Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy—a multicenter randomized trial

Int. J. Radiation Oncology Biol. Phys., Vol. 55, No. 1, pp. 78 –92, 2003 Copyright © 2003 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter

PII S0360-3016(02)03792-6

CLINICAL INVESTIGATION

Head and Neck

LOCOREGIONALLY ADVANCED CARCINOMA OF THE OROPHARYNX: CONVENTIONAL RADIOTHERAPY VS. ACCELERATED HYPERFRACTIONATED RADIOTHERAPY VS. CONCOMITANT RADIOTHERAPY AND CHEMOTHERAPY—A MULTICENTER RANDOMIZED TRIAL PATRIZIA OLMI, M.D.,* SERGIO CRISPINO, M.D.,† CARLO FALLAI, M.D.,‡ VALTER TORRI, M.D., M.S.,§ FRANCESCA ROSSI, M.D.,* ANDREA BOLNER, M.D.,㛳 MAURIZIO AMICHETTI, M.D.,㛳 MARCO SIGNOR, M.D.,¶ RAFFAELLA TAINO, M.D.,# MASSIMO SQUADRELLI, M.D.,# ALESSANDRO COLOMBO, M.D.,** ALESSANDRO ARDIZZOIA, M.D.,** PIETRO PONTICELLI, M.D.,†† GIOVANNI FRANCHIN, M.D.,‡‡ EMILIO MINATEL, M.D.,‡‡ CARLO GOBITTI, M.D.,‡‡ GUIDO ATZENI, M.D.,§§ ALESSANDRO GAVA, M.D.,㛳 㛳 MONICA FLANN, M.D.,§ AND SILVIA MARSONI, M.D.§ *Rep. di Radioterapia, Dipartimento di Fisiopatologia Clinica, Universita`, Firenze, Italy; †Oncologia Medica and ††U.O. di Radioterapia, Osp. S. Donato, Arezzo, Italy; ‡Rep. di Radioterapia, A.O. Careggi, Firenze, Italy; §U. di Biometria, Ist. di Ricerche Farmacologiche M. Negri, Milano, Italy; 㛳U.O. di Radioterapia Oncologica, Osp. S. Chiara, Trento, Italy; ¶U.O. di Radioterapia Oncologica, A.O. S. Maria della Misericordia, Udine, Italy; #Div. di Radioterapia, Ospedali Riuniti, Bergamo, Italy; **Div. di Radioterapia Oncologica, A.O. S. Gerardo, Monza, Italy; ‡‡Div. di Oncologia Radioterapica, I.N.T.-C.R.O., Aviano (PN), Italy; §§U.O. di Radioterapia Oncologica, Spedali Riuniti, Livorno, Italy; 㛳 㛳Ist. di Radioterapia, Osp. Ca` Foncello, ASL 9, Treviso, Italy Purpose: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. Methods and Materials: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66 –70 Gy in 33–35 fractions, 5 days a week, were administered in 6.5–7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64 – 67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2, Days 1– 4; 5-FU 1,000 mg/m2 i.v. over 96 h, Days 1– 4, recycling every 28 days (at 1st, 5th, and 9th week). Results: No statistically significant difference was detected in overall survival (p ⴝ 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p ⴝ 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p ⴝ 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3ⴙ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3ⴙ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3ⴙ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. Conclusions: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone

tigators: Maurizio Portaluri, M.D., Enza Barbieri, M.D., Giovanni Pavanato, M.D., Mario Balli, M.D., Francesco Ducci, M.D., Gian Luigi Negri, M.D., Innocenzo Di Lorenzo, M.D., Gianstefano Gardani, M.D., Lisa Licitra, M.D., Marco Lupattelli, M.D., Bianca Moira Panizza, M.D., and Franco Checcaglini, M.D.. Received Apr 10, 2002, and in revised form Jul 23, 2002. Accepted for publication Jul 31, 2002.

Reprint requests to: Carlo Fallai, M.D., Dipartimento di Radioterapia, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. Tel: 0039 0223902478-80; Fax: 00390223902472; E-mail: [email protected] Supported in part by a grant from the Consiglio Nazionale delle Ricerche. Acknowledgments—The following members of the cooperative group have participated in the collection of data as clinical inves78

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in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity. © 2003 Elsevier Science Inc. Advanced squamous-cell oropharyngeal carcinoma, Randomized Phase III trial, Concomitant radiochemotherapy, Altered fractionation, Radiation therapy.

INTRODUCTION The prognosis of advanced oropharyngeal tumors is severe: Survival rates at 5 years with conventional radiation therapy (RT) and/or surgery are around 30%, at best, for lesions of Stage III and IV (1, 2). In the 1990s, attempts were made to improve local and regional control of disease by altering the radiation treatment schedule, mainly the fractionation regimen. Basically, two rationales were employed: hyperfractionation (HF) and accelerated fractionation (AF). HF decreases the dose per fraction under the conventional 1.8 –2 Gy once daily, and delivers multiple (generally 2) fractions a day, with the aim to give higher total doses without increasing the long-term sequelae. AF keeps the dose per fraction unchanged and achieves a reduction in treatment duration by delivering multiple daily fractions, with the aim of counteracting the tumor cell repopulation. Some schedules, for example accelerated hyperfractionation (AHF), incorporate elements of both rationales. At the beginning of the 1990s, a few randomized trials (3–5) showed that multiple daily fractionation RT could yield better results than conventional fractionation (CF) RT, but it was not universally clear what fractionation schedule should be considered the optimal schedule. The studies of Wang (6), even if not randomized and monocentric, provided excellent results, indeed among the best reported in the literature, for tumors of various head-and-neck sites, including oropharynx. Wang’s schedules were of the AHF type: It was planned that 2 fractions of 1.6 Gy were to be given with an interfraction interval of at least 4 h, 5 days a week (6). After 38.4 Gy, a rest period of 2 weeks was interpolated to allow the mucosal reaction to settle; then the treatment was resumed up to a total dose 64 – 67.2 Gy. Although the overall acceleration of treatment course, if any, was modest, the two segments of treatment were actually accelerated; the reduction of dose per fraction under 1.8 Gy justifies the attribute of (slightly) hyperfractionated regime. The combination of RT and chemotherapy (CT) was the second approach investigated over the 1980s and 1990s to improve results in advanced head-and-neck cancer. Induction CT performed before definitive RT was widely used and easily given, and it obtained a high response rate. However, in the first half of the 1990s, there was growing doubt that this sequential administration of CT and RT could provide a significant benefit in comparison to RT alone in oropharyngeal tumors (7). On the other hand, the concomitant administration of RT and CT with the combination of cisplatin (CDDP) and 5-fluorouracil (5-FU) was emerging as the most interesting

