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Radiation therapy with 5-fluorouracil in head and neck cancer
Radiation Therapy With 5-Fluorouracil in Head and Neck Cancer Karen K. Fu 5-Fluorouracil (5-FU) alone or combined with other drugs, most frequently cisplatin, has been used concurrently or as induction or adjuvant therapy with radiotherapy with or without surgery in the treatment of head and neck cancer. Improved local-regional control and disease-free survival or overall survival have been shown in several randomized trials using a concurrent approach. However, acute mucositis is usually increased with simultaneous 5-FU and radiation administration, especially when other drugs are used in addition to 5-FU. Alternating radiotherapy with 5-FU and cisplatin was shown to improve the local-regional relapse-free, progression-free, and overall survival of unresectable squamous cell carcinoma of the head and neck compared with radiotherapy alone in one randomized trial9 Further evaluation of the alternating chemotherapy and radiotherapy approach is needed, however,
before one can accept this as a standard of practice. Induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in the chemotherapy responders is an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hypopharynx who wish to preserve organ function. Induction or adjuvant chemotherapy with 5-FU infusion and cisplatin may also decrease or delay the occurrence of distant metastasis. Induction chemotherapy, however, has not been shown to improve local-regional control or overall survival9 Further clinical trials combining 5-FU and its biochemical modulators using innovative radiation and drug dose schedules and other treatment modifiers are needed to improve the therapeutic ratio.
hortly after its discovery, 5-Fluorouracil (5-FU) k_3 was shown to increase the effects ot radiation., Subsequent in vitro and in vivo laboratory studies showed enhancement of radiation effects by 5-FU on tumors as well as normal tissuesY The combined effects can be supraadditive, additive, or subadditive, depending on the cell line, tumor, and normal tissue type in addition to the timing of drug administration in relation to radiation and drug and radiation dosage. The mechanism of 5-FU and radiation interaction remains poorly understood. Possible mechanisms include (1) perturbations of nucleotide pool through inhibition of thymidylate synthase, thus inhibiting repair of sublethal DNA damage; (2) induction of cell cycle redistribution with increase of cells in a sensitive cell cycle phase; and (3) incorporation offluorodeoxyuridine triphosphate into DNA. 8 The combined effects of 5-FU and radiation may vatywith the time and schedule of drug and radiation administration. Although in vitro studies by Byfield et al a suggested maximal enhancement of cytotoxicity with prolonged, continuous postradiation exposure to 5-FU, in vivo studies by Weinberg and Rauth 7 showed an additive tumor response independent of
the mode (bolus v infusion), schedule, and timing of drug administration. A detailed description of these interactions can be tbund in the article by Lawrence et al in this issue of Seminars in Radiation Oncology. As a single agent, 5-FU has an overall response rate of 15% in advanced head and neck cancer. 9 Clinical studies suggest superiority of a 4- to 5-day continuous-infusion schedule compared with bolus infusion with 5-FU alone in head and neck cancer and colon cancer.l~ 5-FU has been used either as a single agent or in a multidrug regimen, most ti'equently with cisplatin, when combined with radiotherapy with or without surgery in the treatment of advanced or recurrent head and neck cancer. There have been numerous nonrandomized as well as randomized clinical trials of radiotherapy and 5-FU for head and neck cancer. This article reviews the results of randomized trials of 5-FU combined with radiotherapy or surgery (or both) in the treatment of advanced operable and inoperable head and neck cancer. This article describes the various approaches used, including concurrent therapy, alternating or sequential therapy, and induction and adjuvant therapy.
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From the DepartmentofRadiation Oncology,Universityof CaliJbraia, San Francisco,CA. Address reprintrequeststo KarenK. Fu, MD, DepartmentofRadiation Oncology,UniversityofCalifornia,San Francisco,505ParnassusAve, L-08, San Francisco,CA 94143-0226. Copyright9 1997by W.B. SaundersCompany 1053-4296/97/0704-000155.00/0
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Copyright9 1997 by W.B. Saunders Company
Concurrent Radiation Therapy and 5-FU There have been at least nine randomized trials investigating concurrent 5-FU and radiotherapy for advanced head and neck cancer. 19-2~The results are summarized in Table 1.5-FU was used as a single agent in four of the trials, 12,13,16,18,2~combined with
Seminars in Radiation Oncvlogy, Vol 7, No 4 (October),199Z'pp 274-282
275
Radiotherapy and 5-FU in Head and Neck Cancer
Table 1. Randomized Trials of Concurrent 5-FU With or Without Other Drugs and Radiotherapy for Advanced Head and Neck Cancer
Author(year)
Shigematsu (1971) Is Lo (1978)20
No. of Evaluable Patients
%Local +_ Regional Control (years)
% CR
Drug(s) Control CT Control
CT
% Survival (years) Control
%DFS (years)
CT
Control
CT
63
5-FU (C)
N/A N/A 29 (2)
38 (2)
59 (2)
56 (2)
N/A
N/A
136
5-FU(B)
32
49 (2)
13" (5)
32* (5)
N/A
N/A
44
18 (2)
(P < .05) Sanchiz (1990) ~a
577
5-FU(B)
68
96
N/A
N/A
Weissler (1992) 19
58
5-FU(C) CP
20?
53?
N/A
N/A
Keane (1993) 17
209
Browman (1994) ~6 Adelstein (1996)2~
175 100
Wustrow (1996) 12
270
Brize1(1996) 15
110
5-FU(C) Mito-C 5-FU(C) 5-FU(C) CP 5-FU(C) CP 5-FU(C) CP
(P < .05) 32* (5)
62* (5) 22* (5) 57* (5) (P < .oo~) (P < .ool) Resectable disease: Resectable disease:
64* (2)
52* (2)
N/A
N/A 39* (5)
56 N/A
68 N/A
N/A N/A
N/A N/A
38* (3) 58 (3)
52* (3) 61 (3)
N/A N/A
N/A
N/A
24 (3)
N/A N/A 31 (3)
69 (3)
28 (3)
42* (5)
58* (2)
27* (3) 52 (3)
36* (3) 67 (3)
48 (3)
17 (3)
36 (3)
51 (3)
28 (3)
58 (3)
(n.s.)
(P = .002)
60* (2)
Unresectable disease: Unresectable disease: 10" (2) 40* (2) 0* (2) 42* (2) (p = .o13) (t' = .02) 35* (5) 34* (5) N/A N/A
(t' = .06)
(P = .02)
(e = .02)
*Estimated from survivalcurves. ]'In unresectable patients. Abbreviations:CR, complete remission; CT, chemotherapy;DFS, disease-free survival;CP, cisplatin; Mito-C, mitomycinC; C, continuous infusion; B, bolus infusion;N/A,not available. cisplatin in four trials, 12,15,19,2~ and combined with mitomycin C in one trial. 17With the exception of two trials, 18,2~ 5-FU was administered as a continuous infusion. Radiotherapy was delivered using standard fi'actionation in five trials 13,14,16,18,2~and split-course standard fractionation in one trial.17 Altered fractionation radiotherapy was used in three of the trials, including split-course hyperfractionation in one trial, 19 split-course accelerated fractionation in one trial, 12 and hyperfractionation in another trial. 15 In the trial from Duke University, 5-FU and cisplatin were administered as an adjuvant therapy after completion of radiotherapy as well as concurrent with hypeffractionated radiotherapy. 15 Improved local-regional control was reported in two trials. 15,~~Significantly improved disease-free survival 12,15,18,19,21 and overall survival 12,15,18-2~were shown in five trials.
Single-Agent 5-FU Among the four trials in which 5-FU was used as a single agent, 5-FU was infused intraarterially during radiotherapy for maxillary sinus carcinomas in the randomized study from Japan. 13The recurrence-free rate of patients who received 5-FU was significantly
better at 1 year but not at 2 years; the 2-year crude suFcival was similar tbr the study and control groups. The study from the University of Wisconsin included patients with oropharyngeal as well as oral cavity cancers. 2~Although the 2-year no evidence of disease (NED) rate was significantly better in the combined treatment group, the difference in 5-year survival was statistically significant in patients with oral cavity cancer but not oropharyngeal cancer (13% v 32% for the entire group, 13% v 40% for oral cavity cancer, 15% v 25% for oropharyngeal cancer). The incidence of distant metastasis and second malignancies was similar, however, for both the radiotherapy alone and the combined treatment groups. 5-FU also increased the acute and late normal tissue effects of radiation. Major complications, such as soft tissue or bone necrosis and fistula formation, were seen only in the combined treatment group. This study suggests that the primary site may be important in the outcome of combined 5-FU and radiotherapy. In the trial from Spain, standard fractionated radiotherapy was compared with hyperfractionated radiotherapy and standard fractionated radiotherapy
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Karen K. Fu
plus concurrent 5-FU. 1~ Survival was significantly improved in both the hyperii-actionation and the concurrent 5-FU groups compared with the standard fractionated radiotherapy alone group, but there was no significant difference between the hyperfractionation and the concurrent 5-FU groups. The study reported by Browman et al was a placebo-controlled trial of concurrent 5-FU infusion and standard fractionated radiotherapy. 16 Although there was a trend for improved progression-free and overall survival in the combined treatment group, acute toxicity, including severe stomatitis, skin reaction, and weight loss was also significantly greater.
