Alternating Chemotherapy and Radiotherapy in Locally Advanced Head and Neck Cancer: An Alternative?
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《肿瘤学家》
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
Discuss the results of trials with alternating chemotherapy and radiotherapy for the treatment of locoregionally advanced head and neck cancer.
Describe the rationale for using alternating chemotherapy and radiotherapy in the management of head and neck cancer.
Explain why chemoradiation should preferably be managed by an experienced staff.
Assess the role played by different drugs in the development of mucositis in an alternating chemotherapy and radiotherapy combined treatment.
ABSTRACT
Rapidly alternating chemotherapy and radiotherapy (ACR) is a minor variation of concurrent chemoradiation (CCR). This scheduling has been tested in advanced head and neck cancer and has shown superiority over standard radiation in some randomized trials with only marginally greater toxicity. This paper reviews ACR in advanced head and neck cancer. The hypothesis that this approach could have a better toxicity profile than CCR is discussed in light of the published clinical data. Efficacy is also discussed on the basis of available phase III trials. Published data indicate that rapidly alternating chemoradiation adds to toxicity less than CCR and results in comparable 3-year overall survival rates. In conclusion, ACR could be as active as, and possibly less toxic than, CCR. Comparative trials are highly recommended.
INTRODUCTION
One of the first randomized trials showing a significant survival advantage induced by chemoradiation in advanced head and neck cancer was one of rapidly alternating chemotherapy and radiotherapy (ACR) [1]. ACR is a minor variation of concurrent chemoradiation (CCR) aimed at minimizing toxicity [2]. This scheduling allows uninterrupted treatment of the tumor, with radiotherapy administered during the pauses between cycles of chemotherapy.
Looney and Hopkins [3] were the first to suggest that ACR could allow the simultaneous administration of both treatment modalities without increasing toxicity. This hypothesis was based on results from experimental solid tumor systems.
Decreasing chemoradiation-induced toxicity is a major objective in head and neck cancer. Chemoradiation has proven to be superior to radiotherapy alone [4], but treatment-related toxicities are higher, and an expert staff is required to deliver this complex treatment modality [5–7]. Poor management of toxicity leads to alterations of doses or scheduling of radiation and/or chemotherapy, thus compromising the potential gain in treatment efficacy. Radiotherapy alone may be a more appropriate treatment [6] when proper expertise is not available.
The objective of the present paper is to review the mechanism of action and the clinical results of ACR in terms of toxicity and efficacy, and to explore the reasons why this approach is underinvestigated by the international scientific community.
ACR: SCHEDULES TESTED IN RANDOMIZED TRIALS
In the past two decades, only four phase III trials of ACR were published [1, 8–10]. The study designs were similar because radiotherapy was delivered as a standard single daily fraction and was not given concurrently with chemotherapy in all studies, but the chemotherapy regimens employed were different. The two oldest trials used vinblastine (Velban®; Eli Lilly and Company, Indianapolis), bleomycin (Blenoxane®; Bristol-Myers Squibb, Princeton, NJ), and methotrexate (VBM) with or without fluorouracil [8, 10]. This schema was then replaced with the combination of cisplatin (Platinol®; Bristol-Myers Squibb) and fluorouracil in light of the accepted superiority of this regimen, which was then used in the other two studies [1, 9]. The regimen consisted of cisplatin, 20 mg/m2 per day, and concurrent fluorouracil, 200 mg/m2 per day i.v. bolus, for five consecutive days. Fluorouracil was added to cisplatin because of the supposed synergism between the two drugs. Moreover, it was delivered as an i.v. bolus to minimize mucosal toxicity, which is mainly induced by the continuous infusion of the drug. In this way, the overlapping mucosal toxicity between chemotherapy and radiotherapy is, in theory, reduced. The ACR scheduling tested in the two more recent trials is shown in Table 1.
CHEMORADIATION: MECHANISMS OF ACTION
Hennequin and Favaudon recently reviewed the biological mechanisms of interaction between chemotherapy and radiotherapy [11]. These include interactions at the molecular, cellular, and tissue levels. At the molecular level, radiation and drugs cooperate to target DNA, by increasing DNA damage and interfering with DNA repair. At the cellular level, chemoradiation may induce cytokinetic cooperation. Radiosensitivity changes during the phases of the cell cycle. The S phase is the most radioresistant, whereas S-phase cells are highly sensitive to several anticancer drugs. This is the reason why a greater cell kill is observed when proliferating cells are exposed to drugs and radiation in close temporal proximity [11].