alternative approach to the management of advanced, unresectable head-and-neck cancer (8 –11). The activity of carboplatin (CBDCA)—a platinum derivative with clinical efficacy equivalent to CDDP, but with less oto-, neuro-, and nephrotoxicity (12–14)—in head-andneck cancer was already documented in an early period (15). Some experimental studies showed synergism between RT and the drug in vitro (16, 17); in a clinical setting, CBDCA was at least comparable to CDDP when delivered concomitantly to RT in advanced head-and-neck cancer (18). In a preliminary experience of Colombo et al. (19), the simultaneous administration of RT and CT with CBDCA and 5-FU proved feasible and highly effective in terms of objective response. 5-FU was delivered through continuous i.v. infusion, a method of administration with which 5-FU seems to be more active than with bolus infusion (20). Despite a brisk and treatment-limiting mucositis, an appropriate nutritional support allowed one to apply the treatment correctly in most cases. Myelotoxicity was the second most important side effect after mucositis: G2–G3 leukopenia and thrombocytopenia were observed in 40% of the patients, but no sepsis or hemorrhage occurred. Considering the above-mentioned remarks, we decided that it would be interesting to compare the AHF schedule of Wang (6) and CF RT plus concomitant CT (CBDCA and 5-FU) with the traditional approach of CF RT in terms of results and toxicity for advanced, unresectable epidermoid tumors of oropharynx.

METHODS AND MATERIALS Trial design Between January 1, 1993 and June 30, 1998, 192 patients affected with advanced oropharyngeal carcinoma were accrued in Trial ORO-01 from 18 centers of radiation therapy and medical oncology in Italy (Table 1). This was a multicenter, randomized Phase III trial comparing RT alone with CF (Arm A) vs. a split-course RT-alone arm with a b.i.d. accelerated hyperfractionation schedule (S-AHF: Arm B) vs. the same RT as in Arm A plus concomitant CT (CCT ⫹ CF: Arm C).

Trial objectives The trial had the following aims: (1) to compare results in terms of overall survival, disease-free survival (DFS), and event-free survival; and (2) to evaluate both acute and late sequelae of the three arms.

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Table 1. ORO-01 Trial: Participating centers and accrued patients Center (No.)

No. of patients

Arezzo (01) Bergamo (02) Bologna (04) Firenze (05) Legnago (06) Livorno (07) Milano (08) Monza (09) Novara (10) Perugia (11) Aviano (12) S. Giovanni Rotondo (15) Sondrio (16) Terni (17) Trento (18) Udine (19) Treviso (20) Pisa (21) Total

16 18 4 21 4 15 1 17 2 1 15 6 2 1 28 22 15 4 192

Randomization The randomization was centralized at Istituto Mario Negri, Milan, after histologic confirmation and staging procedures; patients were stratified by center and clinical stage (Stage III; Stage IV, N0 –1; Stage IV, N2–3) and were then randomized to receive one of the three treatments planned in the trial. Selection criteria The entry criteria were the following: histologically proven epidermoid carcinoma of the oropharynx; Stage III and IV (according to the UICC and AJCC 1987– 88 TNM staging system) (21)— however, T1N1 and T2N1 lesions were excluded; no distant metastases (M1) when first diagnosed; no previous surgery (except biopsy), no previous RT and/or CT; patients aged under 70; Karnofsky performance status (KPS) ⱖ70 or ECOG ⬍2; adequate bone marrow reserve (leukocytes or white cells [WC]: ⱖ4,000/␮L, platelets: ⱖ150,000/␮L); serum creatinine ⬍1.5 mg/dL, serum bilirubin ⬍1.5 mg/dL; adequate cardiac and pulmonary function; no previous tumors, except adequately treated in situ carcinoma of the cervix and basal cell carcinoma of the skin; no active infectious disease; no psychosis; availability for correct follow-up; informed consent obtained from each patient. Radiation therapy Treatment techniques. Irradiation was performed with photon beams from 60Co machines (focus–skin distance 80 cm) or 4 – 6-MeV linear accelerators. High-energy electron beams were used to treat the posterior regions of the neck after the spinal cord dose tolerance level was reached. Use of immobilization devices was recommended to provide an adequate treatment reproducibility. Treatment volume. The primary tumor and both cervical

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regions were included in the initial treatment volume and irradiated through parallel-opposed fields (for each treatment session). The supraclavicular area was irradiated with a centrally shielded anterior direct field in case of nodal involvement of the neck. Treatment fields were simulated before the start of RT; portal verification films were performed for both sides at the beginning of the actual treatment. Dose. For Arms A and C, 66 –70 Gy in 33–35 fractions (2 Gy per fraction), 5 days a week in 6.5–7 weeks were recommended for the tumor and positive nodes. For clinically uninvolved neck nodes, 50 Gy was planned. The tolerance dose for the spinal cord was considered to be 44 Gy. In Arm B, 64 – 67.2 Gy were indicated as the dose to be delivered to tumor and involved nodes. Every day, 2 fractions of 1.6 Gy were given with an interfraction interval of at least 4 h, and preferably 6 h, 5 days a week. After reaching the dose of 38.4 Gy in 2 weeks, a 2-week split was planned; after the split, RT was resumed with the same modality up to a dose 64 – 67.2 Gy. More recently, during the trial, Wang et al. (22), who pioneered this schedule, recommended a higher dose on the grounds of their experience with T3 carcinomas; there was consensus among the researchers that a higher dose could be compatible with the aims of the trial. In Arm B, spinal cord dose should not exceed 38.4 Gy over 2.5 weeks. Dose was prescribed to the central axis mid-plane for parallel-opposed fields and to a specified depth for supraclavicular regions (usually 3 cm under the skin). Toxicity and breaks. In any arm, temporary breaks from RT were suggested for G3⫹ (Grade 3 or higher) acute mucositis according to the Radiation Therapy Oncology Group (RTOG) scale (23), and/or leukopenia (WC ⱕ2,000/ ␮l), and/or thrombocytopenia (platelets ⱕ60,000/␮L). Chemotherapy Chemotherapy regimen. The CT regimen employed in Arm C consisted of CBDCA and 5-FU: CBDCA 75 mg/m2 i.v. diluted in 250 mL of normal saline solution infused in 30 min, Days 1– 4; 5-FU 1,000 mg/m2 i.v. infused continuously over 96 h, Days 1– 4. Three cycles lasting 28 days each (at 1st, 5th, and 9th week) were planned, starting contemporaneously with the beginning of RT. Actually, 2 cycles were concomitant to RT, whereas the third cycle was delivered after the end of RT, if the RT course could be completed without breaks. Toxicity and breaks. CT was postponed in the following circumstances: G3⫹ mucositis according to the World Health Organization (24) scoring system; leukopenia (WC ⬍4,000/␮L); thrombocytopenia (platelets ⬍100,000/␮L); and serum creatinine ⬎1.5 mg/dL. CT could be resumed if after 1-week delay WC were ⬎3500/␮L. The use of growth factors was allowed, but they had to be reported. A reduction (50%) of the CBDCA dose was recommended if at the nadir WC were ⬍1,000/␮L and/or platelets were ⬍40,000/␮L. Anti-emetic therapy was given by principle to all patients