5-FU in a Two-Drug Regimen More recently, 5-FU has been combined with other chemotherapeutic agents, most frequently cisplatin, in the treatment of head and neck cancer. In vitro studies on human ovarian carcinoma cells showed that cisplatin increased the intracellular reduced folates necessary for the binding of 5-fluorodeoxyuridine monophosphate, a metabolite of 5-FU, to thymidylate synthase, thus resulting in an enhanced cytotoxicity when combined with 5-FU. 92 Because of increased mucositis with concurrent chemotherapy and radiotherapy, especially when another agent is used in addition to 5-FU, a split-course approach has been used in three of the trials of 5-FU-containing two-drug chemotherapy and radiotherapy. 12,17,19The trial from the University of North Carolina included patients with resectable as well as unresectable disease. 19A survival advantage for cisplatin and 5-FU with concurrent radiotherapy was seen only in patients with unresectable disease. The number of patients was small, however; 32 patients had unresectable and 26 had resectable disease. Among patients with unresectable disease, three patients randomized to the combined treatment arm subsequently underwent surgery and were successfully salvaged. Mitomycin C was combined with 5-FU and radiotherapy in the trial reported by Keane et al from Canada. 17 In the radiotherapy-alone arm, a dose of 50 Gy was delivered in 20 t}actions over 28 days. In the combined treatment arm, two courses of radiotherapy delivering 25 Gy in 10 fractions over 14 days each was split by a 4-week rest period. There was no significant difference in either local or regional relapse-free rates, overall survival, or toxicity between the treatment groups. It is possible that any potential benefit of the chemotherapy may have been obscured by tumor repopulation during the 4-week split. The other three trials combining 5-FU and cis-
platin with radiotherapy have been published only in abstracts at the time of this article. 12,15,21 One trial used standard fractionated radiotherapy. 2t One trial from Germany used split-course accelerated fractionated radiotherapy. 12 The trial from Duke University used hyperfractionated radiotherapy.15 All three trials reported a significant improvement in diseasefree survival in the combined treatment group, although only the trial using split-course accelerated fractionated radiotherapy reported a significantly better overall smwival. 12Acute toxicity, however, was also greater in the combined treatment group. In the trial from the Cleveland Clinic, the incidence of grade HI-IV cutaneous reaction was 10% versus 44%, the incidence raucositis was 26% versus 84%, and the incidence of tube feeding was 30% versus 58% in the radiotherapy alone and the combined treatment groups. 21In the trial from Duke University, confluent mucositis developed in 72% of the patients treated with hyperfractionated radiotherapy alone and in 98% of the patients who received 5-FU and cisplatin in addition to hyperfractionated radiotherapy. Tube feeding was required in 28% of the radiotherapy alone group and 45% of the combined treatment group. 15 Three patients in the radiotherapy alone group and five patients in the combined treatment group developed severe complications (soft tissue necrosis or osteonecrosis).
Alternating or Sequential 5-FU and Radiation Therapy Another approach to circumvent tile problem of increased acute toxicity, specifically mucositis, when 5-FU-containing multidrug chemotherapy is used with concurrent radiotherapy is the use of sequential or alternating chemotherapy and radiotherapy. There have been at least four randomized trials that have compared sequential 5-FU-containing chemotherapy and radiotherapy with simultaneous or alternating chemotherapy and split-course radiotherapy in advanced head and neck cancer. ~4,23-25 As shown in Table 2, the complete response rate was better with the concurrent or alternating chemotherapy and radiotherapy regimen than with the sequential regimen. One trial showed a significantly improved disease-free survival with the concurrent or alternating chemotherapy and radiotherapy regimen compared with the sequential regimen. 14 There was no significant improvement, however, in overall survival. There was no radiotherapy alone control arm in these trials. As a matter of fact, in the trial by the
Radiotherapy and 5-FU in Head and Neck Cancer
277
Table 2. Randomized Trials of Sequential Versus Concurrent or Alternating Chemotherapy with 5-FU Plus Other Drugs and Radiotherapy fbr Advanced Head and Neck Cancer
Author (year)
No. of Evaluable Patients
SECOG (1986) 23
267
Adelstein (1990) 14
48
Drugs
S
% CR
%Local + Regional Control (years)
CO or A
S
CO orA
N/A
N/A
33* (4) 34* (4) 16" (4)
71
43 (3)
VCR, Bleo, MTX, N/A N/A 5-FU (B) CP, 5-FU (C) 32 67
42
(t' = .002)
Taylor (1994) 24 Pinnaro (1994) 25
214 93
CP, 5-1?U (C) CP, 5-FUJ" (C)
50 52 47 41
% Survival (years) S
CO or A
68 (3)
%DES (years) S
39 (3)
(P = .04)
45 (3) 37
56 (3) 61
30* (3) 38* (3) 31" (3) 11 (5) 16 (5) 16 (5)
CO orA
25* (4) (t' = .o7) 6o (3) (P = .03) 42* (3) 2o (5)
*Estimated from survivalcurvcs. tCP and 5-FU for sequential, CP onlyfor concurrent chemotherapy and radiotherapy. Abbreviations: CR, complete remission;DFS, disease-freesurvival;VCR, vincristine; Bleo, bleomycin;MTX, methotrexate; CP, cisplatin; B, bolus infusion; C, continuous infusion; N/A, not available;S, sequential; CO, concurrent; A, alternating. Southeast Cooperative Oncology Group from England (SECOG), the results of the synchronous chemotherapy and radiotherapy were no better than historical data with radiotherapy alone. 2~As a result, a third a r m of radiotherapy alone was added to the trial. Thus far, there has been only one randomized trial that has compared alternating chemotherapy and radiotherapy with radiotherapy alone. 26 In this trial reported by Merlano et al, 157 patients with advanced unresectablc squamous cell carcinoma of the head and neck were randomized to receive four courses ofcisplatin (20 mg/m 2) and 5-FU (200 mg/m 2) daily for 5 consecutive days during weeks 1, 4, 7, and 10 plus three courses of radiotherapy (20 Gy/10 fractions/2 weeks) during weeks 2-3, 5-6, and 8-9 or radiotherapy alone with 70 Gy/35 fractions/7 weeks. Updated results showed a significantly better complete response rate (43% v 22%, P = .037), localregional control (28.8% v 7.8%, P = .028), 5-year local-regional relapse-free survival (64% v 32%, P = .038), progression-free survival (21% v 9%, _P .008), and overall survival (24% v 10%,P = .01) in the alternating chemotherapy and radiotherapy group, although there was no significant difference in the incidence of distant metastases (7.5% v 6.5%) and toxicity (19% v 18% grade III-IV mucositis).27 Several aspects of this trial may be problematic. First, early closure of the trial limits the value of the statistical significance of the observed differences between the two treatment groups. Second, the difference in survival was largely attributed to the poor localregional control in the radiotherapy alone group. The complete response rate was 22%, the local-regional control rate was 7.8%, and the 5-year overall survival was 10% in the radiotherapy alone group. 26,27 The
poor local-regional control rate with radiotherapy alone could have been because of the suboptimal delivery of radiotherapy. 26 Although the protocol prescribed a dose of 70 Gy in 7 weeks in the radiotherapy alone group, the median dose actually delivered was only 62 Gy. Treatment delays were also more frequent in the radiotherapy alone group. T r e a t m e n t delays of 1, 2, and more than 2 weeks occurred in 32%, 11%, and 14% of the patients. It has been shown that treatment interruptions have an adverse effect on the outcome of patients irradiated for head and neck cancer. 28 In view of these deficiencies in treatment delivery and the poor results in the radiotherapy alone arm, the results of this trial concerning the relative efficacy of alternating chemotherapy and radiotherapy versus radiotherapy alone should be regarded as inconclusive and in need of further confirmation.
Induction and Adjuvant 5-FU and Radiation Therapy Because of the high response rates to continuous 5-FU infusion and cisplatin chemotherapy, this regimen has frequently been used as induction or neoadjuvant therapy before radiotherapy with or without surgery or as adjuvant therapy after local-regional therapy for advanced head and neck cancer. In addition to eisplatin, 5-FU has also been combined with carboplatin or other drugs in an induction or adjuvant setting. The response rates to these regimens, however, are not superior to the 5-FU and cisplatin combinations. Tables 3 and 4 summarize the results of randomized trials of induction and adjuvant 5-FU-containing chemotherapy and radio-
278
Karen K. Fu
therapy with or without surgery for head and neck cancer.
Induction Chemotherapy 5-FU has been used in an induction chemotherapy regimen in at least 5 randomized trials of operable ~9-34and 12 trials of operable and inoperable head and neck cancer. 3546 As shown in Table 3, response rates to induction chemotherapy ranged from 21% to 98%, and complete response rates were in the range of 0% to 54% depending on the drug regimen and the number of cycles of drugs administered. Despite high response rates to induction chemotherapy, there was n o significant improvement in local-regional control or survival between the standard treatment groups and the induction chemotherapy groups.
The trial reported by Paccagnella et al included patients with operable or inoperable disease. 43 Although distant metastases were reduced in the induction chemotherapy group, there was no difference in local-regional failure, disease-fi'ee survival, or overall survival. Subset analysis showed improved local control and overall survival with induction chemotherapy for patients who had inoperable disease but not for those who had operable disease. The overall 2-year smvival was poor, however, in both treatment arms for patients with inoperable disease (10% in the control arm and 24% in the induction chemotherapy arm). The results of the combined treatment arm in this trial are no better than those with radiotherapy alone reported in the literature. One cannot conclude that induction chemotherapy improves the
Table 3. Randomized Trials of Induction Chemotherapywith 5-FU With or Without Other Drugs and Radiotherapy With or Without Surgery for Advanced Head and Neck Cancer
Author (year) OperableDisease VALCS (1991)2'~ Wolf (1996)3o Depondt (I993) 31
Di Blasio (1994)32
No. of Evaluable Patients
Drug,s')
% Survival (years)
%DFS (years)
Control
CT
Control
CT
43* (5)
46* (5)
64* (5) 51. (5)
56 (4)
30 (4)
33 (4) N/A
332
CP, 5-FU (C)
300
CBP, 5-FU (C)
85 (31), 92 98 (49)$ 63 (31) 75 (4)
CP, 5-FU (C)
69 (37)
N/A
CP, 5-FU (C) CBP, 5-FU (C)
86 (54) N/A
73 N/A
71 N/A
35 (5) 53
43w (4) N/A (P = .04) 30 (5) 27 (5) 72 N/A
71 (0) N/A
23 N/A
25 N/A
N/A 55 (2)
N/A 22 (2)
N/A N/A
N/A N/A
21 (0)
N/A
N/A
77 (1)
58 (1)
N/A
N/A
68 (5)
53 (2)
35 (2)
43 (2)
31 (2)
N/A
N/A
85 (19) 68 (46) 49 (7)
70 (2) 67 51. (5)
56 (2) 73 50* (5)
70 (2) N/A 36* (5)
56 (2) N/A 32* (5)
N/A 6l (1) N/A
N/A 73 (1) N/A
70 (22) 35* (3) 80 (31) 29.(3)
38* (3) 28* (3)
48* (3) 20 (3)
40* (3) 29(3)
N/A 33 (3)
N/A 37(3)
80 (32) 81 (19) 57 (19)
N/A 84 64 (5)
53 (2) 81 (2) 45w (5)
60 (2) 80 (2) 55w (5)
N/A 72 (2) N/A
N/A 68 (2) N/A
69
Lefebw'e (1996)33 194 Volling (1996)34 97 Operable and~orInoperableDisease von Essen (1968)35 50 Stell (1983)36 86
Toohill (1987)39 Martin (1990)4~ Mazeron (1992)41
60 75 116
Jaulerry (1992)42 Paccagnella
108 237
5-FU (B) VCR, Bleo, H, MTX, 5-Fu (B) VBL, Bleo, CTX, MTX, 5-FU (B) Bleo, M~I~, 5-vu (B), C'~X CP, 5-FU (C) CP, 5-FU (C) Bleo, MTX, 5-vu (B), c P CP, 5-FU (C), Vind CP, 5-FU (C)
280 77 166
CP, 5-FU (C) CP, 5-FU (C) CP, 5-FU (C)
Stol~jk (1985)37
68
Kun (1986)3a
83
(1994) 43
Dalley (1995)44 Chan (1995)45 Domenge (1996)46
%Local +% Response Regional to CT Control(years) (% CR) Control CT
N/A 85 75 (5)
80
65 (4) 46 (4) (P = .04) N/A 74w (4)
25 (5) N/A
*Estimated from survivalcurves. tArter two cyclesof inductionchemotherapy. SAfter three cyclesof inductionchemotherapy. w survival. Abbreviations: CT, chemotherapy;ca, complete response; DFS, disease-free survival; CP, cisplatin; CBP, carboplatin;VCR, vincristine; Bleo, bleomycin;H, bydrocortisone;MTX, methotrexate; VBL,vinblastine; CTX, cytoxan(cyclophosphamide);C, continuousinfusion;B, bolus infusion;N/A,not available.