There is one additional mechanism of action that may be ascribed to ACR. Split-course radiotherapy is considered suboptimal [12] because of the tumor repopulation that occurs during treatment breaks, which negatively affects treatment results [13, 14]. However, in ACR, the breaks between radiotherapy treatments are filled up with chemotherapy, the activity of which is enhanced in rapidly proliferating tissues, such as repopulating tumors. Therefore, a cytokinetic mechanism of cooperation, exploiting tumor repopulation, may be at work in ACR.
At the tissue level, cooperation between radiation and the chemotherapy drugs is the result of rapid tumor shrinkage and reoxygenation resulting from an improved blood supply. This effect could be related to a reduction in interstitial pressure. Interstitial pressure usually increases in tumor tissues and leads to vascular collapse [15], thus compromising the blood supply, which is already defective because of poorly functioning vasculature (immature structure of the vessels as a result of imperfect neoangiogenesis). In the case of rapid tumor mass reduction, interstitial pressure may be reduced and blood flow improved.
TOXICITY OF ACR
The combination of chemotherapy and radiotherapy inevitably induces more toxic effects than chemotherapy or radiotherapy alone. Indeed, both treatments maintain their own toxicities such as chemotherapy-related hematological toxicity or radiotherapy-induced xerostomia. This is one of the reasons why the clinical staff involved in combined chemoradiation must be familiar with the toxicities of both treatment modalities. The failure to meet this requirement may lead to inappropriate delivery of chemotherapy and/or radiotherapy. Mucositis is common to both chemotherapy and radiotherapy and is, therefore, easily enhanced by their combination, thus becoming the limiting factor of this approach.
Stomatitis is the major toxic effect of ACR. Severe stomatitis precludes normal alimentation, leading to a dramatic loss in body weight and dehydration, and may favor infections because of, for example, mucosal ulcers or pneumonia ab ingestis, the latter related to, at least in part, painful dysphagia. Stomatitis induced by ACR appears to be strictly related to the chosen drugs and scheduling. Recent phase II studies may help to clarify this matter. Fuwa et al. [16] reported the results of an ACR trial in which chemotherapy consisted of a combination of cisplatin and fluorouracil: grade III–IV stomatitis was recorded in 10/35 patients enrolled (31%). Benasso et al. [17] described a second phase II study based on ACR. Chemotherapy was a combination of cisplatin and gemcitabine (Gemzar®; Eli Lilly and Company). Treatment resulted in 16 episodes of grade III and 19 episodes of grade IV mucositis. Overall, 81% of the 47 treated patients developed grade III–IV stomatitis. Our group has published a third phase II trial based on ACR. Chemotherapy consisted of paclitaxel (Taxol®; Bristol-Myers Squibb), cisplatin, and fluorouracil. Again, grade III–IV stomatitis occurred in 81% of the 31 treated patients [18].
The difference in the rates of grade III–IV stomatitis among these trials using different drug combinations is impressive, although part of it could be ascribed to the possible variability in the assessment of stomatitis in non-comparative phase II trials. Phase III trials offer additional evidence of the key role played by drugs in mucosal toxicity. An early phase III trial of ACR versus radiotherapy alone, employing a methotrexate-based chemotherapy regimen, resulted in a higher incidence of severe mucositis with ACR than with radiotherapy [8]. On the other hand, in two randomized trials of ACR that included cisplatin-based chemotherapy and fluorouracil given as an i.v. bolus rather than as a continuous infusion, the incidence of stomatitis was similar to that observed with radiotherapy alone [1, 9]. It must be emphasized that neither cisplatin nor bolus fluorouracil induces severe mucositis. The similar incidences of acute toxicity observed in the ACR and radiotherapy groups in these trials must be regarded with interest. If the advantage derived from a two-modality combined therapy is obtained at the expense of greater toxicity, the same advantage could, in theory, be achieved by intensifying either modality alone, until the same higher rate of toxicity was reached. Only if a benefit is gained without significantly more toxicity can we reasonably speculate that this is the result of the synergistic mechanism of the combined approach.
