RADIATION THERAPY ONCOLOGY GROUP / RTOG 99-14

2 Gy / 42 fxs / 6 weeks (AFX-CB^*) plus cisplatin (100 mg/m²) on days 1 and 22 (week 1 and week 3, before initiation of twice a day irradiation).
Accelerated Fractionation with Concomitant Boost:
a. Large Field:

32.4 Gy/18 fx/3 1/2 weeks
1.8 Gy/fx/day, 5 days/week

b. Concomitant Boost:

1.5 Gy/fx/day to boost field for 18.0 Gy/12 fx > 6 hours after large field treatment
Large Field Treatment to receive 21.6 Gy/12 fx, 1.8/fx

Total Dose:

72.0 Gy/42 fx/6 weeks

1.0 BACKGROUND

1.1 Radiotherapy

Surgical resection of advanced resectable stage III and IV head and neck squamous cell carcinomas (HNSCC), often followed by adjuvant radiotherapy, is the current standard of care in most cases  though this is often associated with cosmetic and functional impairment affecting quality of life. Results of conventionally fractionated radiotherapy as a single modality for patients with resectable and unresectable advance HNSCC are rather poor in terms of local control and survival. Several approaches have been used to improve non-surgical results of treatment of advanced head and neck cancers. One approach is to use altered fractionated radiation as the sole modality. Multiple studies have tested hyperfractionation and various accelerated fractionation regimens with positive results.

1.2 RTOG Phase III Trial on Altered Fractionation

RTOG 90-03 is a large randomized trial comparing standard fractionation (SFX) against hyperfractionation (HFX), accelerated fractionation with split-course (AFX-S), and accelerated fractionation by concomitant boost (AFX-CB) in the management of patients with advanced HNSCC. Between September 1991 and August 1997, 1113 patients were enrolled. Analysis undertaken in September of 1999 revealed that AFX-CB and HFX yielded a significantly higher local-regional control rate (LRC) than SFX (p=0.05) but not AFX-S (p=0.67). AFX-CB was associated with a higher transient grade 3 late toxicity. However, there was no difference in the incidence of persistent grade 3 or grade 4 late toxicity among the arms at one year or longer follow-up. The results of this trial reveal that tumor clonogen proliferation during a course of radiotherapy is a major cause of radiation failure. The Head and Neck Committee decided to develop a novel combined therapy regimen based on the AFX-CB regimen because of its logistic convenience.

1.3 Combination of Radiotherapy and Chemotherapy

A second strategy pursued to improve results of non-surgical treatment of advanced HNSCC has been to add chemotherapy to radiation. With this approach, chemotherapy can be delivered sequentially, i.e., before (neoadjuvant) or after (adjuvant) radiation or concurrently with radiation. Sequential radiation-chemotherapy has been studied extensively in prospective pilot and large randomized trials. So far, a survival advantage over standard surgery has not been demonstrated, but organ preservation has been achieved in many patients. Response rates to chemotherapy are high, and a decrease in distant metastases has been demonstrated in some trials. Despite a high response rate in trials comparing neoadjuvant chemotherapy and radiation to radiation alone, improved LRC has not been shown.

Recognizing that a variety of chemotherapeutic agents can enhance the effects of radiation not only through different cytotoxic mechanisms, but also by a direct radiosensitization, more recent efforts have been aimed at studying the effects of concurrent radiation-chemotherapy. Single agent cisplatin, 5-fluorouracil, bleomycin, methotrexate,mitomycin C,and hydroxyureahave been used in combination with radiation therapy in several trials. Response rates have been improved and improvements in survival have been noted in some trials. The addition of some single agents to radiation has improved response rates at the cost of additional toxicity.

Combination chemotherapy has shown increased response rates in recurrent or metastatic disease compared to single agent therapy. Thus more recent studies have applied the concept of multi-agent chemotherapy combined with radiation Recognizing the pitfalls of meta-analysis, there is evidence for a survival advantage in patients receiving concurrent radiation-chemotherapy (though at the expense of increased morbidity).One example of a randomized study evaluating multi-agent chemotherapy and conventional radiation was done by the NCOG and reported by Fu et al. Using concomitant bleomycin, methotrexate and radiation resulted in improved relapse free survival rates but had an incidence of severe late toxicity of 10% (4 patients) in patients treated with combination therapy compared to 2% (1 patient) of patients treated with radiation only. None of the side effects was life threatening.