Radiotherapy and 5-FU in Head and Neck Cancer
supAval of patients with inoperable head and neck cancer based on this trial. Although induction chemotherapy does not improve survival, induction chemotherapy with Continuous 5-FU infusion and cisplatin may be useful in the selection of patients for organ preservation with subsequent radiotherapyg, S~ The trial by the Department of Veterans Affairs Laryngeal Cancer Study group (VALCS) included patients with operable stage III or IV laryngeal cancer? 9,3~ The European Organization for Research and Treatment of Cancer (EORTC) trial included patients with operable stage T2-4, N0-2b squamous cell carcinoma of the piriform sinus and awepiglottic fold. ~3 The study design was similar in both trials. Eligible patients were randomized to receive surgery followed by postoperative radiotherapy or induction chemotherapy with cisplatin and 5-FU infusion. In the VALCS trial, after two cycles of induction chemotherapy, the partial or complete responders received an additional cycle of chemotherapy followed by definitive radiotherapy. Those with residual or recurrent disease after completion of radiotherapy underwent surgery for salvage. Patients who showed no response or progression after two cycles of induction chemotherapy went on to salvage surgery and postoperative radiotherapy. The EORTC trial differed from the VALCS trial in that only patients who had a complete response in the primary site after three cycles of induction chemotherapy were treated with radiotherapy; the others underwent surgery. Both trials showed no significant difference in overall survival between the induction chemotherapy and standard treatment arms. Disease-free survival was lower in the induction chemotherapy arm in the VALCS trial but not the EORTC trial. Distant metastasis was significantly reduced in the EORTC trial. In the VALCS trial, although distant metastasis as a tirst site of relapse was reduced in the induction chemotherapy arm, the overall incidence of distant metastasis was similar in both arms. ~~The proportion of patients in the induction chemotherapy arm who underwent laryngectomy because of lack of response or for salvage after radiotherapy was 38% at 4 years in the VALCS trial and 43% in the EORTC trials. In the VALCS trial, 66% of the patients who were alive at 4 years had a functioning larynx, although this represents only 31% of the 166 patients in the induction chemotherapy arm. In the EORTC trial, for the 100 patients randomized to the induction chemotherapy arm, the estimated survival with a functioning larynx was 28% at 3 years and 17% at 5 years. When only
279
deaths from local disease progression were considered, the estimated survival with a functioning larynx was 42% at 3 years and 35% at 5 years. No increase in morbidity or complications of surgery or radiotherapy following the induction chemotherapy was observed in either trial. The results of these two trials suggest that induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in chemotherapy responders is an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hy-popharynx who desire organ function preservation. Induction chemotherapy can be toxic and costly. It is not known whether similar or better results can be achieved with concurrent chemotherapy and radiotherapy or radiotherapy alone. To address this issue, the Head and Neck Intergroup is conducting a phase III trial in which patients with operable T2, T3, or early T4 squamous cell carcinoma of the glottis or supraglottic larynx are randomized to receive (1) induction chemotherapy with 5-FU infusion and cisplatin followed by radiotherapy in the responders or salvage surgery and radiotherapy in the nonresponders, (2) radiotherapy and concurrent cisplatin chemotherapy, or (3) radiotherapy a l o n e J The induction chemotherapy regimen is the same as that in the VALCS trial. In the concurrent radiotherapy and chemotherapy arm, cisplatin at a dose of 100 mg/m 2 is given every 3 weeks during radiotherapy. The radiotherapy dose schedule is the same in all three arms: 70 Gy in 35 fractions over 7 weeks. This trial is ongoing and is targeted to accrue 546 patients. In addition to survival with preservation of the larynx, quality of life will also be prospectively assessed as an end point of treatment outcome. Results of this trial should determine the relative etticacy of induction versus concurrent chemotherapy and radiotherapy versus radiotherapy alone for larynx preservation in patients with advanced operable carcinoma of the larynx.
AdjuvantChemotherapy The use of adjuvant chemotherapy with 5-FU and eisplatin or other drugs after standard therapy has been evaluated in at least four randomized trials (Table 4). 15,38,48,49Except for the recently closed Head and Neck Intergroup trial (INT 0099) for nasopharyngeal carcinoma, none of these trials showed a significant improvement in overall survival. In this trial, however, patients in the combined treatment group also received concurrent cisplatin during radiotherapy. 49 The relative contributions of adjuvant
280
Karen K. Fu
Table 4. Randomized Trials of Adjuvant Chemotherapy With 5-FU Plus Other Drugs for Advanced Head and Neck Cancer No. of Author (year)
% Survival (years)
%DFS (years)
Evaluable Patients
Drug(s)
Control
CT
Control
CT
Laramore (1992)4~ A1-Sarraf (1996)49
83 448 147
Bleo, CTX, MTX, 5-FU (B) CP, 5-FU (C) CP, 5-FU (C)
43 (2) 44 (4) 47 (3)
N/A 38 (4) 24 (3)
Brizel (1996)15
110
CP, 5-FU (C)
28 (3)
31 (2) 48 (4) 78 (3) (P = .002) 51 (3) (P = .06)
N/A 46 (4) 69 (3) (P < .001) 58 (3) (P = .02)
Kun (1986)3a
28 (3)
Abbreviations:CT, chemotherapy;DFS, disease-freesuIwival;Bteo,bleomycin;CTX, cytoxan (cyclophosphamide);MTX, methotrexate; CP, cisplatin;B, bolusinfusion;C, continuousinfusion;N/A,not available. versus concurrent chemotherapy to the improved survival in the combined treatment group are unclear. One of the major limitations of adjuvant chemotherapy trials has been poor patient compliance. Patient refusal of adjuvant chemotherapy after intensive local-regional treatment has been common. In the Intergroup trial for nasopharyngeal carcinoma, only 55% of the patients randomized to the chemotherapy arm completed three courses of adjuvant 5-FU and cisplatin. Results of these studies suggest that it is unlikely that adjuvant chemotherapy with 5-FU or other drugs would have a significant impact on the prognosis of advanced head and neck cancer. Although induction or adjuvant chemotherapy with 5-FU and cisplatin has not resulted in improved survival, a decreased incidence of distant metastasis has been observed in several trials. 91,3S,43,48,49As localregional control further increases with biochemical modulation of 5-FU or radiation dose intensification, reduction of distant metastasis by systemic therapy may become more important in the overall management of advanced head and neck cancer patients. Conclusions
and Comments
Response to 5-FU depends on schedule of administration. Higher response rates are seen when it is given by continuous infusion than when by bolus injection. Enhanced radiation effect is also most likely to occur with continuous infusion than with bolus injection. 5-FU alone or combined with other drugs appears to enhance the effects of radiation when given concurrently or in an alternating schedule with radiotherapy in the treatment of advanced head and neck cancer. Improved local-regional control, disease-free survival, and overall survival have been reported in randomized trials of concurrent or alternating 5-FUcontaining chemotherapy and radiotherapy. It is not
possible, however, to determine whether the enhanced effect is supraadditive or synergistic, additive, or subadditive. Acute toxicity, primarily mucositis, is also commonly increased with concurrent radiotherapy and 5-FU. No benefit is seen when 5-FU is given alone or in combination with other agents as induction therapy before or adjuvant therapy after local-regional therapy. Although induction chemotherapy with 5-FU infusion and cisplatin may be useful in the selection of patients with advanced resectable lmTngeal or hypophmTngeal carcinoma for organ function preservation with subsequent radiotherapy, induction or adjuvant chemotherapy with 5-FU and cisplatin may also decrease or delay the occurrence of distant metastasis. 5-FU has been most ti:equently combined with cisplatin and radiotherapy in recent clinical trials in head and neck cancer. Other agents such as leucovorin, hydroxyurea, o~-interferon, and paclitaxel have also been combined with 5-FU in attempt to increase its efficacy through biochemical modulation when combined with radiotherapy in the treatment of advanced head and neck cancer. 5~ Although the results of phase I/II studies suggest an enhanced tumor response, acute toxicity is also markedly increased, necessitating a split-course approach or the use of granulocyte colony-stimulating factor. The relative efficacy of these more intense combined chemotherapy and radiotherapy regimens in comparison with radiotherapy alone or other combined modality regimens needs further evaluation in phase III trials. At present, the mechanism of interaction between 5-FU and radiation remains poorly understood. Studies on the molecular mechanisms of the effects of 5-FU and radiation on tumors and normal tissues are needed to provide a rational basis for the optimal integration of 5-FU and radiation in a combined modality therapy for solid tumors, including head
Radiotherapy and 5-FU in Head and Neck Cancer
and neck cancer. Other treatment modifiers that can reduce the severity of normal tissue toxicity, in particular, mucositis, are also needed to improve the therapeutic ratio.