TOXICITY OF CCR AND CCR VERSUS ACR
The chosen drugs play a key role even in CCR-induced stomatitis. Comparison of the toxicities observed by Fu et al. [19] (concurrent bleomycin and radiation) with those reported by Adelstein et al. [20] (concurrent cisplatin and radiation) supports this statement. In the former trial, compliance with the combined regimen was 50%, compared with 85% in the latter trial. The data of Adelstein et al. [20] are very close to those reported in a previous study, the Intergroup 0099, based on an identical chemoradiation program delivered to patients with nasopharyngeal cancer [21].
It is interesting to note that from 1992 to 2003, four phase III studies of chemoradiation with several similarities were published: in all studies, radiotherapy was given as a standard daily fractionation and chemotherapy was cisplatin-based. The major difference among these trials was the scheduling of chemoradiation: alternating in two, and concurrent in the other two. In the ACR trials, the rates of mucosal toxicity with ACR were equivalent to [1] or less than [9] those with radiotherapy alone, whereas in the CCR trials, the rates of mucosal toxicity suggested a disadvantage for CCR [20, 21] (Table 2). It must be noted that the CCR studies employed cisplatin alone, whereas the ACR trials employed a combination of cisplatin and fluorouracil. Moreover, the overall treatment time of ACR is longer than that of CCR and thus the total duration of side effects is also longer. The different behavior between ACR and CCR may suggest a more favorable toxicity profile for ACR.
EFFICACY OF ACR
As mentioned above, one of the first randomized trials showing a significant survival benefit in favor of chemoradiation was an ACR trial [1]. That study reported a survival probability at 3 years of 41% in the ACR arm, compared with 23% in the radiotherapy arm. The difference between the two treatment arms was so evident that the trial was discontinued early (157 patients enrolled instead of 180 planned), as a result of the refusal of the participating centers to continue enrolment in the radiotherapy arm. Notably, 43% of the patients treated with ACR achieved complete responses, compared with 22% of those treated with radiotherapy. The significant difference between ACR and radiotherapy was confirmed in a 5-year update of that study [22].
A second randomized trial based on the same ACR program and recruiting an analogous patient population [9] reported a similar 3-year survival rate, which compared favorably, but without reaching statistical significance, with the control arm: partly accelerated radiotherapy (3-year survival rate, 37% vs. 29%). This scheduling of radiotherapy is very similar to the accelerated fractionation with boost tested in the Radiation Therapy Oncology Group (RTOG) trial 9003 [23], and is considered more effective than standard fractionation in head and neck cancer.
Two older randomized studies of ACR were based on VBM chemotherapy, and therefore employed two drugs (methotrexate and bleomycin) whose combination with radiation is particularly harmful. Both of those trials showed major acute toxicities, in particular, mucositis [8, 10, 24]. A statistically significant survival advantage was observed in only one [8], but both trials compared ACR with neoadjuvant chemotherapy followed by radiotherapy instead of radiotherapy alone. This makes these older trials different from the two reported above. Results of the four randomized trials of ACR are shown in Table 3.
COMPARISON WITH CCR
A large number of randomized trials comparing radiotherapy with CCR in advanced head and neck cancer have been published in the last 15 years. The results of some of these trials [20, 25–28] are reported in Table 4. One of these studies [20] was a three-arm study with (a) a control arm, that is, radiotherapy; (b) a CCR arm (cisplatin and standard radiotherapy); and (c) a partly concurrent chemoradiation arm. The other trials delivered radiotherapy by nonconventional daily fractionation in both the control and concurrent arms. Chemotherapy was cisplatin-based in all studies. The 3-year survival rates with CCR do not appear substantially different from the 3-year survival rates achieved with ACR (Table 1 and Table 2), although a direct comparison of CCR with ACR does not exist. Such a trial is highly recommended.
REASONS WHY ACR IS UNDERINVESTIGATED BY THE SCIENTIFIC COMMUNITY
The literature reports only a limited number of randomized trials based on ACR in advanced head and neck cancer, as shown above. This may be a result of doubts concerning ACR-based clinical trials. The most frequently reported concern is the supposed poor behavior of the control group (radiation) in the published randomized trials [29, 30]. If this is true, the significant survival difference observed in favor of ACR should be ascribed to the poor outcome of the control arm rather than to a real superiority of the ACR arm. Actually, no scientific data support this concern: the 3-year survival rates in the control arms of all the reported studies are in the range of 23%–34%, which is comparable with those observed in the CCR trials (Table 3 and Table 4). A second concern is based on a possible detrimental effect of the split-course radiotherapy used in ACR (Table 1). As stated above, split-course radiotherapy is considered suboptimal compared with continuous scheduling [12] because of tumor repopulation [13, 14]. However, ACR preserves the continuity of treatment because chemotherapy fills up the breaks between radiotherapy treatments. Four randomized clinical trials performed over the past two decades, accruing more than 600 patients, did not show any detrimental effect of alternating chemotherapy and radiation, compared with standard radiotherapy, although the dose of radiotherapy in the combined arm was always lower than the dose given in the radiotherapy arm [1, 8–10]. In fact, two of these trials showed a significant survival advantage of alternating chemotherapy and 60-Gy radiotherapy compared with 70-Gy radiotherapy alone [1, 8].
