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Hyperfractionated Radiotherapy Versus Hyperfractionated Radiotherapy and Concomitant Chemotherapy in Locally Advanced Head and Neck Cancer
Proceedings of the 49th Annual ASTRO Meeting Results: In patients with toxicity, the top 20% portion and 20–80% of the width of the 2D map received a significantly higher mean dose (51 Gy vs 38 Gy). The regions receiving minimum doses from 0 to 35 Gy and 50 to 70 Gy had a significantly larger absolute area. Regions irradiated to doses $ 50 Gy up to doses $ 75 Gy were significantly more eccentric while regions receiving doses $ 10 Gy to $ 30 Gy were significantly more compact. The boundaries of regions receiving at least 70 and 75 Gy (isodose contours at 70, 75 Gy) were significantly more regular in shape. The volume and height of the PTV and the surface area and length of the rectum were all significantly larger. Conclusions: We have further characterized the region which received higher doses in patients who developed late rectal toxicity. We observed a dose-area effect and identified shape and anatomical measures which were correlated with rectal toxicity, including greater regularity of isodose contours. A possible interpretation of the findings on contour regularity is that regions of lower doses between regions of high doses are more prevalent in patients free of rectal toxicity than in patients with rectal toxicity. The presence of such regions may help reduce damage to the rectal wall. The analysis suggests that multiple variables, including dosimetric, anatomic and spatial factors, contribute to the development of late rectal toxicity. [1] Munbodh et al. IJROBP; 66 (3); S76. [2] Haker et al. IEEE Trans Med Imag 2000; 19: 665–670. Author Disclosure: R. Munbodh, None; A. Jackson, None; J.D. Bauer, None; C. Schmidtlein, None; M.J. Zelefsky, None.
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Mitomycin-C and 5-Fluoro-Uracil Containing Chemotherapy With Concurrent Hyperfractionated Accelerated RadioTherapy (C-HART) of 70.6 Gy Is More Effective than Dose Escalated HART of 77.6 Gy Alone–10 Year Results of the German Multicenter Phase III Randomized Trial (ARO 95-06)
V. G. F. Budach1, C. Poettgen2, M. Baumann3, W. Budach4, G. Grabenbauer5, L. Moser6, P. Wust7, D. Kuczer1, K. Jahnke8, K. Wernecke9 1 Dept. for Radiation Oncology, Campus Mitte, Charite´ University Medicine Berlin, Germany, 2Dept. for Radiation Oncology, University Hospitals of Essen, Germany, 3Dept. for Radiation Oncology, University Hospitals of Dresden, Germany, 4Dept. for Radiation Oncology, University Hospitals of Duesseldorf, Germany, 5Dept. for Radiation Oncology, University Hospitals Erlangen, Germany, 6Dept. for Radiation Oncology, CBF, Charite´ University Medicine Berlin, Germany, 7Dept. for Radiation Oncology, Campus Virchow, Charite´ University Medicine Berlin, Germany, 8Dept. for Head and Neck Surgery, University Hospitals of Essen, Germany, 9Sostana Co. for Biometrics, Campus Mitte, Charite´ University Medicine Berlin, Germany
