Учебники / Otolaryngology - Basic Science and Clinical Review

dose of radiation is relatively low (50 Gy over 5 weeks to mucosal surfaces, 55 Gy over 51⁄2 weeks to lymphatics), and the interval between irradiation and surgical intervention is relatively short (1 week per 10 Gy of radiation). Surgery is carefully timed to follow the period of acute inflammation and precede the delayed effects of irradiation (increased fibrosis, decreased vascularity, and decreased cellularity). Surgical salvage follows highdose irradiation ( 70 Gy over 7 weeks) and invariably is performed 4 months or more after the last dose of irradiation,resulting in poor healing and an increased incidence of complications due to the delayed effects of irradiation.

A unique problem arises when the patient received definitive irradiation to the primary combined with planned preoperative radiation to cervical metastases.To avoid complications due to the delayed effects of irradiation, a neck dissection should be performed within 6 weeks following radiation therapy. If a biopsy of the primary site is performed at this time, cancer cells are likely to be found in the specimen. Unfortunately, the viability of these cancer cells cannot be determined at this early interval. Thus the surgeon is faced with a difficult decision regarding the primary site: should the patient undergo extirpative surgery at the time of neck dissection or should the surgeon follow the patient for clinical evidence of a residual (recurrent) primary lesion?

POSTOPERATIVE RADIATION

Postoperative radiation is given when the attempt at surgical extirpation has been completed and healing has begun. Its purpose is to address clinical and pathological findings that are known to lead to failure at the primary and regional node sites. Postoperatively, radiation therapy can be given at greater doses of radiation to less tumor than may be given preoperatively. Several proposed indications for postoperative radiation include positive (close) margins, perineural spread, lymphovascular invasion, bone invasion, extension into soft tissues, multiple involved lymph nodes, positive lymph nodes greater than 3 cm, and extracapsular spread in lymph nodes of any size.

In the United States today, the standard of care for the use of combination surgery and irradiation is surgery followed by postoperative irradiation. Despite the current popularity of this treatment, one should consider planned preoperative irradiation as a safe, effective treatment when given at the correct dose (50 Gy to mucosa, 55 Gy to lymphatics) and followed by surgery at the correct interval (1 week delay per 10 Gy). In a large multiinstitutional double-blinded, randomized prospective protocol treating squamous cell carcinoma of the head

and neck, preoperative external beam radiation therapy compared favorably to postoperative external beam radiation therapy in terms of complications (no difference) and patient 5-year survival (no statistical difference). Patterns of cancer failure were noted (decreased local/regional failure after postoperative external beam radiation therapy, decreased distant metastases after preoperative external beam radiation therapy).

If postoperative irradiation is given, the interval between surgery and the initiation of irradiation is critical. Despite some evidence to the contrary, most retrospective studies (no prospective study has been performed) indicate that a delay no greater than 4 to 6 weeks following surgery is preferable. If a neck dissection is performed prior to irradiation with intent to cure the primary combined with postoperative irradiation to the neck, the delay following surgery until the initiation of radiation therapy should not be greater than 2 weeks.

RADIOBIOLOGY OF

RADIATION THERAPY

The delivery of ionizing radiation in the treatment of tumors also affects normal tissues.The biological consequences of radiation upon these tissues are generally understood. Rational attempts at enhancing the biological effects of the radiation therapy are being formulated with the understanding of these consequences. Among these are not only physical methods of biological enhancement but also therapeutic methods that involve more biologically correct ways of delivering the daily and total doses of radiation therapy.

Radiation striking the tissue of a patient affects the biology of both normal and tumor tissues. Ionizing radiation causes both direct and indirect effects on biological targets.The deoxyribonucleic acid (DNA) of a cell may be affected directly by the secondary electrons generated as ionizing radiation interacts with tissue. The radiation also may have an indirect effect due to the formation of free radicals; these free radicals in turn cause most of the chemical damage to the theoretical target, DNA.This is the predominant reaction that we are concerned with in radiation therapy of the head and neck. In addition, there are several other cellular functions that are disrupted by radiation-induced damage. This damage may be modified by oxygen concentration, temperature, and other intracellular components.The two most important biological consequences of radiation therapy are the loss of reproductive ability and cellular function. In the treatment of head and neck cancers, it is the loss of clonogenic reproductive ability that is the most important consequence of ionizing radiation. This term describes

the loss of the cell’s ability to continue producing normal daughter cells or, in the case of tumors, additional clonogens.