Several groups have evaluated cisplatin with or without 5-FU in combination with radiation, as both agents have been found to have radiation sensitizing effects in vitro. Several trials have given cisplatin and 5-FU throughout radiotherapy. Taylor et al.gave cisplatin 60mg/m² and 5-FU 800mg/m² in 14-day cycles with conventional radiotherapy. They demonstrated an improved freedom from recurrence in patients treated with concurrent radiation compared to sequential chemoradiation. There was however an increase in mucositis requiring supportive care in the concurrent group. Other trials have given cisplatin at doses as high as 100 mg/m² every three weeks with tolerable toxicity. Gandia et al. treated head and neck cancer patients with cisplatin 80mg/m² every 3 weeks for 3 cycles and 5-FU 300mg/m²/day by continuous infusion for 7 weeks during radiotherapy to a total dose of 70 Gy given over 7 weeks with acceptable toxicity.

Investigators at the University of Chicago have investigated the concurrent administration of hydroxyurea and 5-FU with radiation therapy. This is based on established clinical activity of both agents and preclinical evidence of a synergistic interaction of the two drugs (the ribonucleotide reductase inhibitor hydroxyurea depletes cells of the deoxyuridine monophosphate (dUMP) and thereby facilitates binding of the 5-FU metabolite 5-FdUMP to its target enzyme thymidylate synthase). Both agents have been shown to be radiation enhancers in preclinical and clinical settings.

More recently, paclitaxel has generated interest as it has shown in vitro radiosensitization, and has clinically been investigated with radiation both as a single agent and in combination with cisplatin. Paclitaxel (Taxol), a novel diterpene compound, isolated from the bark of the pacific yew Taxus brevifolia, binds to tubulin and induces the formation of stable microtubules. This results in blocking cells in the G2 or M phase of the cell cycle. In phase II trials paclitaxel has been shown to be active in ovary, lung, breast and head and neck cancer. At Johns Hopkins University, and elsewhere, paclitaxel has been studied extensively. Myelosuppression is the primary toxicity, specifically neutropenia. Neurotoxicity is dose limiting when single agent doses exceed 250 mg/m². Mucositis is an uncommon toxicity of paclitaxel in doses less than 300 mg/m

1.4 RTOG Trials on Combined Radiation-Chemotherapy

Available data suggest that concurrent radiation and multi-agent chemotherapy may improve outcome of patients with local-regionally advanced HNSCC. However, there is still a need to refine combined regimen. Questions such as which agents may be most appropriate and what is the optimal timing of drug administration remained to be answered. Ideally, combination schedules should be based on mechanisms of radiation-drug interaction. Unfortunately, the modes of interaction for most drugs are not well understood.

Two ongoing RTOG trials address some relevant questions mentioned above. RTOG 91-11, a phase III trial in patients with T3 and selected T4 laryngeal carcinoma, is assessing the relative efficacy of cisplatin given at days 1, 22, 43 of standard radiotherapy against neoadjuvant chemotherapy (the VA cisplatin-fluorouracil regimen) plus standard radiotherapy⁹ and radiation alone in preserving larynx. RTOG 97-03, a randomized phase II trial in patients with stage III & IV disease, is evaluating different approaches of combining radiation and chemotherapy using both different agents and different timing of radiation-drug administration. The three regimens being tested are: 1) daily cisplatin-fluorouracil given during the last two weeks of the 7-week standard radiotherapy; 2) combination of fluorouracil-hydroxyurea and once-a-day radiotherapy administered every other week for a total of 13 weeks; and 3) weekly cisplatin and paclitaxel during the 7-week standard radiotherapy. These two trials are projected to complete patient accrual in 6-12 months but the final tumor control and toxicity data will not be available for at least 2 additional years.