Purpose/Objective(s): Is accelerated hyperfractionated radiation therapy of 70,6 Gy with concurrent Mitomycin C/5-FU (C-HART) more effective than dose escalated HART with 77.6 Gy alone? The results of the German ARO 95-06 multicenter trial with 10 participating centers are shown in terms of Loco-regional Control (LRC), Overall Survival (OS), Disease-Free Survival (DFS) and distant Metastases-Free Survival (MFS). Materials/Methods: For C-HART the fractionation schedule was 2.0 Gy q.d. to 30 Gy followed by 1.4 Gy b.i.d. to a total dose of 70.6 Gy with concurrent Mitomycin C (10 mg/m2 days 5 and 35) and 5-Fluoro-Uracil (600 mg/m2 c.i. days 1–5). For HART the fractionation schedule was 2.0 Gy to 14 Gy followed by 1.4 Gy b.i.d. to an escalated total dose of 77.6 Gy. The overall treatment time of six weeks was kept constant in both treatment arms. Macroscopic tumor received 70.6 Gy (C-HART) or 77.6 Gy (HART), the lymphatic drainage with high or low risk of metastatic spread 60 Gy or 50 Gy, respectively. Results: The median follow-up period as 120 months. 11/373 patients had to be excluded from the ‘‘intent to treat’’ analysis due to ineligibility criteria. The mean age of the patients was 54.5 years, 84% of all patients were males, 14% females. 59.5% (n = 222) of all patients suffered from oropharyngeal, 32.3% (n = 120) from hypopharyngeal and 8.2% from oral cavity (n = 31) cancer. 93.8% of all cases (n = 350) had stage IV and 6.2% (n = 23) stage III cancer according to the UICC-1987 classification at diagnosis. All patients had squamous cell or undifferentiated histologies. The data were processed according the ‘‘intent to treat’’ principle. The actuarial LRC-rates for C-HART vs. HART, respectively, were 49.6% vs. 36.7% at 10 years (HR: 0.62, 95% CI: 0.47–0.83, plog-rank = 0.001) and OS-rates were 28.3% vs. 22.6% (HR: 0.76, 95% CI: 0.60–0.97, plog-rank = 0.027). The median LRC-period was 57 mos. vs. 15 mos. and 23 mos. vs. 16 mos. for OS, respectively. The actuarial DFS-rates (C-HART vs. HART), respectively, were 42.3% vs. 34.5% at 10 years (HR: 0.74, 95% CI: 0.56–0.99, plog-rank = 0.036) and MFS-rates were 53.4% vs. 55.5% (HR: 0.95, 95% CI: 0.67–1.34, plog-rank = 0.425). The median DFS-period was 33 mos. vs. 22 mos. and not yet reached for the MFS-rates. Twelve documented parameters for late normal tissue reactions showed no significant difference between both treatment arms, in particular also not for L’hermittes Syndrome, plexopathia and osteoradionecrosis of the mandible. Conclusions: C-HART is more effective than HART with a mean follow-up of 10 years in terms of LRC, DFS and OS despite a 10% lower total radiation dose. Since late normal tissue reactions were equivalent for both treatment arms this clearly indicates an improved therapeutic ratio. Distant MFS was equal for both treatment arms thus showing Mitomycin C and 5-FU not being effective in preventing overt metastatic disease. A subsequent multicenter trial (ARO 05-01) was launched in 2005 and meanwhile recruited .250 patients. The aim is a reduction of the distant metastases rates and thereby an improvement of OS. Likewise, C-HART is combined with once weekly DDP (30 mg/m2 6) vs. the classical C-HART arm. Author Disclosure: V.G.F. Budach, None; C. Poettgen, None; M. Baumann, None; W. Budach, None; G. Grabenbauer, None; L. Moser, None; P. Wust, None; D. Kuczer, None; K. Jahnke, None; K. Wernecke, None.
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Hyperfractionated Radiotherapy Versus Hyperfractionated Radiotherapy and Concomitant Chemotherapy in Locally Advanced Head and Neck Cancer
M. Kasibhatla, L. R. Prosnitz, S. R. Fisher, R. L. Scher, R. Clough, D. M. Brizel Duke University Medical Center, Durham, NC Purpose/Objective(s): This report provides long term follow-up of one of the earliest phase III trials comparing accelerated hyperfractionated radiotherapy alone (HFRT) as standard therapy against hyperfractionated radiotherapy with concurrent chemotherapy (HFRT+CT) in locally advanced head and neck cancer (HNC).
