Fractionation is one of the most important factors in the outcome of radiotherapy. Conventional radiotherapy using a fractionation scheme of 1.8 to 2.0 Gy per fraction, five daily fractions per week to a total dose of 65.00­75.00 Gy may not be the optimal treatment for some squamous cell carcinomas of the upper respiratory and digestive tracts (URDT). On the other hand, treatment with multiple fractions per day can potentially provide a significant improvement in the therapeutic ratio using readily available low LET beams.

Recently, a number of strategies have been used in modifying radiotherapy fractionation schemes:

1. Accelerated fractionation: a shortening of the overall treatment duration by giving two or three fractions per day but using similar total dose per fraction as conventional fractionation.

2. Hyperfractionation: an increase in the number of fractions, giving two or three fractions per day, with smaller doses per fraction than conventional, higher total dose but same overall time as conventional.

3. Accelerated hyperfractionation: a greater fraction number, smaller fraction size and a shorter overall treatment duration than conventional.

4. Concomitant boost: a variation of accelerated hyperfractionation, giving a second daily dose of radiation to a reduced "field­within­a­field" during the course of conventional fractionated radiotherapy.

A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.

Fu KK, Int J Radiat Oncol Biol Phys 2000 Aug 1;48(1):7-16

Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Base-of-tongue carcinoma: treatment results using concomitant boost radiotherapy.

Mak AC, Int J Radiat Oncol Biol Phys 1995 Sep 30;33(2):289-96

Division of Radiotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Between September 1984 and July 1992, 54 patients with squamous carcinoma of the base of tongue were treated at The University of Texas M. D. Anderson Cancer Center using the concomitant boost schedule. The distribution of T and N stages was T1-4, T2-27, T3-22, and T4-1; N0-9, N1-11, N2-24, N3-7, and NX-3. American Joint Committee on Cancer (AJCC) stage groupings were II-6, III-14, and IV-34. Before radiation, nodal excision and neck dissection were done in 5 and 10 patients, respectively; 5 patients had neck dissections after radiotherapy. Standard on and off spinal cord fields were irradiated with 1.8 Gy fractions to 54 Gy given over 6 weeks. The boost was given concomitantly during the large field treatment as a second daily (1.5 Gy) fraction, with an interfraction interval of 4-6 h. The median dose to the primary tumor was 72 Gy (range, 66-74 Gy). The median treatment duration was 42 days (range, 39-48 days). Only three patients had treatment interrupted for more than one scheduled treatment day. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates were 59 and 65%, respectively, with a median follow-up of 41 months. The 5-year actuarial locoregional control rate was 76%. The actuarial local control rates achieved with radiotherapy at 5 years for T1, T2, and T3 primary tumors were 100%, 96%, and 67%, respectively; including surgical salvage, the local control rate of T3 primary tumors was 70%. Six patients had regional failures, which in three patients occurred in conjunction with primary tumor recurrence. Twenty-six patients with regional adenopathy were treated with radiation alone to full dose and had a complete clinical response in the neck; no planned neck dissections were performed in these patients. Only 2 of these 26 patients had subsequent regional failures. The 5-year actuarial risk of distant metastases in patients whose disease was controlled locoregionally was 21%. Grade 3 or 4 confluent acute mucositis occurred in 94% of patients. However, late complications were limited to two cases of transient mandibular exposure and three cases of self-limited mucosal ulcerations. CONCLUSION: The concomitant boost fractionation schedule is a very effective regimen for this disease when appropriately selected patients are treated with meticulous technique. The therapeutic ratio is favorable, with a high rate of disease control and no persistent severe late complications. Patients whose neck disease responds completely to treatment with this schedule do not appear to need a planned neck dissection.

Concomitant boost radiotherapy for squamous carcinoma of the tonsillar fossa.

