RADIATION THERAPY ONCOLOGY GROUP

RTOG 96-04

PROTOCOL TO EVALUATE THE LATE EFFECTS OF NORMAL TISSUE
(LENT)
FOR HEAD AND NECK CANCER

 

 

 

 

Study Chairman

Philip Rubin, M.D.

 

University of Rochester

 

Medical Center

 

601 Elmwood Avenue, Box 647

 

Rochester, NY 14642

 

(716) 275-5575

 

FAX# (716) 275-1531

Co-Chairman

Andy Trotti, M.D.

 

(813) 972-8424

 

FAX# (813) 979-7231

Activation Date:

February 1, 1998

CLOSURE DATE:

dECEMBER 9, 1998

Current Edition:

September 8, 1998
Includes Revision 1


 

 

This protocol was designed and developed by the Radiation Therapy Oncology Group (RTOG) of the American College of Radiology (ACR). It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by RTOG nor does RTOG assume any responsibility for unauthorized use of this protocol.

 

 

 

 

Schema
Eligibility Check
1.0 Introduction - Clinical Syndromes
2.0 Objectives
3.0 Patient Selection
4.0 Baseline Treatment Data
5.0 Registration Procedures
6.0 Interventions
7.0 Patient Evaluation
8.0 Data Collection
9.0 Statistical Considerations
References
Appendix 1 Sample Consent Form
Appendix 2 Karnofsky Performance Status
Appendix 3 LENT Scales
Appendix 4, 5, 6 Toxicity Criteria

 

 

 

 

RADIATION THERAPY ONCOLOGY GROUP

RTOG 96-04

PROTOCOL TO EVALUATE THE LATE EFFECTS OF NORMAL TISSUE
(LENT)
FOR HEAD AND NECK CANCER

SCHEMA


TREE DIAGRAM FOR TREATMENT OF HEAD AND NECK CANCER

 

 



Of major concern in patients undergoing multimodal treatment are the late effects which may appear months to years after initial acute toxicities have resolved. Following and documenting late toxicities have been and remain difficult because existing scales/tables do not include many of the late effects described in this protocol. For this reason, a new set of scales and scores has been developed. The purpose of this protocol is to test and validate these new scales and scores. While testing the new scores we hope to also thoroughly, yet concisely, describe the late toxicities that may appear in different structures and organs. When irradiation is administered in a major anatomic site - the head and neck, the thorax, abdomen and pelvis as well as the extremities - many different tissues can be affected in each region. Above is a tree diagram of the potential organs in which the patient who has undergone treatment for a tumor of the head and neck region may experience late effects. This protocol will be utilized in the following manner:

For each patient the organs within the radiation treatment fields will be followed. The four sets of scales SOMA (the LENT scales), ARSC (Acute Radiation Scoring Criteria) LRMSC (Late Radiation Morbidity Scoring Criteria), and the CTC (Common Toxicity Criteria) will be used to assess both acute and late toxicity. Assessments will be made at time points as outlined in Section 7.0. The potential analytical evaluations for Late Effects of Normal Tissues are outlined in the Analytic portion of the SOMA Scales and Scores.

Eligibility:

- Patients who will receive irradiation to the head and neck region
- Estimated life expectancy of > 6 months
- KPS > 40
- No known metastatic disease (M1)
- Pre-existing dysfunction in treatment area must be evaluated and documented
prior to study treatment
- No prior chemotherapy
- Signed study-specific consent form

Required Sample Size: 160          9/8/98










Institution #_______

RTOG 96-04 ELIGIBILITY CHECK (9/8/98)

Case #_______

_______(Y) 1. Will the patient receive radiotherapy to the head or neck region for an upper aeordigestive primary tumor?

_______(Y) 2. Is life expectancy estimated to be at least 6 months?

_______(N) 3. Any prior radiotherapy to the head or neck area?

_______(N) 4. Is the patient receiving irradiation for recurrent disease?

_______(N) 5. Any evidence of distant metastases?

_______(Y) 6. Will the patient be (or has the patient been) evaluated for pre-existing dysfunction in the areas of involved normal tissues prior to starting radiotherapy?

_______(N) 7. Has the patient received prior chemotherapy?

(> 40) 8. What is the Karnofsky Performance Status?

The following questions will be asked by the RTOG registrar:

_______(Y) 1. Has the eligibility checklist (above) been completed?

_______(Y) 2. Is the patient eligible?

_______ 3. Date the study-specific consent form was signed? (must be prior to study entry)

_______ 4. If the patient is on another RTOG study, provide the study number (record 0 if not applicable).

_______ 5. Provide the case number on the other study (record 0 if not applicable).

____________________Patient's Name

____________________ Verifying Physician

____________________ Patient ID #

____________________ Referring Institution # (if different)

____________________ Birthdate

____________________ Sex

____________________ Race

____________________ Social Security Number

____________________ Zip Code (9 digit if available)

____________________ Method of Payment

____________________ Will any component of the patient’s care be given at a military or VA facility?

____________________ Date of Radiotherapy Start

Completed by ____________________ Date ____________________










1.0 CLINICAL SYNDROMES OF LATE EFFECTS

1.1 Mucosa - Oral & Pharyngeal

Late effects of radiation on the mucosal linings of the upper aerodigestive tract are characterized by paleness and thinning of the epithelium, with loss of mucosal pliability, submucosal induration and, occasionally, chronic ulceration and necrosis with exposure of underlying bone and/or soft tissue. Save for the latter two, fortunately uncommon sequelae, most patients are unaware and unaffected by these changes.