References 1. Bagshaw MA: Possible role of pot entiators in radiation therapy. AJR A m J Roentgeno185:822-833, 1961 2. Heidelberger C, Griesbach L, Montag BJ, et al: Studies on fluorinated pyrimidines: II. Effects of transplanted tumors. Cancer Res 18:305-317, 1958 3. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining sensitization of h u m a n tumor cells in vitro to combined 5-fluorouracil or ftorafur and x rays. Int J Radiat Oncoi Biol Phys 8:1923-1933, 1982 4. Fu KK, Rayner PA, Lam KN: Modification of the effects of continuous low dose rate irradiation by concurrent chemotherapy infusion. IntJ Radiat Oncol Biol Phys 10:1473-1478, 1984 5. Maase HV-D: Interactions of radiation and 5-fluorouracil, cyclophosphamide of methotrexate in intestinal ciTpt cells. Int J Radiat Oncol Biol Phys 10:77-86, 1984 6. Vietti T, Eggerding F, Valeriote F: Combined effect of x radiation and 5-fluorouracil on smwival of transplanted leukemic cells.J Natl Cancer Inst 47:865-870, 1971 7. Weinberg MJ, RauthAM: 5-Fluorouracil infusions and fractionated doses of radiation: Studies with a murine squamous cell carcinoma. IntJ Radiat Oncol Biol Phys 13:1691-1699, 1987 8. Pu AT, Robertson JM, Lawrence TS: Current status of" radiation sensitization by tluoropyrimidines. Oncology (Huntingt) 9:707-714, 1995 9. Goldsmith MA, Carter SK: The integration of chemotherapy into a combined modality approach to cancer therapy. Cancer Treat Rev 2:137-158, 1975 10. Kish JA, Ensley JF, Jacobs J, et al: A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer 56:2740-2744, 1985 11. Lokich~J, AhlgrenJD, GulloJJ, et al: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program Study.J Clin Oncoi 7:425-432, 1989 12. YVustrow TPU, Wendt TG, Grabenbauer G, et al: Randomized phase III study for simultaneous radiopolychemotherapy in head and neck cancer, 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 236) 13. Shigematsu Y, Sakai S, Fuchihata H: Recent trials in the treatment of maxillary sinus carcinoma, with special reference to the chemical potentiation of radiation therapy. Acta OtolatTngol 71:63-70, 1971 14. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell bead and neck cancer. Cancer 65:1685-1691, 1990 15. Brizel D, Albers M, Fisher S, et al: A phase III trial of hyperfractionated irradiation -+ concurrent chemotherapy for locally advanced carcinoma of the head and neck: Superiority of combined modality treatment, 4th International Confer-
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
281
ence on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 237) Browman GP, Cripps C, Hodson DI, et al: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer.J Clin Oncol 12:2648-2653, 1994 Keane TJ, Cmnmings BJ, O'Sullivan B, et ai: A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment tbr advanced laryngeal and hypopharyngeal squamous carcinoma. IntJ Radiat Oncol Biol Phys 25:613-618, 1993 Sanchiz F, Milla A, Torner J, et ai: Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 19:1347-1350, 1990 Weissler MC, Melin S, Sailer SL, et al: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118:806-810, 1992 Lo TC, Wiley ALJr, Ansfield FJ, et al: Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharymx: a randomized study. A J R A m J Roentgenot 126:229-235, 1976 Adetstein DJ, SaxtonJP, Lavertu P, et al: Concurrent radiation and chemotherapy (CT) versus (vs) radiotherapy (RT) alone in resectable stage III and IV squamous cell head and neck cancer (SCHNC): A phase KI randomized trial. Proc Am Soc Ciin Oncol 15:26, 1996 (abstr 2015) Scanlon KY, Newman EM, Lu Yea: Biochemical basis for cisplatin and 5-fluorouracil synergism in h m n a n ovarian carcinoma cells. Proc Natl Acad Sci USA 83:8923-8925, 1986 Southeast Cooperative OncologTGroup (SECOG):Arandomized trial of combined multidrug chemotherapy and radiotherapy in advanced squamous celt carcinoma of the head and neck: An interim report from the SECOG participants. South-East Co-operative Oncology Group. Eur J Surg Oncol 12:289-295, 1986 Taylor SG, Murthy A, Vannetzel JM, et al: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer.J Clin Oncol 12:385-395, 1994. Pinnaro P, Cercato MC, Giannarelli D, et al: A randomized phase II study comparing sequential versus simultaneous chemo-radiotherapy in patients with unresectable locally advanced squamous cell cancer of the head and neck. Ann Oncol 5:513-519, 1994 Merlano M, Vitate V, Rosso R, et ah Treatment of advanced squamous cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N EnglJ Med 327:11151121, 1992 Merlano M, Benasso M, Corvo R, et al: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectahle squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583-589, 1996 Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. IntJ Radiat Oncol Biol Phys 23:457-467, 1992 Department of Veterans Afl~airs Laryngeal Cancer Study Group (VALCS): Induction chemotherapy plus radiation com-
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pared with surgery plus radiation in patients with advanced laryngeal cancer. N EnglJ Med 324:1685-1690, 1991 30. Wolf GT, Hong WK, Fisher SG: Neoadjuvant chemotherapy for organ preservation: Current status, in ShahJP, JohnsonJT (eds): 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, pp 89-97 31. Depondt J, Gehanno P, Martin M, et al: Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer. Oncology 50:23-27, 1993 32. Di Blasio B, Barieri W, Bozzetti A, et ali A prospective randomized trial in resectable head and neck carcinoma loco-regional treatment with and without neoadjuvant chemotherapy. Proc Am Soc Clin Oncol 13:286, 1994 (abstr 899) 33. Lefebw'eJL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial: EORTC Head and Neck Cancer Cooperative Group [see comments].J Nati Cancer Inst 88i890-899, 1996 34. Volling P, Schroeder M, Eckel H, et ah Results of a prospective randomized trial with induction chemotherapy in cancer of the oral cavity and the pharynx, 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, TorontO, Canada, 179, 1996, (abstr 484) 35. von Essen CF, Joseph LBM, Simon GT, et ah Sequential chemotherapy and radiation therapy of buccal mucosa carcinoma in South India. AJRAmJ Roentgenol 102:530-540, 1968 36. Stell PM, DalbyJE, Strickland P, et al: Sequential chemotherapy and radiotherapy in advanced head and neck cancer. Clin Radio134:463-467, 1983 37. Stolwijk C, Wagener DJ, Van den Broek P, et al: Randomized neo-adjuvant chemotherapy trial for advanced head and neck cancer. NethJ Med 28:347-351, 1985 38. Kun LE, Toohill RJ, Holoye PY, et al: A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract. Int J Radiat Oncol Biol Phys 12:173-178, 1986 39. Toohill RJ, Anderson T, Byhardt RW, et ah Cisplatin and fiuorouracil as neoadjuvant therapy in head and neck cancer: A preliminary report. Arch Otolaryngol Head Neck Surg 113:758-761, 1987 40. Martin M, Hazan A, Vergnes L, et al: Randomized study of 5 fluorouracil and cis platin as neoadjuvant therapy in head and neck cancer: A preliminary report. Int J Radiat Oncol Biol Phys 19:973-975, 1990 41. MazeronJ-J, Martin M, Brun B, et al: Induction chemotherapy in head and neck cancer. Head Neck 14:85-91, 1992 42. Jaulerry C, RodriguezJ, BruNn F, et al: Induction chemotherapy in advanced head and neck tumors: Results of two
randomized trials. Int J Radiat Oncol Biol Phys 23:483-489, 1992 43: Paccagnelta A, Orlando& Marchiori C, et al: Phase HI trial of initial chemotherapy in stage Ill or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo.J Natl Cancer Inst 86:265-272, 1994 44. DalleyD, Beller E, AroneyR, et ah Thevalue of chemotherapy (CT) prior to definitive local therapy (DLT) in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck (HN). Proc Am Soc Clin Oncol 14:297, 1995 (abstr 856) 45; Chan AT, Teo PM, Leung TW, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. IntJ Radiat Oncol Biol Phys 33:569-577, 1995 46. Domenge C, Coche-Dequeant B, Wibault P, et al: Randomized trial of neoadjuvant chemotherapy before radiotherapy in oropharyngeal carcinoma, 4th International Conference on Head and Neck Cancer, Tile Society of Head and Neck Suicgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 164) 47. Fu KK, Cooper JS, Marciat VA, et al: Evolution of the Radiation Therapy OncoIogy Group clinical trials tot head and neck cancer. IntJ Radiat Oncol Biol Phys 35:425-438, 1996 48. Laramore GE, Scott CB, A1-SarrafM, et ah Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 23:705-713, 1992 49. A1-Sarraf M, LeBlanc M, Shanker G, et al: Chemo-radiotherapy vs. radiotherapy in patients with locally advanced nasopharyngeal cancer: Phase III randomized Intergroup study (0099) (SWOG 8892, RTOG 8817, ECOG 2388).J Clin Onco11997 (submitted) 50. Vokes EE, Haraf DJ, Panje WR, et ah Hydroxyurea with concomitant radiotherapy for locally advanced head and neck cancer. Semin Oncot 19:53-58, 1992 51. Vokes EE, Ratain MJ, Mick R, et al: Cisplatin, fluorouracil, and leucovorin augmented by interferon alfa-2b in head and neck cancer: A clinical and pharmacologic analysis [published erratum appears inJ Clin Oncol 1994 Mar;12(3):643].J Clin Oncol 11:360-368, 1993 52. Vokes EE, Stupp R, Haraf D, et al: Hydroxyurea with continuous infusion paclitaxel, 5-fluorouracil, and concomitant radiotherapy for poor-prognosis head and neck cancer. Semin Onco122:47-52, 1995 53. Stupp R, Vokes EE: 5-fluorouracil plus radiation for head and neck cancer.J Infus Chemother 5:55-60, 1995 54. McGinn CJ, Shewach DS, Lawrence TS: Radiosensitizing nucleosides.J Natl Cancer Inst 88:1193-1203, 1996
before one can accept this as a standard of practice. Induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in the chemotherapy responders is an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hypopharynx who wish to preserve organ function. Induction or adjuvant chemotherapy with 5-FU infusion and cisplatin may also decrease or delay the occurrence of distant metastasis. Induction chemotherapy, however, has not been shown to improve local-regional control or overall survival9 Further clinical trials combining 5-FU and its biochemical modulators using innovative radiation and drug dose schedules and other treatment modifiers are needed to improve the therapeutic ratio.