S11
I. J. Radiation Oncology d Biology d Physics
S12
Volume 69, Number 3, Supplement, 2007
Materials/Methods: Eligibility criteria included T3-4 primary squamous cell HNC with or without cervical lymphadenopathy. Patients with distant metastases were excluded. Patients randomized to HFRT received 75 Gy in 1.25 Gy/fraction twice daily while those randomized to HFRT+CT received 1.25 Gy/fraction twice daily to 70 Gy. Concurrent cisplatin 12 mg/m2/day and 5-FU 600 mg/m2/day were administered over five days during the first and sixth weeks of radiotherapy. Patients with $N2 presentations and a complete primary tumor response underwent neck dissection 6–8 weeks after the completion of radiotherapy. Survival curves were estimated by the Kaplan-Meier method. The Cox-Mantel test was used to compare survival distributions between the HFRT and HFRT+CT groups. Results: Median follow-up is now 113 months for surviving patients. Most enrolled patients had primary tumors of the oropharynx (45%), hypopharynx (20%) or larynx (16%) with either T3-4 (88%) or N2-3 disease (53%). Patients receiving HFRT+CT achieved superior 10 year loco-regional control (LRC) and failure free survival (FFS) compared with HFRT alone (Figs. 1, 2 and Table 1). There was a trend towards improved cause specific survival (CSS). Freedom from distant failure (FFDF) did not significantly differ with HFRT+CT versus HFRT alone. Conclusions: HFRT+CT improved 10 yr FFS and LRC compared with HFRT alone. There is a strong trend towards improved 10 yr CSS. The superiority of HFRT with concurrent CT over HFRT alone has since been confirmed in other phase 3 trials.
Table 1: Outcome with HFRT versus HFRT + CT HFRT (%) 10 year LRF 10 yr FFDF 10 yr FFS 10 yr CSS
44 57 30 32
HFRT + CT (%) 70, p = 0.008 81, p = 0.2 55, p = 0.05 57, p = 0.07
Author Disclosure: M. Kasibhatla, None; L.R. Prosnitz, None; S.R. Fisher, None; R.L. Scher, None; R. Clough, None; D.M. Brizel, None.
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A Phase III Trial to Compare Standard Versus Accelerated Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas (RTOG 0129): Report of Compliance and Toxicity
K. Ang1, T. Pajak2, D. I. Rosenthal1, F. Nguyen3, C. Lu1, H. Kim4, R. Axelrod5, M. List6, C. Silverman7, R. S. Weber1, et al. 1 M.D. Anderson Cancer Center, Houston, TX, 2American College of Radiology, Philadelphia, PA, 3Centre Hospitalier de l’Universite´ de Montreal, Montreal, PQ, Canada, 4Wayne State University Medical School, Detroit, MI, 5Thomas Jefferson University, Philadelphia, PA, 6University of Chicago, Chicago, IL, 7University of Louisville, Louisville, KY
Purpose/Objective(s): A phase III trial was conducted to compare the relative toxicity and efficacy of combining the standard fractionation (SFX) versus an accelerated regimen by concomitant boost (AFX-C) with concurrent cisplatin. Frequent inquiries triggered this first analysis focusing on compliance and toxicity of treatments. Material/Methods: From July 2002 to June 2005, 743 patients with stage III or IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and having Zubrod performance status of 0–1 and adequate hematologic, hepatic, and renal functions were enrolled. A total of 723 were analyzable, of whom 361 received SFX + cisplatin and 362 received AFX-C + cisplatin. The distribution between the 2 arms was balanced in patient age (median: 56–55.5 years), gender (male: 85%–80%), performance status (Zubrod 0: 57%–59%; 1: 43%–41%), primary site (oropharynx: 60%–60%; larynx: 25%–27%; others: 15%–13%), and AJCC stage (IV: 79%–78%). The radiation doses prescribed were 70 Gy/35 F/7 W and 72 Gy/42 F/6 W for the SFX and AFX-C arms, respectively. Cisplatin, 100 mg/m2, was given iv q3W, for 3 and 2 courses, respectively. Acute RT toxicities (#90 days from start of RT) and systemic effects at any time were scored using CTC version 2.0 and late RT complications using the RTOG/EORTC Scheme. Results: Radiotherapy was delivered according to the protocol or with acceptable minor variation in 96% and 92% of patients on the SFX and AFX-C arms, respectively. For cisplatin, 68% on SFX arm received all 3 planned cycles whereas 87% on the AFX-C arm received both planned cycles. Table 1 summarizes the acute toxicity and late morbidity observed after a median follow-up of 2.0 years for all patients and 2.4 years for living patients. The proportions of patients with feeding tube were 25% and 22% before therapy, 68% and 67% at the end of treatment, and 30% and 27% at 1 year from therapy for the 2 arms, respectively. No statistically significant difference was detected for any toxicity endpoint. aFrom all causes up to 30 days after completion of treatment. b Definitely or probably related to treatment.
