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RADIATION THERAPY ONCOLOGY GROUP EVALUATION OF RADI08IOLOGXCAL EFFECTS OF MXSCELLAEWS LOCALLY ADVAWCEO ANIJOR RECURRENT HUMAN SOLID TunORS Protocol for Human Radiobiology Studies ofPi Meson University of New Mexico/Los Alamos Scientific Laboratory Current Edition: May 1, 1981
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Pat hol ogy Patient Consent and Peer Judgment - Karnofsky Performance Status - Sample Consent Form
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RAOIATIOW THERAPY ONCOCOGY GROUP EVALUATION OF RADIOBIOLOGICAL EFFECTS OF NEGATIVE P I MESONS ON HISCELLANEOUS LOCALLY ADVANCED AND/OR RECURRENT Eligible Patients: Patients with biopsy-proven locally advanced o r recurrent neoplasms whose projected survival is atleast three months Non-Randomized Negative Pi k son Radiotherapy Alone or as a Planned Boost Following Conventional Radiotherapy Tumor regression and time t o recurrence. Local and regional tunor control. Evaluation of tissue tolerances f o r pion radiotherapy alone o r as a planned boost following conventional Qualf t y and length o f survival. Adequacy o f tunor localization, treatment planning, and inhomogeneity correction.
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The rationale for pion radiotherapy is primarily related totwo factors: (1) adl ffe rent bio logic response inthe stopping region of the pion beam from t h a t seen i n conventional radiation, and (2) the capability for localizing this differential response within the target volme, largely sparing normal surrounding tissues. neutrons, pions, and heavy ions), there i s increased irreparable damage of critical molecules (i.e. , double-strand breaks i n DNA), as compared t o the type o f damage caused by low-LET radiation (e.g., x-pays. 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. Thuss hypoxic cells,large numbers o f which are usually present i n tumors, are less sensitive t o damage than are well oxygenated cells of the tumor and the surrounding normal tissue. The dense ioniration 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 resistant t o low-LET radiation in certain phases of the cell. cycle than i n others. High-LET rad lat fon reduces differences in cellular sensitivity due to cell cycle variations. Heavy charged particles, such as pions and heavy ions, distribute their dose witha 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 radlation, becuase they deposit low-LET radiation as they pass through tissue (plateau region), but produce a high-LET component i n the stopping (tumor) region. Due to their negative charge, the stopping pions are absorbed by the positively charged nuclei o f 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 ions. These events fncrease
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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 Phase XI trials are proposed t o study the efficacy of pion radiotherapy i n improving local control and, thus, potent tally survfval for patients wlth a variety of locally advanced, non-metastatic neoplasms, and t o assess acute and chronic normal tissue injury associated with such treatment. Sites o f major interest include high grade glianas (glioblastoma and astrocytoma Grade I I X and IY), inoperabl e esophageal carcl nom, inoperabl e epi dermai d 1ung carri - nuna, inoperable pancreatic CarcinaQa, carcinana o f the uterine cervix (Stage 111 and IVA) and locally advanced adenocarcinoma of the prostate (T3/T4, AJC). Patients with lesions amenable t o treatment with conventional radiotherapy and/or surgery with an anticipated five-year survival r a t e greater than approximately 401 would be excluded. Patients must be between 18 and 75 years o f age and have a Karnofsky status 1.1 S ~ r yof the Study. This isa non-randomized pilot study t o evaluate nom1 tissue and tunor response t o pion radiotherapy ina wide variety of human tumor sites, all of which will be biopsy-proven, locally advanced o r recurrent solid tunors. The study of local and regional tumor control as well as tissue tolerances will be the prime goal of this protocol.Additional valuable information will be gained regarding further refinement o f techniques of treatment planning, patient set-up and imnobilization, assessment of tissue inhomogeneities, and other technical aspects o f pion therapy. Patients previously treated with chemotherapy but not d&onstrating objective response will be eli gl ble provided they have alife expectancy ofat least three months.