hortly after its discovery, 5-Fluorouracil (5-FU) k_3 was shown to increase the effects ot radiation., Subsequent in vitro and in vivo laboratory studies showed enhancement of radiation effects by 5-FU on tumors as well as normal tissuesY The combined effects can be supraadditive, additive, or subadditive, depending on the cell line, tumor, and normal tissue type in addition to the timing of drug administration in relation to radiation and drug and radiation dosage. The mechanism of 5-FU and radiation interaction remains poorly understood. Possible mechanisms include (1) perturbations of nucleotide pool through inhibition of thymidylate synthase, thus inhibiting repair of sublethal DNA damage; (2) induction of cell cycle redistribution with increase of cells in a sensitive cell cycle phase; and (3) incorporation offluorodeoxyuridine triphosphate into DNA. 8 The combined effects of 5-FU and radiation may vatywith the time and schedule of drug and radiation administration. Although in vitro studies by Byfield et al a suggested maximal enhancement of cytotoxicity with prolonged, continuous postradiation exposure to 5-FU, in vivo studies by Weinberg and Rauth 7 showed an additive tumor response independent of
the mode (bolus v infusion), schedule, and timing of drug administration. A detailed description of these interactions can be tbund in the article by Lawrence et al in this issue of Seminars in Radiation Oncology. As a single agent, 5-FU has an overall response rate of 15% in advanced head and neck cancer. 9 Clinical studies suggest superiority of a 4- to 5-day continuous-infusion schedule compared with bolus infusion with 5-FU alone in head and neck cancer and colon cancer.l~ 5-FU has been used either as a single agent or in a multidrug regimen, most ti'equently with cisplatin, when combined with radiotherapy with or without surgery in the treatment of advanced or recurrent head and neck cancer. There have been numerous nonrandomized as well as randomized clinical trials of radiotherapy and 5-FU for head and neck cancer. This article reviews the results of randomized trials of 5-FU combined with radiotherapy or surgery (or both) in the treatment of advanced operable and inoperable head and neck cancer. This article describes the various approaches used, including concurrent therapy, alternating or sequential therapy, and induction and adjuvant therapy.
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From the DepartmentofRadiation Oncology,Universityof CaliJbraia, San Francisco,CA. Address reprintrequeststo KarenK. Fu, MD, DepartmentofRadiation Oncology,UniversityofCalifornia,San Francisco,505ParnassusAve, L-08, San Francisco,CA 94143-0226. Copyright9 1997by W.B. SaundersCompany 1053-4296/97/0704-000155.00/0
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Copyright9 1997 by W.B. Saunders Company
Concurrent Radiation Therapy and 5-FU There have been at least nine randomized trials investigating concurrent 5-FU and radiotherapy for advanced head and neck cancer. 19-2~The results are summarized in Table 1.5-FU was used as a single agent in four of the trials, 12,13,16,18,2~combined with
Seminars in Radiation Oncvlogy, Vol 7, No 4 (October),199Z'pp 274-282
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Radiotherapy and 5-FU in Head and Neck Cancer
Table 1. Randomized Trials of Concurrent 5-FU With or Without Other Drugs and Radiotherapy for Advanced Head and Neck Cancer
Author(year)
Shigematsu (1971) Is Lo (1978)20
No. of Evaluable Patients
%Local +_ Regional Control (years)
% CR
Drug(s) Control CT Control
CT
% Survival (years) Control
%DFS (years)
CT
Control
CT
63
5-FU (C)
N/A N/A 29 (2)
38 (2)
59 (2)
56 (2)
N/A
N/A
136
5-FU(B)
32
49 (2)
13" (5)
32* (5)
N/A
N/A
44
18 (2)
(P < .05) Sanchiz (1990) ~a
577
5-FU(B)
68
96
N/A
N/A
Weissler (1992) 19
58
5-FU(C) CP
20?
53?
N/A
N/A
Keane (1993) 17
209
Browman (1994) ~6 Adelstein (1996)2~
175 100
Wustrow (1996) 12
270
Brize1(1996) 15
110
5-FU(C) Mito-C 5-FU(C) 5-FU(C) CP 5-FU(C) CP 5-FU(C) CP
(P < .05) 32* (5)
62* (5) 22* (5) 57* (5) (P < .oo~) (P < .ool) Resectable disease: Resectable disease:
64* (2)
52* (2)
N/A
N/A 39* (5)
56 N/A
68 N/A
N/A N/A
N/A N/A
38* (3) 58 (3)
52* (3) 61 (3)
N/A N/A
N/A
N/A
24 (3)
N/A N/A 31 (3)
69 (3)
28 (3)
42* (5)
58* (2)
27* (3) 52 (3)
36* (3) 67 (3)
48 (3)
17 (3)
36 (3)
51 (3)
28 (3)
58 (3)
(n.s.)
(P = .002)
60* (2)
Unresectable disease: Unresectable disease: 10" (2) 40* (2) 0* (2) 42* (2) (p = .o13) (t' = .02) 35* (5) 34* (5) N/A N/A
(t' = .06)
(P = .02)
(e = .02)
*Estimated from survivalcurves. ]'In unresectable patients. Abbreviations:CR, complete remission; CT, chemotherapy;DFS, disease-free survival;CP, cisplatin; Mito-C, mitomycinC; C, continuous infusion; B, bolus infusion;N/A,not available. cisplatin in four trials, 12,15,19,2~ and combined with mitomycin C in one trial. 17With the exception of two trials, 18,2~ 5-FU was administered as a continuous infusion. Radiotherapy was delivered using standard fi'actionation in five trials 13,14,16,18,2~and split-course standard fractionation in one trial.17 Altered fractionation radiotherapy was used in three of the trials, including split-course hyperfractionation in one trial, 19 split-course accelerated fractionation in one trial, 12 and hyperfractionation in another trial. 15 In the trial from Duke University, 5-FU and cisplatin were administered as an adjuvant therapy after completion of radiotherapy as well as concurrent with hypeffractionated radiotherapy. 15 Improved local-regional control was reported in two trials. 15,~~Significantly improved disease-free survival 12,15,18,19,21 and overall survival 12,15,18-2~were shown in five trials.
Single-Agent 5-FU Among the four trials in which 5-FU was used as a single agent, 5-FU was infused intraarterially during radiotherapy for maxillary sinus carcinomas in the randomized study from Japan. 13The recurrence-free rate of patients who received 5-FU was significantly
better at 1 year but not at 2 years; the 2-year crude suFcival was similar tbr the study and control groups. The study from the University of Wisconsin included patients with oropharyngeal as well as oral cavity cancers. 2~Although the 2-year no evidence of disease (NED) rate was significantly better in the combined treatment group, the difference in 5-year survival was statistically significant in patients with oral cavity cancer but not oropharyngeal cancer (13% v 32% for the entire group, 13% v 40% for oral cavity cancer, 15% v 25% for oropharyngeal cancer). The incidence of distant metastasis and second malignancies was similar, however, for both the radiotherapy alone and the combined treatment groups. 5-FU also increased the acute and late normal tissue effects of radiation. Major complications, such as soft tissue or bone necrosis and fistula formation, were seen only in the combined treatment group. This study suggests that the primary site may be important in the outcome of combined 5-FU and radiotherapy. In the trial from Spain, standard fractionated radiotherapy was compared with hyperfractionated radiotherapy and standard fractionated radiotherapy
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Karen K. Fu
plus concurrent 5-FU. 1~ Survival was significantly improved in both the hyperii-actionation and the concurrent 5-FU groups compared with the standard fractionated radiotherapy alone group, but there was no significant difference between the hyperfractionation and the concurrent 5-FU groups. The study reported by Browman et al was a placebo-controlled trial of concurrent 5-FU infusion and standard fractionated radiotherapy. 16 Although there was a trend for improved progression-free and overall survival in the combined treatment group, acute toxicity, including severe stomatitis, skin reaction, and weight loss was also significantly greater.
5-FU in a Two-Drug Regimen More recently, 5-FU has been combined with other chemotherapeutic agents, most frequently cisplatin, in the treatment of head and neck cancer. In vitro studies on human ovarian carcinoma cells showed that cisplatin increased the intracellular reduced folates necessary for the binding of 5-fluorodeoxyuridine monophosphate, a metabolite of 5-FU, to thymidylate synthase, thus resulting in an enhanced cytotoxicity when combined with 5-FU. 92 Because of increased mucositis with concurrent chemotherapy and radiotherapy, especially when another agent is used in addition to 5-FU, a split-course approach has been used in three of the trials of 5-FU-containing two-drug chemotherapy and radiotherapy. 12,17,19The trial from the University of North Carolina included patients with resectable as well as unresectable disease. 19A survival advantage for cisplatin and 5-FU with concurrent radiotherapy was seen only in patients with unresectable disease. The number of patients was small, however; 32 patients had unresectable and 26 had resectable disease. Among patients with unresectable disease, three patients randomized to the combined treatment arm subsequently underwent surgery and were successfully salvaged. Mitomycin C was combined with 5-FU and radiotherapy in the trial reported by Keane et al from Canada. 17 In the radiotherapy-alone arm, a dose of 50 Gy was delivered in 20 t}actions over 28 days. In the combined treatment arm, two courses of radiotherapy delivering 25 Gy in 10 fractions over 14 days each was split by a 4-week rest period. There was no significant difference in either local or regional relapse-free rates, overall survival, or toxicity between the treatment groups. It is possible that any potential benefit of the chemotherapy may have been obscured by tumor repopulation during the 4-week split. The other three trials combining 5-FU and cis-
platin with radiotherapy have been published only in abstracts at the time of this article. 12,15,21 One trial used standard fractionated radiotherapy. 2t One trial from Germany used split-course accelerated fractionated radiotherapy. 12 The trial from Duke University used hyperfractionated radiotherapy.15 All three trials reported a significant improvement in diseasefree survival in the combined treatment group, although only the trial using split-course accelerated fractionated radiotherapy reported a significantly better overall smwival. 12Acute toxicity, however, was also greater in the combined treatment group. In the trial from the Cleveland Clinic, the incidence of grade HI-IV cutaneous reaction was 10% versus 44%, the incidence raucositis was 26% versus 84%, and the incidence of tube feeding was 30% versus 58% in the radiotherapy alone and the combined treatment groups. 21In the trial from Duke University, confluent mucositis developed in 72% of the patients treated with hyperfractionated radiotherapy alone and in 98% of the patients who received 5-FU and cisplatin in addition to hyperfractionated radiotherapy. Tube feeding was required in 28% of the radiotherapy alone group and 45% of the combined treatment group. 15 Three patients in the radiotherapy alone group and five patients in the combined treatment group developed severe complications (soft tissue necrosis or osteonecrosis).