Moreover, if we consider all the above-described chemoradiation trials (ACR and CCR) together, no clear evidence appears of different efficacies among the combination arms, in which 3-year survival rates were in the range of 37%–41% with alternating scheduling and in the range of 37%–55% with concurrent scheduling (Table 3 and Table 4). In conclusion, there is substantial evidence that chemotherapy is effective in filling up the breaks in a rapidly alternating chemoradiation program and compensates for the tumor repopulation that occurs during split-course radiotherapy.
CONCLUSIONS
Toxicity is the major problem of CCR. Some authors suggest that delivery of this treatment should be limited to those centers in which expert staff is available because of the severity of acute toxicities [5, 6, 14]. Moreover, comorbidities in several head and neck cancer patients further limit the use of any toxic treatment. The combination of these two factors makes it difficult to extend CCR to the whole patient population. Therefore, the search for a less toxic scheduling of chemoradiation is mandatory.
Experimental data suggest that ACR may reconcile the need for early administration of chemotherapy and radiotherapy with the need for a more favorable toxicity profile of the combined approach [3]. Clinical data support the hypothesis that ACR adds to radiotherapy-induced acute toxicity less than CCR. However, it must be noted that this effect is largely drug-dependent. Potent radiosensitizing drugs induce formidable acute toxicity regardless of the scheduling of the combined treatment, ACR or CCR.
In contrast, published data do not support the concern of a possible lower efficacy with ACR than with CCR, at least for trials with cisplatin-based chemotherapy. For these reasons, ACR may be regarded as an opportunity to extend the benefit of chemoradiation to larger patient populations. However, randomized trials comparing ACR with CCR are mandatory in order to definitively establish the role of these two different schedules of chemoradiation.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The author indicates no potential conflicts of interest.
ACKNOWLEDGMENT
The author thanks Dr. Milena Gasco for assisting with English editing.
REFERENCES
Merlano M, Vitale V, Rosso R et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992;327:1115–1121.
Haffty GB. Concurrent chemoradiation in the treatment of head and neck cancer. Hematol Oncol Clin North Am 1999;13:719–742.
Looney WB, Hopkins HA. Alternation of chemotherapy and radiotherapy in cancer management. III. Results in experimental solid tumor systems and their relationship to clinical studies. Cancer Treat Rep 1986;70: 141–162.
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. Lancet 2000;355:949–955.
Merlano M, Marchetti G. Radiochemotherapy in head and neck cancer. Cancer Treat Rev 2003;29:291–296.
Forastiere A, Koch W, Trotti A et al. Head and neck cancer. N Engl J Med 2001;345:1890–1900.
Adelstein DJ, Saxton JP, Lavertu P et al. Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer, with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 2002;20:1405–1410.
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Corvò R, Benasso M, Sanguineti G. Alternating chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck: results from a phase III randomized trial. Cancer 2001;92:2856–2867.
SECOG participants. A randomized trial of combined multidrug chemotherapy and radiotherapy in advanced squamous cell carcinoma of the head and neck. Eur J Surg Oncol 1986;12:289–295.
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Glynne-Jones R, Sebag-Montefiore D. Chemoradiation schedules--what radiotherapy? Eur J Cancer 2002;38:258–269.
Pajak TF, Laramore GE, Marcial VA et al. Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG report. Int J Radiat Oncol Biol Phys 1991;20:13–20.
Vokes EE, Haraf DJ, Kies MS. The use of concurrent chemotherapy and radiotherapy for locoregionally advanced head and neck cancer. Semin Oncol 2000;27(suppl 8):34–38.
Koukourakis MI. Tumour angiogenesis and response to radiotherapy. Anticancer Res 2001;21:4285–4300.