Advanced oropharyngeal carcinoma

undergoing CT; ondansetron (90 ofran) was suggested in case of vomit, despite conventional anti-emetic drugs. Surgery Neck dissection was suggested for residual disease or nodal relapse; the choice of a surgical intervention for persistence or progression of the primary tumor was left to the physician’s discretion. Visit procedures Patient prerandomization evaluation. Patient prerandomization evaluation included medical history and physical examination; complete blood count (CBC); and blood tests, including serum bilirubin, AST, ALT, lactate dehydrogenase (LDH), gammaglutamyltransferase (GGT), alkaline phosphatase, serum creatinine and electrolytes, glycemia, and urine test. CAT scanning and/or MRI and neck ultrasonography were recommended to accurately outline the local and regional disease spread; electrocardiogram and chest X-ray were requested by protocol. Liver ultrasound scan was performed only if indicated by the clinical status. Triple endoscopy was suggested, but not compulsory. Follow-up during treatment. In Arm C CBC, blood tests and urine test were requested every week; in Arms A and B, CBC was planned every 2 weeks. In all arms, regular clinical examinations were scheduled every week during treatment and until the settlement of major acute reactions. Follow-up after treatment. Visits and blood tests were scheduled every 2 months during the first year, every 3 months the second year, and every 6 months thereafter. A chest X-ray was recommended every 4 months the first year, every 6 months the second year, and annually thereafter. CAT and/or MRI, neck ultrasound scan, and other investigations were performed when indicated by the clinical conditions. Statistical methods A preliminary hypothesis was formulated that a 5-year overall survival rate for the worst arm would be 30% and for the best arm would be 55%. Assuming an accrual of 60 to 70 cases per year, at least 260 patients in 4 years were considered necessary to validate the hypothesis on the study, if the analysis were planned for 6 years after randomization of the first patient. For the calculation of total figures of enrollment, a probability was accepted of 5% false-positive (␣ ⫽ 0.05, two tails) and 20% false-negative results (␤ ⫽ 0.20). If the overall test were found to reject the hypothesis of no difference among the three arms, a pairwise comparison between arms would be performed. Survival estimates were performed with the KaplanMeier product limit method and compared using the log– rank test and the Cox proportional hazards model. Overall survival was calculated as the difference between the date of death (or last day when the patient was known to be alive) and the date when treatment was started. Diseasefree survival was considered the difference between the date of occurrence of any relapse (i.e., local and/or regional

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and/or distant relapse) and the date when treatment started. Patients without relapse were censored at the date of death or on the last day they were known to be alive. Event-free survival was calculated from the date when treatment was started to the date of any relapse or death from any cause, whichever came first, or occurrence of a second tumor. Survival analysis was performed by intent to treat, and no patient was excluded. Toxicity of RT developing within 90 days from the beginning of irradiation (acute toxicity) was assessed according to the scoring system of RTOG (23). RT toxicity developing after 90 days (chronic/late toxicity) was graded with the same scale for late sequelae and evaluated every 6 months. As for the acute toxicity more specifically related to CT, the World Health Organization scoring system (24) was chosen.

RESULTS Characteristics of the series Overall, 192 patients were enrolled in the trial: 63 in Arm A, 65 in Arm B, and 64 in Arm C. The trial was officially closed in June 1998 before reaching the planned accrual of 260 patients; because the accrual rate had slowed down over the years, it was considered impractical to prolong the trial any further. Overall, there seemed to be no major loss in strength for the statistical estimates. The patient characteristics in this series are reported in Table 2. When information regarding a certain parameter is missing (with total number of patients amounting to less than 192), percentage is calculated using the number of patients with available data as the denominator for the resulting fraction, when not otherwise specified. Gender Males were most commonly seen (170 out of 192 patients, 88.5%), and the male:female ratio was 7.7:1. Age The age belt between 50 and 65 years was the most commonly represented (106/192, 55.2%). Median age was 56.1 years (range: 38 –70 years). Histology The histology was of epithelial origin in all cases, and virtually all tumors were of squamous cell type. Grading was available in 130 patients, with a slight prevalence of G2 (histologic Grade 2) over G3 (histologic Grade 3) cases (58 vs. 43). KPS The patients were more often in relatively good general condition: 134 of 147 patients (91.1%) had a KPS of 90⫹, as opposed to 13 patients (8.8%) who had a KPS of 70.

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Table 2. Trial ORO-01: patient characteristics Arm A Category Gender Males (%) Females (%) Total Age ⬍50 yr 50–65 yr ⬎65 yr Total Histology SCC UC Total Grading G1 G2 G3 Total KPS 90⫹ 80 70 Total Weight loss ⬍5 kg 5–10 kg ⬎10 kg Total Comorbidity Alcoholic hepatopathy Gastric ulcer Others No comorbidity Total

B

C

Total

No.

%

No.

%

No.

%

No. (⫹MD)

%

55 8 63

28.6 4.1

57 8 65

29.6 4.1

58 6 64

30.2 3.1

170 22 192

88.5 11.5

19 34 10 63

9.9 17.7 5.2

22 38 5 65

11.4 19.7 2.6

18 34 12 64

9.3 17.7 6.2

59 106 27 192

30.7 55.2 14.0

60 1 61

31.2 0.5

59 2 61

30.7 1.0

61 0 61

31.7 0

180 3 183 (⫹9)

92.9 1.5

10 21 13 44

5.2 10.9 6.7

12 20 17 49

6.2 10.4 8.8

7 17 13 37

3.6 13.0 8.8

29 58 43 130 (⫹62)

15.1 30.2 22.3

44 12 3 59

22.9 6.2 1.5

48 11 5 64

25.0 5.7 2.6

42 13 5 60

21.8 6.7 2.6

134 36 13 183 (⫹9)

69.7 18.7 6.7

32 6 0 38

16.6 3.1 0

36 5 1 42

18.7 2.6 0.5

29 9 2 40

15.1 4.6 1.0

97 20 3 120 (⫹72)

50.5 10.4 1.5

7 2 7 42 58

3.6 1.0 3.6 21.8

11 2 10 35 58

5.7 1.0 5.2 18.2

7 3 6 44 60

3.6 1.5 3.1 22.9

25 7 23 121 176 (⫹16)

13.0 3.6 11.9 63.0

Abbreviations: MD ⫽ missing data, (reported in parenthesis); yr ⫽ years; SCC ⫽ squamous cell carcinoma; UC ⫽ undifferentiated carcinoma; KPS ⫽ Karnofsky performance status.