Gwozdz JT, Int J Radiat Oncol Biol Phys 1997 Aug 1;39(1):127-35

The Division of Radiotherapy, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Between December 1983 and November 1992, 83 patients with squamous carcinoma of the tonsil were treated with concomitant boost fractionation. The distribution of American Joint Committee on Cancer T stages was TX-4, T1-5, T2-29, T3-41, T4-4; N stages were NX-1, N0-26, N1-13, N2-31, N3-12. Patients were treated with standard large fields to 54 Gy in 6 weeks. The boost treatment consisted of a second daily 1.5 Gy fraction for 10-12 fractions, usually delivered during the final phase of treatment. The tumor dose was 69-72 Gy, given over 6 weeks. Twenty-one patients, who all had N2 or N3 regional disease, underwent neck dissections, either before (13 patients) or 6 weeks after radiotherapy (8 patients); the other patients were treated with radiotherapy alone. RESULTS: The 5-year actuarial disease-specific survival and overall survival rates were 71 and 60%, respectively. Patients with T2 and T3 primary tumors had 5-year actuarial local control rates of 96 and 78%, respectively. Patients with T3 disease who received the final-phase boost had a 5-year actuarial local control rate of 82%. Actuarial 5-year regional disease control rates were N0, 92%; N1, 76%; N2, 89%; and N3, 89%. The 21 patients who had neck dissections all had their disease regionally controlled. Patients presenting with nodal disease or after a node excision who were treated with radiation alone had a 5-year actuarial regional disease control rate of 79%. All but five patients had confluent Grade 4 mucositis during treatment. Severe late complications attributable to radiation included mandibular necrosis [1], in-field osteosarcoma [1], and chronic dysphagia for solid foods [5]. CONCLUSIONS: High rates of local and regional disease control were achieved with the concomitant boost fractionation schedule, with few cases of severe late morbidity. Patients with N2 and N3 neck disease were effectively treated with radiation and the selective use of neck dissections. The concomitant boost schedule is our preferred fractionation approach for treating patients with intermediate stage tonsil cancer who are not participating in our current research protocols.

Accelerated concomitant boost radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma.

Wolden SL,  Clin Oncol 2001 Feb 15;19(4):1105-10

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. woldens@mskcc.org

From 1988 through 1999, 50 patients with American Joint Committee on Cancer stage II-IVb nasopharyngeal carcinoma were treated with 70-Gy concomitant boost RT (1.8 Gy/d, weeks 1 through 6; 1.6 Gy second daily fraction, weeks 5 through 6) and two cycles of concurrent cisplatin 100 mg/m(2) days 1 and 22. Thirty-seven patients also received three cycles of cisplatin-based adjuvant chemotherapy. These 50 patients were compared with a nonrandomized cohort of 51 patients with nasopharyngeal cancer treated with 70-Gy standard fractionation RT (1.8 Gy/d) without chemotherapy from 1988 through 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost RT/chemotherapy group was more advanced (54%, T3-4; 54%, N2-3; 44%, stage IV) compared with the standard RT group (31%, T3-4, P =.03; 22%, N2-3, P <.001; 20%, stage IV, P <.01). RESULTS: With a median follow-up of 42 months (range, 12 to 129 months), the 3-year actuarial local control, progression-free survival, and survival rates were 89% v 74% (P <.01), 66% v 54% (P =.01), and 84% v 71% (P =.04) for the concomitant boost RT/chemotherapy group and the standard RT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% v 43% (P <.001), resulting in a higher rate of temporary gastrostomy tube placement, 46% v 20% (P <.01). CONCLUSION: Concomitant boost RT with cisplatin-based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced nasopharyngeal cancer compared with standard RT alone.

Concurrent chemotherapy and "concomitant boost" radiotherapy for unresectable head and neck cancer.

Teh BS, Am J Otolaryngol 2000 Sep-Oct;21(5):306-11

Department of Radiation Oncology, Veterans Affairs Medical Center and Baylor College of Medicine, Houston TX, USA.

PURPOSE: For patients with advanced head and neck cancer, various combined chemoradiotherapy regimens have been used to improve local control. This study was carried out to assess the outcome of concomitant chemotherapy with a "concomitant boost" radiotherapy in the treatment of advanced unresectable head and neck cancer patients. MATERIALS AND METHODS: Forty-eight patients were treated with combined chemoradiotherapy between the years of 1990 and 1995. Cisplatinum (100 mg/m2) was given intravenously during week 1 and week 5. A "concomitant boost" external beam radiotherapy approach was used with twice-daily treatment delivered during the last 2 weeks. A total of 70 Gy was delivered over 6 weeks. Median follow-up was 23.5 months (2-79 months). RESULTS: Thirty-one (65%) and 17 (35%) patients achieved complete and partial response, respectively. Median survival in complete responders has not been reached. Overall survival at 2 years, 3 years, and 5 years were 58.7%, 52.8%, and 42.4%, respectively. Median overall survival was 38.8 months. Acute confluent mucositis (Radiation Therapy Oncology [RTOG] grade 3) developed in 50% of patients, but there was no severe long-term treatment-related toxicity. CONCLUSION: This combined chemoradiotherapy approach is safe and efficacious for advanced unresectable head and neck cancer. Treatment-related toxicity was acceptable with 50% of patients developing acute confluent mucositis. There was no severe long-term treatment-related toxicity.