Late-appearing soft tissue changes tend to be more obvious to patients, although these, too, generally are not incapacitating. Constricting fibrosis, or (its more common, milder form) loss of elasticity, can be annoying to patients. These effects can be particularly troublesome for patients who require both surgery and radiotherapy for management of their malignancy. Although, by itself, irradiation of the neck produces little or no impairment of shoulder function, in the postoperative setting it may exacerbate surgically induced limitations in motion of the head and neck by up to 20%.1, 2

Soft tissue necrosis (i.e., the occurrence of a mucosal/submucosal ulcer(s) in irradiated tissue that has no residual cancer) is related to dose, time, and volume irradiated. The risk is far greater following interstitial implantation and intraoral techniques because of the greater doses used.

Late effects of chemotherapy on the integrity and function of the mucous membranes have not posed clinical problems and have not been studied extensively.

1.2 Teeth & Mandible

Damage of the teeth is an indirect effect of radiation-induced parotid damage, resulting in a pronounced shift toward a highly acidogenic, highly cariogenic oral microflora. Adult patients who have not shown any degree of caries activity for years may develop dental decay and varying degrees of disintegration after irradiation. The cervical areas, along the gumline, are most typically affected. This condition appears to be due both to the lack of saliva as well as to changes in its chemical composition.3-10 The protective influence of saliva has been demonstrated by the extensive dental destruction found in animals subjected to salivary gland ligation or removal and in patients who have xerostomia caused by drugs (e.g., diuretics, antidepressants) or disease (e.g., Sjogren's syndrome) .11

The reported incidence of osteoradionecrosis varies widely depending upon the reporting institution, aggressiveness of radiotherapy, and follow-up time.12-16 Osteonecrosis first manifests objectively as a nondescript erythematous change of the overlying mucosa, which then ulcerates to reveal the necrotic bone below (necrotic bone has a dull appearance, unlike the pearly color of healthy periosteum).

Subjectively, patients experience severe persistent pain and tenderness in the affected region. Radiographically, lytic destruction and periosteal thickening are common; mottled sclerosis is possible but nonspecific. In advanced cases, fracture occurs.

1.3 Skin/Subcutaneous Tissue

The late effect sequence occurs later than 10 weeks following irradiation. A time period of varying length during which the skin appears "normal" follows the acute reaction. Then after time periods that may be as long as several years, late effect changes of scaling, atrophy, telangiectasia, subcutaneous fibrosis, and necrosis develop and continue to progress. This progression is well- known and described. The degree of telangiectasia in postmastectomy chest wall, head and neck, and breast fields continues to evolve and to increase in severity over a period up to 10 years.17-19, 20-22, 23-29

The dose schedules that produce late reactions are similar to those that produce acute reactions. However, while total dose is critical in determining the severity, late effects are more severe following schedules that employ daily dose fractions of 2.5-3.0 Gy or higher, than follow dose schedules using 1.8-2.0 Gy daily.18, 23, 25-31

Telangiectasia develops in an atrophic dermis under a thinned epidermis as an area of reddish discoloration displaying multiple, prominent, thin walled and dilated vessels. The histologic appearance is that of dilated vascular channels in the dermis. Histologically, some channels are in direct contact with the basement membrane.22, 32, 33

Fibrosis may occur and is characterized by a progressive induration, edema formation and thickening of the dermis and subcutaneous tissues.22,32,34-36 It is most severe in those areas where there was an earlier moist reaction. Onset and progression of fibrosis is dose dependent and, once started, slowly progressive. The papillary dermis consists of a layer of multiple distorted acellular collagenous bundles. In obese areas such as the breast or the abdominal panniculus, there is extensive cellular fibrosis which lacks a consistent pattern.

1.4 Salivary Gland

Transient tenderness and, occasionally marked swelling of the salivary glands may occur within a few hours after the first dose of a fractionated course of radiotherapy to the head and neck. This early reaction usually subsides within a few days and the long-term significance of the acute response is unknown. A decrease in salivary output has also been detected as early as 24 hours after a single dose of 2.25 Gy.37 A 50% or more decrease of stimulated salivary flow has been detected after the first week of fractionated radiotherapy to the head and neck.6, 21, 38, 39 Concurrently, amylases9 and tissue polypeptide antigen (TPA) 40 are released into the blood stream, producing a transient rise in their serum concentrations.

The salivary flow continues to decline throughout a typical course of treatment and may become barely measurable by the end of a 6–8 week course6,38,41 The decreased salivary flow is accompanied by increased salivary viscosity, decreased pH, increased concentration of sodium, chloride, calcium, magnesium, and protein and a decreased concentration of bicarbonate and IgA in the saliva.38,42 Xerostomia usually persists for several months to years and may or may not recover, depending on the volume of salivary glands irradiated, the total radiation dose, and individual patient variation. As a consequence, patients may experience impaired ability to swallow, chew, talk, and/or wear dentures comfortably. Most patients need to change the nature of their diet to some degree. Alteration of the normal oral microflora to a more cariogenic one occurs as a result of changes in the salivary contents and a lowering of the oral pH.