Weight loss Despite good KPS, the interference of disease with a correct food intake was documented by the incidence of weight loss during the 6 months before the first examination; in fact, 23 patients of 120 (19.1%) were reported to have lost 5 or more kg. Comorbidities Furthermore, apart from the oropharyngeal tumor, patients suffered with a variety of other concomitant diseases, mainly alcoholic liver disturbances and gastric ulcer, and clinically relevant comorbidities were present in 55 of 176 patients (31.2%). Stage and sites of disease All patients had advanced lesions; although there are some missing data regarding the stage of T and N, all cases were recorded at the randomization as Stage III

(excluding T1N1 and T2N1) or IV according to the TNM classification UICC/AJCC 1989 (21). Stage III lesions accounted for roughly one-third (49/182, 27%), and Stage IV lesions for the remaining two-thirds (133/182, 73%). The breakdown of T and N stage is shown in Table 3; T3 and T4 tumors were more commonly diagnosed than early T lesions (153/182, 84%). The site of involvement is reported in Table 4. Numbers indicate how many times a site was involved rather than identify the most likely site of origin of the neoplasm; in fact, considering the usually advanced stage of the disease, finding out the original region would have been an uncertain guess. As expected, lateral and anterior walls were the most frequently involved sites (in 139 and 99 patients, respectively). As for the nodal disease status, the involvement of the lymph nodes of the neck was a common feature (143 of 182, 78.5%); the adenopathies were located

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Table 3. Distribution according to TNM (UICC 1989) (21)

Arm A T1 T2 T3 T4 MD Total Arm B T1 T2 T3 T4 MD Total Arm C T1 T2 T3 T4 MD Total

N0

%

N1

%

N2

%

N3

%

0 0 9 6

0 0 4.6 3.1

0 0 4 2

0 0 2.0 1.0

3 7 19 8

1.5 3.6 9.8 4.1

1 0 2 1

0.5 0 1.0 0.5

15

7.8

6

3.1

37

19.2

4

2.0

0 0 9 3

0 0 4.6 1.5

0 0 11 2

0 0 5.7 1.0

1 7 12 11

0.5 3.6 6.2 5.7

0 0 2 3

0 0 1.0 1.5

12

6.2

13

6.7

31

16.1

5

2.6

0 0 10 2

0 0 5.2 1.0

0 0 6 4

0 0 3.1 2.0

1 7 16 8

0.5 3.6 8.3 4.1

0 2 2 1

0 1.0 1.0 0.5

12

6.2

10

5.2

32

16.6

5

2.6

MD

Total

%

4 7 34 17 1 63

2.0 3.6 17.7 8.8 0.5 32.8

4 1

1 7 34 19 4 65

0.5 3.6 32.8 9.8 2.0 33.8

5 4

1 10 33 15 5 64

0.5 5.2 17.1 7.8 2.6 33.3

1

Abbreviation: MD ⫽ missing data.

mainly in the upper (102) or middle (60) level of the neck. Absence or presence of nodal involvement, region of nodal involvement, and status of fixity were evenly distributed among the three arms (Tables 3 and 4). Balance Overall, the distribution of patients in terms of gender, age, histology type and grading, KPS, history of weight loss, presence of comorbidities, and T and N stage was well balanced among the three arms. Compliance to RT The dose (Gy) delivered to the tumor and nodal volume in each treatment arm is reported in Table 5. As for the CF

arm, the mean tumor dose approximated 69 Gy, whereas the suggested range was 66 –70 Gy; this was slightly higher than the mean dose, i.e., 64 Gy, given in Arm C, which employed the same schedule. The AHF was initially planned to give 64 – 67 Gy, and the mean tumor dose was 65.9 Gy. A course of RT was considered full if patients had been given at least the minimum dose of the suggested range. Sixty of 61 patients (in other 2 patients, missing data) undergoing RT in Arm A (98.3%) completed the treatment, i.e., received ⱖ66 Gy as compared to 59 of 61 patients (96.7%) (in other 4 patients, missing data) in Arm B, who were given ⱖ64 Gy; in Arm C, 50 out of 60 patients (83.3%) (in other 4 patients, missing data) were given ⱖ66

Table 4. Distribution by involved T site, involved nodal level, and nodal pattern (mobility/fixity)

T: involved site Anterior wall Base of tongue Lateral wall Posterior wall Upper wall N: side N: involved regions I II III IV Nodal pattern Fixed node(s) Mobile node(s)

Arm A, No

Arm B, No

Arm C, No

Total, No

35 31 47 6 17 R/L

33 30 47 9 16 R/L

31 29 45 10 22 R/L

99 90 139 25 55 R/L

1/0 17/19 11/11 2/2

1/0 20/17 8/7 4/2

3/0 18/11 12/11 5/2

5/0 55/47 31/29 11/6

10/9 17/18

9/12 17/10

16/9 16/11

35/30 50/39

Abbreviations: T ⫽ primary tumor; N ⫽ node(s); R/L ⫽ no. of cases with involvement of right side of the neck vs. no. of cases with involvement of left side of the neck.

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Table 5. RT dose to tumor and nodal volumes by treatment arm RT dose T dose Mean Minimum Maximum N dose Mean Minimum Maximum

Arm A (Gy ⫾ SD)

Arm B (Gy ⫾ SD)

Arm C (Gy ⫾ SD)

68.8 ⫾ 2.2 60 73.8

65.9 ⫾ 4.6 41.6 73.6

64 ⫾ 12 10 76

64.3 44 73.6

63.5 41.6 75

61.2 10 74

apparently no residual disease at autopsy), 1 acute renal failure (with occult myeloma), 1 pulmonary embolism, and 1 pulmonary edema. A toxic death was considered likely in the first 3 cases, and could not be excluded in the other 2 patients. RT-related acute toxicity The RT-related acute toxicity is reported by treatment arm in Table 7. Information on the score of acute toxicity was available in 54 patients in Arm A, 52 patients in Arm B, and 50 patients in Arm C. Patients in Arm A less frequently developed G3⫹ (Grade 3 or higher) mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Similarly, skin reaction was milder in Arm A vs. Arm B or C (G3⫹: 3.7%, 7.6%, and 16%, respectively). However, cutaneous reactions rarely caused treatment breaks.

Gy and were considered to have finished the RT course. Independently from the treatment completion, delays occurring during treatment were analyzed. Thirty-seven out of 61 patients (60.6%) in Arm A needed a split during the treatment course, whereas 49% of 61 patients in Arm B had no further delay beyond the scheduled 2-week split. Finally, there was no delay in 21 of 61 patients (35%) in Arm C. The mean delay observed for RT was 5 days in Arm A and B and 7 days in Arm C.

CT-related acute toxicity The CT-related acute toxicity is shown in Table 8. Apart from 1 case of fatal nephrotoxicity (See above), only hematologic G3⫹ acute sequelae were observed, more commonly leukopenia (22.7%) than thrombocytopenia (4.5%) or anemia (2.3%).

