Report: Radiation Therapy Oncology Group Rtog 78-28, Pi Meson Radiotherapy* of Carcinoma of the Oral Cavity (Excluding Lip) and Pharynx

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RADIATION THERAPY OWCOLOGY GROUP PI *so# RADIOTHERAPY+ OF CARCIWOU OF THE *PI Meson Radiation Therapy a t University o f New MexicolLos Alamos Current Edition: Way 1. 1981

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5.0 Admission to Study and Randomization 7.0 Endpoints o f Study & Response Criteria 13.0 Statist i cal Considerations 14.0 Patient Consent and Peer Judgment

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P I HESON RADIOTHERAPY OF CARCINW OF THE ORAL WIN (EXCLUDIK LIP) AND PHARYNX c. Hinimun o f 3600 peak pion rad ata minimum o f 100 peak pion rad/day, calculated a t the 80% isodose line. (The minim dose i s approximately 2 an peripheral t o the 9% isodose line.) Maximum o f 4500 peak pion rad a t 125 rad/day at 100% isodose line. Cone-down boost to a total of 3840 peak pion rad minimum and 4800 peak pion rad maximum may be added f o r persistent disease.

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1.1 Definition of the Problem. Patients presenting with nntcosal (squamous) carcinomas o f the head and mck region form a therapeutic challenge. These patients frequently present with advanced tumors i n an inoperable state due t o erttensive primaries o r advanced lymph node metastases, o r both. Several studies have reported overall survi Val rates varying from 7to 45% i n Stage 111 and I V (T3 and T4) carcinomas o f the oral cavity and oropharynx. I n patients presenting with clinically palpable cervical lymph nodes, the five - year survival is approximately one-thi r d that o f patients without pal pabl e nodes, even when adjusted f o r T-Stage. Treatment failure for oral cavity cancer i s frequent i n higher stages o f the disease. However, failures are generally due t o locally and regionally recurrent cancer. This site, therefore, i s a favorable one for evaluating the possible beneficfal effects o f pion radiation therapy. Table I emphasizes the relationship o f failure rate to stage, as derived from data presented by Chu and Fletcher i n 1973 (1). Strictly comparable data for lesions o f the lower gingivae and buccal mucosa are not available. However, the data (2) o f Table 2 are indicative of the problem o f local control Five-year survival data (3) collected i n an A JC field trial of 1,570 patient records (Table 3) illustrate a marked difference i n prognosis for cases categorized as Stage I11 .and IV, compared with Stage I and I1 (according to 1968 staging criteria).

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Table 2. Failure t o Control Primary Lesions of Buccal Mucosa and Lower Gun with Radical Radiatfon (3YR F/U) T2 3-5 centimeters (minimal extent t o adjacent Hasstve invasion o r bone infiltration Source: Fletcher, MacComb, and Braun (2)

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Posteri or 1/3 Tongue -umber o f patients livinq five years Total number o f patients i n group

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Lower A1 veol a r Ridge *Nunrber of patients livin q five years Total number of patients in group

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Similar data and conrents are appropriate Inthe consideration o f advanced (T3-T4) cancer sites within the oropharynx. Table 4 tCllMritCS data from several RTDG studies relevant t o stage, * local control, and median survival. Table 4. Reported Parameters for RTOG Head and Meck Studies 2 with T3 & T4 Clinically at Survival S i t e Lesi ons Positive Nodes 1 yr.(X) (ms. 1 Tonsil 1a r Fossa aa 75 59 (T3) 26 Advanced carcinomas o f the nasopharynx (bone destruction, cranial nerve involvement) have unacceptably high failure rates with only it few patients, i n most series, reported with control o f primary Carcinomas involving the hypopharynx may spread t o involve other structures, such as the larynx(particularly through the laryngeal ventricle,infiltrating the true and false vocal cords), the lateral wing o f the thyroid cartilage, o r the internal carotid artery, or may produce an external tumefaction. Lymphatic metastases, which are very frequent, are routed through channels existing from the thy ro hyoid membrane tothe jugul odi agastric, jugulocarot i d , or jugul o-omohyoid nodes.

