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JOURNAL OF CLINICAL ONCOLOGY
A S C O 50TH A N N I V E R S A R Y
Milestones in the Use of Combined-Modality Radiation Therapy and Chemotherapy Theodore S. Lawrence, University of Michigan, Ann Arbor, MI Bruce G. Haffty, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ Jay R. Harris, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA
Radiation therapy is now more than 100 years old. For the first 60 years, attempts to improve outcome were based on technical improvements in radiation sources, planning, and delivery and in exploration of altered fractionation. The concept of combining radiation therapy with chemotherapy was born shortly after the discovery of fluoruracil (as reviewed by McGinn et al1). Indeed, we feel that among the most important developments in the treatment of locally advanced cancers in the last 50 years are the initiation of and continuing improvement in combining chemotherapy (and more recently, molecularly targeted therapies) with radiation therapy. Combined-modality therapy (CMT) has been shown in randomized trials to improve survival, compared with either radiation therapy or chemotherapy alone, in the treatment of high-grade gliomas and locally advanced cancers of the head and neck, lung, esophagus, breast, stomach, pancreas, and rectum. Furthermore, CMT permits organ conservation with high cure rates in cancers of the breast, larynx, and anus and sarcomas of the extremities. Thousands of patients are alive today with improved quality of life because of the development of CMT. Although CMT improves survival in multiple cancers, these gains have typically come at the price of increased toxicity. The increase in toxicity sometimes occurs because of irradiation of bone marrow (eg, cervical cancer) but, more commonly, results from damage to normal tissue that surrounds the tumor. Therefore, the traditional research on radiation therapy focusing on improving technical delivery through more precise targeting (which we will not discuss in this article), beneficial in its own right, has also permitted continued improvements in CMT by minimizing the toxicity of treatment of normal tissues. CMT can be used to improve control of the local disease through the additive killing of tumor cells by two different modalities (additivity) or through tumor selective synergy of agents with radiation therapy (synergy).2 If all the benefits of CMT were attributable to additivity, then sequential therapy and concurrent therapy should produce similar results. However, when sequential and concurrent therapies are compared directly for treatment of gross disease, concurrent therapy is more effective (and more toxic). There are at least two reasons why this could be the case. The most obvious is that concurrent chemotherapy increases the susceptibility of the tumor cell to radiation-induced killing compared with normal cells, so the effects of the drug need to be present at the time of irradiation. (Spalding and Lawrence3 provide a review of the biologic factors underlying CMT.) Journal of Clinical Oncology, Vol 32, No 12 (April 20), 2014: pp 1173-1179
A second possible reason is that sequential treatment causes the protraction of total treatment time, which permits tumor cell repopulation during the course of treatment. For head and neck cancer treated with radiation therapy alone, protraction decreases tumor control, equivalent to a loss of approximately 0.75 Gy per day.4 Likewise, it has been proposed that the inferior results produced by chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone in anal cancer could be because of protraction of treatment.5 Sequential therapy has been successful in adjuvant treatment. The best example of successful sequential therapy may be in breast cancer, where the tumor bed after resection contains perhaps 1% of the cell numbers encountered with gross disease and where the use of chemotherapy or hormonal therapy contributes to the treatment of these residual cells before radiation therapy. Adjuvant radiation therapy for locally advanced soft tissue sarcoma presents a similar case. Radiation is sometimes administered before surgery (and chemotherapy afterward) or vice versa, with overall similar results. Thus, because surgery lowers the tumor burden, high tumor bed control rates can be achieved without the need to push the intensity of treatment to the edge of tolerability, and a greater emphasis can be placed on balancing multiple issues such as acute toxicity, cosmesis (for breast cancer), and function (for sarcoma). An additional factor is that the chemotherapeutic agents used for the treatment of breast and soft tissue sarcomas tend to produce substantial skin reactions when administred concurrently with radiation therapy, but similar reactions are deemed tolerable in head and neck cancer when required for cure. In addition to these purely local effects, CMT can improve survival through better systemic control. The most obvious mechanism by which improved systemic control can be achieved is through the treatment of occult metastatic disease by drug (which has been called spatial additivity6). However, as is the case for local control, there may be more than one mechanism, in that improved local control can eliminate the source of metastasis. For instance, in the case of breast cancer, it is clear that local irradiation decreases both local recurrence and distant metastasis.7 This improvement emerged with the introduction of effective systemic chemotherapy, which prevented many women from succumbing to the early development of metastatic disease.8 This finding has led to the hypothesis that the effect of adjuvant radiation therapy on survival depends on the efficacy of adjuvant chemotherapy. If chemotherapy is either ineffective or very effective, radiation therapy as part of © 2014 by American Society of Clinical Oncology
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sequential CMT may have little influence on survival in a disease in which systemic relapse dominates survival. Radiation therapy will have its greatest impact on the development of metastatic disease, when chemotherapy is moderately effective.9 In this review, we will trace the history of CMT with the goal of illustrating the development of the key principles of CMT regarding improved patient outcome. Rather than attempting to discuss every cancer, we have chosen to illustrate these principles by focusing on three common cancer types: breast, head and neck, and GI cancers. The focus of this review will be on chemoradiotherapy, although in the case of head and neck cancer, we have our first randomized trial showing a survival improvement using concurrent radiation therapy and cetuximab, which targets the epidermal growth factor receptor. (In fact, tamoxifen was the first successful targeted therapy and has been administered both sequentially and concurrently with radiation therapy.) Finally, we will look toward the future of CMT, where we see increasing incorporation of targeted therapies into the treatment of patients selected as most likely to respond. CMT for Breast Cancer Since the introduction of breast-conserving therapy, there has been a gradual but substantial lowering of the in-breast tumor recurrence (local recurrence) rate. In early series from the United States, local recurrence at 5 years was in the range of 10% and approximately twice that at 10 years. Improvements in mammographic and pathologic evaluation contributed to this lowering of local recurrence, but a major contributing factor was the introduction of the routine use of adjuvant systemic therapy. Adjuvant systemic therapy, either hormonal or chemotherapy or more recently anti– human epidermal growth factor receptor 2 (HER2) therapy, was developed to address the problem of micrometastases and subsequent distant recurrence, but serendipitously resulted in a substantial lowering of local recurrence rates. This is illustrated in the 10-year rates of local recurrence in successive National Surgical Adjuvant Breast and Bowel Project (NSABP) trials in node-negative patients treated with breastconserving therapy.10 In NSABP B-13, in which patients with estrogen receptor–negative cancer were randomly assigned to adjuvant chemotherapy or not, 10-year local recurrence was 15.3% without chemotherapy and only 2.6% with chemotherapy. Similarly, in NSABP B-14, in which patients with estrogen receptor–positive cancer were randomly assigned to adjuvant tamoxifen or placebo, 10-year local recurrence was 11.0% with placebo and only 3.6% with tamoxifen. Subsequent trials of systemic therapy showed a 10-year local recurrence rate of approximately 5%. Studies examining the impact of adding trastuzumab to adjuvant chemotherapy in women with HER2-overexpressing tumors have demonstrated an additional 40% reduction in the risk of local recurrence, with a median follow-up of 1.5 to 2.0 years.11 Updated results from a study by the Dana-Farber Cancer Institute/Brigham and Women’s Hospital and Massachusetts General Hospital, which included 1,434 patients (91% of whom were treated with adjuvant systemic therapy [not including trastuzumab]) and had a median follow-up of 85 months, showed the 5-year rate of local recurrence to be 1.6% and the overall crude rate of local recurrence to be 3.1%.12 These rates are expected to double at a median follow-up of 10 years. In this study, as well as in several others, the main prognostic factor for local recurrence was biologic subtype approximated by hormonal receptors (HRs), HER2 status, and histologic grade, with luminal A defined as HR positive, HER2 negative, 1174