Compliance to CT Regarding CT in Arm C, 37 patients were delivered all 3 cycles of CT, whereas 15 patients had 2 cycles and 8 patients only 1 cycle. Three patients refused chemotherapy, and data are not available for another patient. There were only a few delays in the administration of the second cycle (Table 6), whereas 62% of the patients received the third cycle with a delay of 1⫹ weeks.

Late toxicity Late sequelae at 2 years are reported in Table 9. Information on late toxicity score was available in 35, 37, and 39 patients in Arm A, B, and C, respectively. Arm C showed slightly more G3⫹ skin, s.c. tissue, and mucosal side effects, although significant late sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms.

Early deaths Treatment was stopped because of early death (during treatment) in 8 patients. In Arm B, 1 patient died because of tumor progression both locally and in the liver. In Arm C, 2 patients died because of a sudden and massive hemorrhage from branches of the carotid artery; the fast tumor regression might have played a role in the genesis of the event. The other causes of death are as follows: 1 cardiac failure secondary to a mycotic pneumonia (The patient had extensive pulmonary fibrotic tuberculosis remains, and the diagnosis was confirmed by autopsy), 1 septic shock (with

Causes of failures and second tumors The main cause of treatment failure was the local (primary tumor) relapse. T relapse was observed in 70% of 124 failures; isolated nodal failure occurred in 9% of the failed patients, but nodal disease was a component of the recurrence also in other patients (27.5%), reaching an overall percentage of 37% of all relapses. Distant metastases occurred in nearly one-third of the patients (28%), even though distant metastases alone were less common (15%).

Table 6. Delays observed during RT and/or CT administration No delay

%

1–7 days

Delays observed in the administration of radiotherapy Arm A 37/61 60.6 B 30/61 49.1 C 21/60 35.0 Delays observed in the administration of chemotherapy Arm C (2 cycles) 10/15 66.5 C (3 cycles) 14/37 37.8

%

8–14 days

%

15⫹ days

%

Total

9 19 13

14.7 31.1 21.6

11 8 18

18.0 13.1 30.0

4 4 8

6.5 6.5 13.3

61 61 60

3 11

20.0 29.7

2 6

13.5 16.2

0 6

0 16.2

15 37

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Table 7. RT-related acute toxicity; no. of patients with available data/total no. of patients: Arm A 54/63 pts, Arm B 52/65 pts, Arm C 50/64 pts Grade* of acute toxicity (RT) 0 Site Skin Mucosa Ear Salivary glands Pharynx Larynx

1

2

3

4

Arm

No.

%

No.

%

No.

%

No.

%

No.

%

A B C A B C A B C

8 13 11 9 6 6 46 41 42

14.8 25.0 22.0 16.6 11.5 12.0 85.1 78.8 84.0

29 17 18 10 6 3 5 7 6

53.7 32.6 36.0 18.5 11.5 6.0 9.2 13.4 12.0

15 18 13 27 19 17 3 2 2

27.7 34.6 26.0 50.0 36.5 34.0 5.5 3.8 4.0

2 3 8 7 21 22 0 2 0

3.7 5.7 16.0 12.9 40.3 44.0 0 3.8 0

0 1 0 1 0 2 0 0 0

0 1.9 0 1.8 0 4.0 0 0 0

A B C A B C A B C

16 16 11 23 18 14 38 35 32

29.6 30.7 22.0 42.5 34.6 28.0 70.3 67.3 64.0

18 10 14 11 7 10 9 12 11

33.3 19.2 28.0 20.3 13.4 20.0 16.6 23.0 22.0

20 25 25 14 15 14 7 5 6

37.0 48.0 50.0 25.9 28.8 28.0 12.9 9.6 12.0

0 1 0 6 12 12 0 0 1

0 1.9 0 11.1 23.0 24.0 0 0 2.0

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

* RTOG (reference 23).

The most peculiar feature is the lower incidence rate of T recurrences in Arm C, which is counterbalanced by a higher number of nodal relapses (48% vs. 29% in Arm B and 41% in Arm A) and distant metastases (43% vs. 13.5% in Arm B and 36% in Arm A). Ten second tumors (2 in Arm A, 4 in Arms B and C) were diagnosed in other sites: 3 lung tumors, 2 oral cavity tumors, and 1 tumor each for larynx, esophagus, pancreas, liver (hepatocarcinoma), and myeloma. Three second tumors were recorded as cause of death (2 in Arm B, 1 in Arm C).

plus nodal site (Arm A, 13; Arm B, 9; Arm C, 8). Salvage was achieved in 4 patients with T progression (Arm A, 2; Arm B, 1; Arm C, 1), in 5 patients with nodal disease (Arm A, 1; Arm B, 1; Arm C, 3), and in 3 patients with T and N disease (1 patient for each arm). In Arm B, 2 patients were salvaged after relapse with RT and CT: One patient with limited local recurrence underwent interstitial brachytherapy (40 Gy) and CT; the second patient had a nodal failure and was irradiated (36 Gy 1.2 and concomitant chemotherapy with CDDP and 5-FU).

Surgical salvage Surgery was performed in 30 patients with residual or progressive disease at the primary (T), nodal (N), or primary

Palliative CT and RT Chemotherapy alone with palliative intent was performed in 15 patients with T or N progression and in 11 patients

Table 8. CT-related acute toxicity Grade* of acute toxicity (CT) 0

1

2

3

4

Symptom

No

%

No

%

No

%

No

%

No

%

Nausea/vomit Leukopenia Anemia Thrombocytopenia Alopecia Anorexia Nephrotoxicity Neurotoxicity

21 12 19 32 28 43 43 43

47.7 27.3 43.2 72.7 63.6 97.7 97.7 97.7

18 11 16 3 12 – – 1

40.9 25 36.4 6.8 27.3 – – 2.3

5 11 8 7 4 – – –

11.4 25 18.2 15.9 9.1 – – –

– 8 1 – – – – –

– 18.2 2.3 – – – – –

– 2 – 2 – 1 1 –

– 4.5 – 4.5 – 2.3 2.3 –

* WHO (reference 24). Abbreviation: CT ⫽ chemotherapy.