The relationship between the dose of radiation and the loss of reproductive ability is demonstrated by cell survival curves. These curves demonstrate the ability to survive a given dose of radiation. Both normal and tumor tissues have characteristic shapes for cell-survival curves. The most frequently described relationship for mammalian tumor cells is described by the equation

S 1 (1 e D/Do)n.

In this equation, which demonstrates surviving fraction (S), as a function of dose (D) and predicts a singlehit multi-target model, there is demonstrated an initial part of the curve that is a “shoulder.” The extrapolation number “n” is a measure of the “shoulder” of the survival curve. In this “shoulder” is the amount of damage that the cell can incur and must accumulate before cellular lethality.The term Do is the final slope of the curve and represents the dose required to reduce survival from 0.1 to 0.037 or from 0.01 to 0.037.

Another model that has become significant in its popularity is the linear-quadratic model. This assumes that cell killing has two components; one is proportional to the dose (D), and the other is proportional to the dose squared (D2).This equation is:

LogeS D D2.

Survival is represented by S. The linear single-hit killing component is represented by . The quadratic multiple-hit component is represented by . Tumors that are clinically responsive to radiation therapy demonstrate a high : ratio.Tumors with low : ratio are frequently radioresistant. Early-reacting tissues in this equation also give rise to the concept of acutely reacting tissues (e.g., tumor cells), and mucosal tissues and late-responding tissues such as nerve, muscle, bone, and fat. The linear-quadratic model forms the basis for the development of newer fractionation strategies that allow the : ratios of tumors and normal tissues to be exploited to the advantage of controlling tumors while keeping complications (late-responding tissue effects) to a minimum.

There are several factors that will influence the radiation survival curves depicted by the previous formulas. These include the oxygen content of the cells, the repair of the cellular processes following either sublethal or potentially lethal injury (e.g., the position in the cell cycle), the potential for clonogen proliferation, and the inherent radiosensitivity of the cell. All of these factors have consequences in the way the tissues respond to

radiation. The tissues are broadly divided into earlyor acute-responding tissues (of which mucous membrane and tumor are included) and late-responding tissues, in which the effects of radiation will occur many weeks or months after the radiation has been given. Late-responding tissues are predominantly those in which we see complications of radiation therapy and include muscles, nerve, bone, and fat.Available radiobiological evidence leads us to believe that these late-responding tissues act significantly differently in response to the amount of radiation given in each fraction of radiation. It is the size of this individual fraction (e.g., 1.8–2.0 Gy qid) that influences these late tissue effects the most.

The response of tumors to radiation is highly dependent on the size of the tumor as well as the several concepts that play a role in the eradication of tumors. The processes of repair of radiation-induced damage, repopulation of clonogens, reoxygenation of hypoxic tumors, and redistribution of cells into radiation-sensitive positions in the cell cycle are very important in the control of tumors. These constitute the four R’s of radiobiology. These four R’s are the basis for the clinical delivery of radiation therapy.

FRACTIONATION OF TREATMENT IN RADIATION THERAPY

The aforementioned biological principles of radiation therapy are most important in developing a rationale for the fractionation of treatment in radiotherapy for head and neck malignancy. Fractionation is a term used to describe the clinical manner in which the daily dose of radiation is given. It remains one of the foundations of contemporary radiation therapy for head and neck carcinoma.

There is, however, no universally accepted standard for fractionation. The existence of many “conventional” schemes has been influenced by personal opinion, socioeconomic factors, equipment availability, and historical and traditional prejudices. In the United States, the standard is 1.8 to 2.0 gray (Gy) or 180–200 centigray (cGy) once daily, Monday through Friday, over approximately 7 weeks. In Canada, treatment is 250 cGy per day 4 days a week over 5 weeks. In England, the therapy may extend through the weekend at higher fraction totals per day, for example, 150 cGy 3 times a day.

Recently, an attempt to use radiobiological therapy as it pertains to the differences in earlyand late-reacting tissues has come into prominence. Examples of earlyreacting tissues are tumor cells, mucous membrane cells, and gastrointestinal mucosa. Late-effects tissues include, but are not limited to, those in which we see complications of therapy such as muscle, nerve, and bone.