Fuwa N, Kano M, Toita T et al. Alternating chemoradiotherapy for naso-pharyngeal cancer using cisplatin and 5-fluorouracil: a preliminary report of phase II study. Radiother Oncol 2001;61:257–260.
Benasso M, Corvò R, Ponzanelli A et al. Alternating gemcitabine and cisplatin with gemcitabine and radiation in stage IV squamous cell carcinoma of the head and neck. Ann Oncol 2004;15:646–652.
Merlano M, Russi EG, Numico G et al. Paclitaxel, cisplatin, 5-fluorouracil and radiotherapy in the management of advanced squamous cell carcinoma of the head and neck: a phase II trial. Radiother Oncol 2005;75: 193–196.
Fu KK, Phillips TL, Silverberg IJ et al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of Northern California Oncology Group randomized trial. J Clin Oncol 1987;5:1410–1418.
Adelstein DJ, Li Y, Adams GL et al. An Intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92–98.
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 1998;16:1310–1317.
Merlano M, Benasso M, Corvò R et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996;88:583–589.
Fu KK, Pajak T, Trotti A et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7–16.
Merlano M, Rosso R, Sertoli MR et al. Randomized comparison of two chemotherapy, radiotherapy schemes for stage III and IV unresectable squamous cell carcinoma of the head and neck. Laryngoscope 1990;100:531–535.
Wendt TG, Grabenbauer GG, Rodel CM et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16:1318–1324.
Brizel DM, Albers ME, Fisher SR et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338:1798–1804.
Jeremic B, Shibamoto Y, Milicic B et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000;18:1458–1464.
Huguenin P, Beer KT, Allal A et al. Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol 2004;22:4665–4673.
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Adelstein DJ. Recent randomized trials of chemoradiation in the management of locally advanced head and neck cancer. Curr Opin Oncol 1998;10:213–218.(Marco Merlano)
After completing this course, the reader will be able to:
Discuss the results of trials with alternating chemotherapy and radiotherapy for the treatment of locoregionally advanced head and neck cancer.
Describe the rationale for using alternating chemotherapy and radiotherapy in the management of head and neck cancer.
Explain why chemoradiation should preferably be managed by an experienced staff.
Assess the role played by different drugs in the development of mucositis in an alternating chemotherapy and radiotherapy combined treatment.
ABSTRACT
Rapidly alternating chemotherapy and radiotherapy (ACR) is a minor variation of concurrent chemoradiation (CCR). This scheduling has been tested in advanced head and neck cancer and has shown superiority over standard radiation in some randomized trials with only marginally greater toxicity. This paper reviews ACR in advanced head and neck cancer. The hypothesis that this approach could have a better toxicity profile than CCR is discussed in light of the published clinical data. Efficacy is also discussed on the basis of available phase III trials. Published data indicate that rapidly alternating chemoradiation adds to toxicity less than CCR and results in comparable 3-year overall survival rates. In conclusion, ACR could be as active as, and possibly less toxic than, CCR. Comparative trials are highly recommended.
INTRODUCTION
One of the first randomized trials showing a significant survival advantage induced by chemoradiation in advanced head and neck cancer was one of rapidly alternating chemotherapy and radiotherapy (ACR) [1]. ACR is a minor variation of concurrent chemoradiation (CCR) aimed at minimizing toxicity [2]. This scheduling allows uninterrupted treatment of the tumor, with radiotherapy administered during the pauses between cycles of chemotherapy.
Looney and Hopkins [3] were the first to suggest that ACR could allow the simultaneous administration of both treatment modalities without increasing toxicity. This hypothesis was based on results from experimental solid tumor systems.
Decreasing chemoradiation-induced toxicity is a major objective in head and neck cancer. Chemoradiation has proven to be superior to radiotherapy alone [4], but treatment-related toxicities are higher, and an expert staff is required to deliver this complex treatment modality [5–7]. Poor management of toxicity leads to alterations of doses or scheduling of radiation and/or chemotherapy, thus compromising the potential gain in treatment efficacy. Radiotherapy alone may be a more appropriate treatment [6] when proper expertise is not available.
The objective of the present paper is to review the mechanism of action and the clinical results of ACR in terms of toxicity and efficacy, and to explore the reasons why this approach is underinvestigated by the international scientific community.