Feasibility and outcome of a progressively accelerated concomitant boost radiotherapy schedule for head and neck carcinomas.

Allal AS, Int J Radiat Oncol Biol Phys 1997 Jul 1;38(4):685-9

Division of Radiation Oncology, University Hospital, Geneva, Switzerland.

The basic treatment delivered 50.4 Gy in 28 fractions, once a day, to the primary site and both sides of the neck. During the last 3.5 weeks, a boost to the initial gross disease was delivered in 13 fractions of 1.5 Gy each as a second daily fraction in a progressively accelerated schedule (total dose 69.9 Gy). According to the RTOG scoring system, 57 patients (67%) presented with Grade 3-4 acute toxicity. Grade 3 dysphagia was observed in 20 patients (23.5%). Three patients died during the 3 months following the treatment. Among 73 patients evaluable for late effects, five developed Grade 3-4 complications. At 3 years actuarial loco-regional control was 67% and overall survival was 62%. CONCLUSIONS: Although longer follow-up is needed to evaluate the definitive results, we conclude that this particular concomitant boost schedule is feasible and appears to be effective.

Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

Johnson CR, Cancer 1992 Jun 1;69(11):2749-54

Department of Radiation Oncology, Medical College of Virginia, Richmond 23298-0058.

Of 142 patients irradiated for American Joint Committee on Cancer Stage III or IV head and neck carcinoma, 100 patients were eligible for analysis with a minimum follow-up of 12 months. In one group, 50 patients were treated with conventional once-a-day (QD) fractionation to doses in excess of 6600 cGy. The other 50 patients were treated prospectively with accelerated superfractionated radiation therapy using a concomitant boost twice-a-day schedule (BID). Patients received conventional fractionation (180 cGy/fraction) combined with a boost field of 160 cGy/fraction BID after a 4-hour to 6-hour interval 3 days per week during part of their treatment course. After 3 years, locoregional tumor control was 62% in the BID group versus 33% in the QD group (P = 0.003). Disease-free survival was 60% and 30%, respectively, for the BID and QD groups (P = 0.002), and adjusted survival was 66% and 38%, respectively, for the BID and QD groups (P = 0.03). Overall survival approached statistical significance in favor of the BID group (P = 0.06). Complete tumor responses were observed in 63% of patients treated in the BID group 1 to 3 months after completion of radiation therapy. Of these, 84% remain free of local recurrence. Of the 19 patients with persistent disease 1 to 3 months after treatment, 47% remain locally controlled. Superfractionated accelerated radiation therapy produced superior local control and disease-free and adjusted survival rates relative to a group of patients treated QD.

Simultaneous radiochemotherapy versus concomitant boost radiation for advanced inoperable head and neck cancer.

Schafer U, Acta Oncol 2000;39(4):523-8

Department of Radiation Oncology, University of Munster, Germany.

In this prospective, non-randomized study we compare the results of simultaneous radiochemotherapy (RCT) with those of concomitant boost treatment (CBT) in advanced head and neck cancer. From January 1993 to March 1999, 77 patients were treated with cisplatin, 5-FU, and 70.2 Gy (accelerated split-course); from January 1995 to March 1999, a further 33 patients received CBT to a total dose of 72 Gy. Toxicities were prospectively recorded according to RTOG/EORTC criteria. Acute and subacute reactions did not differ significantly. Severe late effects (III/IV) remained anecdotal (one fistula). Therapy-associated mortalities were 3%(RCT) vs. 0% (CBT), most tumors responding well to therapy (CR + PR: RCT: 72%, CBT: 63%). The 2-year probabilities for freedom from locoregional progression amounted to 42% (RCT) and 31% (CBT); p > 0.05. Tumor-specific 2-year survival amounted to 40% (RCT) and 34% (CBT); p > 0.05. Both of the treatment concepts yield high remission rates with moderate toxicities. Nevertheless, median time to recurrence is still fairly short. We could not find any differences for local control and survival. For patients who are not able to complete the full three courses of radiochemotherapy, the concomitant boost schedule presents a good alternative.