Patients receiving chemotherapy may also have decreased salivary flow, salivary amylase and IgA, and increased oral carriage of opportunistic pathogens.3 However, chemotherapy- induced changes are usually much less severe and transient.11 Agents that may cause transient xerostomia include 5-FU, cisplatin, bleomycin, methotrexate, adriamycin, cyclophosphamide, and vinblastine. Combined chemo/radiotherapy regimens pose, at least theoretically, an enhanced risk of salivary dysfunction.

1.5 Cervical Spinal Cord

Myelopathies are unusual, but not rare complications of cancer and cancer treatment. Myelopathies can result from extrinsic spinal cord compression, intramedullary metastases, paraneoplastic syndromes, or toxicity of treatments. Because the various signs and symptoms of radiation myelopathy can occur in many combinations and at different rates of progression, it is not possible to make the diagnosis of radiation myelopathy on symptoms alone. The initial signs are subtle and may not be noticed by the patient. These may include: sensory deficit (either unilateral or bilateral) that often are manifest as diminished temperature sensation, leg weakness, clumsiness, and diminished proprioception. L'hermitte syndrome may precede permanent radiation myelopathy. Objective signs and symptoms include changes in gait (often foot drop), spasticity, weakness, hemiparesis Brown-Sequard syndrome, and possibly incontinence. Hyperreflexia and Babinski signs are often found on neurological exam. Pain may accompany these symptoms. In many cases, the patient may have been asymptomatic until some trauma initiated a progressive neurological deficit. No combination of signs or symptoms distinguish radiation myelopathy from myelopathies of many other etiologies. The severity of the symptoms is usually progressive but may stabilize at any level. As time elapses, the symptoms are often attributable to increasingly higher anatomical levels.

1.6 Larynx & Esophagus

The complications to the larynx from radiation therapy occur usually within the first year post RT but can occur many years later. The incident for moderate to severe reactions is up to 3%.44

The symptoms of radiation damage to the larynx are dryness, hoarseness, edema, pain, hoarseness with dyspnea, odynophagia, dysphagia, respiratory distress, dehydration, weight loss and fever.45,46 The signs of damage include: edema, telangiectasis, impairment of cord mobility, erythema, skin changes, fistula, fetor oris, fixation of skin to larynx, and laryngeal obstruction. 45

Radiation to the larynx produces histologic alterations to the respiratory epithelium, muscles, vessels and cartilage. The epithelium is effected by impairment of ciliary and secretory gland function which leads to loss of effective mucous blanket protection. The muscles can atrophy and fibrose. Vascular and lymphatic endothelium is highly susceptible to radiation damage. Chronic changes to the vascular system include vessel atrophy, fibrosis and loss of elasticity45 which can lead to any of the following: irreversible obliterative endarteritis, microvascular insufficiency, tissue ischemia, diffuse laryngeal edema involving epiglottis, aryepiglottic folds and false cords, supraglottic edema, vocal cord fixation, increased density of vocal cords due muscle atrophy, and chondronecrosis.46 Chondronecrosis (radiation necrosis) is a debilitating disease associated with pain, dysphagia, and respiratory obstruction. The treatment options for a patient with this include antibiotics combined with steam, hyperbaric oxygen therapy or surgery. Persistent poor wound healing after surgery can lead to death.

The late effects on the esophagus manifest clinically by symptoms of difficulty swallowing. These effects are caused by the occasional formation of a benign stricture and also to changes in motility as the result of muscle and nerve damage. Persistent ulceration is uncommon in the absence of tumor but may occur following high dose radiation. Other rare late complications include pseudodiverticulae development and fistula formation. Stricture is generally not seen before 3 months postradiation47,48 and the median time to stricture development was 6 months in one study.49 A barium swallow is useful to demonstrate stricture formation and decreased peristalsis in the irradiated segment of the esophagus.

1.7 Eye

The eye is composed of several tissues that vary greatly in their radiosensitivity. Acute reactions in decreasing order of severity include iridocyclitis, keratitis, conjunctivitis, and blepharitis. Delayed reactions, which generally occur after six months, include retinopathy, optic neuropathy, lacrimal gland atrophy or duct stenosis, glaucoma resulting from iridocyclitis, cataract, corneal vascularization and scarring, conjunctival telangiectasia, and eyelid atrophy with entropion or ectropion. These several manifestation of injury translate into symptoms of pain and visual loss. In the retina, telangiectasia, microaneurysms, hemorrhages, and exudates develop. In general, radiation retinopathy is rare at total doses of less than 45.0 Gy after either 2.25 Gy fractions of photons or with Co60 or I125 brachytherapy. Occasionally, clinically detectable vascular damage will be observed in eyes that received 35.0 Gy, but this is not usually visually significant. In a series reported by Nakissa et al. all patients who received over 45.0 Gy to the posterior pole had recognizable changes; however, most of these did not affect vision.50 Decreased visual acuity occurred only in patients receiving over 65.0 Gy.

Cataract is a well-known radiation complication. A number of issues remain unresolved despite studies since the early 20th century.51-55 Radiation damage to the germinative zone of lens epithelial cell DNA is probably responsible for most post treatment cataracts.56-59 In addition to DNA damage, direct cytoplasmic effects, such as disruption of membrane channels, protein cross-linking, and ion pump abnormalities are also important in postradiation cataract progression.60-62 Abnormal lens epithelial cells, termed Wedl cells, migrate posteriorly and form a posterior subcapsular opacity (due to retaining their nuclear detrie). Older patients probably have more preexisting lenticular DNA errors, protein cross-linking, and lens membrane alterations, and develop cataracts sooner as a result of the additional insult of ionizing radiation.