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Table 9. Two-year treatment-related late toxicity; no. of patients with available data/total no. of patients: Arm A 35/63 pts, Arm B 37/65 pts, Arm C 39/64 pts Grade* of late toxicity 0 Site Skin Subcutaneous tissue Mucosa Salivary glands Spinal cord Larynx

1

2

Arm

No

%

No

%

A B C

15 16 14

42.8 43.2 35.9

18 16 21

51.4 43.2 53.8

A B C A B C A B C A B C A B C

15 16 7 11 8 7 7 9 5 34 35 38 27 29 24

42.8 43.2 17.9 31.4 21.6 17.9 20 24.3 12.8 97.1 97.2 97.4 77.1 80.5 61.5

18 13 22 18 18 19 13 7 8 1 1 1 6 5 14

51.4 35.1 56.4 51.4 48.6 48.7 37.1 18.9 20.5 2.8 2.7 2.5 17.1 13.8 35.9

No

3

4

%

No

%

No

%

2 5 3

5.7 13.5 7.6

0 0 1

0 0 2.5

0 0 0

0 0 0

2 7 8 5 9 11 13 18 24 0 0 0 1 2 1

5.7 18.9 20.5 14.2 24.3 28.2 37.1 48.6 61.5 0 0 0 2.8 5.5 2.5

0 0 2 0 1 2 2 3 2 0 0 0 0 0 0

0 0 5.1 0 2.7 5.1 5.7 8.1 5.1 0 0 0 0 0 0

0 1 0 1 1 0 0 0 0 0 0 0 1 0 0

0 2.7 0 2.8 2.7 0 0 0 0 0 0 0 2.8 0 0

* RTOG (reference 23).

with distant metastases. In Arms A and B, CDDP and 5-FU were chosen as first-line chemotherapy, whereas in Arm C, VBM (vinblastin, bleomycin, and methotrexate) and EBM (epidoxorubicin, bleomycin, methotrexate) were chosen as an alternative to platinum derivatives ⫹ 5-FU. Palliative RT was used for relief of pain or other symptoms whenever clinically indicated. Survival Survival rates of the three arms are reported in Figs. 1–3.

Overall, there were 121 deaths and 124 disease progressions. At the time of analysis, 105 out of 124 patients in progression had died, whereas 16 patients died before progression. Three patients are alive with a second neoplasm. There is no statistically significant difference in overall survival (p ⫽ 0.129). The survival estimates at 24 months are as follows: 40%, Arm A vs. 37%, Arm B vs. 51%, Arm C. An initial loss of patients in Arm C pointed out the relevance of early death in this arm. Similarly, there was no statistically significant difference in terms of event-free

Fig. 1. Study ORO 93-01: Overall survival (OS) by treatment arm (prob ⫽ probability).

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Fig. 2. Study ORO 93-01: Event-free survival (EFS) by treatment arm (prob ⫽ probability).

survival (p ⫽ 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C. On the contrary, DFS was significantly different among the three arms (p ⫽ 0.022), with Arm C faring better than Arms A and B (Arm A vs. C: hazard ratio ⫽ 1.76, 95% CI ⫽ 1.11–2.80, p ⫽ 0.017; Arm B vs. C: hazard ratio ⫽ 1.83, 95% CI ⫽ 1.15–2.91, p ⫽ 0.011). Two-year DFS was 23% for Arm A, 20% for Arm B, and 42% for Arm C. DISCUSSION Radiation therapy There has been considerable debate and research over the past 20 years about which irradiation schedule should be considered optimal. Various overviews have been dedicated to this topic outlining the evolution of the issue through

Phase II and Phase III trials (25–29). The results of EORTC (European Organization for the Research and Treatment of Cancer) and RTOG, the two largest research groups, are of particular relevance, because, after more than 20 years of study, they have recently concluded that two different schedules deserve further research as a candidate to substitute CF as standard fractionation (Table 10). Horiot et al. (5, 30) reported the results of EORTC Trial 22791. CF (70 Gy, 2 Gy daily) was compared to HF (80.56 Gy, 1.15 Gy b.i.d.) in T2–3 N0 –1 (⬍3 cm) oropharyngeal carcinomas; base-of-tongue lesions were excluded. A significant improvement in 5-year LRC (locoregional control) was observed that did not translate into a corresponding survival gain. G2⫹ late damage was reported as nonsignificantly different for HF as compared to CF. The EORTC Trial 22851 (31) comparing AHF vs. CF did not prove to

Fig. 3. Study ORO 93-01: Disease-free survival (DFS) by treatment arm (prob ⫽ probability).

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Table 10. Randomized trials of RT with conventional fractionation vs. RT with nonconventional fractionation schedule in advanced head-and-neck cancer

Author (Ref.) year Sanchiz et al., (3) 90

Pts no

Arm (RT)

577 CF HF Pinto et al., (4) 91 98 CF HF Horiot et al., (5) 92 323 CF EORTC 22791 HF Horiot et al., (30) 94 410 CF EORTC 22851 AHF Fu et al., (32) 00 1,113 CF RTOG 9003 HF S-AHF CB Poulsen et al., (57) 01 350 CF AF Skladowski et al., (35) 00 100 CF AF

% OS (yr)

SS

17 (10) ⬍0.001 40 (10) 8 (3.5) 0.03 27 (3.5) ⬃30 (5) ns ⬃40 (5) ns ⬃24 (5) ns ⬃16 (5) 46 (2) ns 54 (2) 47 (2) 54 (2) – – – 32 (3) ⬍0.0001 78 (3)

% DFS (yr)

SS

% LRC (yr)

SS

17 (10) ⬍0.001 – – 37 (10) – 7 (3.5) ns – – 25 (3.5) – – – 38 (5) 0.01 – 56 (5) – – 46 (5) ⬍0.02 – 59 (5) 31 (2) ns 46 (2) 0.045 37 (2) 54 (2) 33 (2) 46 (2) ns 39 (2) 50 (2) 0.005 35 (5) ns 47 (5) ns 41 (5) 52 (5) – – 37 (3) ⬍0.0001 – 82 (3)

% G3⫹ acute tox 10 4 – – 49 66.5 34 70 35 54 50 58 71 94 71 93

SS

% G3⫹ late tox

SS

⫽ CF

– – – ⫽ CF – – – 0.01 14 ns 27 ⬎CF 15 ⬍0.001 48 ⬍0.0001 26 ns 28 0.0002 27 ⬍0.0001 37 ⫽0.011 ⬍0.001 29 ns† 25 – 4* ns 8*

Abbreviations: Ref. ⫽ reference; Pts no ⫽ number of patients; RT ⫽ radiation therapy; OS ⫽ overall survival; (yr) ⫽ years; SS ⫽ statistical significance (p values); DFS ⫽ disease-free survival; LRC ⫽ locoregional control; tox ⫽ toxicity; CF ⫽ conventional fractionation RT; HF ⫽ hyperfractionation RT; ns ⫽ not significant; EORTC ⫽ European Organization for the Research and Treatment of Cancer; AHF ⫽ accelerated hyperfractionation RT; RTOG ⫽ Radiation Therapy Oncology Group; S- ⫽ split-course RT; CB ⫽ concomitant boost. * Crude values. † Mucous membranes, late toxicity.