TABLE 11-1 FRACTIONATION

Biological basis

: ratio

Tumor cell proliferation

Objective

Exploit inherent tissue differences Treat in a shorter time period

Currently, altered fractionation (nonstandard) reforms are being designed to account for this clonogen growth or to exploit the different biological responses of acute (tumor) and late- (complication) reacting tissues.These two biological strategies are the main foundations of contemporary fractionation policies (Table 11-1).

RATIONALE FOR FRACTIONATION

It has been demonstrated over the last several years that tumor cell growth actually accelerates exponentially during the course of radiation therapy. It is therefore not unreasonable to deliver radiation therapy in a more accelerated manner so as to overcome this exponential growth. These two biological strategies, differentiating early and late effects and overcoming tumor proliferation, are the main foundations of contemporary fractionation policies.

Several physical factors are important in the discussion of any fractionation regime. Dose per fraction, total dose (number of fractions), overall time, and time interval between the delivery of radiation fractions are the most critical of these factors. The dose per fraction is most commonly described as being either a rad (old) or a gray (new). A rad is a measure of energy absorption of 100 erg/g. A gray is energy absorption of 1 Joule/kg. One gray is equal to 100 cGy (rads). One cGy equals 1 rad. Decreases in the size of the dose per fraction spares lateresponding normal tissue (e.g., nerves, bone, and muscle) more than it spares tumor cell killing.This is one of the implications of the linear-quadratic model ( : ratio).

Overall time is also important for any given effect; total dose delivered to the tumor has to be increased if overall time in which the treatment is given is increased. Small fractions are less effective than large fractions and require compensation for proliferation in normal tissue and, of course, tumors. In the treatment of head and neck cancer it is often a possibility that the overall time in which the treatment is given has to be prolonged. In this case, the total dose must be increased. Small fractions are less effective than larger fractions in doing this, and one must compensate for proliferation both in normal tissues and in tumor tissues. It is important, however, not to consider time alone. Normal tissue effects in early-reacting

tissues start compensatory proliferation in 2 to 4 weeks after the start of radiation therapy. Late-reacting tissues, which are the origin of complications, have no proliferation during the weeks of radiation therapy. It is important to try to keep the overall treatment period as short as reasonably possible. However, we try not to do this by greatly increasing the size of the daily fractions. Late effects (complications) are fraction size dependent.This is another implication of the linear-quadratic model. Prolonging the overall time decreases damage to acute tissues and therefore makes the treatment more tolerable to patients with less acute side effects. However, this dose does not cause a decrease in the damage to late tissues. Prolonging the overall treatment time will result in less damage to the tumor cells that we are trying to control and therefore will result in less local control. Shortening the overall treatment time will increase the damage to acute tissues with no increase in damage to the late tissues unless the dose per fraction is increased significantly in its daily size. Shortening also results in an increased tumor kill.

In conventional treatment the total dose is determined by type of tumor and volume being treated as well as the tolerance of normal tissue in the volume. As stated earlier, altered fractionation schemes either try to exploit the difference between earlyand late-reacting tissues or take into consideration the new tumor cell kinetic information that has shown us tumors will become rapidly exponential in their growth while under treatment. Hyperfractionation, accelerated fractionation, and dose escalation (e.g., concomitant boost) are several strategies that have become popular throughout the world (Table 11-2).

Hyperfractionation is administered by a decrease in the size of the administered fraction.There is an increase in the total number of fractions and an increase in the total dose. However, the overall treatment time is maintained at what would have been expected from a conventional treatment.The most classic example of this is the delivery of 1.2 gray fractions twice a day for approximately 7 weeks.This is the same 7-week period in which conventional fractionation at 2 Gy once a day may have been delivered. Using the linear-quadratic model as the basis for computing the biological effects of doing this results in an 84 Gy tumor dose in the same amount of time that a 70 Gy tumor dose would have been delivered conventionally. Theoretically, this smaller fraction size allows sparing of late tissue damage while an increased total dose can be given to the tumor.

Accelerated treatment seeks to decrease the overall time it takes to deliver a course of radiation therapy. During this time the fraction size, fraction number, and

total dose are either maintained or very slightly altered. For example, if one were to deliver a treatment once a day for 5 weeks, from Monday through Friday, this treatment might deliver the same 25 individual treatments but with no break for Saturday or Sunday. Thus the 5 weeks required for treatment would become 31⁄2 weeks. This shortening of the overall treatment time theoretically defeats the tumor proliferation that takes place during the course of the standard treatment of 5 to 7 weeks.

