative radiotherapy improves local control rates has been provided by two separate trials. The EORTC 22921 trial has a two by two factorial design and randomized between preoperative radiotherapy and preoperative 5-FU-based chemoradiotherapy. A second randomization took place for postoperative chemotherapy versus no adjuvant treatment. The results demonstrated an increased local control rate for the chemoradiation arm: 92% versus 87%. A similar result was found in the French FFCD 9203 study, which randomized between preoperative radiotherapy and preoperative 5-FU-based chemoradiotherapy, with local recurrence rates of 16.5% and 8%, respectively. All studies that compare preoperative radiotherapy with preoperative chemoradiotherapy demonstrate an increase in toxicity in the combined modality arm.

It became clear that apart from cytotoxic agents, biological agents may play a role in the achievement of tumor response. In an experimental study,  VEGF blockade enhanced radiotherapeutic activity, probably due to reduction of tumor vascular permeability and tumor interstitial pressure, thereby increasing the delivery of large therapeutic compounds to the tumor. In an early report on a small number of patients treated with the combination of an anti-VEGF monoclonal antibody, bevacizumab, 5-FU, and radiotherapy, significant downstaging occurred in all six patients.

Chemoradiotherapy for Anal Cancer

Over the past decades, the treatment of anal cancer has shifted from a surgical approach toward organ-sparing radiotherapy with or without concurrent chemotherapy. It was shown in two randomized studies that concomitant radiotherapy and 5-FU and  mitomycin C (MMC) is superior to radiotherapy alone and significantly reduced the number of local recurrences. These anal cancer trials also clearly demonstrated the advantage of organ preservation by combined modality treatment as it results in an improved colostomy-free survival. The enhanced acute toxicity observed during these combined regimens did not translate in a significant increase in late side effects. MMC has contributed significantly to these results. In a RTOG study, patients were randomized to radiotherapy and 5-FU or radiotherapy, 5-FU, and MMC. The colostomy-free survival rate at 4 years was significantly better in patients who received both 5-FU and MMC compared with those who received 5-FU only (71% and 59%, respectively). In addition, others found that by deleting MMC from a comparable combined treatment protocol, the local tumor control rate at 2 years dropped from 87% to 58%. In order to minimize treatment-related toxicity, cisplatin has been evaluated as a replacement for MMC, with good results in nonrandomized studies. Randomized trials are now underway to confirm at least equal efficacy of cisplatin and MMC. The RTOG 98-11 phase III study compared 5-FU plus MMC and radiation to 5-FU plus cisplatin and radiation in 632 anal carcinoma patients. The results showed that the combination of radiotherapy with 5-FU plus MMC had a statistically significant, clinically meaningful impact on disease-free and overall survival, as compared to induction plus concurrent 5-FU and cisplatin. It was concluded that MMC, 5-FU (frequently given as oral capecitabine), and radiotherapy remain the standard of care for patients with anal canal carcinoma. Further improvements in treatment results are expected from the application of novel biological agents.

Chemoradiotherapy for Glioblastoma

Glioblastoma has a dismal prognosis with most patients dying within 2 years after diagnosis. Standard therapy consisted of surgical resection, followed by radiotherapy. Although a meta-analysis of 12 randomized trials suggested a small survival advantage by the addition of chemotherapy, Stupp et al. in 2004 were the first to demonstrate a clinically meaningful and statistically significant survival benefit from the addition of temozolomide (TMZ) to radiotherapy with minimal additional toxicity. The subsequent 5-year analysis of this EORTC-NCIC randomized phase III trial confirmed these results with the 2-year overall survival improving from 10.9% after surgery only to 27.2% with adjuvant TMZ and radiotherapy. The MGMT promoter methylation status of the tumor was identified as a prognostic biomarker, selecting those patients most likely to benefit from the addition of TMZ.

Concluding Remarks

The combination of radiotherapy and chemotherapy has resulted in a major step forward in the treatment of patients with advanced solid tumors. The recognition that concurrent chemoradiotherapy is superior to sequential regimens may be viewed as one of the major achievements in clinical oncology of the past decades. In general, the interaction between radiation and cytostatic agents is time-, dose-, and sequence-dependent as shown for cisplatin, the most widely used  radiosensitizer. In the near future, the combination of radiotherapy with biological agents and a number of new cytostatic drugs will become available for testing in concomitant chemotherapy or biotherapy and radiotherapy approaches. These agents should be selected based upon their mechanisms of action. Given the results of many randomized clinical studies, it is quite likely that chemo- or bioradiotherapy will be the standard of care for an increasing number of advanced squamous cell cancers, but until the best regimen of each disease has been determined, there is now more than ever an urgent need to encourage treatment of patients within the framework of carefully controlled clinical trials.