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2.1 To evaluate tumor response t o pion radiation. 2.2 To study local and regional control o f tuor. 2.3 To eva lw tenom1tissue response and tolerance t o large field multi - fraction pion therapy, orto pion therapy delivered as a planned boost following conventional 2.4 To evaluate important aspects o f treatment planning and technical aspects of delivering the radiation in an attempt t o maximize the therapeutic ratio by minimizing the normal tissue vol me to be irradiated. 3.1 Conditions of Eligibility. The following conditions must be met before a patient can be admitted i n the study: 3.1.5 Little or no chance o f cure with conventional Locally advanced o r recurrent cancer. Patient age between 18 and 75. Understanding by the patient o f the provisions o f the study and voluntary informed consent to participate 3.2.1 Moderate t o high chance o f cure by other treatment 3.2.3 L i f e expectancy less than three months or Karnofsky status o f less than 60 and age < 18 o r > 75. 3.2.4 Active uncontrollable infection in area o f 3.2.5 Medical, psychological o r other contraindication t o 3.2 Conditions of Ineligibility.
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Pratreatmnt evaluation will be perfomad a t the University of New Mexico Cancer Research and Treatment Center (CIITC) o r by t h e rrferring physician a t another institution, with findings verified and studies augwnted as required by the CRTC study team. The evaluation will include: 4.2 Physical exmi nation. 4.3.4 Serum chemistry profile 4.3.5 Others as indicated 4. Chest x-ray, other radiographs and rad ,onucl i d e studies as 4.5' Staging procedures as indicated w i t h careful mapping and c l ippi ng of tm or where possi b l e. 4.6 An ophthalmologic examination t o assess lens opacity ( t o be performed upon admission t o the study). 5.0 AOMISSION TO THE STUDY Any patient who meets the required eligibility and pretreatment evaluation criteria will be admitted t o the protocol for pion radiotherapy atLWF. The following records will be generated by the study team and participating institutions for storage, retrieval and analysi s : 1. Patient eligibility form. 2. Pretreatment evaluation form. This form, docunenting the h i story and physi cal information, 1aboratory tests and special studies including surgery, w i l l be submitted on those patients referred f o r treatment. Study entrance form (patient name, address, referring A study case number will be assigned t o each patient by RTOG
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All patlents will receive non-randoapird pion therapy a t the Clinton P. Andenon Weson Physics Facility(WF)in Los Alamos, Nen lkxico, either alone or as a planned boost i n conjunction with conventional radlotherapy. Pion doses ape based upon previous experience with pion Irradiation of various human tumors' and for representative sites are outlined below. Current Treatment Pol i c y Maximum Dose Minim Dose -S I t e (Peak Pion Rad) (Peak Pion Rad) Fractions Days *May be treated by conventional wide-field irradiation and pion boost **Boost, fields treated t o 5000 peak pion cGy (rad) maximum *HCombi ned with pl ann& external beam conventi onal therapy Variations in total dose i n the range o f + 10% about the above doses will be explored to further evaluate tumor response and normal tissue tolerance. Doses in this range will be considered definitive and will be combined with other convent ional -therapy as outlined i n Section 10.0 Additional Therapy,
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Planned cad i nations of conventional radiation therapy with cone-tiom pion boost therapy will be applied i n selected situ at i onr based upon previous experience regarding nornal tissue tolerance inpatients receivfng pions alone. The estimated biological equivalent o f combined pion and convent ional treatment will not exceed that recognized as tolerance for pion or conventional therapy alone. Treatment methods will be those developed previously for pion therapy with the fixed vertical beam a t LAMPF with appropriate modifications and improvements consistent with improved techniques.* Single or multiple port therapy with or witt mt cone-down therapy w i l l be applied on an individualized basis t o maximize nornal tissue sparing and t o accomnodate part ic - u lar difficult fes with patient positioning o r disease site. Treatment p l anni ng will be performed by cm puteri zed calculation from CT data o f necessary compensation for body and tumor contours and tissue in hom ~ gene i ties. ~V er if i cation of treat - ment volumes w i l l be accomplished by simulation using orthodiagraphic scanning and routine --i n vivo dosimetry. 7.1 Tumor regression and time t o recurrence. 7.2 Local and regional tunor control. 7.3 Evaluation of tissue tolerances for pion radiotherapy a as a planned boost following conventional radiotherapy. 7.4 Quality and length o f survival. 7.5 Adequacy o f tumor localization, treatment planning, and This will be a non-randomized trial consisting of individual studies comparing local control and survival statistics with best reported results using conventional treatment for those sites mentioned above. Approximately 15-30 patients will receive