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grade 1 to 2; luminal B as HR positive, HER2 negative, grade 3; luminal HER as HR positive, HER2 positive; HER2 as HR negative, HER2 positive; and triple negative as HR negative, HER2 negative. The crude rate of local recurrence by subtype was 1.5% for luminal A, 4.0% for luminal B, 1.0% for luminal HER, 10.9% for HER2-positive, and 8.8% for triple-negative cancers. Age was also in the final model, but the magnitude of the effect was much smaller, with a crude rate of local recurrence of 6.5% for the patients in the lowest age quartile (age 23 to 46 years) compared with only 0.9% for patients in the highest age quartile (age 64 to 88 years). Margin status was not in the final model of prognostic factors for local recurrence. These and other data indicate that the biologic features of the tumor are most important in determining the risk of local recurrence. The timing of systemic therapy and radiation therapy has been the subject of extensive study. When adjuvant chemotherapy consisted of nonanthracycline regimens, studies were conducted with concurrent radiation therapy and chemotherapy, suggesting a benefit with concurrent treatment. However, since the introduction of anthracyclines (and taxanes), which greatly increase the toxicity of radiation therapy when administered concurrently, the main approach to CMT has been sequential treatment. To determine the optimal sequencing schedule of chemotherapy and radiation therapy, investigators from the Harvard Medical School/Dana-Farber Cancer Institute conducted a randomized trial that compared four cycles of doxorubicin-based combination chemotherapy followed by radiation therapy or radiation therapy followed by the same chemotherapy. The initial report of this study demonstrated the superiority of initial chemotherapy, helping to establish this approach as standard.13 A second important study from Cancer and Leukemia Group B addressed whether a more extended delay in radiation therapy to allow treatment with both anthracyclines and taxanes increased local recurrence risk. These investigators reported that patients treated with paclitaxel after anthracyclines had lower risk of isolated locoregional recurrence than those treated with just four cycles of anthracyclines (3.7% v 9.7%, respectively; P ⫽ .04).14 Given this information, it has become standard that patients receive initial chemotherapy followed by radiation therapy. No randomized trials have directly compared concurrent tamoxifen and radiation therapy versus radiation therapy followed by tamoxifen. However, three retrospective reports found no difference in outcome according to sequence of radiation and hormonal therapies.15-17 In low-risk patients, it is often convenient to deliver sequential radiation therapy followed by hormonal therapy so patients do not have to deal with the adverse effects of both treatments at the same time. Finally, most patients receiving adjuvant trastuzumab continue this therapy concurrently during radiation treatment, and the data thus far suggest that this combination is not associated with increased complication rates. Data from the NSABP B-31 trial showed a rate of congestive heart failure of 3.2% for patients treated with trastuzumab and left-sided irradiation compared with a rate of 4% for those treated with trastuzumab and no left-sided irradiation (P ⫽ .80).18 These data were supported by the North Central Cancer Treatment Group N9831 trial, which compared the rate of cardiac events in patients treated with trastuzumab with (1.5%) or without (6.3%) radiation therapy. Furthermore, none of the radiation-associated adverse events were increased in those treated concurrently with trastuzumab versus those who were not.19 JOURNAL OF CLINICAL ONCOLOGY
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In summary, sequential CMT has been extraordinarily successful in the treatment of breast cancer, producing high local control rates, organ conservation with excellent cosmesis, and improved survival. Because CMT is sequential, toxicity has been modest, particularly as radiation techniques have improved. CMT for Head and Neck Cancers Radiation therapy and surgery have traditionally been the mainstays of treatment in cancers of the head and neck, focusing on optimizing locoregional control while maintaining organ function when feasible. Although preclinical data and early-phase trials in squamous cell carcinoma of the head and neck demonstrated encouraging response rates with the addition of chemotherapy, early randomized trials were discouraging.20 Not even 20 years ago, Tannock and Browman21 concluded that “chemotherapy has no place in the routine management of primary head and neck cancer.”21(p1121) Over the ensuing two decades, significant advances were made such that concurrent chemotherapy and radiation therapy is now considered the standard of care for a majority of patients with advanced head and neck cancer in both the primary and postoperative settings,22,23 resulting in significant improvements in disease-free and overall survival as well as improvements in organ preservation. Historically, one of the theoretic barriers in controlling solid tumors of the head and neck with radiation therapy was the existence within tumors of relatively radiation-resistant hypoxic cells.24 The early years of CMT in head and neck cancers were dominated by chemotherapeutic agents aimed at radiation sensitization or directed at hypoxic cells. The discovery that the nitroimidazole family of drugs sensitized hypoxic cells to radiation led to a series of prospective randomized trials, with mixed results.25,26 Building on the concept of hypoxia-directed therapies, the Yale group and others conducted a series of studies employing mitomycin, which is preferentially cytotoxic to hypoxic cells.27,28 These studies showed improvement in locoregional control, with no improvement in survival.28 Subsequent investigations employed the drug tirapazamine, which is also selectively toxic against hypoxic cells. Although tirapazamine was promising in preclinical and phase I/II studies, the TROG (Trans Tasman Radiation Oncology Group) Head Start randomized trial demonstrated, in patients not specifically selected for tumors with a known hypoxic component, no improvement in outcome in patients with head and neck cancer when tirapazamine was added to platinumbased chemoradiotherapy.29 The randomized ARCON (Accelerated Radiotherapy With Carbogen and Nicotinamide) trial, also addressing hypoxia in head and neck cancer, showed no therapeutic gain.30 Future studies of hypoxic cell sensitizers in head and neck cancers should focus on patients selected for having hypoxic tumors.31 Platinum-based chemotherapy has been the most thoroughly investigated agent in head and neck cancers.23 Extensive preclinical and early-phase trials provided encouraging data, on which subsequent randomized trials were based. One of the first trials reporting an overall survival advantage with chemoradiotherapy over radiation therapy alone was in nasopharyngeal cancer.32 The MACH-NC (Meta-Analysis of Chemotherapy in Head and Neck Cancer) metaanalysis of multiple subsequent randomized chemoradiotherapy trials in head and neck cancers showed that concurrent chemotherapy and radiation therapy, dominated by platinum-based regimens, was associated with an 8% overall survival benefit over radiation therapy alone in advanced head and neck cancers.22 Furthermore, within the monowww.jco.org