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Mitomycin-C and 5-Fluoro-Uracil Containing Chemotherapy With Concurrent Hyperfractionated Accelerated RadioTherapy (C-HART) of 70.6 Gy Is More Effective than Dose Escalated HART of 77.6 Gy Alone–10 Year Results of the German Multicenter Phase III Randomized Trial (ARO 95-06)
V. G. F. Budach1, C. Poettgen2, M. Baumann3, W. Budach4, G. Grabenbauer5, L. Moser6, P. Wust7, D. Kuczer1, K. Jahnke8, K. Wernecke9 1 Dept. for Radiation Oncology, Campus Mitte, Charite´ University Medicine Berlin, Germany, 2Dept. for Radiation Oncology, University Hospitals of Essen, Germany, 3Dept. for Radiation Oncology, University Hospitals of Dresden, Germany, 4Dept. for Radiation Oncology, University Hospitals of Duesseldorf, Germany, 5Dept. for Radiation Oncology, University Hospitals Erlangen, Germany, 6Dept. for Radiation Oncology, CBF, Charite´ University Medicine Berlin, Germany, 7Dept. for Radiation Oncology, Campus Virchow, Charite´ University Medicine Berlin, Germany, 8Dept. for Head and Neck Surgery, University Hospitals of Essen, Germany, 9Sostana Co. for Biometrics, Campus Mitte, Charite´ University Medicine Berlin, Germany
Purpose/Objective(s): Is accelerated hyperfractionated radiation therapy of 70,6 Gy with concurrent Mitomycin C/5-FU (C-HART) more effective than dose escalated HART with 77.6 Gy alone? The results of the German ARO 95-06 multicenter trial with 10 participating centers are shown in terms of Loco-regional Control (LRC), Overall Survival (OS), Disease-Free Survival (DFS) and distant Metastases-Free Survival (MFS). Materials/Methods: For C-HART the fractionation schedule was 2.0 Gy q.d. to 30 Gy followed by 1.4 Gy b.i.d. to a total dose of 70.6 Gy with concurrent Mitomycin C (10 mg/m2 days 5 and 35) and 5-Fluoro-Uracil (600 mg/m2 c.i. days 1–5). For HART the fractionation schedule was 2.0 Gy to 14 Gy followed by 1.4 Gy b.i.d. to an escalated total dose of 77.6 Gy. The overall treatment time of six weeks was kept constant in both treatment arms. Macroscopic tumor received 70.6 Gy (C-HART) or 77.6 Gy (HART), the lymphatic drainage with high or low risk of metastatic spread 60 Gy or 50 Gy, respectively. Results: The median follow-up period as 120 months. 11/373 patients had to be excluded from the ‘‘intent to treat’’ analysis due to ineligibility criteria. The mean age of the patients was 54.5 years, 84% of all patients were males, 14% females. 59.5% (n = 222) of all patients suffered from oropharyngeal, 32.3% (n = 120) from hypopharyngeal and 8.2% from oral cavity (n = 31) cancer. 93.8% of all cases (n = 350) had stage IV and 6.2% (n = 23) stage III cancer according to the UICC-1987 classification at diagnosis. All patients had squamous cell or undifferentiated histologies. The data were processed according the ‘‘intent to treat’’ principle. The actuarial LRC-rates for C-HART vs. HART, respectively, were 49.6% vs. 36.7% at 10 years (HR: 0.62, 95% CI: 0.47–0.83, plog-rank = 0.001) and OS-rates were 28.3% vs. 22.6% (HR: 0.76, 95% CI: 0.60–0.97, plog-rank = 0.027). The median LRC-period was 57 mos. vs. 15 mos. and 23 mos. vs. 16 mos. for OS, respectively. The actuarial DFS-rates (C-HART vs. HART), respectively, were 42.3% vs. 34.5% at 10 years (HR: 0.74, 95% CI: 0.56–0.99, plog-rank = 0.036) and MFS-rates were 53.4% vs. 55.5% (HR: 0.95, 95% CI: 0.67–1.34, plog-rank = 0.425). The median DFS-period