ACR: SCHEDULES TESTED IN RANDOMIZED TRIALS
In the past two decades, only four phase III trials of ACR were published [1, 8–10]. The study designs were similar because radiotherapy was delivered as a standard single daily fraction and was not given concurrently with chemotherapy in all studies, but the chemotherapy regimens employed were different. The two oldest trials used vinblastine (Velban®; Eli Lilly and Company, Indianapolis), bleomycin (Blenoxane®; Bristol-Myers Squibb, Princeton, NJ), and methotrexate (VBM) with or without fluorouracil [8, 10]. This schema was then replaced with the combination of cisplatin (Platinol®; Bristol-Myers Squibb) and fluorouracil in light of the accepted superiority of this regimen, which was then used in the other two studies [1, 9]. The regimen consisted of cisplatin, 20 mg/m2 per day, and concurrent fluorouracil, 200 mg/m2 per day i.v. bolus, for five consecutive days. Fluorouracil was added to cisplatin because of the supposed synergism between the two drugs. Moreover, it was delivered as an i.v. bolus to minimize mucosal toxicity, which is mainly induced by the continuous infusion of the drug. In this way, the overlapping mucosal toxicity between chemotherapy and radiotherapy is, in theory, reduced. The ACR scheduling tested in the two more recent trials is shown in Table 1.
CHEMORADIATION: MECHANISMS OF ACTION
Hennequin and Favaudon recently reviewed the biological mechanisms of interaction between chemotherapy and radiotherapy [11]. These include interactions at the molecular, cellular, and tissue levels. At the molecular level, radiation and drugs cooperate to target DNA, by increasing DNA damage and interfering with DNA repair. At the cellular level, chemoradiation may induce cytokinetic cooperation. Radiosensitivity changes during the phases of the cell cycle. The S phase is the most radioresistant, whereas S-phase cells are highly sensitive to several anticancer drugs. This is the reason why a greater cell kill is observed when proliferating cells are exposed to drugs and radiation in close temporal proximity [11].
There is one additional mechanism of action that may be ascribed to ACR. Split-course radiotherapy is considered suboptimal [12] because of the tumor repopulation that occurs during treatment breaks, which negatively affects treatment results [13, 14]. However, in ACR, the breaks between radiotherapy treatments are filled up with chemotherapy, the activity of which is enhanced in rapidly proliferating tissues, such as repopulating tumors. Therefore, a cytokinetic mechanism of cooperation, exploiting tumor repopulation, may be at work in ACR.
At the tissue level, cooperation between radiation and the chemotherapy drugs is the result of rapid tumor shrinkage and reoxygenation resulting from an improved blood supply. This effect could be related to a reduction in interstitial pressure. Interstitial pressure usually increases in tumor tissues and leads to vascular collapse [15], thus compromising the blood supply, which is already defective because of poorly functioning vasculature (immature structure of the vessels as a result of imperfect neoangiogenesis). In the case of rapid tumor mass reduction, interstitial pressure may be reduced and blood flow improved.
TOXICITY OF ACR
The combination of chemotherapy and radiotherapy inevitably induces more toxic effects than chemotherapy or radiotherapy alone. Indeed, both treatments maintain their own toxicities such as chemotherapy-related hematological toxicity or radiotherapy-induced xerostomia. This is one of the reasons why the clinical staff involved in combined chemoradiation must be familiar with the toxicities of both treatment modalities. The failure to meet this requirement may lead to inappropriate delivery of chemotherapy and/or radiotherapy. Mucositis is common to both chemotherapy and radiotherapy and is, therefore, easily enhanced by their combination, thus becoming the limiting factor of this approach.
Stomatitis is the major toxic effect of ACR. Severe stomatitis precludes normal alimentation, leading to a dramatic loss in body weight and dehydration, and may favor infections because of, for example, mucosal ulcers or pneumonia ab ingestis, the latter related to, at least in part, painful dysphagia. Stomatitis induced by ACR appears to be strictly related to the chosen drugs and scheduling. Recent phase II studies may help to clarify this matter. Fuwa et al. [16] reported the results of an ACR trial in which chemotherapy consisted of a combination of cisplatin and fluorouracil: grade III–IV stomatitis was recorded in 10/35 patients enrolled (31%). Benasso et al. [17] described a second phase II study based on ACR. Chemotherapy was a combination of cisplatin and gemcitabine (Gemzar®; Eli Lilly and Company). Treatment resulted in 16 episodes of grade III and 19 episodes of grade IV mucositis. Overall, 81% of the 47 treated patients developed grade III–IV stomatitis. Our group has published a third phase II trial based on ACR. Chemotherapy consisted of paclitaxel (Taxol®; Bristol-Myers Squibb), cisplatin, and fluorouracil. Again, grade III–IV stomatitis occurred in 81% of the 31 treated patients [18].