therapy trials, the effect of a platin was significantly better than that of other monotherapy agents.23 Two randomized trials also demonstrated significant gains with concurrent platinum-based chemotherapy and radiation therapy in the postoperative setting, providing further support for concurrent platinum-based chemotherapy.33,34 Although questions remain regarding patient selection, optimal chemotherapeutic regimen, and optimal scheduling, dosing, and timing of chemotherapy and radiation therapy, concurrent platinum-based chemoradiotherapy has emerged as a standard of care in a majority of patients with head and neck cancer.20 Induction chemotherapy has played a controversial role in CMT for head and neck cancer. Induction therapy can produce dramatic responses, and in the case of sequential therapy, induction chemotherapy with docetaxel, cisplatin, and fluorouracil (FU) is superior to induction with cisplatin plus FU. However, the one randomized trial comparing induction chemotherapy plus CMT versus CMT alone found no difference in survival.22,35-38 A recent meta-analysis of randomized trials comparing platinum plus FU– based chemotherapy with or without the addition of taxanes demonstrated superiority with the addition of taxanes but concluded that the role of induction chemotherapy in head and neck cancer remains to be defined.35,39 One of the most significant practice-changing randomized studies was the Veterans Affairs Laryngeal Cancer Study Group trial.40 This trial compared induction chemotherapy followed by chemoradiotherapy with total laryngectomy and postoperative radiation therapy and demonstrated that larynx preservation could be achieved in a high percentage of patients treated with induction chemotherapy, without compromising survival. Subsequently, the Radiation Therapy Oncology Group (RTOG) conducted a three-arm trial of radiation therapy alone, induction chemotherapy followed by chemoradiotherapy, or concurrent chemoradiotherapy in laryngeal cancers. This study demonstrated improved locoregional control and laryngeal preservation with concurrent chemoradiotherapy compared with radiation therapy alone or induction chemotherapy followed by chemoradiotherapy.41,42 These and other studies have established CMT as a standard of care for organ preservation in a majority of patietns with advanced laryngeal or hypopharyngeal cancer, but as we have stated, the role of induction therapy remains unresolved. A striking recent development is the discovery that human papillomavirus (HPV) –associated head and neck cancers, which can readily be identified with currently available molecular testing, represent a unique biologic entity with a more favorable prognosis.43 As suggested in a recent evaluation of patients with head and neck cancer treated with radiation therapy alone or chemoradiotherapy, subsets of HPV-associated advanced head and neck cancers may benefit from a deintensification of treatment.43 Ongoing trials are comparing chemoradiotherapy with cetuximab plus radiation therapy in this setting. In summary, the use of concurrent CMT in head and neck cancers has improved survival in both unresectable and resectable disease and has permitted larynx preservation in up to two thirds of patients who would have previously undergone laryngectomy. Because CMT is concurrent, the toxicity of treatment remains significant, which is only partially ameliorated by sophisticated irradiation techniques. HPV-associated oropharynx cancers present a new opportunity for de-escalating CMT while preserving high rates of cure and organ conservation. CMT using targeted therapies and chemoradiotherapy is discussed later in this article. © 2014 by American Society of Clinical Oncology
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CMT for GI Cancers CMT has produced substantial improvements in the outcome of patients with GI cancer. A key initial study involved anal cancer; investigators at Wayne State University designed a clinical trial for preoperative radiation therapy and chemotherapy (mitomycin and infusional FU) for patients with anal cancer, a disease that had previously been treated with abdominal perineal resection. A surprisingly high fraction of patients were found to have had a complete response after surgery, leading to the concept that CMT alone might be definitive therapy.44 Indeed, this approach produced results that were superior to those of historical series using abdominal perineal resection and, of course, offered the opportunity for avoiding a permanent colostomy. A randomized trial that aimed to eliminate mitomycin showed that FU alone produced inferior results.45 Subsequent studies aiming to replace mitomycin with cisplatin46,47 produced mixed results. The overall conclusion is that treatment with FU plus mitomycin is still a standard (although cisplatin may be as effective, if neoadjuvant chemotherapy can be avoided),47 and it remains a triumph of CMT (as in laryngeal cancer), permitting high cure rates with organ preservation, even in the presence of gross disease. A different path was taken in rectal cancer in the United States, where the initial studies of CMT were postoperative. The GI Tumor Study Group conducted a four-arm study, which by today’s standards would be considered seriously underpowered, of surgery only, surgery followed by radiation therapy alone, FU alone, or the combination of FU and radiation therapy, suggesting improved survival for the combination therapy group.48 This conclusion was supported by a subsequent (appropriately powered) study comparing surgery followed by radiation therapy versus surgery followed by chemoradiotherapy, which again favored the CMT arm for survival and local control, establishing this approach as a standard therapy.49 At the same time, Swedish50 and Dutch51 studies emphasized preoperative radiation therapy, with the former trial showing improved survival with radiation therapy plus surgery compared with surgery alone. Preoperative therapy would seem to offer some advantages over postoperative therapy; in the latter case, the small bowel often becomes adherent in the pelvis, where it becomes impossible to prevent it from receiving a full radiation dose with attendant toxicity. These findings and this logic set the stage for a randomized trial of preoper-
ative versus postoperative CMT, which confirmed that preoperative treatment was both more effective and less toxic than postoperative therapy, thereby establishing preoperative CMT as the standard of care.52 With the establishment of preoperative CMT for locally advanced rectal cancer, it became possible to assess the effects of neoadjuvant treatment on the tumor. Pathologic complete response rates after CMT are approximately 20%. Substantial efforts have been made to try to increase local control and pathologic complete response with the addition of new agents such as oxaliplatin53 and the antiangiogenic agent bevacizumab.54 Unfortunately, none of the new agents have improved the pathologic complete response rate or local control compared with FU alone (and more recently capecitabine,55 as summarized by Tepper and Wang56). Furthermore, a significant fraction of patients with distal locally advanced rectal cancer still require colostomy, and it is important to develop strategies analogous to those used for anal cancer to achieve cure with sphincter preservation. Some intriguing results have suggested that patients who achieve a pathologic complete response after neoadjuvant therapy may indeed not require surgery,57 which would represent a major advance if it could be replicated in larger studies. The propensity of pancreatic cancer to recur both locally and systemically,58 along with results from preclinical studies,59 made this site an early candidate for the use of both concurrent and sequential CMT. Both old60 and recent61 randomized trials have demonstrated that the combination of CMT and either FU or gemcitabine is superior to chemotherapy alone for locally advanced unresectable disease (although a recent French study did not support this,62 it had substantial design flaws63). The role of CMT in resected disease is controversial, and the conclusion that radiation therapy does not play a role64 has been questioned because of a lack of quality control for both surgery and radiation therapy.65 An ongoing RTOG trial with appropriate quality control measures, lacking in prior studies, should be able to determine whether radiation therapy plays a role in the approximately 15% of patients with pancreatic cancer who are able to have negative margins of resection. There is also controversy regarding neoadjuvant therapy versus adjuvant therapy for patients with resectable disease, because there are not direct comparisons. Finally, CMT seems to permit some patients with unresectable or borderline resectable disease to undergo resection.66,67
Capecitabine + temozolomide FU
Year
Cisplatin
1984
1990
Immune checkpoint inhibitors?
Gemcitabine 1997
Mitomycin + FU
1999
2001 2002
Cetuximab
Future…
DNA damage response inhibitors?
Novel chemotherapies?