have a comparable therapeutic ratio, producing too much late normal-tissue damage, despite an increased local control. Considering these data, the group started the EORTC Trial 22962 in 1996 comparing HF (80.56 Gy, 1.15 Gy b.i.d.) vs. CF (70 Gy, 2 Gy daily) with or without concomitant CT (CDDP 100 mg/m2 Days 1, 22, 43). On the other hand, the RTOG tested the efficacy of hyperfractionation (81.6 Gy, 1.2 Gy b.i.d.), accelerated fractionation (S-AHF 67.2 Gy, 1.6 b.i.d., the same as in the present study), accelerated fractionation with concomitant boost (CB) (CB-AF, 1.8 Gy daily plus 1.5 Gy as second fraction the last 12 treatment days), and CF in locally advanced squamous-cell carcinoma of the head and neck (32). CB-AF resulted in better 2-year LRC and disease-free survival than CF. Acute late toxicity was significantly increased (but late sequelae were mostly transient). On the basis of these results, the RTOG decided that CB-AHF would serve as the control arm in future trials for locally advanced head-and-neck cancer. However, a longer follow-up is needed because the results of HF are also promising. The comparisons between CF and S-AHF of our study are in agreement with the RTOG conclusions that the two schedules yield equivalent survival results in terms of statistical significance. Furthermore, the acute mucosal toxicity from S-AHF is similarly increased, as compared to CF. The Head and Neck Cancer Disease Site Group reviewed the randomized clinical trials on accelerated and hyperfractionated RT. The meta-analysis of Mackenzie et al. (33, 34),

based on published data and focusing on only accelerated RT, detected no significant 2-year survival benefit favoring accelerated RT (RR [relative risk]: 0.99); however, there was a significant improvement in terms of local control at 2 years (RR: 0.86) that became a nonsignificant trend after removing the trial of Skladowski et al. (35) to reduce the overall heterogeneity. Nevertheless, according to the authors, emerging evidence suggests that a modest acceleration of RT can improve LRC compared to CF and may enhance overall survival, but longer follow-up will be needed. Therefore, they concluded that neither rapid acceleration nor hyperfractionation could be recommended as standard therapy for advanced squamous-cell carcinoma of the head and neck. A meta-analysis based on individual patient data is under way by the MARCH group of Pignon et al. (meta-analysis of RT in carcinomas of head and neck). Results are eagerly waited, but are not yet available. Concomitant chemotherapy Traditionally, radiation therapy has been the mainstay of treatment for patients with locally advanced head-and-neck cancers that are unresectable or, sometimes, resectable with mutilating surgery. In an attempt to improve local control and survival, chemotherapy has been investigated as an adjunct to locoregional treatment. The timing of chemotherapy and radiation therapy is various, because chemotherapy can be given before RT (neoadjuvant or induction CT), after RT (adjuvant CT), or concomitantly to RT; schedules alter-

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Table 11. Randomized trials of radiation therapy alone with conventional fractionation vs. radiotherapy and concomitant multiagent chemotherapy in locally advanced head-and-neck cancer Author year (Ref.)

Pts no

Haddad et al. 96 (44)

67

Adelstein et al. 97 (42)

100

Arm (RT)

% LRC (yr)

% OS (yr)

CF CF

39 (3) 44 (3)

ns

– –

–

31 (3) 32 (3)

ns

CP⫹Fu*

CF CF

58 (3) 58 (3)

ns

52 (3) 67 (3)

0.03

35 (3) 55 (3)

0.02

CP⫹Fu

ns

– – –

–

– – –

Adelstein et al. 00 (43)

295

CF CF S-CF

– CP CP⫹Fu

20 (3) 37 (3) 29 (3)

Merlano et al. 96 (46)

157

Alt CF Alt CF

– CP⫹Fu

10 (5) 24 (5)

Calais et al. 01 (45)

226

CF CF

Garden et al. 01 (47)

241

CF Alt CF CF CF CF

RTOG 8117 HND

% DFS (yr)

Arm (CCT)

– CbP⫹Fu CP⫹Fu Hy⫹Fu CP⫹Px CP –

20.4 14.9 60 (2) 65 (2) 67 (2) 46 (2) 35 (2)

SS

0.01

9 (5) 21 (5)

ns

15.1 29.2

–

– – – – –

– –

SS

0.008

32 (5) 64 (5)

0.025 26.5 52.7 – – –

– – – – –

SS

–

0.038 0.0025 – – –

% G3⫹ acute tox

SS

Serious late tox

SS

⫽ CF

11 11

⫽ CF

⬎ CF

– –

–

53 86 77

⬎CF

– – –

–

18 19

ns

– –

–

36 67

SS

4 8

ns

–

– – – – –

27 29 – –

25 (G4) 32 (G4) 29 (G4) – –

– –

– – –

Abbreviations: Ref. ⫽ reference; Pts no ⫽ number of patients; RT ⫽ radiation therapy; OS ⫽ overall survival; (yr) ⫽ years; SS ⫽ statistical significance (p values); DFS ⫽ disease-free survival; LRC ⫽ locoregional control; tox ⫽ toxicity; CF ⫽ conventional fractionation RT; CP ⫽ cisplatin; Fu ⫽ 5-fluorouracil; ns ⫽ not significant; S-⫽ split-course RT; Alt ⫽ alternating; CbP ⫽ carboplatin; Hy ⫽ Hydroxyurea; Px ⫽ paclitaxel; HND ⫽ RTOG Head and Neck Database. * All pts had also induction CT (3 cycles with CP and F).

nating cycles of CT and RT can be considered a variant of the concomitant radiochemotherapy. Although it is not entirely clear which is the best timing, there is a general trend to consider the concomitant approach as the most effective. In a meta-analysis of the published results from 54 randomized clinical trials (36), single-agent CT given synchronously with RT increased survival by 12.1%, whereas the benefit from neoadjuvant CT was less evident (3.7%). The results suggested an investigation of optimal agents and scheduling for synchronous RT and CT. A systematic review of the literature was conducted by Browman et al. (37, 38) of the Cancer Care Ontario Practice Guideline Initiative to develop clinical recommendations for patients with locally advanced squamous-cell head-andneck cancer treated with concomitant CT and RT. A pooled analysis of 18 randomized clinical trials, based on published data, detected a reduction in mortality for concomitant CT compared with RT alone (RR: 0.83). Platinum-based regimens were the most effective. The authors concluded that concomitant CT with conventionally fractionated RT should be the treatment of choice for patients with advanced squamous-cell head-and-neck cancer who can tolerate this combined approach. Pignon et al. of the MACH-NC group (39) reviewed 63 randomized trials conducted between 1965 and 1993 comparing combinations of locoregional treatment and CT vs.

locoregional treatment alone. The trials included patients with carcinoma of the oropharynx, oral cavity, larynx, and hypopharynx. This was a meta-analysis based on individual patient data. The absolute survival benefit in favor of chemotherapy was 4% at 2 and 5 years; however, no significant benefit was associated with adjuvant or neoadjuvant chemotherapy. The meta-analysis of 6 trials comparing alternating/concomitant RT and CT with neoadjuvant CT and RT yielded results in favor of the alternating/concomitant arm. Concomitant CT achieved significant benefits: Absolute survival rate increase at 5 years was 8% with this combination (39, 40). The MACH-NC group updated its data recently (41). After the exclusion of 5 trials to reduce the heterogeneity between trials, the effect of timing (i.e., adjuvant vs. neoadjuvant, vs. concomitant CT) was no longer significant. It must be stressed that 4 out of 5 excluded trials were about concomitant CT and RT vs. RT. The relative risk of death was 0.91 in the adjuvant group, 0.88 in the concomitant group, and 0.95 in the neoadjuvant group. In this group, there was a significant benefit of platin ⫹ 5-FU trials. A further update will clarify, hopefully, the topic of timing by adding more data, especially on CT given concomitantly with RT. Various trials have investigated the role of multiagent CT concomitantly to RT with CF (42– 47), AHF (48), continuous AHF (49), S-AHF (50, 51), HF (52), CB (53), or other