The difference in the rates of grade III–IV stomatitis among these trials using different drug combinations is impressive, although part of it could be ascribed to the possible variability in the assessment of stomatitis in non-comparative phase II trials. Phase III trials offer additional evidence of the key role played by drugs in mucosal toxicity. An early phase III trial of ACR versus radiotherapy alone, employing a methotrexate-based chemotherapy regimen, resulted in a higher incidence of severe mucositis with ACR than with radiotherapy [8]. On the other hand, in two randomized trials of ACR that included cisplatin-based chemotherapy and fluorouracil given as an i.v. bolus rather than as a continuous infusion, the incidence of stomatitis was similar to that observed with radiotherapy alone [1, 9]. It must be emphasized that neither cisplatin nor bolus fluorouracil induces severe mucositis. The similar incidences of acute toxicity observed in the ACR and radiotherapy groups in these trials must be regarded with interest. If the advantage derived from a two-modality combined therapy is obtained at the expense of greater toxicity, the same advantage could, in theory, be achieved by intensifying either modality alone, until the same higher rate of toxicity was reached. Only if a benefit is gained without significantly more toxicity can we reasonably speculate that this is the result of the synergistic mechanism of the combined approach.
TOXICITY OF CCR AND CCR VERSUS ACR
The chosen drugs play a key role even in CCR-induced stomatitis. Comparison of the toxicities observed by Fu et al. [19] (concurrent bleomycin and radiation) with those reported by Adelstein et al. [20] (concurrent cisplatin and radiation) supports this statement. In the former trial, compliance with the combined regimen was 50%, compared with 85% in the latter trial. The data of Adelstein et al. [20] are very close to those reported in a previous study, the Intergroup 0099, based on an identical chemoradiation program delivered to patients with nasopharyngeal cancer [21].
It is interesting to note that from 1992 to 2003, four phase III studies of chemoradiation with several similarities were published: in all studies, radiotherapy was given as a standard daily fractionation and chemotherapy was cisplatin-based. The major difference among these trials was the scheduling of chemoradiation: alternating in two, and concurrent in the other two. In the ACR trials, the rates of mucosal toxicity with ACR were equivalent to [1] or less than [9] those with radiotherapy alone, whereas in the CCR trials, the rates of mucosal toxicity suggested a disadvantage for CCR [20, 21] (Table 2). It must be noted that the CCR studies employed cisplatin alone, whereas the ACR trials employed a combination of cisplatin and fluorouracil. Moreover, the overall treatment time of ACR is longer than that of CCR and thus the total duration of side effects is also longer. The different behavior between ACR and CCR may suggest a more favorable toxicity profile for ACR.
EFFICACY OF ACR
As mentioned above, one of the first randomized trials showing a significant survival benefit in favor of chemoradiation was an ACR trial [1]. That study reported a survival probability at 3 years of 41% in the ACR arm, compared with 23% in the radiotherapy arm. The difference between the two treatment arms was so evident that the trial was discontinued early (157 patients enrolled instead of 180 planned), as a result of the refusal of the participating centers to continue enrolment in the radiotherapy arm. Notably, 43% of the patients treated with ACR achieved complete responses, compared with 22% of those treated with radiotherapy. The significant difference between ACR and radiotherapy was confirmed in a 5-year update of that study [22].
A second randomized trial based on the same ACR program and recruiting an analogous patient population [9] reported a similar 3-year survival rate, which compared favorably, but without reaching statistical significance, with the control arm: partly accelerated radiotherapy (3-year survival rate, 37% vs. 29%). This scheduling of radiotherapy is very similar to the accelerated fractionation with boost tested in the Radiation Therapy Oncology Group (RTOG) trial 9003 [23], and is considered more effective than standard fractionation in head and neck cancer.