Fig 1. Timeline of advances in concurrent chemoradiotherapy. In this figure, we note major advances in concurrent chemoradiotherapy, as documented in first Journal of Clinical Oncology (JCO) articles to describe them. Fluorouracil (FU): A phase I trial of FU with radiation therapy for advanced head and neck cancer. Although FU is no longer used alone as radiation sensitizer in head and neck cancer, this article set the stage for use of concurrent FU and radiation therapy in multiple malignancies.74 Cisplatin: This landmark trial describing use of concurrent cisplatin with radiation therapy in nasopharyngeal cancer led to use of concurrent cisplatin-based therapy in lung, esophageal, head and neck, and cervical cancers.75 Mitomycin and FU: Although this combination had been used with radiation therapy to treat anal cancer before this JCO reference, this article was key to establishing superiority of combined-modality therapy (CMT) over radiation therapy alone.76 Gemcitabine: First trial combining radiation therapy with gemcitabine in locally advanced pancreatic cancer, which contributed to this combination becoming standard therapy for this disease.77 Cetuximab: This phase I trial documented first use of cetuximab with radiation therapy and established doses used in subsequent positive phase III trial.78 Capecitabine: This phase I trial described safe dose of capecitabine with radiation therapy and made possible subsequent studies establishing role of capecitabine, when combined with radiation therapy, in rectal and pancreatic cancers.79 Temozolomide: First report of trial that ultimately defined new standard of treatment for glioblastoma.80 1176
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In summary, CMT has enabled the achievement of high cure rates with organ preservation in anal cancer, with decreasing toxicity as a result of the use of sophisticated irradiation techniques. These goals have been partially achieved in rectal cancer, with high cure rates but with a significant fraction of patients requiring colostomy. These goals remain elusive in pancreatic cancer, with only modest improvements in local control and survival, even with intensive chemotherapy and sophisticated irradiation techniques. As we alluded at the end of the Introduction, CMT will not achieve its full potential in locally advanced or resectable pancreatic cancer until systemic therapy improves. CMT Using Targeted Therapies and Chemoradiotherapy Because EGFR is overexpressed in a majority of head and neck cancers and is associated with poor outcome, anti-EGFR drugs have been explored as potential agents to be used in combination with radiation therapy. Cetuximab was the first anti-EGFR drug extensively tested, and preclinical studies identified it as a radiosensitizer, forming the basis of a phase III clinical trial comparing radiation therapy alone with radiation therapy plus cetuximab.68 The addition of cetuximab to radiation therapy in advanced head and neck cancers improved locoregional control and reduced mortality. This study paved the way for additional studies evaluating targeted agents in head and neck cancers.69 Some early-phase and single-institution series have suggested superior results with platin plus radiation therapy compared with cetuximab plus radiation therapy, although conflicting data exist.70,71 Unfortunately, there is as yet no level-one evidence that directly compares concurrent platinum administration and radiation therapy with concurrent cetuximab administration and radiation therapy. However, in one trial, the addition of cetuximab to cisplatin plus radiation therapy was compared with cisplatin plus radiation therapy alone. Unfortunately, there was no improvement in survival with the triple therapy compared with cisplatin plus radiation therapy alone, and toxicity was increased.72 It is disappointing that no preclinical data were used to structure this study, and it will be important in the future to use more sophisticated approaches to combining targeted therapies with chemoradiotherapy.73 Discussion CMT has evolved over the past two decades to the point at which it is the standard of care for the majority of patients with the cancers we have chosen to focus on in this review, as well as many others. In Figure 1, we present a timeline of chemotherapeutic agents used concurrently with radiation therapy, along with the first time they appeared in Journal of Clinical Oncology (JCO). Of note, each of these reports was key in establishing a new aspect of CMT. Implementation of more sophisticated irradiation techniques resulting in more optimal dose distributions, along with the introduction of novel drugs and targeted agents, is certain to continue to shape this field, improving locoregional control, distant metastasis–free survival, overall survival, and quality of life in patients with locally advanced disease. JCO will continue to be the major journal for the dissemination of these studies as they become available and a valuable resource for discussions, commentaries, and editorials, which will help to shape the clinical interpretation and implementation of these contributions. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. www.jco.org
AUTHOR CONTRIBUTIONS
Administrative support: Theodore S. Lawrence Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. McGinn CJ, Shewach DS, Lawrence TS: Radiosensitizing nucleosides. J Natl Cancer Inst 88:1193-1203, 1996 2. Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapychemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys 5:85-91, 1979 3. Spalding AC, Lawrence TS: New and emerging radiosensitizers and radioprotectors. Cancer Invest 24:444-456, 2006 4. Tarnawski R, Fowler J, Skladowski K, et al: How fast is repopulation of tumor cells during the treatment gap? Int J Radiat Oncol Biol Phys 54:229-236, 2002 5. Ben-Josef E, Moughan J, Ajani JA, et al: Impact of overall treatment time on survival and local control in patients with anal cancer: A pooled data analysis of Radiation Therapy Oncology Group trials 87-04 and 98-11. J Clin Oncol 28:5061-5066, 2010 6. Tannock IF: Treatment of cancer with radiation and drugs. J Clin Oncol 14:3156-3174, 1996 7. Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breastconserving surgery on 10-year recurrence and 15-year breast cancer death: Metaanalysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011 8. Hellman S: Stopping metastases at their source. N Engl J Med 337:996997, 1997 9. Marks LB, Prosnitz LR: Postoperative radiotherapy for lung cancer: The breast cancer story all over again? Int J Radiat Oncol Biol Phys 48:625-627, 2000 10. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breastconserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27:2466-2473, 2009 11. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353: 1673-1684, 2005 12. Arvold ND, Taghian AG, Niemierko A, et al: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 29:3885-3891, 2011 13. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996 14. Sartor CI, Peterson BL, Woolf S, et al: Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node-positive breast cancer: Cancer and Leukemia Group B 9344. J Clin Oncol 23:30-40, 2005 15. Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24-29, 2005 16. Ahn PH, Vu HT, Lannin D, et al: Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 23:17-23, 2005 17. Harris EE, Christensen VJ, Hwang WT, et al: Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 23:11-16, 2005 18. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2– overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811-7819, 2005 19. Halyard MY, Pisansky TM, Dueck AC, et al: Radiotherapy and adjuvant trastuzumab in operable breast cancer: Tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol 27:2638-2644, 2009 20. Salama JK, Seiwert TY, Vokes EE: Chemoradiotherapy for locally advanced head and neck cancer. J Clin Oncol 25:4118-4126, 2007 21. Tannock IF, Browman G: Lack of evidence for a role of chemotherapy in the routine management of locally advanced head and neck cancer. J Clin Oncol 4:1121-1126, 1986 22. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data—MACH-NC Collaborative Group: Meta-analysis of chemotherapy on head and neck cancer. Lancet 355:949-955, 2000
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23. Pignon JP, le Maıˆtre A, Maillard E, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4-14, 2009 24. Brown JM, Siim BG: Hypoxia-specific cytotoxins in cancer therapy. Semin Radiat Oncol 6:22-36, 1996 25. Overgaard J: Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Radiother Oncol 100:22-32, 2011 26. Overgaard J: Hypoxic radiosensitization: Adored and ignored. J Clin Oncol 25:4066-4074, 2007 27. Grau C, Prakash Agarwal J, Jabeen K, et al: Radiotherapy with or without mitomycin C in the treatment of locally advanced head and neck cancer: Results of the IAEA multicentre randomised trial. Radiother Oncol 67:17-26, 2003 28. Haffty BG, Son YH, Papac R, et al: Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: Results of the Yale mitomycin randomized trials. J Clin Oncol 15:268-276, 1997 29. Rischin D, Peters LJ, O’Sullivan B, et al: Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): A phase III trial of the Trans Tasman Radiation Oncology Group. J Clin Oncol 28:2989-2995, 2010 30. Janssens GO, Rademakers SE, Terhaard CH, et al: Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: Results of a phase III randomized trial. J Clin Oncol 30:1777-1783, 2012 31. Peters L, Rischin D: Elusive goal of targeting tumor hypoxia for therapeutic gain. J Clin Oncol 30:1741-1743, 2012 32. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 16:1310-1317, 1998 33. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945-1952, 2004 34. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004 35. Forastiere AA, Adelstein DJ, Manola J: Induction chemotherapy metaanalysis in head and neck cancer: Right answer, wrong question. J Clin Oncol 31:2844-2846, 2013 36. Haddad R, O’Neill A, Rabinowits G, et al: Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet Oncol 14:257-264, 2013 37. Hanna GJ, Haddad RI, Lorch JH: Induction chemotherapy for locoregionally advanced head and neck cancer: Past, present, future? Oncologist 18:288-293, 2013 38. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715, 2007 39. Blanchard P, Bourhis J, Lacas B, et al: Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: An individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 31:2854-2860, 2013 40. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685-1690, 1991 41. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 42. Forastiere AA, Zhang Q, Weber RS, et al: Long-term results of RTOG 91-11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31:845-852, 2013 43. O’Sullivan B, Huang SH, Siu LL, et al: Deintensification candidate subgroups in human papillomavirus–related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 31:543-550, 2013 44. Nigro ND, Vaitkevicius VK, Considine B Jr: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 17:354-356, 1974 45. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 14:2527-2539, 1996 46. Gunderson LL, Winter KA, Ajani JA, et al: Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 30:4344-4351, 2012 1178