A combination of both of the previously mentioned strategies is an accelerated hyperfractionation strategy. This combines the shortening of the overall treatment time to defeat tumor proliferation and the smaller fraction size to spare late tissue damage. Examples of this include the delivery of 35 fractions at 1.5 Gy delivered 3 times a day in 12 days or 1.6 Gy twice a day at 24 fractions in 3.4 weeks with a break to allow for the early-reacting tissue to decrease its bothersome response, followed by resumption of treatment at 1.6 Gy twice a day to the 64 to 67.2 Gy level.

Another strategy is a type of dose escalation or concomitant boost.With this strategy, a small booster field is delivered within a larger field on the same day.These treatments are delivered at least 6 hours apart, and, although approximately the same total dose as a standard treatment is given, there is a change in the fraction sizes delivered once in the morning and once in the afternoon.The diminished size of the booster dose decreases the volume to which radiation is given and thus decreases the effects early-reacting tissues such as mucosa while having a great effect on the tumor tissue. Treating the tumor tissue twice in a single day at near standard fractionation overcomes the tumor cell proliferation.

Another advantage of accelerated fractionation schedules is a reduction of overall duration of treatment.This allows tumor proliferation to be overcome without causing additional injury to late-reacting tissues. There are several caveats to be considered in the delivery of altered fractionation schemes based on the radiobiological rationales of late/early tissue sparing and overcoming

tumor cell proliferation. Although several pilot studies using hyperfractionation and accelerated fractionation suggest a therapeutic advantage, there is no convincing evidence of an improvement in the therapeutic ratio. Several trials are ongoing.

Both hyperfractionation and accelerated fractionation are associated with increased acute normal tissue reactions that may be dose limiting.This is certainly the case when fractionation is delivered three times a day.

Altered fractionation regimes may also be associated with unexpected late normal tissue complications. These may be due to the normally expected sequelae of treatment or may actually be related to the size of the dose per fraction, the number of fractions delivered in a single day, and the time between these fractions.

Most normal tissue reactions can be held to a minimum if an interfraction interval of 6 hours is allowed. The only exception to this may be the spinal cord, where even a 6-hour interfraction interval may not be enough to overcome the effects.

SELECTED READINGS

Amdur RJ, Parsons JT, Mendenhall WM, et al. Postoperative rradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int J Radiat Oncol Biol Physiol 1989;16:25–36

Byers RM, Clayman GL, Guillamondequi OM, et al. Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract. Head Neck 1992;14:133–138

Fein DA, Lee WR, Amos WR, et al. Oropharyngeal carcinoma treated with radiotherapy: a 30 year experience. Int J Radiat Biol Physiol 1996;34:289–296

Hall E. Radiobiology for the Radiologist. 4th ed. Philadelphia: JB Lippincott; 1993

Kahn F. The Physics of Radiation Therapy. Baltimore: Williams & Wilkins; 1993

Marcial VA, Gelber R. Kramer S, et al. Does preoperative irradiation increase the rate of surgical complications in carcinoma of the head and neck? A Radiation Therapy Oncology Group Report. Cancer 1982;49:1297–1301

Mendenhall WM, Parsons JT, Stringer SP, et al. Squamous cell carcinoma of the head and neck treated with irradiation: management of the neck. Sem Radiat Oncol 1992;2:163–170 Peters LJ, Ang KK.The role of altered fractionation head and neck

cancers. Sem Radiat Oncol 1992;2:180–194

Taylor JMF, Withers HR, Mendenhall WM. Dose time consideration of head and neck squamous cell carcinomas treated with irradiation. Radiother Oncol 1990;17:95–102

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 715.

1.When hyperfractionation is used to treat head and neck cancer with curative intent, which of the following statements is true?

A.The daily fraction size is “standard” in size.

B.The overall time is shortened.

C.The overall dose is increased.

D.Acute toxicity is less.

2.When accelerated treatment schemes are used to treat head and neck cancer with curative intent, which of the following statements is true?

A.The daily fraction size is increased so the treatment will finish faster.

B.The total dose is increased.

C.The toxicity is lessened.

D.The overall treatment time is significantly decreased.