2.0 OBJECTIVES

2.1 To determine the validity of the Late Effects of Normal Tissue(LENT) SOM scales (Subjective, Objective, Management elements) through comparisons with the ARSC (Acute Radiation Scoring Criteria) LRMSC (Late Radiation Morbidity Scoring Criteria) and the CTC (Common Toxicity Criteria).

3.0 PATIENT SELECTION

3.1 Eligibility Criteria (9/8/98)

3.1.1 Patients who will receive irradiation to the head and neck region (includes upper aerodigestive sites only). Patients who have started radiation therapy <7 days prior to study entry are eligible provided the baseline evaluations for this study have been performed and all information is available.

3.1.2 Patients with an estimated life expectancy of six months or more.

3.1.3 Patients must sign informed consent meeting all federal and institutional guidelines. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the responsible family member.

3.1.4 Patients with KPS >40.

3.1.5 Patients registered to another RTOG-coordinated head and neck protocol are eligible.

3.2 Ineligibility Criteria

3.2.1 Patients who fail to meet criteria in Section 3.1 are ineligible.

3.2.2 Patients with known metastatic disease (M1) or recurrent disease.

3.2.3 Patients with pre-existing dysfunction in areas of involved normal tissue(s) not evaluated and documented prior to treatment.

3.2.4 Prior chemotherapy.

3.2.5 Prior radiotherapy to the head and neck area.

4.0 TREATMENT DATA

Radiotherapy: Doses and dates of treatment will be listed.

4.2 Chemotherapy: Chemotherapeutic agents used, and dates of treatment will be listed.

4.3 Surgery: The extent of the surgical procedure and dates of surgery will be noted from the surgical report.

5.0 REGISTRATION PROCEDURES

Patients can be registered only after registration evaluation is complete and eligibility criteria are met. Patients are registered by calling RTOG Headquarters at (215) 574-3191 between 8:30 AM and 5:00 PM Eastern time Monday through Friday. The patient will be registered and a case number will be assigned and confirmed by mail. The following information must be provided:

- Institution Name & Number

- Patient's Name & ID Number

- Verifying Physician's Name

- Eligibility Criteria Information

- Demographic Data

- If patients on another RTOG head and neck protocol, the study and case numbers must be provided.



6.0 INTERVENTIONS

6.1 Routine care for complications should be given.

7.0 PATIENT EVALUATION

7.1 Validity

Comparison of toxicity grading will be made using the SOM, ARSC, LRMSC and CTC scales.





7.2 Table of Patient Assessments (assess all/any organ in the radiation field)

Pre-R
T
3 MO
S
6 MO
S
@ 18 &
24 month
s
TNM Classification X
SOMa X X X X
ARSCa X X X X
LRMSCa X X X X
CTCa X X X X
Weight X X X X
Tumor Status X X X X


a. See Appendices for SOM, ARSC, LRMSC and CTC scales

7.2.1 At baseline, prior to start of radiotherapy, an assessment of the patient will be separately recorded using the CTC, the ARSC and the SOM scales.

7.2.2 At each follow-up, toxicity assessments will be separately recorded using the CTC, the LRMSC and the SOM scales.

7.2.3 The “analytic” score included on the LENT Evaluation Form is not required.

7.2.4 Assessments using CTC are recorded on all cases regardless of absence of treatment with chemotherapy.

7.3 Patient assessment at each follow-up visit will include toxicity and tumor status. Confirmation by radiographs or biopsy is preferable and agreement by two physicians of different specialties is advisable. The following will be evaluated:

7.3.1 Primary tumor

7.3.2 Regional disease (excluding primary site) and regional nodes

7.3.3 Distant metastatic spread

7.3.4 Second malignancy

7.4 Additional post-radiotherapy treatment must be reported when given.

8.0 DATA COLLECTION

8.1 Summary of Data Submission

Demographic Form (A5)
On Study Form (I1)
LENT Evaluation Form (LE)		 Within 2 weeks of study entry
Treatment Form (T1) At end of treatment
Followup Form (F1)
LENT Evaluation Form (LE)		 At 3, 6, 18, and 24 months following completion of radiotherapy.


8.2 RTOG 96-04 specific data forms must be submitted regardless of patient’s enrollment in another RTOG study.

9.0 STATISTICAL CONSIDERATIONS

9.1 Study Endpoints

9.1.1 To determine the reliability and validity of the Late Effects of Normal Tissue (LENT) Subjective, Objective, and Management scales (SOM).

9.1.2 To refine the scoring criteria for SOM scales.

9.2 Sample Size

9.2.1 Reliability

There are two methods for assessing reliability of SOM. Test-retest will be used on patients that are clinically stable from 3 to 6 months. Clinically stable is defined as patients that have neither primary, nodal, nor metastatic progression. These patients will also not have any new treatment morbidity noted on either the Late Radiation Morbidity Scoring Criteria (LRMSC) or the Common Toxicity Criteria (CTC) from 3 to 6 months. Based upon the RTOG database, 18% of patients enrolled will be alive, progression-free, and have stable morbidity status for the 3-6 month period from the start of therapy. Forty clinically stable patients will be required for the test-retest reliability providing 95% statistical power with one- sided Type I error in testing the reliability is high (at least 0.70). The null hypothesis will be moderate reliability of 0.30.