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47. James RD, Glynne-Jones R, Meadows HM, et al: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous- cell carcinoma of the anus (ACT II): A randomised, phase 3, open-label, 2 ⫻ 2 factorial trial. Lancet Oncol 14:516-524, 2013 48. Prolongation of the disease-free interval in surgically treated rectal carcinoma: Gastrointestinal Tumor Study Group. N Engl J Med 312:1465-1472, 1985 49. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991 50. Improved survival with preoperative radiotherapy in resectable rectal cancer: Swedish Rectal Cancer Trial. N Engl J Med 336:980-987, 1997 51. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 52. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 53. Ge´rard JP, Azria D, Gourgou-Bourgade S, et al: Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: Results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 28:16381644, 2010 54. Willett CG, Duda DG, di Tomaso E, et al: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27:3020-3026, 2009 55. Hofheinz RD, Wenz F, Post S, et al: Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomised, multicentre, non- inferiority, phase 3 trial. Lancet Oncol 13:579-588, 2012 56. Tepper JE, Wang AZ: Improving local control in rectal cancer: Radiation sensitizers or radiation dose? J Clin Oncol 28:1623-1624, 2010 57. Maas M, Beets-Tan RG, Lambregts DM, et al: Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 29:4633-4640, 2011 58. Iacobuzio-Donahue CA, Fu B, Yachida S, et al: DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27:1806-1813, 2009 59. Shewach DS, Lawrence TS: Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 23:65-71, 1996 (suppl) 60. Moertel CG, Frytak S, Hahn RG, et al: Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads ⫹ 5-fluorouracil), and high dose radiation ⫹ 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48:1705-1710, 1981 61. Loehrer PJ Sr, Feng Y, Cardenes H, et al: Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group trial. J Clin Oncol 29:4105-4112, 2011 62. Chauffert B, Mornex F, Bonnetain F, et al: Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer: Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 19:1592-1599, 2008 63. Ben-Josef E, Lawrence TS: Radiotherapy: The importance of local control in pancreatic cancer. Nat Rev Clin Oncol 9:9-10, 2012 64. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004 65. Goodman KA: Quality assurance for radiotherapy: A priority for clinical trials. J Natl Cancer Inst 105:376-377, 2013 66. Ben-Josef E, Schipper M, Francis IR, et al: A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 84:1166-1171, 2012 67. Crane CH, Varadhachary GR, Yordy JS, et al: Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: Correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol 29:3037-3043, 2011 68. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 69. Martins RG, Parvathaneni U, Bauman JE, et al: Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial. J Clin Oncol 31:1415-1421, 2013 70. Caudell JJ, Sawrie SM, Spencer SA, et al: Locoregionally advanced head and neck cancer treated with primary radiotherapy: A comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 71:676-681, 2008 JOURNAL OF CLINICAL ONCOLOGY
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71. Riaz N, Sherman EJ, Fury M, et al: Should cetuximab replace cisplatin for definitive chemoradiotherapy in locally advanced head and neck cancer? J Clin Oncol 31:287-288, 2013 72. Ang KK, Zhang QE, Rosenthal DI, et al: A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol 29:360s, 2011 (suppl; abstr 5500) 73. Morgan MA, Parsels LA, Maybaum J, et al: Improving the efficacy of chemoradiation with targeted agents. Cancer Discov 4:1-12, 2014 74. Byfield JE, Sharp TR, Frankel SS, et al: Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck. J Clin Oncol 2:406-413, 1984 75. Al-Sarraf M, Pajak TF, Cooper JS, et al: Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: A Radiation Therapy Oncology Group study. J Clin Oncol 8:1342-1351, 1990 76. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European
Organisation for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997 77. Blackstock AW, Bernard SA, Richards F, et al: Phase I trial of twice- weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 17:2208-2212, 1999 78. Robert F, Ezekiel MP, Spencer SA, et al: Phase I study of anti–epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 19:3234-3243, 2001 79. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983-3991, 2002 80. Stupp R, Dietrich PY, Ostermann Kraljevic S, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375-1382, 2002
DOI: 10.1200/JCO.2014.55.2281; published online ahead of print at www.jco.org on March 24, 2014
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Resource for Fellows Oncology fellows can interact with colleagues and peers by subscribing to ASCO’s fellows listserve. The fellows listserve is an unmoderated online discussion, which means that all replies to an e-mail are posted immediately to the entire group of subscribers. There is no better way to keep up with your peers and ask those tough questions than ASCO’s fellows listserve. To subscribe, please email [email protected]. For more information, visit asco.org and click the Education & Training tab, Resources for Fellows, ASCO Fellows Listserve.
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Acknowledgment We thank Mary McKeever and Mary Davis for help in preparing the manuscript and Steven Kronenberg for preparing the figure.
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Milestones in the Use of Combined-Modality Radiation Therapy and Chemotherapy Theodore S. Lawrence, University of Michigan, Ann Arbor, MI Bruce G. Haffty, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ Jay R. Harris, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA
Radiation therapy is now more than 100 years old. For the first 60 years, attempts to improve outcome were based on technical improvements in radiation sources, planning, and delivery and in exploration of altered fractionation. The concept of combining radiation therapy with chemotherapy was born shortly after the discovery of fluoruracil (as reviewed by McGinn et al1). Indeed, we feel that among the most important developments in the treatment of locally advanced cancers in the last 50 years are the initiation of and continuing improvement in combining chemotherapy (and more recently, molecularly targeted therapies) with radiation therapy. Combined-modality therapy (CMT) has been shown in randomized trials to improve survival, compared with either radiation therapy or chemotherapy alone, in the treatment of high-grade gliomas and locally advanced cancers of the head and neck, lung, esophagus, breast, stomach, pancreas, and rectum. Furthermore, CMT permits organ conservation with high cure rates in cancers of the breast, larynx, and anus and sarcomas of the extremities. Thousands of patients are alive today with improved quality of life because of the development of CMT. Although CMT improves survival in multiple cancers, these gains have typically come at the price of increased toxicity. The increase in toxicity sometimes occurs because of irradiation of bone marrow (eg, cervical cancer) but, more commonly, results from damage to normal tissue that surrounds the tumor. Therefore, the traditional research on radiation therapy focusing on improving technical delivery through more precise targeting (which we will not discuss in this article), beneficial in its own right, has also permitted continued improvements in CMT by minimizing the toxicity of treatment of normal tissues. CMT can be used to improve control of the local disease through the additive killing of tumor cells by two different modalities (additivity) or through tumor selective synergy of agents with radiation therapy (synergy).2 If all the benefits of CMT were attributable to additivity, then sequential therapy and concurrent therapy should produce similar results. However, when sequential and concurrent therapies are compared directly for treatment of gross disease, concurrent therapy is more effective (and more toxic). There are at least two reasons why this could be the case. The most obvious is that concurrent chemotherapy increases the susceptibility of the tumor cell to radiation-induced killing compared with normal cells, so the effects of the drug need to be present at the time of irradiation. (Spalding and Lawrence3 provide a review of the biologic factors underlying CMT.) Journal of Clinical Oncology, Vol 32, No 12 (April 20), 2014: pp 1173-1179
A second possible reason is that sequential treatment causes the protraction of total treatment time, which permits tumor cell repopulation during the course of treatment. For head and neck cancer treated with radiation therapy alone, protraction decreases tumor control, equivalent to a loss of approximately 0.75 Gy per day.4 Likewise, it has been proposed that the inferior results produced by chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone in anal cancer could be because of protraction of treatment.5 Sequential therapy has been successful in adjuvant treatment. The best example of successful sequential therapy may be in breast cancer, where the tumor bed after resection contains perhaps 1% of the cell numbers encountered with gross disease and where the use of chemotherapy or hormonal therapy contributes to the treatment of these residual cells before radiation therapy. Adjuvant radiation therapy for locally advanced soft tissue sarcoma presents a similar case. Radiation is sometimes administered before surgery (and chemotherapy afterward) or vice versa, with overall similar results. Thus, because surgery lowers the tumor burden, high tumor bed control rates can be achieved without the need to push the intensity of treatment to the edge of tolerability, and a greater emphasis can be placed on balancing multiple issues such as acute toxicity, cosmesis (for breast cancer), and function (for sarcoma). An additional factor is that the chemotherapeutic agents used for the treatment of breast and soft tissue sarcomas tend to produce substantial skin reactions when administred concurrently with radiation therapy, but similar reactions are deemed tolerable in head and neck cancer when required for cure. In addition to these purely local effects, CMT can improve survival through better systemic control. The most obvious mechanism by which improved systemic control can be achieved is through the treatment of occult metastatic disease by drug (which has been called spatial additivity6). However, as is the case for local control, there may be more than one mechanism, in that improved local control can eliminate the source of metastasis. For instance, in the case of breast cancer, it is clear that local irradiation decreases both local recurrence and distant metastasis.7 This improvement emerged with the introduction of effective systemic chemotherapy, which prevented many women from succumbing to the early development of metastatic disease.8 This finding has led to the hypothesis that the effect of adjuvant radiation therapy on survival depends on the efficacy of adjuvant chemotherapy. If chemotherapy is either ineffective or very effective, radiation therapy as part of © 2014 by American Society of Clinical Oncology