Alternating or Sequential 5-FU and Radiation Therapy Another approach to circumvent tile problem of increased acute toxicity, specifically mucositis, when 5-FU-containing multidrug chemotherapy is used with concurrent radiotherapy is the use of sequential or alternating chemotherapy and radiotherapy. There have been at least four randomized trials that have compared sequential 5-FU-containing chemotherapy and radiotherapy with simultaneous or alternating chemotherapy and split-course radiotherapy in advanced head and neck cancer. ~4,23-25 As shown in Table 2, the complete response rate was better with the concurrent or alternating chemotherapy and radiotherapy regimen than with the sequential regimen. One trial showed a significantly improved disease-free survival with the concurrent or alternating chemotherapy and radiotherapy regimen compared with the sequential regimen. 14 There was no significant improvement, however, in overall survival. There was no radiotherapy alone control arm in these trials. As a matter of fact, in the trial by the
Radiotherapy and 5-FU in Head and Neck Cancer
277
Table 2. Randomized Trials of Sequential Versus Concurrent or Alternating Chemotherapy with 5-FU Plus Other Drugs and Radiotherapy fbr Advanced Head and Neck Cancer
Author (year)
No. of Evaluable Patients
SECOG (1986) 23
267
Adelstein (1990) 14
48
Drugs
S
% CR
%Local + Regional Control (years)
CO or A
S
CO orA
N/A
N/A
33* (4) 34* (4) 16" (4)
71
43 (3)
VCR, Bleo, MTX, N/A N/A 5-FU (B) CP, 5-FU (C) 32 67
42
(t' = .002)
Taylor (1994) 24 Pinnaro (1994) 25
214 93
CP, 5-1?U (C) CP, 5-FUJ" (C)
50 52 47 41
% Survival (years) S
CO or A
68 (3)
%DES (years) S
39 (3)
(P = .04)
45 (3) 37
56 (3) 61
30* (3) 38* (3) 31" (3) 11 (5) 16 (5) 16 (5)
CO orA
25* (4) (t' = .o7) 6o (3) (P = .03) 42* (3) 2o (5)
*Estimated from survivalcurvcs. tCP and 5-FU for sequential, CP onlyfor concurrent chemotherapy and radiotherapy. Abbreviations: CR, complete remission;DFS, disease-freesurvival;VCR, vincristine; Bleo, bleomycin;MTX, methotrexate; CP, cisplatin; B, bolus infusion; C, continuous infusion; N/A, not available;S, sequential; CO, concurrent; A, alternating. Southeast Cooperative Oncology Group from England (SECOG), the results of the synchronous chemotherapy and radiotherapy were no better than historical data with radiotherapy alone. 2~As a result, a third a r m of radiotherapy alone was added to the trial. Thus far, there has been only one randomized trial that has compared alternating chemotherapy and radiotherapy with radiotherapy alone. 26 In this trial reported by Merlano et al, 157 patients with advanced unresectablc squamous cell carcinoma of the head and neck were randomized to receive four courses ofcisplatin (20 mg/m 2) and 5-FU (200 mg/m 2) daily for 5 consecutive days during weeks 1, 4, 7, and 10 plus three courses of radiotherapy (20 Gy/10 fractions/2 weeks) during weeks 2-3, 5-6, and 8-9 or radiotherapy alone with 70 Gy/35 fractions/7 weeks. Updated results showed a significantly better complete response rate (43% v 22%, P = .037), localregional control (28.8% v 7.8%, P = .028), 5-year local-regional relapse-free survival (64% v 32%, P = .038), progression-free survival (21% v 9%, _P .008), and overall survival (24% v 10%,P = .01) in the alternating chemotherapy and radiotherapy group, although there was no significant difference in the incidence of distant metastases (7.5% v 6.5%) and toxicity (19% v 18% grade III-IV mucositis).27 Several aspects of this trial may be problematic. First, early closure of the trial limits the value of the statistical significance of the observed differences between the two treatment groups. Second, the difference in survival was largely attributed to the poor localregional control in the radiotherapy alone group. The complete response rate was 22%, the local-regional control rate was 7.8%, and the 5-year overall survival was 10% in the radiotherapy alone group. 26,27 The
poor local-regional control rate with radiotherapy alone could have been because of the suboptimal delivery of radiotherapy. 26 Although the protocol prescribed a dose of 70 Gy in 7 weeks in the radiotherapy alone group, the median dose actually delivered was only 62 Gy. Treatment delays were also more frequent in the radiotherapy alone group. T r e a t m e n t delays of 1, 2, and more than 2 weeks occurred in 32%, 11%, and 14% of the patients. It has been shown that treatment interruptions have an adverse effect on the outcome of patients irradiated for head and neck cancer. 28 In view of these deficiencies in treatment delivery and the poor results in the radiotherapy alone arm, the results of this trial concerning the relative efficacy of alternating chemotherapy and radiotherapy versus radiotherapy alone should be regarded as inconclusive and in need of further confirmation.
Induction and Adjuvant 5-FU and Radiation Therapy Because of the high response rates to continuous 5-FU infusion and cisplatin chemotherapy, this regimen has frequently been used as induction or neoadjuvant therapy before radiotherapy with or without surgery or as adjuvant therapy after local-regional therapy for advanced head and neck cancer. In addition to eisplatin, 5-FU has also been combined with carboplatin or other drugs in an induction or adjuvant setting. The response rates to these regimens, however, are not superior to the 5-FU and cisplatin combinations. Tables 3 and 4 summarize the results of randomized trials of induction and adjuvant 5-FU-containing chemotherapy and radio-
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Karen K. Fu
therapy with or without surgery for head and neck cancer.
Induction Chemotherapy 5-FU has been used in an induction chemotherapy regimen in at least 5 randomized trials of operable ~9-34and 12 trials of operable and inoperable head and neck cancer. 3546 As shown in Table 3, response rates to induction chemotherapy ranged from 21% to 98%, and complete response rates were in the range of 0% to 54% depending on the drug regimen and the number of cycles of drugs administered. Despite high response rates to induction chemotherapy, there was n o significant improvement in local-regional control or survival between the standard treatment groups and the induction chemotherapy groups.
The trial reported by Paccagnella et al included patients with operable or inoperable disease. 43 Although distant metastases were reduced in the induction chemotherapy group, there was no difference in local-regional failure, disease-fi'ee survival, or overall survival. Subset analysis showed improved local control and overall survival with induction chemotherapy for patients who had inoperable disease but not for those who had operable disease. The overall 2-year smvival was poor, however, in both treatment arms for patients with inoperable disease (10% in the control arm and 24% in the induction chemotherapy arm). The results of the combined treatment arm in this trial are no better than those with radiotherapy alone reported in the literature. One cannot conclude that induction chemotherapy improves the
Table 3. Randomized Trials of Induction Chemotherapywith 5-FU With or Without Other Drugs and Radiotherapy With or Without Surgery for Advanced Head and Neck Cancer
Author (year) OperableDisease VALCS (1991)2'~ Wolf (1996)3o Depondt (I993) 31
Di Blasio (1994)32
No. of Evaluable Patients
Drug,s')
% Survival (years)
%DFS (years)
Control
CT
Control
CT
43* (5)
46* (5)
64* (5) 51. (5)
56 (4)
30 (4)
33 (4) N/A
332
CP, 5-FU (C)
300
CBP, 5-FU (C)
85 (31), 92 98 (49)$ 63 (31) 75 (4)
CP, 5-FU (C)
69 (37)
N/A
CP, 5-FU (C) CBP, 5-FU (C)
86 (54) N/A
73 N/A
71 N/A
35 (5) 53
43w (4) N/A (P = .04) 30 (5) 27 (5) 72 N/A
71 (0) N/A
23 N/A
25 N/A
N/A 55 (2)
N/A 22 (2)
N/A N/A
N/A N/A
21 (0)
N/A
N/A
77 (1)
58 (1)
N/A
N/A
68 (5)
53 (2)
35 (2)
43 (2)
31 (2)
N/A
N/A
85 (19) 68 (46) 49 (7)
70 (2) 67 51. (5)
56 (2) 73 50* (5)
70 (2) N/A 36* (5)
56 (2) N/A 32* (5)
N/A 6l (1) N/A
N/A 73 (1) N/A
70 (22) 35* (3) 80 (31) 29.(3)
38* (3) 28* (3)
48* (3) 20 (3)
40* (3) 29(3)
N/A 33 (3)
N/A 37(3)
80 (32) 81 (19) 57 (19)
N/A 84 64 (5)
53 (2) 81 (2) 45w (5)
60 (2) 80 (2) 55w (5)
N/A 72 (2) N/A
N/A 68 (2) N/A
69
Lefebw'e (1996)33 194 Volling (1996)34 97 Operable and~orInoperableDisease von Essen (1968)35 50 Stell (1983)36 86
Toohill (1987)39 Martin (1990)4~ Mazeron (1992)41
60 75 116
Jaulerry (1992)42 Paccagnella
108 237
5-FU (B) VCR, Bleo, H, MTX, 5-Fu (B) VBL, Bleo, CTX, MTX, 5-FU (B) Bleo, M~I~, 5-vu (B), C'~X CP, 5-FU (C) CP, 5-FU (C) Bleo, MTX, 5-vu (B), c P CP, 5-FU (C), Vind CP, 5-FU (C)
280 77 166
CP, 5-FU (C) CP, 5-FU (C) CP, 5-FU (C)
Stol~jk (1985)37
68
Kun (1986)3a
83
(1994) 43
Dalley (1995)44 Chan (1995)45 Domenge (1996)46
%Local +% Response Regional to CT Control(years) (% CR) Control CT
N/A 85 75 (5)
80
65 (4) 46 (4) (P = .04) N/A 74w (4)
25 (5) N/A
*Estimated from survivalcurves. tArter two cyclesof inductionchemotherapy. SAfter three cyclesof inductionchemotherapy. w survival. Abbreviations: CT, chemotherapy;ca, complete response; DFS, disease-free survival; CP, cisplatin; CBP, carboplatin;VCR, vincristine; Bleo, bleomycin;H, bydrocortisone;MTX, methotrexate; VBL,vinblastine; CTX, cytoxan(cyclophosphamide);C, continuousinfusion;B, bolus infusion;N/A,not available.