was 33 mos. vs. 22 mos. and not yet reached for the MFS-rates. Twelve documented parameters for late normal tissue reactions showed no significant difference between both treatment arms, in particular also not for L’hermittes Syndrome, plexopathia and osteoradionecrosis of the mandible. Conclusions: C-HART is more effective than HART with a mean follow-up of 10 years in terms of LRC, DFS and OS despite a 10% lower total radiation dose. Since late normal tissue reactions were equivalent for both treatment arms this clearly indicates an improved therapeutic ratio. Distant MFS was equal for both treatment arms thus showing Mitomycin C and 5-FU not being effective in preventing overt metastatic disease. A subsequent multicenter trial (ARO 05-01) was launched in 2005 and meanwhile recruited .250 patients. The aim is a reduction of the distant metastases rates and thereby an improvement of OS. Likewise, C-HART is combined with once weekly DDP (30 mg/m2 6) vs. the classical C-HART arm. Author Disclosure: V.G.F. Budach, None; C. Poettgen, None; M. Baumann, None; W. Budach, None; G. Grabenbauer, None; L. Moser, None; P. Wust, None; D. Kuczer, None; K. Jahnke, None; K. Wernecke, None.
20
Hyperfractionated Radiotherapy Versus Hyperfractionated Radiotherapy and Concomitant Chemotherapy in Locally Advanced Head and Neck Cancer
M. Kasibhatla, L. R. Prosnitz, S. R. Fisher, R. L. Scher, R. Clough, D. M. Brizel Duke University Medical Center, Durham, NC Purpose/Objective(s): This report provides long term follow-up of one of the earliest phase III trials comparing accelerated hyperfractionated radiotherapy alone (HFRT) as standard therapy against hyperfractionated radiotherapy with concurrent chemotherapy (HFRT+CT) in locally advanced head and neck cancer (HNC).
S11
I. J. Radiation Oncology d Biology d Physics
S12
Volume 69, Number 3, Supplement, 2007
Materials/Methods: Eligibility criteria included T3-4 primary squamous cell HNC with or without cervical lymphadenopathy. Patients with distant metastases were excluded. Patients randomized to HFRT received 75 Gy in 1.25 Gy/fraction twice daily while those randomized to HFRT+CT received 1.25 Gy/fraction twice daily to 70 Gy. Concurrent cisplatin 12 mg/m2/day and 5-FU 600 mg/m2/day were administered over five days during the first and sixth weeks of radiotherapy. Patients with $N2 presentations and a complete primary tumor response underwent neck dissection 6–8 weeks after the completion of radiotherapy. Survival curves were estimated by the Kaplan-Meier method. The Cox-Mantel test was used to compare survival distributions between the HFRT and HFRT+CT groups. Results: Median follow-up is now 113 months for surviving patients. Most enrolled patients had primary tumors of the oropharynx (45%), hypopharynx (20%) or larynx (16%) with either T3-4 (88%) or N2-3 disease (53%). Patients receiving HFRT+CT achieved superior 10 year loco-regional control (LRC) and failure free survival (FFS) compared with HFRT alone (Figs. 1, 2 and Table 1). There was a trend towards improved cause specific survival (CSS). Freedom from distant failure (FFDF) did not significantly differ with HFRT+CT versus HFRT alone. Conclusions: HFRT+CT improved 10 yr FFS and LRC compared with HFRT alone. There is a strong trend towards improved 10 yr CSS. The superiority of HFRT with concurrent CT over HFRT alone has since been confirmed in other phase 3 trials.