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sequential CMT may have little influence on survival in a disease in which systemic relapse dominates survival. Radiation therapy will have its greatest impact on the development of metastatic disease, when chemotherapy is moderately effective.9 In this review, we will trace the history of CMT with the goal of illustrating the development of the key principles of CMT regarding improved patient outcome. Rather than attempting to discuss every cancer, we have chosen to illustrate these principles by focusing on three common cancer types: breast, head and neck, and GI cancers. The focus of this review will be on chemoradiotherapy, although in the case of head and neck cancer, we have our first randomized trial showing a survival improvement using concurrent radiation therapy and cetuximab, which targets the epidermal growth factor receptor. (In fact, tamoxifen was the first successful targeted therapy and has been administered both sequentially and concurrently with radiation therapy.) Finally, we will look toward the future of CMT, where we see increasing incorporation of targeted therapies into the treatment of patients selected as most likely to respond. CMT for Breast Cancer Since the introduction of breast-conserving therapy, there has been a gradual but substantial lowering of the in-breast tumor recurrence (local recurrence) rate. In early series from the United States, local recurrence at 5 years was in the range of 10% and approximately twice that at 10 years. Improvements in mammographic and pathologic evaluation contributed to this lowering of local recurrence, but a major contributing factor was the introduction of the routine use of adjuvant systemic therapy. Adjuvant systemic therapy, either hormonal or chemotherapy or more recently anti– human epidermal growth factor receptor 2 (HER2) therapy, was developed to address the problem of micrometastases and subsequent distant recurrence, but serendipitously resulted in a substantial lowering of local recurrence rates. This is illustrated in the 10-year rates of local recurrence in successive National Surgical Adjuvant Breast and Bowel Project (NSABP) trials in node-negative patients treated with breastconserving therapy.10 In NSABP B-13, in which patients with estrogen receptor–negative cancer were randomly assigned to adjuvant chemotherapy or not, 10-year local recurrence was 15.3% without chemotherapy and only 2.6% with chemotherapy. Similarly, in NSABP B-14, in which patients with estrogen receptor–positive cancer were randomly assigned to adjuvant tamoxifen or placebo, 10-year local recurrence was 11.0% with placebo and only 3.6% with tamoxifen. Subsequent trials of systemic therapy showed a 10-year local recurrence rate of approximately 5%. Studies examining the impact of adding trastuzumab to adjuvant chemotherapy in women with HER2-overexpressing tumors have demonstrated an additional 40% reduction in the risk of local recurrence, with a median follow-up of 1.5 to 2.0 years.11 Updated results from a study by the Dana-Farber Cancer Institute/Brigham and Women’s Hospital and Massachusetts General Hospital, which included 1,434 patients (91% of whom were treated with adjuvant systemic therapy [not including trastuzumab]) and had a median follow-up of 85 months, showed the 5-year rate of local recurrence to be 1.6% and the overall crude rate of local recurrence to be 3.1%.12 These rates are expected to double at a median follow-up of 10 years. In this study, as well as in several others, the main prognostic factor for local recurrence was biologic subtype approximated by hormonal receptors (HRs), HER2 status, and histologic grade, with luminal A defined as HR positive, HER2 negative, 1174
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grade 1 to 2; luminal B as HR positive, HER2 negative, grade 3; luminal HER as HR positive, HER2 positive; HER2 as HR negative, HER2 positive; and triple negative as HR negative, HER2 negative. The crude rate of local recurrence by subtype was 1.5% for luminal A, 4.0% for luminal B, 1.0% for luminal HER, 10.9% for HER2-positive, and 8.8% for triple-negative cancers. Age was also in the final model, but the magnitude of the effect was much smaller, with a crude rate of local recurrence of 6.5% for the patients in the lowest age quartile (age 23 to 46 years) compared with only 0.9% for patients in the highest age quartile (age 64 to 88 years). Margin status was not in the final model of prognostic factors for local recurrence. These and other data indicate that the biologic features of the tumor are most important in determining the risk of local recurrence. The timing of systemic therapy and radiation therapy has been the subject of extensive study. When adjuvant chemotherapy consisted of nonanthracycline regimens, studies were conducted with concurrent radiation therapy and chemotherapy, suggesting a benefit with concurrent treatment. However, since the introduction of anthracyclines (and taxanes), which greatly increase the toxicity of radiation therapy when administered concurrently, the main approach to CMT has been sequential treatment. To determine the optimal sequencing schedule of chemotherapy and radiation therapy, investigators from the Harvard Medical School/Dana-Farber Cancer Institute conducted a randomized trial that compared four cycles of doxorubicin-based combination chemotherapy followed by radiation therapy or radiation therapy followed by the same chemotherapy. The initial report of this study demonstrated the superiority of initial chemotherapy, helping to establish this approach as standard.13 A second important study from Cancer and Leukemia Group B addressed whether a more extended delay in radiation therapy to allow treatment with both anthracyclines and taxanes increased local recurrence risk. These investigators reported that patients treated with paclitaxel after anthracyclines had lower risk of isolated locoregional recurrence than those treated with just four cycles of anthracyclines (3.7% v 9.7%, respectively; P ⫽ .04).14 Given this information, it has become standard that patients receive initial chemotherapy followed by radiation therapy. No randomized trials have directly compared concurrent tamoxifen and radiation therapy versus radiation therapy followed by tamoxifen. However, three retrospective reports found no difference in outcome according to sequence of radiation and hormonal therapies.15-17 In low-risk patients, it is often convenient to deliver sequential radiation therapy followed by hormonal therapy so patients do not have to deal with the adverse effects of both treatments at the same time. Finally, most patients receiving adjuvant trastuzumab continue this therapy concurrently during radiation treatment, and the data thus far suggest that this combination is not associated with increased complication rates. Data from the NSABP B-31 trial showed a rate of congestive heart failure of 3.2% for patients treated with trastuzumab and left-sided irradiation compared with a rate of 4% for those treated with trastuzumab and no left-sided irradiation (P ⫽ .80).18 These data were supported by the North Central Cancer Treatment Group N9831 trial, which compared the rate of cardiac events in patients treated with trastuzumab with (1.5%) or without (6.3%) radiation therapy. Furthermore, none of the radiation-associated adverse events were increased in those treated concurrently with trastuzumab versus those who were not.19 JOURNAL OF CLINICAL ONCOLOGY
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In summary, sequential CMT has been extraordinarily successful in the treatment of breast cancer, producing high local control rates, organ conservation with excellent cosmesis, and improved survival. Because CMT is sequential, toxicity has been modest, particularly as radiation techniques have improved. CMT for Head and Neck Cancers Radiation therapy and surgery have traditionally been the mainstays of treatment in cancers of the head and neck, focusing on optimizing locoregional control while maintaining organ function when feasible. Although preclinical data and early-phase trials in squamous cell carcinoma of the head and neck demonstrated encouraging response rates with the addition of chemotherapy, early randomized trials were discouraging.20 Not even 20 years ago, Tannock and Browman21 concluded that “chemotherapy has no place in the routine management of primary head and neck cancer.”21(p1121) Over the ensuing two decades, significant advances were made such that concurrent chemotherapy and radiation therapy is now considered the standard of care for a majority of patients with advanced head and neck cancer in both the primary and postoperative settings,22,23 resulting in significant improvements in disease-free and overall survival as well as improvements in organ preservation. Historically, one of the theoretic barriers in controlling solid tumors of the head and neck with radiation therapy was the existence within tumors of relatively radiation-resistant hypoxic cells.24 The early years of CMT in head and neck cancers were dominated by chemotherapeutic agents aimed at radiation sensitization or directed at hypoxic cells. The discovery that the nitroimidazole family of drugs sensitized hypoxic cells to radiation led to a series of prospective randomized trials, with mixed results.25,26 Building on the concept of hypoxia-directed therapies, the Yale group and others