Objective of the Proposed Study: This trial builds on the results of RTOG 90-03 showing that accelerated fractionation by concomitant boost (AFX-CB) yielded a significantly higher LRC than standard fractionation without increasing the persistent grade 3-4 toxicity. The primary objective of the present study is to test the feasibility of combining AFX-CB with cytotoxic or biologic agents selected preferentially based on mechanisms of action/interaction.

1.5 Rationale and Preliminary Data of Proposed Combined Regimen

1.5.1 This regimen consists of combination of AFX-CB with cisplatin. Cisplatin has been shown to enhance radiation response though the exact mechanisms are not well understood. RTOG has studied and is testing combinations of standard radiotherapy with cisplatin in advanced HNSCC (e.g., RTOG 81-17, RTOG 91-11). It is thus desirable to assess the feasibility of combining AFX-CB with cisplatin. This arm is considered the closest to the potential new standard treatment. The 6-week overall duration of AFX-CB provides the opportunity for administration of two doses of cisplatin concurrently with radiotherapy. To minimize potential interference with normal tissue cellular repair of sublethal radiation injury, cisplatin will be given on days 1 and 22, i.e., before initiation of twice daily irradiation.


6.0 RADIATION THERAPY

6.1 Dose Fractionation

6.1.1 Radiotherapy will be given according to the concomitant boost regimen. The initial target volume encompassing primary tumor and upper neck nodes will receive 1.8 Gy per fraction, five fractions a week to 54 Gy in 30 fractions over 6 weeks to the primary tumor and upper neck nodes. At 32.4 Gy/18 Fx (i.e., latter part of week 4), the boost target volume covering gross tumor and clinically/radiologically involved nodes will receive boost irradiation of 1.5 Gy/Fx as second daily fraction (at least 6 h interval) for a total of 12 treatment days. The use of IMRT is not allowed.

6.1.2 The primary treatment fields must be reduced off the spinal cord at 45 Gy.

6.1.3 Clinically/radiologically involved nodes should receive a minimum dose of 72 Gy, 42 fractions in 6 weeks. Clinically/radiologically negative posterior neck should receive a minimum dose of 50.4 Gy at 3 cm. To supplement the dose to clinically positive/negative nodes, the posterior neck may be treated with electron beams of appropriate energies. The anterior lower neck field will be treated with 1.8 Gy per fraction at 3 cm depth to a total dose of 50.4 Gy in 28 fractions in 5.6 weeks. All treatment times must be documented on the treatment record.

6.4 Target Volume

The primary tumor and known or suspected lymph node disease will be treated with either lateral-opposed fields or several beam-directed fields with a margin. All fields will start with a 2-3 cm margin around gross primary and nodal disease. A reduction off the spinal cord to limit its dose to > 45 Gy is mandatory. These reduced fields will have a 1-1.5 cm margin around gross disease. A single anterior field will be used to treat the neck and supraclavicular fossa below the fields encompassing the primary tumors. This field should match the lateral fields on the skin, and should have an appropriate method to avoid overlap on the spinal cord at the junction of the fields. The inferior border of this field will be 1 cm below the clavicles.

6.5.5 Neck Dissection: If a neck dissection is planned for lymph nodes which were > 3 cm prior to RT, the dose to the involved lymph nodes may be limited to 50.4-63 Gy. This information must be clearly documented in the treatment record. When there is (are) positive node (s) in the lower neck, and additional posterior field may be necessary to deliver a supplemental dose to the positive node (s).

For all patients with clinically positive nodes greater than 6 cm, positive supraclavicular nodes, or pyriform sinus tumors that are T3 or T4 or have clinically positive nodes, a mediastinal T field should be used. The lateral limbs of the T extend to 1 cm below the clavicle and the central portion of the field extends 5 cm more inferiorly to include the upper mediastinum.

6.6 Dose Constraint, Anticipated Side Effects and Toxicities

6.6.1 Suggested maximum dose to the spinal cord is 45 Gy/25 fx/5 weeks.

6.6.2 Reversible mucositis is expected and its timing with dose and severity should be noted and graded.

6.6.3 Also expected will be epilation of treated areas and various degrees of skin reaction in the treated area.

6.6.4 Other expected acute reactions include xerostomia, hypogeusia, and dysphagia. Unusual severity of either of these should be noted, as well as whether a supplemental feeding tube was used.