Equivalent forms reliability will be examined using weight changes. Weight will be measured pretreatment and at each follow-up point. Objective weight loss will be compared to coding of morbidity within SOM on the Mucosa SOM scoring scales. Weight changes will contribute computing the equivalent forms reliability. Approximately 25% will have significant changes in their weight from baseline (> + 5% change in pretreatment weight). Thirty patients with weight changes are needed to establish reliability at the levels given above. This will provide 95% statistical power and a one-sided 5% Type I error.

9.2.2 Validity

There are two primary aspects of validity - content and construct validity. Content validity is defined as degree to which SOM covers the range of late effects. This is a component of the design of SOM and can not be empirically tested.63 Construct validity involves specifying factors or constructs and testing hypotheses about the patterns of response. If different measures of the same construct are positively correlated then this is convergent validity.

Convergent validity will be examined using evaluations on SOM, LRMSC, and CTC. Salivary gland, mucosal, esophageal, laryngeal, and skin morbidities are the most prevalent late effects in head and neck cancer. Based upon RTOG 83-13 most late effects will occur within 12 months from the start of therapy. However, only about 60% of patients will survive at least 12 months. Incorporating survival as a competing risk in the cumulative incidence model64 then 43% of all patients will develop a late skin toxicity (grade 1-5); 67% late salivary gland toxicity; 19% late laryngeal toxicity. All percentages are within the first year. The null hypothesis is that the correlation between the LRMSC and SOM for esophageal and respiratory late effects will be 0.3 or lower. The alternative hypothesis is that the correlation is at least 0.70. Forty patients with late skin toxicities will be required. It is estimated that 160 patients will be needed to find 40 that will develop a late skin morbidity and will live 12 months. A sample size of 160 patients will provide 95% statistical power for a one-sided test of the above hypothesis.

9.2.3 Patient Accrual

Based upon the RTOG's accrual to head and neck studies, the accrual is expected to be 20 patients per month. Therefore, this study should take eight months to complete the accrual phase.

9.3 Analyses Plans

9.3.1 Interim Analyses of Accrual and Completion Rates

Interim reports with statistical analyses will be prepared every six months until the initial paper reporting the results of the reliability and validity data has been submitted. In general, the interim reports will contain information about:

a) the patient accrual rate with projected completion date for the accrual phase;

b) the distribution of patients with respect to pretreatment characteristics;

c) compliance and completion rates for SOM;

9.3.2 Analysis and Reporting of Reliability and Validity Data

The major analysis will be undertaken when each patient has been potentially followed for a minimum of 1 year.

9.3.2.1 Correlation Analysis

Correlations between SOM scales, LRMSC, CTC, and clinical tests will be computed using Spearman rank correlations. These correlations will be used as specified in Section 9.2 to test the properties of the SOM scales. Test-retest reliability will be computed using the kappa statistic.

9.3.2.2 Scoring Analyses

Every subjective, objective, and management subscale has at least two subcategories for each late effect. For example, the SOM for esophagus has two subcategories for subjective, five subcategories for objective, and four subcategories for management. There are two possibilities for scoring these SOM scales: 1) summing across SOM and taking the average; 2) summing within subjective, objective, and management and taking the average for each. The correlation analyses discussed in Section 9.3.2.1 will be done on scoring system 2. One summary SOM score (system 1) and individual component scores (system 2) will be evaluated by which produces the best properties for SOM. Furthermore, interpretability of SOM scores are an important component in order to design future interventions and evaluation of aggressive therapy. Therefore, sensitivity to change will be evaluated between the two scoring systems.

REFERENCES

1. Nowak, P.; Parzuchowski, J.; Jacobs, J. R. Effects of combined modality therapy of head and neck carcinoma on shoulder and head mobility. J. Surg. Oncol. 41:143–147; 1989.

2. Short, S. O.; Kaplan, J. N.; Laramore, G. Shoulder pain and function after neck dissection with or without preservation of the spinal accessory nerve. Am. J. Surg. 148:478–502; 1984.

3. Brown, L. R.; Dreizen, S.; Handler, S. H.; Johnston, D. A. Effect of radiation-induced xerostomia on human oral microflora. J. Dent. Res. 54:740; 1975.

4. Council on Dental Therapeutics: Concensus: Oral health effects of products that increase salivary flow rate. J. Am. Dent. Assoc. 116:757; 1988.

5. Cowman, R. A.; Baron, S. S.; Glassman, A. H.; Davis, M. E.; Strosberg, A. M. Changes in protein composition of saliva from radiation-induced xerostomia patients and its effect on growth by oral streptococci. J. Dent. Res. 62:336; 1983.

6. Dreizen, S.; Brown, L. R.; Handler, S.; Levy, B. M. Radiation-induced xerostomia in cancer patients. Cancer 38:273–278; 1976.

7. Keene, H. J.; Fleming, T. J. Prevalence of caries-associated microflora after radiotherapy in patients with cancer of the head and neck. Oral Surg. Oral Med. Oral Pathol. 64:421; 1987.

8. Makkonen, T. A.; Tenuvuo, J.; Vilja, P.; Heimdahl, A. Changes in the protein composition of whole saliva during radiotherapy in patients with oral oropharyngeal cancer. Oral Surg. Oral Med. Oral Pathol. 62:270; 1986.

9. Mossman, K. L.; Shatzman, A.; Chencharick, J. Long-term effects of radiotherapy on taste and salivary function in man. Int. J. Radiat. Oncol. Biol. Phys. 8:991–997; 1982.