conducted a series of studies employing mitomycin, which is preferentially cytotoxic to hypoxic cells.27,28 These studies showed improvement in locoregional control, with no improvement in survival.28 Subsequent investigations employed the drug tirapazamine, which is also selectively toxic against hypoxic cells. Although tirapazamine was promising in preclinical and phase I/II studies, the TROG (Trans Tasman Radiation Oncology Group) Head Start randomized trial demonstrated, in patients not specifically selected for tumors with a known hypoxic component, no improvement in outcome in patients with head and neck cancer when tirapazamine was added to platinumbased chemoradiotherapy.29 The randomized ARCON (Accelerated Radiotherapy With Carbogen and Nicotinamide) trial, also addressing hypoxia in head and neck cancer, showed no therapeutic gain.30 Future studies of hypoxic cell sensitizers in head and neck cancers should focus on patients selected for having hypoxic tumors.31 Platinum-based chemotherapy has been the most thoroughly investigated agent in head and neck cancers.23 Extensive preclinical and early-phase trials provided encouraging data, on which subsequent randomized trials were based. One of the first trials reporting an overall survival advantage with chemoradiotherapy over radiation therapy alone was in nasopharyngeal cancer.32 The MACH-NC (Meta-Analysis of Chemotherapy in Head and Neck Cancer) metaanalysis of multiple subsequent randomized chemoradiotherapy trials in head and neck cancers showed that concurrent chemotherapy and radiation therapy, dominated by platinum-based regimens, was associated with an 8% overall survival benefit over radiation therapy alone in advanced head and neck cancers.22 Furthermore, within the monowww.jco.org
therapy trials, the effect of a platin was significantly better than that of other monotherapy agents.23 Two randomized trials also demonstrated significant gains with concurrent platinum-based chemotherapy and radiation therapy in the postoperative setting, providing further support for concurrent platinum-based chemotherapy.33,34 Although questions remain regarding patient selection, optimal chemotherapeutic regimen, and optimal scheduling, dosing, and timing of chemotherapy and radiation therapy, concurrent platinum-based chemoradiotherapy has emerged as a standard of care in a majority of patients with head and neck cancer.20 Induction chemotherapy has played a controversial role in CMT for head and neck cancer. Induction therapy can produce dramatic responses, and in the case of sequential therapy, induction chemotherapy with docetaxel, cisplatin, and fluorouracil (FU) is superior to induction with cisplatin plus FU. However, the one randomized trial comparing induction chemotherapy plus CMT versus CMT alone found no difference in survival.22,35-38 A recent meta-analysis of randomized trials comparing platinum plus FU– based chemotherapy with or without the addition of taxanes demonstrated superiority with the addition of taxanes but concluded that the role of induction chemotherapy in head and neck cancer remains to be defined.35,39 One of the most significant practice-changing randomized studies was the Veterans Affairs Laryngeal Cancer Study Group trial.40 This trial compared induction chemotherapy followed by chemoradiotherapy with total laryngectomy and postoperative radiation therapy and demonstrated that larynx preservation could be achieved in a high percentage of patients treated with induction chemotherapy, without compromising survival. Subsequently, the Radiation Therapy Oncology Group (RTOG) conducted a three-arm trial of radiation therapy alone, induction chemotherapy followed by chemoradiotherapy, or concurrent chemoradiotherapy in laryngeal cancers. This study demonstrated improved locoregional control and laryngeal preservation with concurrent chemoradiotherapy compared with radiation therapy alone or induction chemotherapy followed by chemoradiotherapy.41,42 These and other studies have established CMT as a standard of care for organ preservation in a majority of patietns with advanced laryngeal or hypopharyngeal cancer, but as we have stated, the role of induction therapy remains unresolved. A striking recent development is the discovery that human papillomavirus (HPV) –associated head and neck cancers, which can readily be identified with currently available molecular testing, represent a unique biologic entity with a more favorable prognosis.43 As suggested in a recent evaluation of patients with head and neck cancer treated with radiation therapy alone or chemoradiotherapy, subsets of HPV-associated advanced head and neck cancers may benefit from a deintensification of treatment.43 Ongoing trials are comparing chemoradiotherapy with cetuximab plus radiation therapy in this setting. In summary, the use of concurrent CMT in head and neck cancers has improved survival in both unresectable and resectable disease and has permitted larynx preservation in up to two thirds of patients who would have previously undergone laryngectomy. Because CMT is concurrent, the toxicity of treatment remains significant, which is only partially ameliorated by sophisticated irradiation techniques. HPV-associated oropharynx cancers present a new opportunity for de-escalating CMT while preserving high rates of cure and organ conservation. CMT using targeted therapies and chemoradiotherapy is discussed later in this article. © 2014 by American Society of Clinical Oncology
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CMT for GI Cancers CMT has produced substantial improvements in the outcome of patients with GI cancer. A key initial study involved anal cancer; investigators at Wayne State University designed a clinical trial for preoperative radiation therapy and chemotherapy (mitomycin and infusional FU) for patients with anal cancer, a disease that had previously been treated with abdominal perineal resection. A surprisingly high fraction of patients were found to have had a complete response after surgery, leading to the concept that CMT alone might be definitive therapy.44 Indeed, this approach produced results that were superior to those of historical series using abdominal perineal resection and, of course, offered the opportunity for avoiding a permanent colostomy. A randomized trial that aimed to eliminate mitomycin showed that FU alone produced inferior results.45 Subsequent studies aiming to replace mitomycin with cisplatin46,47 produced mixed results. The overall conclusion is that treatment with FU plus mitomycin is still a standard (although cisplatin may be as effective, if neoadjuvant chemotherapy can be avoided),47 and it remains a triumph of CMT (as in laryngeal cancer), permitting high cure rates with organ preservation, even in the presence of gross disease. A different path was taken in rectal cancer in the United States, where the initial studies of CMT were postoperative. The GI Tumor Study Group conducted a four-arm study, which by today’s standards would be considered seriously underpowered, of surgery only, surgery followed by radiation therapy alone, FU alone, or the combination of FU and radiation therapy, suggesting improved survival for the combination therapy group.48 This conclusion was supported by a subsequent (appropriately powered) study comparing surgery followed by radiation therapy versus surgery followed by chemoradiotherapy, which again favored the CMT arm for survival and local control, establishing this approach as a standard therapy.49 At the same time, Swedish50 and Dutch51 studies emphasized preoperative radiation therapy, with the former trial showing improved survival with radiation therapy plus surgery compared with surgery alone. Preoperative therapy would seem to offer some advantages over postoperative therapy; in the latter case, the small bowel often becomes adherent in the pelvis, where it becomes impossible to prevent it from receiving a full radiation dose with attendant toxicity. These findings and this logic set the stage for a randomized trial of preoper-
ative versus postoperative CMT, which confirmed that preoperative treatment was both more effective and less toxic than postoperative therapy, thereby establishing preoperative CMT as the standard of care.52 With the establishment of preoperative CMT for locally advanced rectal cancer, it became possible to assess the effects of neoadjuvant treatment on the tumor. Pathologic complete response rates after CMT are approximately 20%. Substantial efforts have been made to try to increase local control and pathologic complete response with the addition of new agents such as oxaliplatin53 and the antiangiogenic agent bevacizumab.54 Unfortunately, none of the new agents have improved the pathologic complete response rate or local control compared with FU alone (and more recently capecitabine,55 as summarized by Tepper and Wang56). Furthermore, a significant fraction of patients with distal locally advanced rectal cancer still require colostomy, and it is important to develop strategies analogous to those used for anal cancer to achieve cure with sphincter preservation. Some intriguing results have suggested that patients who achieve a pathologic complete response after neoadjuvant therapy may indeed not require surgery,57 which would represent a major advance if it could be replicated in larger studies. The propensity of pancreatic cancer to recur both locally and systemically,58 along with results from preclinical studies,59 made this site an early candidate for the use of both concurrent and sequential CMT. Both old60 and recent61 randomized trials have demonstrated that the combination of CMT and either FU or gemcitabine is superior to chemotherapy alone for locally advanced unresectable disease (although a recent French study did not support this,62 it had substantial design flaws63). The role of CMT in resected disease is controversial, and the conclusion that radiation therapy does not play a role64 has been questioned because of a lack of quality control for both surgery and radiation therapy.65 An ongoing RTOG trial with appropriate quality control measures, lacking in prior studies, should be able to determine whether radiation therapy plays a role in the approximately 15% of patients with pancreatic cancer who are able to have negative margins of resection. There is also controversy regarding neoadjuvant therapy versus adjuvant therapy for patients with resectable disease, because there are not direct comparisons. Finally, CMT seems to permit some patients with unresectable or borderline resectable disease to undergo resection.66,67
Capecitabine + temozolomide FU
Year
Cisplatin
1984
1990
Immune checkpoint inhibitors?