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Table 12. Randomized trials of radiation therapy alone with altered fractionation vs. radiotherapy and concomitant multiagent chemotherapy in locally advanced head-and-neck cancer Author Year (Ref.) Keane et al. 93 (54) Budach et al. 01 (48)

Pts no

Arm (RT)

Arm (CCT)

209 RT* S-RT* (CF⫹) 384 AHF (CF⫹) AHF

– M ⫹ Fu

Dobrowsky et al. 00 (49) 229 CF cAHF cAHF Sailer et al. 92 (50) 32 S-AHF S-AHF Wendt et al. 98 (51) 270 S-AHF S-AHF Brizel et al. 98 (52) 116 HF HF Staar et al. 01 (53) 240 CB CB

% OS (yr) ⬃36 (5) ⬃35 (5)

SS

% DFS (yr)

SS

ns

– –

–

39 (2) 0.05

–

–

49 (2)

–

M

24 (4) 0.03 31 (4) 41 (4)

– – –

– CP ⫹ Fu

19 (1.5) 40 (1.5)

– CP ⫹ Fu

24 (3) 0.0003 48 (3)

– CP ⫹ Fu

34 (3) 55 (3)

– M ⫹ Fu – –

– CbP ⫹ Fu

– –

–

ns –

– –

SS

–

– – 41 (3) 61 (3)

% G3⫹ acute tox

SS

ns

13 10

–

46.4 (2) 0.03

–

ns

57 (2)

19 (1.5) 0.01‡ 40 (1.5)

– –

% LRC (yr)

–

31 (4) 0.03 32 (4) 48 (4) 0.05 15 (1.5) 46 (1.5)

⬃33 95 95

Serious late tox 3 0 –

SS – 0.01†

– ⬎ CF

– – –

–

–

42 53

–

0 0

–

–

17 36

0.004

16 38

⬍0.001

6 10

ns

ns

44 70

0.01

75 77

ns

15§ 19§

–

–

51 (2) 45 (2)

ns

68 52

0.01

– –

–

Abbreviations: Ref. ⫽ reference; Pts no ⫽ number of patients; RT ⫽ radiation therapy; OS ⫽ overall survival; (yr) ⫽ years; SS ⫽ statistical significance (p values); DFS ⫽ disease-free survival; LRC ⫽ locoregional control; tox ⫽ toxicity; CF ⫽ conventional fractionation RT; AHF ⫽ accelerated hyperfractionation RT; M ⫽ mitomycin-C; Fu ⫽ 5-fluorouracil; ns ⫽ not significant; cAHF ⫽ continuous AHF; S-split-course RT; CP ⫽ cisplatin; HF ⫽ hyperfractionation RT; CB ⫽ concomitant boost; CbP ⫽ carboplatin. * Hypofractionated RT schedule (2.5 Gy/fraction). † For dysphagia only. ‡ p value refers to mean time to death from disease. § Long-term adverse effects of treatment. 2 osteonecroses and 7 soft-tissue necroses (9/60) for HF vs. 11/56 soft-tissue necroses for HF ⫹ CCT.

schedule (54) (Tables 11 and 12). Chemotherapy regimens are more commonly based on cisplatin or carboplatin, usually combined with 5-FU; the use of other drugs, such as hydroxyurea or Mitomycin-C, is less well documented in randomized trials in this setting. Data on paclitaxel, although promising, are not yet mature (47). According to Pignon et al. (39), the heterogeneity of data precludes firm conclusions about survival benefits. However, on the whole, data seem to support the opinion that the simultaneous administration of RT and CT may increase LRC and/or disease-free survival (55), whereas an improved overall survival is less commonly observed. Causes of death other than tumor (including second tumors and toxic deaths) could contribute toward explaining this fact. The survival results of our study show a similar trend with statistically significantly better time to relapse. Eventfree and overall survivals were improved for the concomitant CT RT arm, but statistical significance was not reached. Toxicity is a relevant matter when comparing new regimens against the standard ones. Henk (56) reviewed 19 publications of trials of simultaneous radiotherapy and CT for morbidity data and found that the addition of CT significantly enhanced both acute and late effects. Actually, the

combination of CT and CF RT is reported by Adelstein et al. to increase acute toxicity (42); on the contrary, Merlano et al. (10, 46) did not detect any difference, but their alternating regimen and the long breaks on the CF RT arm can easily explain the reason. In our trial, the treatmentlimiting mucosal reaction was significantly more frequent in the CT RT arm vs. the CF RT arm, but this did not prevent giving the full planned dose in ⬎83% of patients. Conclusions about late sequelae are less clear, because data are scanty; none of the trials reported in Table 12 reported significant difference, although serious late sequelae seem to be slightly more frequent after combinations of RT and CT. Once again, our results follow the same trend. CONCLUSIONS Not many trials have addressed the issue of the comparison of conventional RT and altered-fractionation RT and/or concomitant CT plus RT in a specific head-and-neck sites; more often, patients with advanced tumors from multiple sites have been enrolled. Oropharyngeal carcinoma, although not uncommon, can be considered a sporadic dis-

Advanced oropharyngeal carcinoma

ease: 2 new cases in 100,000 inhabitants were recorded per year in Italy in the period 1994 –1999. Furthermore, simultaneous competing trials reduced the potential accrual of our study. Consequently, accrual was slower than planned and longer than desirable. Nevertheless, we feel that the relative homogeneity of the series led to more reliable conclusions than if cancer from multiple sites with different natural histories had been included. The combination of simultaneous CT and RT with the regimen experimented in this trial seems to be more efficacious than RT alone in advanced oropharyngeal squamouscell carcinomas, by increasing significantly the DFS. This improvement did not translate into a statistically significant overall survival improvement, maybe because of the inci-

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dence of distant metastases and causes of death other than cancer. In any case, we believe that CT, as part of primary therapy, has to be used judiciously, because this aggressive treatment approach can lead to significant incidences of local morbidity that require accurate supportive therapy, both during the treatment and until major reactions settle. Furthermore, systemic toxicity may be added to local effects. For the same reason, CT plus RT may not be indiscriminately appropriate for all patients with advanced head-and-neck cancer, especially those already affected with important comorbidities. Nevertheless, continuing the research is warranted, to improve treatment results and control toxicity.

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