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optimized pion therapy for each of the disease sites of primary t o Phase 111 trials will include a canparison of local control, median survival, and five-year survival rates for recentty reported historical controls and pion-treated patfents. Endpoints of interest in determining whether t o proceed 9.1 The m fet ring physician will be encouraged t o see the patient in accordance with h i s customary schedule. The patient will be seen a t t h e Cancer Research and Treatment Center a t one month after treatment, then every three months f o r 12 months counting from Day 1, and semi-annwlly thereafter until survival reaches five years. If the patient cannot return to the CRTC, arrangements will be made t o have him examined a t another hospital by his referring physician and preferably his radiotherapist and a report of this examination submitted tothe CRTC. The following information w i l l be recorded on the follow-up form a t each visit : 9.2.1 Brief interval history related t o disease. Wei ght a blood pressure Appropriate aspects o f physical examination Regression o f palpable or visible twr Laboratory tests and routine x-rays; appropriate studies as indicated. Specific diagnostic studies, o r studies which gave the most reliable information regarding the initial extent o f tumor will be repeated a t periodic Recording and scoring of late reactions and pathologic studies by re-biopsy/autopsy as
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9.2.7 Ophthalmologic exam t o assess lens opacity Parameters t o be recorded throughout the study include: Degree and time of regression and regrowth. Assessment of acute radiation effects. Assessanent of long-term radiation effects. Sumnary o f Study Parameters History and Physical Chemi s try Profile Opthalmol ogic Exam nucl e a r scans, etc. ) Clinical evidence of lack of tumor control should be docunented by biopsy If possible. If such evidence is equivocal, re-exploration should be encouraged if the patient is a good surgical candidate, until such time asa pattern of recurrence is established and excised tissue or biopsy specimen should be carefully examined by the study pathologist with assistance from the involved radiation oncologist. I f the primary tunor is not controlled o r if distant metastases develop, subsequent therapy should proceed a t the discretion of the patient ' s responsible physician. The patient or physician will notify the investigator of any treatment instituted t h a t has not been prescribed by the investigator. In the event that surgery o r biopsy is performed, the
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11.1 Initial Surqical (Biopsy) Specimcns. Representative slides and copies o f biopsy reports will be submitted tothe study center and reviewhd by the study pathologists. Copies ofthe reports from these pathologists will be forwarded to the referring and/or follow-up physician. Any tissue surgically removed from anatomic sites will be examined by pathologists a t the participating institution where surgery was performed. and pathological reports will be forwarded t o the study center f o r review by the study pathologists. Autopsies are strongly urged on all study patients by pathologists at the participating institutions. Post-mortem studies should include a description of irradiated tissues and the character and extent of persistent, recurrent o r metastatic tumor. Autopsy reports and representative microscopic slides will be forwarded tothe study center for review by the study pathologists. 11.2 Subsequent Sumical Specimens. Appropriate microscopic slides Two copies o f each study form must be submitted t o RTOG Headquarters. Data will be recorded on standard fon m to be supplied to participating Institutions by RTOG Headquarters. b. Patient eligibility form. c. Pretreatment evaluation form. d. Study entrance form. e. Radiation treatment sumnary. A dally schedule o f pion therapy will be prepared a t LAMPF. include an end o f treatment examination t o include weight, pertinent general physical examination, performance status, current medications, and i f posslble, an assessment o f tumor response. Photocopy of patient consent form. This report will also
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13.0 PATIEMT COWSUCT AND PEER JUDGMENT All institutional,Fd and Drug Administration, and National Cancer Inrtl tute regul ati ons requi ring suhi ssi on tothe in ttt tut fon al human experimentation cannittee and the use of procedures for obtaining and recording in for wd consent will be followed. A patient may be removed from t h e study i f the study is not i n the best interest o f the patient. A patient may withdraw voluntarily fm the study a t any time, as will be indicated i n the Results o f hue I / I I trials o f pion radi-. In P Ming s of the Second R a r e Internattonal Symposfu on BlologEal Bases and Clinical Implications o f Radioresistance, i n press. immobilization and positioning for more efficient radiotherapy. --I n t J Radiat Oncol Biol Phys 2:1141-1144, 1977. Berardo, P.A., Zink, S.M.: Static pion beam treatment planning of deep seated tumors using computerized tomographic scans a t LAMPF. Kligerman, M.: Localization o f structures for pion radiotherapy by computerized tomography and orthodiagraphic projection.Int3
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Nomal; no cr la in ts ; no evidence o f disease. Able t o carry on noma1 activity ; minor signs or symptoms or Normal activity with effort ; some sign o r symptoms of …
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