Gemcitabine 1997
Mitomycin + FU
1999
2001 2002
Cetuximab
Future…
DNA damage response inhibitors?
Novel chemotherapies?
Fig 1. Timeline of advances in concurrent chemoradiotherapy. In this figure, we note major advances in concurrent chemoradiotherapy, as documented in first Journal of Clinical Oncology (JCO) articles to describe them. Fluorouracil (FU): A phase I trial of FU with radiation therapy for advanced head and neck cancer. Although FU is no longer used alone as radiation sensitizer in head and neck cancer, this article set the stage for use of concurrent FU and radiation therapy in multiple malignancies.74 Cisplatin: This landmark trial describing use of concurrent cisplatin with radiation therapy in nasopharyngeal cancer led to use of concurrent cisplatin-based therapy in lung, esophageal, head and neck, and cervical cancers.75 Mitomycin and FU: Although this combination had been used with radiation therapy to treat anal cancer before this JCO reference, this article was key to establishing superiority of combined-modality therapy (CMT) over radiation therapy alone.76 Gemcitabine: First trial combining radiation therapy with gemcitabine in locally advanced pancreatic cancer, which contributed to this combination becoming standard therapy for this disease.77 Cetuximab: This phase I trial documented first use of cetuximab with radiation therapy and established doses used in subsequent positive phase III trial.78 Capecitabine: This phase I trial described safe dose of capecitabine with radiation therapy and made possible subsequent studies establishing role of capecitabine, when combined with radiation therapy, in rectal and pancreatic cancers.79 Temozolomide: First report of trial that ultimately defined new standard of treatment for glioblastoma.80 1176
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In summary, CMT has enabled the achievement of high cure rates with organ preservation in anal cancer, with decreasing toxicity as a result of the use of sophisticated irradiation techniques. These goals have been partially achieved in rectal cancer, with high cure rates but with a significant fraction of patients requiring colostomy. These goals remain elusive in pancreatic cancer, with only modest improvements in local control and survival, even with intensive chemotherapy and sophisticated irradiation techniques. As we alluded at the end of the Introduction, CMT will not achieve its full potential in locally advanced or resectable pancreatic cancer until systemic therapy improves. CMT Using Targeted Therapies and Chemoradiotherapy Because EGFR is overexpressed in a majority of head and neck cancers and is associated with poor outcome, anti-EGFR drugs have been explored as potential agents to be used in combination with radiation therapy. Cetuximab was the first anti-EGFR drug extensively tested, and preclinical studies identified it as a radiosensitizer, forming the basis of a phase III clinical trial comparing radiation therapy alone with radiation therapy plus cetuximab.68 The addition of cetuximab to radiation therapy in advanced head and neck cancers improved locoregional control and reduced mortality. This study paved the way for additional studies evaluating targeted agents in head and neck cancers.69 Some early-phase and single-institution series have suggested superior results with platin plus radiation therapy compared with cetuximab plus radiation therapy, although conflicting data exist.70,71 Unfortunately, there is as yet no level-one evidence that directly compares concurrent platinum administration and radiation therapy with concurrent cetuximab administration and radiation therapy. However, in one trial, the addition of cetuximab to cisplatin plus radiation therapy was compared with cisplatin plus radiation therapy alone. Unfortunately, there was no improvement in survival with the triple therapy compared with cisplatin plus radiation therapy alone, and toxicity was increased.72 It is disappointing that no preclinical data were used to structure this study, and it will be important in the future to use more sophisticated approaches to combining targeted therapies with chemoradiotherapy.73 Discussion CMT has evolved over the past two decades to the point at which it is the standard of care for the majority of patients with the cancers we have chosen to focus on in this review, as well as many others. In Figure 1, we present a timeline of chemotherapeutic agents used concurrently with radiation therapy, along with the first time they appeared in Journal of Clinical Oncology (JCO). Of note, each of these reports was key in establishing a new aspect of CMT. Implementation of more sophisticated irradiation techniques resulting in more optimal dose distributions, along with the introduction of novel drugs and targeted agents, is certain to continue to shape this field, improving locoregional control, distant metastasis–free survival, overall survival, and quality of life in patients with locally advanced disease. JCO will continue to be the major journal for the dissemination of these studies as they become available and a valuable resource for discussions, commentaries, and editorials, which will help to shape the clinical interpretation and implementation of these contributions. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. www.jco.org
AUTHOR CONTRIBUTIONS
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71. Riaz N, Sherman EJ, Fury M, et al: Should cetuximab replace cisplatin for definitive chemoradiotherapy in locally advanced head and neck cancer? J Clin Oncol 31:287-288, 2013 72. Ang KK, Zhang QE, Rosenthal DI, et al: A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol 29:360s, 2011 (suppl; abstr 5500) 73. Morgan MA, Parsels LA, Maybaum J, et al: Improving the efficacy of chemoradiation with targeted agents. Cancer Discov 4:1-12, 2014 74. Byfield JE, Sharp TR, Frankel SS, et al: Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck. J Clin Oncol 2:406-413, 1984 75. Al-Sarraf M, Pajak TF, Cooper JS, et al: Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: A Radiation Therapy Oncology Group study. J Clin Oncol 8:1342-1351, 1990 76. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European
Organisation for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997 77. Blackstock AW, Bernard SA, Richards F, et al: Phase I trial of twice- weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 17:2208-2212, 1999 78. Robert F, Ezekiel MP, Spencer SA, et al: Phase I study of anti–epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 19:3234-3243, 2001 79. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983-3991, 2002 80. Stupp R, Dietrich PY, Ostermann Kraljevic S, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375-1382, 2002
DOI: 10.1200/JCO.2014.55.2281; published online ahead of print at www.jco.org on March 24, 2014
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Acknowledgment We thank Mary McKeever and Mary Davis for help in preparing the manuscript and Steven Kronenberg for preparing the figure.
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