10. Shannon, I. L.; Starcke, E. N.; Wescott, W. B. Effect of radiotherapy on whole saliva flow. J. Dent. Res. 56:693; 1977.

11. Schubert, M. M.; Izutsu, K. T. Iatrogenic causes of salivary gland dysfunction. J. Dent. Res. 66:680-688; 1987.

12. Bedwinek, J. M.; Shukovsky, L. J.; Fletcher, G. H.; Daley, T. E. Osteonecrosis in patients treated with definitive radiotherapy for squamous cell carcinoma of the oral cavity and naso- and oropharynx. Radiology 119:665; 1976.

13. Beumer, J., III; Curtis, T. A.; Morrish, R. B., Jr. Radiation complications in edentulous patients. J. Prosthet. Dent. 36:193; 1976.

14. Morrish, R. B.; Chan, E.; Silverman, S., Jr.; Meyer, J.; Fu, K. K.; Greenspan, D. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 47:1980; 1981.

15. Murray, C. G.; Herson, J.; Daly, T. E.; Zimmerman, S. Radiation necrosis of the mandible: A 10-year study. Part I. Factors influencing the onset of necrosis. Int. J. Radiat. Oncol. Biol. Phys. 6:543; 1980.

16. Murray, C. G.; Herson, J.; Daly, T. E.; Zimmerman, S. Radiation necrosis of the mandible: A 10-year study. Part II. Dental factors; Onset, duration and management of necrosis. Int. J. Radiat. Oncol. Biol. Phys. 6:549; 1980.

17. Bentzen, S. M.; Christensen, J. J.; Overgaard, J.; Overgaard, M. Some methodological problems in estimating radiobiological parameters from clinical data. Acta Oncol. 27:105–116; 1987.

18. Bentzen, S. M.; Overgaard, M.; Thames, H. D.; Christensen, J. J.; Overgaard, J. Early and late normal-tissue injury after postmastectomy radiotherapy alone or combined with chemotherapy. Int. J. Radiat. Biol. 56:711– 715; 1989.

19. Bentzen, S. M.; Turesson, I.; Thames, H. D. Fractionation sensitivity and latency of telangiectasia after postmastectomy radiotherapy: A graded-response analysis. Radiother. Oncol. 18:95–106; 1990.

20. Emami, B.; Lyman, J.; Brown, A.; Coia, L.; Goitein, M.; Munzenrider, J. E.; Shank, B.; Solin, L. J.; Wesson, M. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21:109–122; 1991.

21. Eneroth, C. M.; Herikson, C. O.; Jakobsson, P. A. Effect of fractionated radiotherapy on salivary gland function. Cancer 30:1147–1153; 1972.

22. Fajardo, L. F. Pathology of radiation injury. New York: Masson; 1982:186–200.

23. Thames, H. D.; Bentzen, S. M.; Turesson, I.; Overgaard, M.; Van den Bogaert, W. Time-dose factors in radiotherapy: A review of the human data. Radiother. Oncol. 19:219-235; 1990.

24. Tsouskas, L. I.; Fentiman, I. S. Breast compliance: A new method for evaluation of cosmetic outcome after conservative treatment of early breast cancer. Breast Cancer Res. Treat. 15:185-190; 1990.

25. Turesson, I. Characteristics of dose–response relationships for late radiation effects: An analysis of skin telangiectasia and of head and neck morbidity. Radiother. Oncol. 20:149–158; 1991.

26. Turesson, I. The progression rate of late radiation effects in normal tissue and its impact on dose–response relationships. Radiother. Oncol. 15:217–226; 1989.

27. Turesson, I.; Notter, G. The influence of fraction size in radiotherapy on the late normal tissue reaction-I: Comparison of the effects of daily and once-a-week fractionation on human skin. Int. J. Radiat. Oncol. Biol. Phys. 10:593–598; 1984.

28. Turesson, I.; Thames, H. D. Repair capacity and kinetics of human skin during fractionated radiotherapy: Erythema, desquamation, and telangiectasia after 3 and 5 years follow-up. Radiother. Oncol. 15:169–188; 1989.

29. Turesson, I; Notter, G. The influence of the overall treatment time in radiotherapy on the acute reaction: Comparison of the effects of daily and twice-a-week fractionation on human skin. Int. J. Radiat. Oncol. Biol. Phys. 10:607–618; 1984.

30. Bentzen, S. M.; Thames, H. D.; Travis, E. L.; Ang, K.K.; van der Schuren, E.; Dewit, L.; Dixon, D. O. Direct estimation of latent time for radiation injury in late-responding normal tissues: Gut, lung, and spinal cord. Int. J. Radiat. Biol. 55:27–43; 198

31. Van Limbergen, E.; Van der Schueren, E.; Van Tongelen, K. Cosmetic evaluation of breast conserving treatment for mammary cancer. 1. Proposal of a quantitative scoring system. Radiother. Oncol. 16:159–167; 1989.

32. Fajardo, L. F.; Berthrong, M. Radiation injury in surgical pathology. Part I. Am. J. Surg. Pathol. 2:159–199; 1978.

33. White, D. C. An atlas of radiation histopathology. Technical information center, Office of Public Affairs U.S. Energy Research and Development Administration; 1975.

34. Hopewell, J. W.; Foster, J. L.; Young, C. M. A.; Wiernik, G. Late radiation damage to pig skin. Radiology 130:783–788; 1979.

