Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial

Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial
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  Combined Chemotherapy and Radiation Therapy in Advanced Inoperable Squamous Cell Carcinoma of the Head and Neck The Final Report of a Randomized Trial M. Merlano, MD, R. Corvo', MD,*,f. G. Margarino, MD,* M. Benasso, MD, R. Rosso, MD, M. R. Sertoli, MD,* M. Cavallari, MD,* M. Scala, MD,* M. Guenzi, MD,* A. Siragusa, MD,t F. Brema, MD,$ G. Luzi, MD,$ G. Bottero, MD,§ G. Biondi, MD,/I F. Scasso, MD,I G. Garaventa, MD,# E. Accomando, MD,# A. Santelli, MD,# G. Cordone, MD,# G. Comella, MD,** S. Vitriolo, MD,# and L. Santi, MD* Between 1983 and 1986, he National Institute for Cancer Research in Genoa and affiliated institutions conducted a randomized study to compare two different ways of combining chemotherapy (CT) and radiation therapy (RT). One hundred sixteen patients were randomized to receive neoadjuvant CT followed by definitive RT (treatment arm A) or alternating CT and RT. In treatment arm A, RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction, five fractions per week. In treatment arm B, RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each, 2 Gy/fraction, ten fraction& weeks alternated with four courses of CT. CT consisted of vinblastine 6 mg/mz intravenously followed 6 hours later by bleomycin 30 U intramuscularly, day 1; methotrexate 200 mg intravenously, day 2; leucovorin rescue, day 3. CT was repeated every 2 weeks up to four courses. The same CT was used in both treatment arms of the study. Fifty-five patients were entered in treatment arm A and 61 n treatment arm B. Complete responses were 7/48 and 19/57 n treatment arms A and B, respectively P < 0.03). Four-year progression-free survival was 4 in treatment arm A and 12 in treatment arm B (P < 0.02 , and four-year survival was 10 in A and 22 in B (P < 0.02). Mucosal tolerance was significantly worse in treatment arm B (P < 0.00004). The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics. Cancer 67:915-921, 1991. ECAUSE OF THE UNSATISFACTORY RESULTS B chieved by local treatments, a multidisciplinary approach to advanced squamous cell carcinoma of the head and neck has been added to front-line treatments From the *Istituto Nazionale per la Ricerca sul Cancro, Genova; the tOspedale Galliera, Genova; the $Ospedale Civile, Savona: the 4Ospedale Civile, Alessandria; the llospedale Civile Sestn Ponente, Genova; the lIOspedale Celesia, Genova; the Ospedale S. Martino. Genova; and the **Istituto Tumori, Napoli. Italy. Supported in part by the Italian Research Council, grant 8400803.44. Address for reprints: Marco Merlano, MD, Istituto Nazionale per la Accepted for publication November 15, 1990 Ricerca sul Cancro, Viale Benedetto XV, 10, 16132 Genova, Italy. since the late seventies. In this line, many trials tested the role of neoadjuvant chemotherapy in advanced disease, while other investigators attempted a more biologic in- teraction between chemotherapy and radiation therapy. To date there is no evidence that neoadjuvant chemo- therapy may increase results over standard local treat- ment~.'-~ n the contrary, some positive results have been reported by the simultaneous administration of chemo- therapy and radiation therapy in different randomized trials.425 he simultaneous administration of chemother- apy (cisplatin and 5-Fu) and radiation therapy resulted in an impressive rate of complete responses in a large 915  916 CANCER ebruary 15 199 1 Vol. 67 Phase I1 study by Taylor et aL6 The alternating delivery of chemotherapy and radiation therapy has also been te~ted.~-~ he alternation of chemotherapy and radiation therapy is supported by theoretic and experimental models: 1. In terms of cytokinetics, according to Peter Clifford,’o the alternating delivery of the former therapy may in- duce cell recruitment, making the latter more effective. 2. Experimental in vivo studies with rodents performed at the University of Virginia showed a strong superi- ority of alternating chemotherapy and radiation ther- apy over chemotherapy alone, radiation therapy alone, and the sequence of chemotherapy and radiation therapy.