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The Incldence of clinically recognized distant blood-borne aetastases would be much higher ifl ocal control was better and long-term survival more frequent. About one-half o f those patients enjoying local tuar control eventually (within three tO: seven years) suffer dfstant metastases. tocal control o f tumr and consequent long-term, tunor-free survival vary with tumor extent. Inasmuch as more than. two-thirds o f these pattents have Stage I11 or I V disease atthe time o f diagnosis (6), the overall tumor-free survival islow - The rationale for pion radiotherapy is primarily related t o tw factors: (1) a different biological response i n the stopping region o f the pion beam from that seen i n conventional radiation, and (2) the capability for localizing this differential response within the target volme, largely sparing normal surrounding 1.2 Rationale for Pion Radiotherapy. example, neutrons, pions, and heavy ions), there i s increased irreparable damage of critical molecules (i.e., double-strand breaks i n OM), as compared t o the type o f danagt caused b2 low-LET radiation (e.g., x-rays, gama rays o f cobalt, electrons, and protons). I n addition, cells exposed t o low-LET radiation exhibit up t o three times more resistance to injury if they are not well oxygenated. Thus, hypoxic cells, large numbers o f which are usually present i n tumors, are less sensitive t o damage than are we11 oxygenated cells of the tunor and the surrounding normal . tissue. The dense ionization of high-LET radiation may overcome the protective effect of hypoxia, killing those cells almost as effectively as well-oxygenated cells. Further, cells are more reststant t o low-LET radiation in certain phases o f the cell cycle than i n others. High-LET radiation reduces differences i n cellular sensitivity due to cell cycle variations.

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Heavy charged particles, such as pions and heavy ions, distribute their dose with a Bragg peak, a region o f intense radiation which can be located i n the tumor volune. Pions have the advantages o f both high-LET and low-LET radiation, Use they deposit law-LET radiation as they pass througb tissue (plateau region), but produce a high-lET component inthe stopping (tumor) region. Due to their negative charge, the stopping pions are absorbed by the positively charged nuclei of oxygen, carbon, and nitrogen atoms. This excess energy makes the nuclei unstable and they disintegrate, producing neutrons, protons, deuterons, triton s, alpha particles, and heavy ionsThese events increase the total dose inthe pion stopping region and alter the biological effectiveness o f the dose in that region because o f the dense ionization produced mainly by the alpha particles, heavy ions and neutrons. Results t o date o f Phase I - I I studies o f pion radiotherapy, being conducted at the Los Alamos Meson Physics Facility (LAMPF), by the University o f New Mexico Cancer Research and Treatment Center, suggest therapeutic advantages i n the treatment o f many advanced solid tumors with pion radiotherapy. Patients with primary and metastatic tur or s of the skin, head and neck, lung, abdaen and pelvis have been irradiated with pions t o assess tolerance o f normal tissues and tumor response. Early studies with metastatic tumor nodules i n the skin established a relative biological effectiveness (RBE) o f 1.42 for pions, as compared t o 100 kVP x-rays, for acute skin injury (8). Subsequently, analysis o f time t o regrowth o f 16 nodules (primary breast) i n . one patient participating in that study who could be followed for 346 days suggested the possibility of therapeutic gain o f 37% for A report on '40 patients treated f o r large deep-seated lesions, allof whom were followed for6to 15 months, showed that pion radiotherapy was well tolerated a t doses ranging from 1000 t o

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4600 pea& pion rads delivered generally in five fractions per week with daily fraction sizes o f 110 t o 140 peak pion rad ~ ~ ( 1 ~ 1 1 .Complete regressions occurnd i n approximately h a l f thos8 patients treated with pions alone a t maximum doses o f more than 2700 peak pion rad. No complete regressions occurred i n patfents treated with pions alone a t doses under 2700 peak pion rad. Conventional radiation and/or suqery was well tolerated by those patients requiring those treatments after pion radiotherapy. Reactions i n the normal tissues within the plateau and the peak regions have been similar to those which would be expected with conventional radiation delivered to acute tolerance. Severe l a t e reactions have included one patient with chr or ti ~ , severe laryngeal edema following 5000 peak pion rad given in7 weeks fora T4 carcinoma o f the larynx. The patient expired o f lung metastases 14 months after therapy with no evidence o f local disease. A patient with a T3, NZA, MO carcinoma of the tonsil developed severe soft tissue and mandibular necrosis5 months after 4600 peak pion rad in6 weeks necessitating extensi ve surgical reconstruction. It i s estimated that some 60,000 perons diein the United States each year because o f lack o f tumor control a t the primary site. Pions are being tested on those types of large tw rs uhich are not well managed by any other treatment o r combination o f treatments, t o attempt t o improve the survival in this group o f patients. I n addition, any large reduction i n the body's total burden o f tumor cells may improve the chances f o r cure by conventional techniques (surgery, radiotherapy, and chemotherapy, alone or i n combination). Thus, potentially additional patients can be helped by pion radiotherapy if their large tumor masses can be eliminated or significantly reduced. Considering the modest 1-year tumor control rates f o r Stage 111 and I V cancers of the oral cavity and pharynx, controlled clinical trials using p i mesons seem warranted.