35. Withers, R. H.; Thames, H. D.; Hussey, D. H.; Flow,[jyB. I.; Mason, K. A. Relative biological effectiveness (RBE) of 50 Mv (Be) neutrons for acute and late skin injury. Int. J. Radiat. Oncol. Biol. Phys. 4:603–608; 1978.

36. Withers, R. H. Predicting late normal tissue responses. Int. J. Radiat. Oncol. Biol. Phys. 12:693–698; 1986.

37. Mira, J. G.; Wescott, W. B.; Starcke, E. N.; Shannon, I. L. Some factors influencing salivary function when treating with radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 7:535–541; 1981.

38. Franzen, L.; Funegard, U.; Ericson, T.; Henriksson, R. Parotid gland function during and following radiotherapy of malignancies in the head and neck: A consecutive study of salivary flow and patient discomfort. Eur. J. Cancer 28:457–462; 1992.

39. Mossman, K. L.; Shatzman, A. R.; Chencharick, J. D. Effects of radiotherapy on human parotid saliva. Radiat. Res. 88:403–412; 1981.

40. Becciolini, A.; Tommasi, M. S.; Porciani, S.; Fantappie, B.; Cellai, E.; Chiavacci, A. Serum tissue polypeptide antigen (TPA): A marker of acute injury of salivary glands during radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 13:1339–1342; 1987.

41. Mossman, K. L. Gustatory tissue injury in man: Radiation dose response relationships and mechanisms of taste loss. Br. J. Cancer 53:(Suppl. VII):9–11; 1986.

42. Marks, J. E.; Davis, C. C.; Gottsman, V. L.; Purdy, J. E.; Lee, F. The effects of radiation on parotid salivary function. Int. J. Radiat. Oncol. Biol. Phys. 7:1013–1019; 1981.

43. Main, B. E.; Calman, K. C.; Ferguson, M. M.; Kaye, S. B.; MacFarlane, T. W.; Mairs, R. J.; Samaranoyake, L. P.; Willox, J.; Welsh, J. The effect of cytotoxic therapy on saliva and oral flora. Oral Surg. 58:545–548; 1984.

44. Fu KK. Pajak TF. Marcial VA. Ortiz HG. Rotman M. Asbell SO. Coia LR. Vora NL. Byhardt R. Rubin P. et al. Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: long-term follow-up results of RTOG 83-13 Int. J. Rad. Onc. Bio. Phy. 32(3):577-588; 1995.

45. Ferguson BJ. Hudson WR. Farmer JC Jr. Hyperbaric oxygen therapy for laryngeal radionecrosis. Annals of Otology, Rhinology & Laryngology. 96(1 Pt 1):1-6; 1987.

46. Tartaglino LM. Rao VM. Markiewicz DA. Imaging of radiation changes in the head and neck. Seminars in Roentgenology. 29(1):81-91, 1994.

47. Earlham, R.; Cunha-Melo, J. R. Oesophageal squamous cell carcinoma. II. A Critical review of radiotherapy. Br. J. Surg. 67:451–461; 1980.

48. Seaman, W. B. The effect of radiation of the esophagus. Radiology 68:534–540; 1957.

49. O'Rourke, I. C.; Tiver, K.; Bull, C.; Gebski, V.; Langlands, A. O. Swallowing performance after radiation therapy for carcinoma of the esophagus. Cancer 61:2022–2026; 1988.

50. Nakissa, N.; Rubin, P.; Strohl, R.; Keys, H. Ocular and orbital complications following radiation therapy of paranasal sinus malignancies and review of literature. Cancer 51:980-986; 1983.

51. Dean, G.; Alderson, M.; Maximilien, R. Increased risk of cataract in patients receiving radiotherapy to the eye: A pilot study. Br. J. Radiol. 61:309-311; 1988.

52. Deeg, H.; Flournoy, N.; Sullivan, K.; Sheehan, K.; Nuckner, C. D.; Sanders, J. E.; Storb, R.; Witherspoon, R. P.; Thomas, E. D. Cataracts after total body irradiation and marrow transplant: A sparing effect of dose fraction radiation. Int. J. Rad. Onc. Bio. Phy. 10:957-964; 1984.

53. Merriam,. G. R., Jr.; Focht, E. F. A clinical study of radiation cataracts and the relationship to dose. Am. J. Reontgen, Radium Therapy, Nuc. Med. 77:759-785; 1957.

54. Merriam, G. R.; Worgul, B. V. Experimental radiation cataract: Its clinical relevance. Bull. N.Y. Acad. Med. 59:372-92; 1983.

55. Stallard, H. B. Radiant energy as (a) a pathogenic (b) a therapeutic agent in ophthalmic disorders. Br. J. Ophthalmol., monograph suppl. VI:70; 1933.

56. Jose, J. G. The role of DNA Damage, its repair and its misrepair in the etiology of cataract: A review. Ophthal. Res. 10:42-62; 1978.

57. von Sallman, L. The lens epithelium in the pathogenesis of cataract: The XIII Edward Jackson memorial lecture. Am. J. Ophthalmol. 44:159-170; 1957.

58. Worgul, B. V.; Merriam, G. R.; Medvedovsky, C. Cortical cataract development: An expression of primary damage to the lens epithelium. Lens Eye Toxicity Res. 6:559-571; 1989.