Two older randomized studies of ACR were based on VBM chemotherapy, and therefore employed two drugs (methotrexate and bleomycin) whose combination with radiation is particularly harmful. Both of those trials showed major acute toxicities, in particular, mucositis [8, 10, 24]. A statistically significant survival advantage was observed in only one [8], but both trials compared ACR with neoadjuvant chemotherapy followed by radiotherapy instead of radiotherapy alone. This makes these older trials different from the two reported above. Results of the four randomized trials of ACR are shown in Table 3.
COMPARISON WITH CCR
A large number of randomized trials comparing radiotherapy with CCR in advanced head and neck cancer have been published in the last 15 years. The results of some of these trials [20, 25–28] are reported in Table 4. One of these studies [20] was a three-arm study with (a) a control arm, that is, radiotherapy; (b) a CCR arm (cisplatin and standard radiotherapy); and (c) a partly concurrent chemoradiation arm. The other trials delivered radiotherapy by nonconventional daily fractionation in both the control and concurrent arms. Chemotherapy was cisplatin-based in all studies. The 3-year survival rates with CCR do not appear substantially different from the 3-year survival rates achieved with ACR (Table 1 and Table 2), although a direct comparison of CCR with ACR does not exist. Such a trial is highly recommended.
REASONS WHY ACR IS UNDERINVESTIGATED BY THE SCIENTIFIC COMMUNITY
The literature reports only a limited number of randomized trials based on ACR in advanced head and neck cancer, as shown above. This may be a result of doubts concerning ACR-based clinical trials. The most frequently reported concern is the supposed poor behavior of the control group (radiation) in the published randomized trials [29, 30]. If this is true, the significant survival difference observed in favor of ACR should be ascribed to the poor outcome of the control arm rather than to a real superiority of the ACR arm. Actually, no scientific data support this concern: the 3-year survival rates in the control arms of all the reported studies are in the range of 23%–34%, which is comparable with those observed in the CCR trials (Table 3 and Table 4). A second concern is based on a possible detrimental effect of the split-course radiotherapy used in ACR (Table 1). As stated above, split-course radiotherapy is considered suboptimal compared with continuous scheduling [12] because of tumor repopulation [13, 14]. However, ACR preserves the continuity of treatment because chemotherapy fills up the breaks between radiotherapy treatments. Four randomized clinical trials performed over the past two decades, accruing more than 600 patients, did not show any detrimental effect of alternating chemotherapy and radiation, compared with standard radiotherapy, although the dose of radiotherapy in the combined arm was always lower than the dose given in the radiotherapy arm [1, 8–10]. In fact, two of these trials showed a significant survival advantage of alternating chemotherapy and 60-Gy radiotherapy compared with 70-Gy radiotherapy alone [1, 8].
Moreover, if we consider all the above-described chemoradiation trials (ACR and CCR) together, no clear evidence appears of different efficacies among the combination arms, in which 3-year survival rates were in the range of 37%–41% with alternating scheduling and in the range of 37%–55% with concurrent scheduling (Table 3 and Table 4). In conclusion, there is substantial evidence that chemotherapy is effective in filling up the breaks in a rapidly alternating chemoradiation program and compensates for the tumor repopulation that occurs during split-course radiotherapy.
CONCLUSIONS
Toxicity is the major problem of CCR. Some authors suggest that delivery of this treatment should be limited to those centers in which expert staff is available because of the severity of acute toxicities [5, 6, 14]. Moreover, comorbidities in several head and neck cancer patients further limit the use of any toxic treatment. The combination of these two factors makes it difficult to extend CCR to the whole patient population. Therefore, the search for a less toxic scheduling of chemoradiation is mandatory.
Experimental data suggest that ACR may reconcile the need for early administration of chemotherapy and radiotherapy with the need for a more favorable toxicity profile of the combined approach [3]. Clinical data support the hypothesis that ACR adds to radiotherapy-induced acute toxicity less than CCR. However, it must be noted that this effect is largely drug-dependent. Potent radiosensitizing drugs induce formidable acute toxicity regardless of the scheduling of the combined treatment, ACR or CCR.
In contrast, published data do not support the concern of a possible lower efficacy with ACR than with CCR, at least for trials with cisplatin-based chemotherapy. For these reasons, ACR may be regarded as an opportunity to extend the benefit of chemoradiation to larger patient populations. However, randomized trials comparing ACR with CCR are mandatory in order to definitively establish the role of these two different schedules of chemoradiation.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The author indicates no potential conflicts of interest.
ACKNOWLEDGMENT
The author thanks Dr. Milena Gasco for assisting with English editing.
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