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In patients with Stage SIS o r SV (T3 and T4) squamous cell carcinoma o f the oral cavity and pharynx: 2.1 To dcterrfm if local tumor control o f the primary is i a pro vd using pion radfothcrapy cornpared t o conventional treatment. 2.2 To detemim the incidence of distant netartases as related to the various for# o f treatment. 2.3 To deternine if pat lent survival i s improved using pion radi othempy coapared t o conventi anal treatment. 2.4 To determine the morbidity o f radiotherapy. 2.5 To assess the canplications o f therapy. 2.6 To assess the qual ityof survival related tuthe various for w of cell carcinoma o f the oral cavity (except lip)or oropharynx, nasopharynx o r hypopharynx. Patients with tumors originating i n the following regions and sites: Oral Cavity Oral Tongue 3.1.2 Biopsy proven squamous cell carcinoma. Lower G i ngi va

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Oropharynx Faucial Arch Tonsillar Fossa and Tonsil (Lateral and Posterior Wall, Posterior Tonsil lar Pl llar) Nasopharynx Posterior Superior Wall (Vault) Hypopharynx Pyriform S i nus Posterior Hypopkryvqml Wall Able to travel to and be treated a t Los Alamos if randomized t o pion radiotherapy. Patients with previous malignancies who have been disease free for more than eight years or for at least three years f o r primary skin cancer (excl udi ng melanoma and carcinoma o f the lip). Agreement o f the patient's physician tothe conditions o f the protocol (including diagnostic studies and treatment randmi r a tions) and t o re1inqui sh management of the patient's treatment t o the study team. Completion o f the required investigational consent Patient must not be < 18 or > 75 years o f age. 3.2. In e liq ibi 1ity Criteria. 3.2.2 Carcinoma o f the lip. Verrucous carci noma o r histology other than squamous Evidence o f distant metastases (beyond the cervical

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L2.5 Previous definitive therapy o f the primary tumor and regional adenopathy, including prior definitive radiation therapy or potcntlally curative surgical Previous chemotherapy, which, i n the opinion o f the study team, might conrpronise treatment o r evaluation. Previous radiotherapy t o areas overlapping the projected treatment portal s. Active, uncontrollable infection in the area o f Mical, psychological o r other contraindication t o the contemplated diagnostic o r therapeutic measures and their evaluation, orto long term follow-up. Evidence o f a second malignancy, other than skin cancer. (For patients with second mal ignancies other than skin cancer, the disease-free interval must exceed eight years. For patients with skin cancer, the disease must have been under control for at l e a s t three years. Skin cancer, for the purposes of this study, does not include melanoma or cancer o f the lip.) Excision o f a trror-bearing node 1s not Consistent with good medical practice, the following w i l l be performed on initial evaluation prior to admitting the patient t o the study. Results of the evaluation will be used t o determine patient eligibility for the study and i n management ofhis treatment regimen. 4.1.4 Date o f onset o f symptoms (month and year i n which the patient first noticed definite symptoms o r signs which are later explained by the disease). Date (month and year) of definite diagnosis o f disease.4.1.5

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4.1.8 Medications currently used. 4.1.9 Pmvlous therapy (if any). Performance Status (Karnofsky function assessment). Drawing o f primary tunar and regional adenopathy (with centimeter dimensions); a1 so, photographs, i f possible. Complete blood count including white count, 4.3 Routine Laboratory Tests. different fal and platelets. Blood chemistries including serum alka SGOT, total protein, and albumin. Imnune react1v ity tests , when possible Others, as indicated by the individual 4.4 Routine Imaging Procedures. Others, as indicated (e.g., bone scan o r x-rays of mandible and maxilla, i f bone involvement i s CT scans i f available; i f not, this will be performed atthe Study Center. Cardiopulmonary assessment, i f indicated, t o tolerate 7000 feet altitude of Los Alams. Other studies as indicated, particularly to rule out 4.6.1 Biopsy o f primary tumor. 4.6.2 Random biopsies of oral mucosa if field cancerization i s suspected; map area.

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5.0 ADHISSION TO STUDY AND RAIQ)(WIIZATIOW Patients will be admitted t o the study only after the pretreatment evaluation is coapleted and the eligibility criteria are met. Copies of a11 necessary forms will be fomardcd t o RTO6 Headquarters. 5.1 All therapy will be scheduled through the Cancer Research and Treatarent Center i n Albuquerque. It is planned t o have all patients receive radiotherapy planning CT scans and localization i n Loo Alarnos even i f randomized t o conventional treatment a t the referring institution. Ophthalmologic examination t o assess lens opacity will be performed upon admission t o the study. The fol 1owi ng steps must be compl eted: 5.1.1 Identification and registration (see 5.1.2) ofall patients entering the particdpating institution with a diagnosis o f carcinoma o f …