3.Hyperfractionation is used to

A.Rapidly finish treatment

B.Exploit the radiobiological difference between acutely and late-reacting tissues

Tupchong L, Phil D, Scott CB, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG Study 73–03. Int J Radiat Oncol Biol Physiol 1991;20: 21–28

Withers HR,Taylor JMF, Maciejewski B.The hazard of accelerated tumor clonogen repopulation during radiotherapy.Acta Oncol 1988;27:131–146

C.Achieve a higher total dose

D.Lessen toxicity

4.The point on a survival curve where the single-hit component equals the multiple-hit component is known as

A.Nirvana

B.Therapeutic index

C.Survival equilibrium

D.: ratio

5.The biological rationale behind accelerated fractionation schemes shortens the overall treatment time dramatically because

A.Tumor doubling time is slow, and therefore damage can accumulate.

B.Large-dose per fraction treatment is therapeutically better.

C.Patients become fatigued following long periods of radiation.

D.Tumor clonogens start to grow rapidly while under treatment.

Many inhaled materials from the environment have a detrimental effect on the nose, paranasal sinuses, larynx, and trachea. Oxidant gases, in particular, produce a variety of changes in the airway, increasing in severity from injury and exfoliation of ciliated cells to severe airway damage, resulting in exposure of the basement membrane of both mature and undifferentiated cells. The airway responds to these insults with adaptive mechanisms, including decreased sensitivity of airway receptors, decreased airway permeability, increased number of secretory cells, and increased mucus production. Additionally, damage to the ciliated cells results in an increased need for coughing to clear both inhaled particles and excess secretions.

TOXICITY

The toxicity of each inhalational agent depends on its intrinsic toxicity, its absorption and transport to the target organ, its ability to biotransform into a more or less toxic substance, and its ability to bind to essential macromolecules. The pathophysiological effects will be mediated by multiple factors, including the concentration of the agent and the exposure time, the gas solubility, and certain environmental characteristics, such as temperature, humidity, and airflow.The simultaneous presence of other gases or pathogens can also mediate the severity of the injury. At the cellular level, the acute effect of toxic chemicals on the respiratory epithelium results in

increases in intracellular calcium, dysfunction of sodium regulation, vacuolization of the cytoplasm, dilation of the endoplasmic reticulum, condensation of matrix proteins, and apical membrane blebbing.

CHEMICAL POLLUTANTS

Common examples of damaging gases in the indoor environment are carbon monoxide and nitrogen dioxide. These ubiquitous pollutants are by-products of cigarette smoking and the use of certain heating systems. Excessive exposure to nitrogen dioxide may cause a reduction in cellular defense mechanisms and may lead to dyspnea, restlessness, coughing, wheezing, nausea, and vomiting.

Numerous other chemicals have been shown to damage the respiratory system. Formaldehyde, which can be released by certain insulation materials or be present in high concentrations in anatomy and pathology laboratories, can cause eye, nose, throat, and lung irritation. Chronic exposure has been associated with sinonasal, nasopharyngeal, and hypopharyngeal cancers.Additionally, an increased rate of leukemias is found in embalmers, anatomists, and pathology technicians. Benzene, still used as a solvent in many laboratories, can cause bone marrow suppression.Volatile organic compounds associated with chronic airway irritation may come from common office equipment such as copiers and computer printers. Exposure to the above volatile compounds has also been associated with aplastic anemias and leukemias. Other

polychlorinated solvents, notably aromatics (e.g., xylene), and polychlorinated solvents (e.g., carbon tetrachloride, tetrachloroethylene, and trichloroethylene), have all been associated with liver degeneration, hepatitis, and renal disease.

Excessive exposure to isopropyl alcohol has been linked to cancer of the paranasal sinuses and larynx. Bis(chloromethyl)ether exposure has been found to produce esthesioneuroblastomas in a rat model.The organic solvents may also cause chronic encephalopathies and peripheral neuropathies. Toluene and xylene are both associated with menstrual disorders. Ethylene oxide has been found to cause chronic airway irritation. Inhalation of hydrazine has been associated with polyps, carcinoma, and, possibly, amyloidosis.

Chronic inhalation of tobacco smoke has been proven to cause significant airway damage, ranging from sinusitis and laryngitis to carcinoma of the entire respiratory tract. Inhalation of marijuana in heavy smokers has been shown to cause rhinitis, pharyngitis, and laryngitis. Other contaminants in smoke (such as Aspergillus) may compound the problem. Inhalation of cigarette smoke may produce atypism and cellular hyperplasia, loss of cilia, and possible carcinogenesis. Cocaine inhalation causes chronic rhinitis and pharyngitis, and its effects are believed to be related both to its vasoconstrictive properties and to the presence of adulterants.