59. Worgul, B. V.; Merriam, G. R.; Szechter, A.; Srini Vasan, B. D. Lens epithelium and radiation cataract: Preliminary studies. Arch. Ophthalmol. 94:996-999; 1976.

60. Hightower, K. R.; Giblin, F. J.; Reddy, V. N. Changes in the distribution of lens calcium during development of X-ray cataract. Invest. Ophthalmol. Vis. Sci. 24:1189-1193; 1983.

61. Lambert, B. W.; Kinsohita, J. H. The effects of ionizing irradiation on lenscation permeability, transport, and hydration. Inv. Ophthalmol. Vis. Sci. 6:624-634; 1967.

62. Matsuda, H.; Giblin, F. J.; Reddy, V. N. The effect of X-irradiation on Na-K ATPase and cation distribution in rabbit lens. Invest. Ophthalmol. Vis. Sci. 22:180-185; 1982.

63. Tulsky DS, An Introduction to Test Theory. Oncology 4:43-48, 1990.

64. Caplan RJ, Pajak TF, Cox JD: Analysis of the probability and risk of cause-specific failure. Int J Radiat Oncol Biol Phys 29:1183-1186, 1994.

APPENDIX I
RTOG 96-04
PROTOCOL TO EVALUATE THE LATE EFFECTS OF NORMAL TISSUE
(LENT)
FOR HEAD AND NECK CANCER
Sample Patient Consent Form

RESEARCH STUDY

I have the right to know about the procedures used in clinical research. This explanation is an effort to make me better informed. I may give or withhold my consent to participate in clinical research. I am being asked to take part in this study because I have head and neck cancer and will receive radiation therapy as part of my treatment.

PURPOSE OF THE STUDY

The purpose of this research study is to test new scales (paper forms) for measuring and scoring the side effects (unpleasant or harmful discomforts) from radiation treatment for head and neck cancer.

After treatment with radiation therapy, patients may develop side effects months or even years after the early side effects have disappeared or healed. There are currently no good measurement scales for measuring the late effects of treatment. For this reason new scales have been developed. They will be used in this study to measure and record treatment side effects. This study compares the new set of forms to an older set of forms to see which is better at measuring side effects. My doctor will examine me and use these new forms to score any late side effects related to my cancer treatment.

It is expected that there will be 160 persons taking part in this study nationwide.

DESCRIPTION OF PROCEDURES

This study involves measuring all side effects from my radiation therapy. This study does not involve any experimental treatments. The actual treatment for my cancer will not be part of this study but the side effects of that treatment will be recorded.

If I agree to join this research study, my doctor will evaluate and record side effects from my cancer treatment during scheduled visits for my regular medical care. I will be examined for side effects at the following times: before starting radiation therapy treatment and at 3, 6, 12, 18, and 24 months after finishing radiation therapy. At the same time, my doctors will also evaluate the status of my disease. This is part of my normal care except that my doctor will use the new paper forms to record and score the treatment side effects in the areas where I received radiation therapy. I will be asked specific questions about how I feel and function with regards to things like swallowing, pain, speaking, neck stiffness.

There will be no additional tests or costs specifically required for this study.

RISKS AND DISCOMFORTS

There are no unpleasant or harmful side effects from taking part in this research study. This is not a treatment study.

CONTACT PERSONS

For more information concerning this research, I can notify Dr.____________________, the investigator in charge at____________________. In addition, I may contact ____________________ at ____________________for information regarding patients’ rights in research studies.

BENEFITS

If I take part in this research study, the overall knowledge of the late side effects of treatment for head and neck cancer and how to measure them may be improved. If these new tools for measuring late side effects prove to be useful, these forms will be used to measure effects of radiation treatments on other patients in the future.

ALTERNATIVES TO PARTICIPATING IN THIS STUDY

The alternative to participating in this study is to not participate. I may decide either way.

VOLUNTARY PARTICIPATION

Participation in this study is voluntary. No compensation for participation will be given. I am free to withdraw my consent to participate at any time. Refusal to participate will involve no penalty or loss of benefits. If I do not take part in or withdraw from the study, I will continue to receive care.

CONFIDENTIALITY

I understand that records of my progress while on the study will be kept in a confidential form at this institution and also in a computer file at the headquarters of the Radiation Therapy Oncology Group (RTOG). The confidentiality of the central computer record is carefully guarded. During their required reviews, representatives of the Food and Drug Administration (FDA), the National Cancer Institute (NCI), and other groups or organizations that have a role in this study may have access to medical records which contain my identity. However, no information by which I can be identified will be released or published.

I have read all the above, asked questions, received answers concerning areas I did not understand, and willingly give my consent to participate in this program. Upon signing this form I will receive a copy.





Signature of Participant Date



APPENDIX II
KARNOFSKY PERFORMANCE SCALE


100 Normal; no complaints; no evidence of disease

90 Able to carry on normal activity; minor signs or symptoms of disease

80 Normal activity with effort; some sign or symptoms of disease

70 Cares for self; unable to carry on normal activity or do active work

60 Requires occasional assistance, but is able to care for most personal needs

50 Requires considerable assistance and frequent medical care

40 Disabled; requires special care and assistance

30 Severely disabled; hospitalization is indicated, although death not imminent

20 Very sick; hospitalization necessary; active support treatment is necessary

10 Moribund; fatal processes progressing rapidly

0 Dead



APPENDIX III

LENT Forms - please contact RTOG Headquarters for forms.
APPENDICES IV, V, VI

Common, Acute and Late Toxicity Tables