Table 1: Outcome with HFRT versus HFRT + CT HFRT (%) 10 year LRF 10 yr FFDF 10 yr FFS 10 yr CSS
44 57 30 32
HFRT + CT (%) 70, p = 0.008 81, p = 0.2 55, p = 0.05 57, p = 0.07
Author Disclosure: M. Kasibhatla, None; L.R. Prosnitz, None; S.R. Fisher, None; R.L. Scher, None; R. Clough, None; D.M. Brizel, None.
21
A Phase III Trial to Compare Standard Versus Accelerated Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas (RTOG 0129): Report of Compliance and Toxicity
K. Ang1, T. Pajak2, D. I. Rosenthal1, F. Nguyen3, C. Lu1, H. Kim4, R. Axelrod5, M. List6, C. Silverman7, R. S. Weber1, et al. 1 M.D. Anderson Cancer Center, Houston, TX, 2American College of Radiology, Philadelphia, PA, 3Centre Hospitalier de l’Universite´ de Montreal, Montreal, PQ, Canada, 4Wayne State University Medical School, Detroit, MI, 5Thomas Jefferson University, Philadelphia, PA, 6University of Chicago, Chicago, IL, 7University of Louisville, Louisville, KY
Purpose/Objective(s): A phase III trial was conducted to compare the relative toxicity and efficacy of combining the standard fractionation (SFX) versus an accelerated regimen by concomitant boost (AFX-C) with concurrent cisplatin. Frequent inquiries triggered this first analysis focusing on compliance and toxicity of treatments. Material/Methods: From July 2002 to June 2005, 743 patients with stage III or IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and having Zubrod performance status of 0–1 and adequate hematologic, hepatic, and renal functions were enrolled. A total of 723 were analyzable, of whom 361 received SFX + cisplatin and 362 received AFX-C + cisplatin. The distribution between the 2 arms was balanced in patient age (median: 56–55.5 years), gender (male: 85%–80%), performance status (Zubrod 0: 57%–59%; 1: 43%–41%), primary site (oropharynx: 60%–60%; larynx: 25%–27%; others: 15%–13%), and AJCC stage (IV: 79%–78%). The radiation doses prescribed were 70 Gy/35 F/7 W and 72 Gy/42 F/6 W for the SFX and AFX-C arms, respectively. Cisplatin, 100 mg/m2, was given iv q3W, for 3 and 2 courses, respectively. Acute RT toxicities (#90 days from start of RT) and systemic effects at any time were scored using CTC version 2.0 and late RT complications using the RTOG/EORTC Scheme. Results: Radiotherapy was delivered according to the protocol or with acceptable minor variation in 96% and 92% of patients on the SFX and AFX-C arms, respectively. For cisplatin, 68% on SFX arm received all 3 planned cycles whereas 87% on the AFX-C arm received both planned cycles. Table 1 summarizes the acute toxicity and late morbidity observed after a median follow-up of 2.0 years for all patients and 2.4 years for living patients. The proportions of patients with feeding tube were 25% and 22% before therapy, 68% and 67% at the end of treatment, and 30% and 27% at 1 year from therapy for the 2 arms, respectively. No statistically significant difference was detected for any toxicity endpoint. aFrom all causes up to 30 days after completion of treatment. b Definitely or probably related to treatment.