“ 3. The Goldie and Coldman hypothesis suggests that the alternating delivery of two active, non-cross-resistant treatments could increase the cure rate because of the possibility of each treatment extinguishing the residual resistant cell clones, avoiding the development of dou- ble-resistant clones.” Clinical data over a period of 10 years, mainly from Phase I1 studies, suggest that alter- nating chemotherapy and radiation therapy is feasible and is usually able to achieve a high complete response For the above mentioned reasons, our group started a randomized comparison of alternating chemo-radiation therapy versus neoadjuvant chemotherapy followed by radiation therapy. The present update reports the final analysis of the study, whose interim results were already performed in 1987 and 1988.’5-16 rate.9.13.14 Methods Patient Selection Between August 1, 1983, and December 31, 1986, I16 patients with inoperable, Stage 111-IV squamous cell car- cinoma of the head and neck were entered into the study. Patients considered eligible were those with age less than 76, performance status of 3 or less (Eastern Cooperative Oncology Group [ECOG] scale), and no major impair- ment of liver, kidney, bone marrow, lung, or heart func- tion. Patients with distant metastases were considered in- eligible. Criteria for inoperability were: (1) technical unresect- ability (tumor fixation to any bone structure in the region or involvement of the nasopharynx), (2) low surgical cur- ability, and (3) medical contraindication to surgery. Study Design Patients were initially stratified according to the insti- tution where the patient was treated and thereafter in two groups according to main prognostic factors (Table 1). TABLE . Prognostic Stratification Group I Group 2 Site of primary (5-yr survival rate 21%-38%) Soft palate and uvula Posterior pharyngeal wall Base of the tongue Retrornolar trigone Buccal rnucosa Pyriform sinus Oral tongue Tumor grading Poor differentiation Site of primary (5-yr surival rate 43%-75%) Floor of mouth Nasopharynx Gingiva Tonsillar pillar and tonsillar fossa Larynx Tumor grading Well differentiation Moderate differentiation Patient characteristics are shown in Table 2. The T- and N-stage distribution is shown in Table 3. Study design is shown in Table 4. All the patients had the same drug scheduling, dosage, and resting time. Treatment arm A consists of four courses of chemotherapy followed within 3 weeks by radiation therapy. In case of progressive disease during chemotherapy, radiation therapy was immediately started. In treatment arm B, four courses of chemotherapy were alternated with three courses of radiation therapy (20 Gy each). Radiation was given after the second, third, and fourth chemotherapy course. In case of severe toxicity, treatment was discontinued until recovery. Chemotherapy consists of a combination of vinblastine (6 mg/m2, intravenously) followed by bleomycin (30 IU, intramuscularly) 6 hours later, day 1; methotrexate (200 mg, intravenously), day 2; and leucovorin rescue (45 mg orally), day 3. Chemotherapy was repeated every 14 days. All patients were treated with external beam megavoltage irradiation. Techniques were individualized according to site and extent of the disease with differential loading, shrinking field, and boosting dose. Tumors of the oral cavity, oropharynx, hypopharynx, and larynx were treated through two opposite fields with dose distribution 2: 1 to the involved side in case of unilateral tumors (tonsil, ret- romolar trigone, lateral pharyngeal wall). Nasopharynx tumors were treated by a “three-fields technique” (full protection of the ocular bulbs). The margins of the target volumes were set according to the usual radiation therapy practice.17 Upper nodes were always included in the field, but the lower nodes were treated if involved or, if clinically negative, when the microscopic invasion was highly prob- able. Spinal nodes were treated if the primary tumor was in the pharynx. Lateral and supraclavicular nodes, if clin- ically negative, were treated with a direct anteroposterior field. If involved, these nodes were treated with two op- posite anteroposterior fields. The spinal cord received no more than 46 Gy. The irradiated fields were reduced at a total dose of 50 Gy/25 fractions.  CHEMO-RADIATION HERAPY N HEAD ND NECK CA Merlano et al. 917 No. 4 TABLE . Patients Characteristics Arm A Arm B Male/female Median age in yr (range) Median PS (range) Tumor grading 1-2 3 Unknown Site of primary Nasopharynx Oropharynx Hypopharynx Oral cavity Larynx (supraglottic) Stage 111 IV 4619 59 (34-75) l(0-3) 37 6 12 3 21 11 18 2 22 33 51/10 61 (37-75) 1 (0-3) 44 10 7 6 34 7 11 3 22 39 PS: performance status. Radiation therapy was given with radical intent in Group A, up to 70 Gy/35 fractions to the involved areas and 50 Gy/25 fractions to the uninvolved neck. Group B received 60 Gy/30 fractions in three courses of ten frac- tions each. In the same group, when an unresectable re- sidual tumor was found at the end of