Radiotherapy and 5-FU in Head and Neck Cancer
supAval of patients with inoperable head and neck cancer based on this trial. Although induction chemotherapy does not improve survival, induction chemotherapy with Continuous 5-FU infusion and cisplatin may be useful in the selection of patients for organ preservation with subsequent radiotherapyg, S~ The trial by the Department of Veterans Affairs Laryngeal Cancer Study group (VALCS) included patients with operable stage III or IV laryngeal cancer? 9,3~ The European Organization for Research and Treatment of Cancer (EORTC) trial included patients with operable stage T2-4, N0-2b squamous cell carcinoma of the piriform sinus and awepiglottic fold. ~3 The study design was similar in both trials. Eligible patients were randomized to receive surgery followed by postoperative radiotherapy or induction chemotherapy with cisplatin and 5-FU infusion. In the VALCS trial, after two cycles of induction chemotherapy, the partial or complete responders received an additional cycle of chemotherapy followed by definitive radiotherapy. Those with residual or recurrent disease after completion of radiotherapy underwent surgery for salvage. Patients who showed no response or progression after two cycles of induction chemotherapy went on to salvage surgery and postoperative radiotherapy. The EORTC trial differed from the VALCS trial in that only patients who had a complete response in the primary site after three cycles of induction chemotherapy were treated with radiotherapy; the others underwent surgery. Both trials showed no significant difference in overall survival between the induction chemotherapy and standard treatment arms. Disease-free survival was lower in the induction chemotherapy arm in the VALCS trial but not the EORTC trial. Distant metastasis was significantly reduced in the EORTC trial. In the VALCS trial, although distant metastasis as a tirst site of relapse was reduced in the induction chemotherapy arm, the overall incidence of distant metastasis was similar in both arms. ~~The proportion of patients in the induction chemotherapy arm who underwent laryngectomy because of lack of response or for salvage after radiotherapy was 38% at 4 years in the VALCS trial and 43% in the EORTC trials. In the VALCS trial, 66% of the patients who were alive at 4 years had a functioning larynx, although this represents only 31% of the 166 patients in the induction chemotherapy arm. In the EORTC trial, for the 100 patients randomized to the induction chemotherapy arm, the estimated survival with a functioning larynx was 28% at 3 years and 17% at 5 years. When only
279
deaths from local disease progression were considered, the estimated survival with a functioning larynx was 42% at 3 years and 35% at 5 years. No increase in morbidity or complications of surgery or radiotherapy following the induction chemotherapy was observed in either trial. The results of these two trials suggest that induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in chemotherapy responders is an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hy-popharynx who desire organ function preservation. Induction chemotherapy can be toxic and costly. It is not known whether similar or better results can be achieved with concurrent chemotherapy and radiotherapy or radiotherapy alone. To address this issue, the Head and Neck Intergroup is conducting a phase III trial in which patients with operable T2, T3, or early T4 squamous cell carcinoma of the glottis or supraglottic larynx are randomized to receive (1) induction chemotherapy with 5-FU infusion and cisplatin followed by radiotherapy in the responders or salvage surgery and radiotherapy in the nonresponders, (2) radiotherapy and concurrent cisplatin chemotherapy, or (3) radiotherapy a l o n e J The induction chemotherapy regimen is the same as that in the VALCS trial. In the concurrent radiotherapy and chemotherapy arm, cisplatin at a dose of 100 mg/m 2 is given every 3 weeks during radiotherapy. The radiotherapy dose schedule is the same in all three arms: 70 Gy in 35 fractions over 7 weeks. This trial is ongoing and is targeted to accrue 546 patients. In addition to survival with preservation of the larynx, quality of life will also be prospectively assessed as an end point of treatment outcome. Results of this trial should determine the relative etticacy of induction versus concurrent chemotherapy and radiotherapy versus radiotherapy alone for larynx preservation in patients with advanced operable carcinoma of the larynx.
AdjuvantChemotherapy The use of adjuvant chemotherapy with 5-FU and eisplatin or other drugs after standard therapy has been evaluated in at least four randomized trials (Table 4). 15,38,48,49Except for the recently closed Head and Neck Intergroup trial (INT 0099) for nasopharyngeal carcinoma, none of these trials showed a significant improvement in overall survival. In this trial, however, patients in the combined treatment group also received concurrent cisplatin during radiotherapy. 49 The relative contributions of adjuvant
280
Karen K. Fu
Table 4. Randomized Trials of Adjuvant Chemotherapy With 5-FU Plus Other Drugs for Advanced Head and Neck Cancer No. of Author (year)
% Survival (years)
%DFS (years)
Evaluable Patients
Drug(s)
Control
CT
Control
CT
Laramore (1992)4~ A1-Sarraf (1996)49
83 448 147
Bleo, CTX, MTX, 5-FU (B) CP, 5-FU (C) CP, 5-FU (C)
43 (2) 44 (4) 47 (3)
N/A 38 (4) 24 (3)
Brizel (1996)15
110
CP, 5-FU (C)
28 (3)
31 (2) 48 (4) 78 (3) (P = .002) 51 (3) (P = .06)
N/A 46 (4) 69 (3) (P < .001) 58 (3) (P = .02)
Kun (1986)3a
28 (3)
Abbreviations:CT, chemotherapy;DFS, disease-freesuIwival;Bteo,bleomycin;CTX, cytoxan (cyclophosphamide);MTX, methotrexate; CP, cisplatin;B, bolusinfusion;C, continuousinfusion;N/A,not available. versus concurrent chemotherapy to the improved survival in the combined treatment group are unclear. One of the major limitations of adjuvant chemotherapy trials has been poor patient compliance. Patient refusal of adjuvant chemotherapy after intensive local-regional treatment has been common. In the Intergroup trial for nasopharyngeal carcinoma, only 55% of the patients randomized to the chemotherapy arm completed three courses of adjuvant 5-FU and cisplatin. Results of these studies suggest that it is unlikely that adjuvant chemotherapy with 5-FU or other drugs would have a significant impact on the prognosis of advanced head and neck cancer. Although induction or adjuvant chemotherapy with 5-FU and cisplatin has not resulted in improved survival, a decreased incidence of distant metastasis has been observed in several trials. 91,3S,43,48,49As localregional control further increases with biochemical modulation of 5-FU or radiation dose intensification, reduction of distant metastasis by systemic therapy may become more important in the overall management of advanced head and neck cancer patients. Conclusions
and Comments
Response to 5-FU depends on schedule of administration. Higher response rates are seen when it is given by continuous infusion than when by bolus injection. Enhanced radiation effect is also most likely to occur with continuous infusion than with bolus injection. 5-FU alone or combined with other drugs appears to enhance the effects of radiation when given concurrently or in an alternating schedule with radiotherapy in the treatment of advanced head and neck cancer. Improved local-regional control, disease-free survival, and overall survival have been reported in randomized trials of concurrent or alternating 5-FUcontaining chemotherapy and radiotherapy. It is not
possible, however, to determine whether the enhanced effect is supraadditive or synergistic, additive, or subadditive. Acute toxicity, primarily mucositis, is also commonly increased with concurrent radiotherapy and 5-FU. No benefit is seen when 5-FU is given alone or in combination with other agents as induction therapy before or adjuvant therapy after local-regional therapy. Although induction chemotherapy with 5-FU infusion and cisplatin may be useful in the selection of patients with advanced resectable lmTngeal or hypophmTngeal carcinoma for organ function preservation with subsequent radiotherapy, induction or adjuvant chemotherapy with 5-FU and cisplatin may also decrease or delay the occurrence of distant metastasis. 5-FU has been most ti:equently combined with cisplatin and radiotherapy in recent clinical trials in head and neck cancer. Other agents such as leucovorin, hydroxyurea, o~-interferon, and paclitaxel have also been combined with 5-FU in attempt to increase its efficacy through biochemical modulation when combined with radiotherapy in the treatment of advanced head and neck cancer. 5~ Although the results of phase I/II studies suggest an enhanced tumor response, acute toxicity is also markedly increased, necessitating a split-course approach or the use of granulocyte colony-stimulating factor. The relative efficacy of these more intense combined chemotherapy and radiotherapy regimens in comparison with radiotherapy alone or other combined modality regimens needs further evaluation in phase III trials. At present, the mechanism of interaction between 5-FU and radiation remains poorly understood. Studies on the molecular mechanisms of the effects of 5-FU and radiation on tumors and normal tissues are needed to provide a rational basis for the optimal integration of 5-FU and radiation in a combined modality therapy for solid tumors, including head
Radiotherapy and 5-FU in Head and Neck Cancer
and neck cancer. Other treatment modifiers that can reduce the severity of normal tissue toxicity, in particular, mucositis, are also needed to improve the therapeutic ratio.