the integrated ther- apy, a complementary dose (10 Gy/5 fractions) was im- mediately given. The uninvolved neck was treated as in Group A. Pauses due to toxicity have been corrected according to the time dose fractionation. No corrections were per- formed when pauses were filled up by chemotherapy (treatment arm B). At the end of the combined therapy, each patient was reevaluated from a surgical point of view. When techni- cally feasible, all the partial responders had a surgical re- section of all residual disease if it was considered poten- tially curative by our ENT (ears, nose, and throat) sur- geons. At relapse, patients eligible for palliative chemotherapy received the same treatment based on cisplatin and 5-Fu, irrespective of prior therapy. Evaluation and Statistical Methods At the end of the treatment, patients were reevaluated, and responses to therapy were assessed. The following response criteria were used: complete response (CR) was defined as the complete disappearance of all clinically ev- ident tumor for at least 1 month; partial response (PR) was defined as a 50 or more reduction in the product of two major perpendicular diameters of the measurable tumor for at least 1 month; and no response (NR) was defined as anything less than above. Early death was considered any death that occurred before the end of treatment, was unrelated to toxicity, and had no evidence of progressive disease. Progression-free survival (PFS) was considered the time from the beginning of treatment to progression or the last follow-up. Cancer-unrelated deaths were considered to have a disease progression at the time of death. Disease- free survival (DFS) was considered to occur in patients reaching a complete response. Because of the difficulty of exactly assessing the time of disappearance of any clini- cally evident disease, DFS was considered from the start of therapy to relapse of disease. therefore including the time required to reach the complete response. Survival was considered as the time from the start of therapy to last follow-up or death. All patients entered have been considered in survival analysis, irrespective of evaluability status and/or causes of death. Responses in the two treat- ment arms were compared by the chi-square test, and survival and PFS were analyzed by a log-rank analysis.20 Results One hundred sixteen patients were randomized into the present trial. The follow-up ranges from 30 to 66 months (median, 47). All patients have been evaluated for survival 55 in treatment arm A and 61 in B). One hundred twelve (53 in A and 59 in B) have been considered in toxicity analysis. One hundred five (48 and 57 in A and B, respectively) were evaluated for response and pro- gression-free survival (unevaluability rate = 9.4%). The reasons for patients being unevaluable are summarized in Table 5. Treatment responses include 7 CRs and 18 PRs in treatment arm A (52% response rate) and 19 CRs and 18 PRs in treatment arm B (65% response rate). At the end of combined therapy, 2 1 partial responders underwent surgery and 18 (7 in treatment arm A and 1 1 in treatment arm B) were rendered disease-free. Therefore, including responses reached by surgery, we recorded 14 CRs and 1 I PRs in treatment arm A and 30 CRs and 7 PRs in TABLE . Tumor (T) and Node (N) Staging T stage N Arm stage 1 2 3 4 Total A 0 11 7 18 1 5 6 3 14 3 3 1 6 3 10 20 Total 1 11 23 20 B 0 4 6 10 1 2 5 I 4 22 2 2 1 3 3 1 10 9 6 26 Total 3 15 26 17  918 CANCER ebruary 15 199 Vol. 67 TABLE . Study Design Arm A: VBM VBM VBM VBM 65-75 Gy * surge0 days 1-3 15-17 29-3 43-45 Arm B: VBM VBM VBM VBM * surgery 20 Gy 20 Gy 20 Gy treatment arm B. The difference in CR between the two arms is statistically significant both before surgery (X 2 = 4.9; P < 0.03) or after surgery (X 2 = 5.1; P < 0.03). Time o Progression Figure shows the overall progression-free survival. Curves indicate that the probability of being progression- free at 4 years is as high as 4% in treatment arm A and 12% in B (X 2 = 6.48; P < 0.02). At the time of the current analysis, two patients in treatment arm A and ten in B are progression-free. Disease-Free Survival The probability of being disease-free at 4 years is 14% and 22% in treatment arms A and B, respectively. The difference is not statistically significant. All the relapses observed in treatment arm A and 19/2 in treatment arm B occurred within 24 months. Survival Figure 2 shows overall survival. Actuarial 4-year sur- vival is 10% in treatment arm A and 22% in treatment arm B. The difference reaches statistical significance at P < 0.02 (X 2 = 6.22). Five patients in