References 1. Bagshaw MA: Possible role of pot entiators in radiation therapy. AJR A m J Roentgeno185:822-833, 1961 2. Heidelberger C, Griesbach L, Montag BJ, et al: Studies on fluorinated pyrimidines: II. Effects of transplanted tumors. Cancer Res 18:305-317, 1958 3. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining sensitization of h u m a n tumor cells in vitro to combined 5-fluorouracil or ftorafur and x rays. Int J Radiat Oncoi Biol Phys 8:1923-1933, 1982 4. Fu KK, Rayner PA, Lam KN: Modification of the effects of continuous low dose rate irradiation by concurrent chemotherapy infusion. IntJ Radiat Oncol Biol Phys 10:1473-1478, 1984 5. Maase HV-D: Interactions of radiation and 5-fluorouracil, cyclophosphamide of methotrexate in intestinal ciTpt cells. Int J Radiat Oncol Biol Phys 10:77-86, 1984 6. Vietti T, Eggerding F, Valeriote F: Combined effect of x radiation and 5-fluorouracil on smwival of transplanted leukemic cells.J Natl Cancer Inst 47:865-870, 1971 7. Weinberg MJ, RauthAM: 5-Fluorouracil infusions and fractionated doses of radiation: Studies with a murine squamous cell carcinoma. IntJ Radiat Oncol Biol Phys 13:1691-1699, 1987 8. Pu AT, Robertson JM, Lawrence TS: Current status of" radiation sensitization by tluoropyrimidines. Oncology (Huntingt) 9:707-714, 1995 9. Goldsmith MA, Carter SK: The integration of chemotherapy into a combined modality approach to cancer therapy. Cancer Treat Rev 2:137-158, 1975 10. Kish JA, Ensley JF, Jacobs J, et al: A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer 56:2740-2744, 1985 11. Lokich~J, AhlgrenJD, GulloJJ, et al: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program Study.J Clin Oncoi 7:425-432, 1989 12. YVustrow TPU, Wendt TG, Grabenbauer G, et al: Randomized phase III study for simultaneous radiopolychemotherapy in head and neck cancer, 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 236) 13. Shigematsu Y, Sakai S, Fuchihata H: Recent trials in the treatment of maxillary sinus carcinoma, with special reference to the chemical potentiation of radiation therapy. Acta OtolatTngol 71:63-70, 1971 14. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell bead and neck cancer. Cancer 65:1685-1691, 1990 15. Brizel D, Albers M, Fisher S, et al: A phase III trial of hyperfractionated irradiation -+ concurrent chemotherapy for locally advanced carcinoma of the head and neck: Superiority of combined modality treatment, 4th International Confer-
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
281
ence on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 237) Browman GP, Cripps C, Hodson DI, et al: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer.J Clin Oncol 12:2648-2653, 1994 Keane TJ, Cmnmings BJ, O'Sullivan B, et ai: A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment tbr advanced laryngeal and hypopharyngeal squamous carcinoma. IntJ Radiat Oncol Biol Phys 25:613-618, 1993 Sanchiz F, Milla A, Torner J, et ai: Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 19:1347-1350, 1990 Weissler MC, Melin S, Sailer SL, et al: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118:806-810, 1992 Lo TC, Wiley ALJr, Ansfield FJ, et al: Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharymx: a randomized study. A J R A m J Roentgenot 126:229-235, 1976 Adetstein DJ, SaxtonJP, Lavertu P, et al: Concurrent radiation and chemotherapy (CT) versus (vs) radiotherapy (RT) alone in resectable stage III and IV squamous cell head and neck cancer (SCHNC): A phase KI randomized trial. Proc Am Soc Ciin Oncol 15:26, 1996 (abstr 2015) Scanlon KY, Newman EM, Lu Yea: Biochemical basis for cisplatin and 5-fluorouracil synergism in h m n a n ovarian carcinoma cells. Proc Natl Acad Sci USA 83:8923-8925, 1986 Southeast Cooperative OncologTGroup (SECOG):Arandomized trial of combined multidrug chemotherapy and radiotherapy in advanced squamous celt carcinoma of the head and neck: An interim report from the SECOG participants. South-East Co-operative Oncology Group. Eur J Surg Oncol 12:289-295, 1986 Taylor SG, Murthy A, Vannetzel JM, et al: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer.J Clin Oncol 12:385-395, 1994. Pinnaro P, Cercato MC, Giannarelli D, et al: A randomized phase II study comparing sequential versus simultaneous chemo-radiotherapy in patients with unresectable locally advanced squamous cell cancer of the head and neck. Ann Oncol 5:513-519, 1994 Merlano M, Vitate V, Rosso R, et ah Treatment of advanced squamous cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N EnglJ Med 327:11151121, 1992 Merlano M, Benasso M, Corvo R, et al: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectahle squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583-589, 1996 Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. IntJ Radiat Oncol Biol Phys 23:457-467, 1992 Department of Veterans Afl~airs Laryngeal Cancer Study Group (VALCS): Induction chemotherapy plus radiation com-
282
KawnK. Fu
pared with surgery plus radiation in patients with advanced laryngeal cancer. N EnglJ Med 324:1685-1690, 1991 30. Wolf GT, Hong WK, Fisher SG: Neoadjuvant chemotherapy for organ preservation: Current status, in ShahJP, JohnsonJT (eds): 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, pp 89-97 31. Depondt J, Gehanno P, Martin M, et al: Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer. Oncology 50:23-27, 1993 32. Di Blasio B, Barieri W, Bozzetti A, et ali A prospective randomized trial in resectable head and neck carcinoma loco-regional treatment with and without neoadjuvant chemotherapy. Proc Am Soc Clin Oncol 13:286, 1994 (abstr 899) 33. Lefebw'eJL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial: EORTC Head and Neck Cancer Cooperative Group [see comments].J Nati Cancer Inst 88i890-899, 1996 34. Volling P, Schroeder M, Eckel H, et ah Results of a prospective randomized trial with induction chemotherapy in cancer of the oral cavity and the pharynx, 4th International Conference on Head and Neck Cancer, The Society of Head and Neck Surgeons and American Society of Head and Neck Surgery, TorontO, Canada, 179, 1996, (abstr 484) 35. von Essen CF, Joseph LBM, Simon GT, et ah Sequential chemotherapy and radiation therapy of buccal mucosa carcinoma in South India. AJRAmJ Roentgenol 102:530-540, 1968 36. Stell PM, DalbyJE, Strickland P, et al: Sequential chemotherapy and radiotherapy in advanced head and neck cancer. Clin Radio134:463-467, 1983 37. Stolwijk C, Wagener DJ, Van den Broek P, et al: Randomized neo-adjuvant chemotherapy trial for advanced head and neck cancer. NethJ Med 28:347-351, 1985 38. Kun LE, Toohill RJ, Holoye PY, et al: A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract. Int J Radiat Oncol Biol Phys 12:173-178, 1986 39. Toohill RJ, Anderson T, Byhardt RW, et ah Cisplatin and fiuorouracil as neoadjuvant therapy in head and neck cancer: A preliminary report. Arch Otolaryngol Head Neck Surg 113:758-761, 1987 40. Martin M, Hazan A, Vergnes L, et al: Randomized study of 5 fluorouracil and cis platin as neoadjuvant therapy in head and neck cancer: A preliminary report. Int J Radiat Oncol Biol Phys 19:973-975, 1990 41. MazeronJ-J, Martin M, Brun B, et al: Induction chemotherapy in head and neck cancer. Head Neck 14:85-91, 1992 42. Jaulerry C, RodriguezJ, BruNn F, et al: Induction chemotherapy in advanced head and neck tumors: Results of two
randomized trials. Int J Radiat Oncol Biol Phys 23:483-489, 1992 43: Paccagnelta A, Orlando& Marchiori C, et al: Phase HI trial of initial chemotherapy in stage Ill or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo.J Natl Cancer Inst 86:265-272, 1994 44. DalleyD, Beller E, AroneyR, et ah Thevalue of chemotherapy (CT) prior to definitive local therapy (DLT) in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck (HN). Proc Am Soc Clin Oncol 14:297, 1995 (abstr 856) 45; Chan AT, Teo PM, Leung TW, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. IntJ Radiat Oncol Biol Phys 33:569-577, 1995 46. Domenge C, Coche-Dequeant B, Wibault P, et al: Randomized trial of neoadjuvant chemotherapy before radiotherapy in oropharyngeal carcinoma, 4th International Conference on Head and Neck Cancer, Tile Society of Head and Neck Suicgeons and American Society of Head and Neck Surgery, Toronto, Canada, 1996, (abstr 164) 47. Fu KK, Cooper JS, Marciat VA, et al: Evolution of the Radiation Therapy OncoIogy Group clinical trials tot head and neck cancer. IntJ Radiat Oncol Biol Phys 35:425-438, 1996 48. Laramore GE, Scott CB, A1-SarrafM, et ah Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 23:705-713, 1992 49. A1-Sarraf M, LeBlanc M, Shanker G, et al: Chemo-radiotherapy vs. radiotherapy in patients with locally advanced nasopharyngeal cancer: Phase III randomized Intergroup study (0099) (SWOG 8892, RTOG 8817, ECOG 2388).J Clin Onco11997 (submitted) 50. Vokes EE, Haraf DJ, Panje WR, et ah Hydroxyurea with concomitant radiotherapy for locally advanced head and neck cancer. Semin Oncot 19:53-58, 1992 51. Vokes EE, Ratain MJ, Mick R, et al: Cisplatin, fluorouracil, and leucovorin augmented by interferon alfa-2b in head and neck cancer: A clinical and pharmacologic analysis [published erratum appears inJ Clin Oncol 1994 Mar;12(3):643].J Clin Oncol 11:360-368, 1993 52. Vokes EE, Stupp R, Haraf D, et al: Hydroxyurea with continuous infusion paclitaxel, 5-fluorouracil, and concomitant radiotherapy for poor-prognosis head and neck cancer. Semin Onco122:47-52, 1995 53. Stupp R, Vokes EE: 5-fluorouracil plus radiation for head and neck cancer.J Infus Chemother 5:55-60, 1995 54. McGinn CJ, Shewach DS, Lawrence TS: Radiosensitizing nucleosides.J Natl Cancer Inst 88:1193-1203, 1996