treatment arm A and 18 in B are still alive. Very Advanced Disease Patients with lesions as advanced as T4 or N3 were defined as having “very advanced disease.” Sixty-six pa- TABLE . Reasons for Unevaluability Arm A Arm B Patients randomized 61 Evatuable for survival 55 61 Evaluable for toxicity (4 patients refused to start treatment) 53 59 Evaluable for time to progression 48 57 Protocol violation 4 0 Inelegible I 2 Refuse 2 2 Evaluable for response 48 57 tients of the total enrolled (57%) had very advanced dis- ease, including 20 T4 NO-2 (10 in treatment arm A and 10 in treatment arm B), 30 TI-3 N3 (I0 and 20, respec- tively), and 16 T4 N3 (1 0 and 6, respectively). A complete response was seen in 24 of these patients (6/30 in A [20%], and 18/36 in B [50 ]; 2 = 6.3, P < 0.02). These com- plete responders included 8 T4 (I and 7 n A and B, re- spectively), 14 N3 (4 and 10, respectively), and 2 T4 N3 (1 and 1, respectively). Progression-free survival analysis in this subset confirms a clear advantage of the alternating arm (4% progression- free in arm A versus 12% in B at 4 years; X 2 = 7,1, P < 0.008). A similar behavior is noted in survival analysis (4% survival in A and 2 19 in B at 4 years; X 2 = 6.1, P < 0.02 . Stages Analysis according to stage shows a difference in the behavior of Stage 111 and Stage IV. Considering only pa- tients with Stage 111 disease, no differences are detectable between treatment arms A and B in terms of complete response (7/2 1 in A and 10/2 1 in B), progression-free sur- vival (5.5% in A and 6% in B at 3 years), and survival (20% in A and 2 1 in B at 4 years). On the contrary, the statistical analysis suggests a major role of alternating X loo 50 arm B 2 3 4 5 6 FIG. I. Overall progression-free survival. Arm A: 55 patients; Am B: 61 patients.  No. 4 CHEMO-RADIATION THERAPY N HEAD ND NECK CA Mer/ano el a/. 919 chemotherapy and radiation therapy in the management of Stage IV disease. The differences between the two treat- ment arms are statistically significant in terms of complete responses (7/33 in A and 20/39 in B; X 2 = 6.89, P < 0.009), progression-free survival (4% and 15% at 4 years in treatment arms A and B, respectively; X 2 = 7.0, P < 0.009), and survival (4% and 23 at 4 years, respec- tively; X 2 = 6.0, P < 0.02). Sites Patients enrolled were recorded, but not stratified, ac- cording to the region involved. The distribution by site is reported in Table 2. A statistical analysis was performed only in the two largest groups (oropharynx: 55 patients; oral cavity: 26 patients). Analysis took into account the difference in CR, PFS, and survival. None of the men- tioned points reaches statistical significance in the two groups. Prognostic Strat ijication At the time of their enrollment, patients were stratified into two prognostic groups on the basis of the 5-year sur- vival (see Table 1). No significant statistical difference was recorded between treatment arms A and B in the low-risk group as far as CR rate, PFS, and survival are concerned. On the contrary, all these factors were significantly im- proved in favor of treatment arm B in the high-risk group: complete response A versus B, P < 0.04; progression-free survival A verszis B, X 2 = 4.6, P < 0.03; survival A verszis B, X 2 = 6.1, P < 0.02 (Figs. 3 and 4). Toxicitv Toxicity is reported in Table 6. The most common side effect was mucositis. In treatment arm B we recorded 18 cases ofGrade 111-IV mucosal toxicity (30.5%); t occurred X I 2 3 5 years FIG. 3. High-risk group progression-free survival. Arm A: 36 patients; Arm B: 4 patients. usually after the second course of radiation therapy. On the contrary, in treatment arm A only three cases were detected. The statistical difference is highly significant (X 2 = 13.5, P < 0.00004). In treatment arm B, toxicity resulted in a treatment delay in eight patients (2 weeks in three patients and 1 week in five patients) and interruption of therapy in two patients (3.2%); these patients were con- sidered as NRs in response analysis (failure due to tox- icity). Discussion The present study is part of a continuing program of clinical trials devoted to the investigation of integrating chemotherapy and radiation therapy in squamous cell carcinoma of the head and neck. The end point of the study is a comparison between two different ways of in- tegrating chemotherapy and radiation therapy. Our results L 1 2 3 5 6 years 1 2 3 4 5 6 years FIG. 2. Overall survival. Arm A: 55 patients; Arm B: 6 1 patients. FIG. 4. High-risk group survival. Arm A: 36 patients; Am B: 40 pa- tients.
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