Chloroform is now rarely used; its well-described dangers have prompted the U.S. Food and Drug Administration to ban its use in drugs and cosmetics. However, it is still used commonly in certain endodontic procedures. Chronic exposure to chloroform, especially in small, confined areas, places these dental workers at increased risk for lung and liver disease.

Anesthetic gases represent a major environmental hazard in the operating room. Several studies performed in the 1970s concluded that the rate of spontaneous abortions was substantially higher in female anesthesiologists compared with female physicians working outside the operating room. Furthermore, the incidence of congenital anomalies seen in children of both male and female anesthesiologists was higher than in the control group of physicians. The presence of malignancy was similar in both anesthesiologists and controls. Liver disease, however, was more prevalent in male anesthesiologists.

It has been shown that concentrations of nitrous oxide as low as 50 ppm, either alone or in combination with 1 ppm of halothane, result in decreased behavioral performance. Although the data have been disputed by other researchers, they show that anesthetic gases may have an insidious effect on the operating room

personnel. Gas-scavenging techniques have been employed to minimize exposure. New data, however, suggest that even with the use of scavenging techniques, chronic inhalation of trace concentrations of anesthetic gases may be harmful.

Another potentially harmful exposure in the operating room is related to the increased use of laser surgery. With vaporization of lesions, a smoke plume (the socalled laser plume) is produced, composed mostly of water vapor and carbon particles. However, in lesions such as papillomas, live viral particles and bacteria have been found. Measuring on average 0.31 m (range 0.1–0.8 m), these pose a risk of inhalation to operating room personnel, given the fact that most surgical masks do not trap particles this size. Thus great efforts need to be taken to scavenge the laser plume using specialized ventilation/evacuation systems.

Acrylic monomers, commonly used for cranioplasty, orthopedic, or dental procedures, may cause airway irritation and hepatotoxicity. As inhalants, acrylic monomers represent a particular risk to dental personnel because they are aerosolized during dental procedures. Chronic exposure can cause central nervous system (CNS) disturbances, including tremor, ataxia, nervousness, irritability, paresthesias, and visual changes.

Other inhalational agents noxious to the airway are metals, such as mercury, magnesium, zinc, cadmium, and nickel. Mercury is particularly risky to dental personnel. Its aerosolized form, used in dental procedures, can lead to chronic CNS effects similar to those already described for acrylates. Magnesium is also irritating to the airway and may cause cough, rhinitis, and increased mucus production. Zinc is used to galvanize iron and is found in paints, pigments, glazes, enamels, and certain paper manufacturing processes. Acute inhalation of zinc fumes may cause “metal fume fever” and significant airway irritation. Cadmium is also terribly noxious to the airway.The major nonindustrial source is cigarette smoke. Exposure is associated with cancers of the respiratory tract, lung, and prostate. Cadmium fume inhalation resulting from exposure to industrial processes such as stainless steel production, plating, tanning, and pigment and wood preservative manufacturing may cause nasal irritation and septal perforations, as well as chronic rhinosinusitis, pharyngitis, laryngitis, and lung cancer. Nickel fumes are associated with chronic airway irritation and lung cancer.

ENVIRONMENTAL INHALANTS

Environmental inhalants can cause a constellation of constitutional symptoms, ranging from mild to severe. Most large buildings use water-cooled ventilation systems,

which are often contaminated with molds, mildews, and bacteria. Central ventilation ensures that these contaminants are efficiently pumped throughout the entire building. The best known example is that of the Legionella pneumophila epidemic of 1976, which caused 189 cases of pneumonia and 29 deaths in residents of a Philadelphia hotel. Legionella was found to have grown in the stagnant water of a cooling tower and to have been spread as an aerosol within the ventilation system.

Humidifiers associated with cooling systems are a source of air contaminants such as fungi and dust mites, as are air-conditioning filters. A common fungal organism spread in hospital ventilation systems is Aspergillus. The spread of fungal spores may be particularly dangerous for immunocompromised patients. However, even in immunocompetent hosts, fungal contamination of the ventilation systems has been associated with allergic alveolitis, rhinitis, and sinusitis.Tuberculosis has also been found in ventilation systems, and this could pose a particularly difficult problem with the emergence of new, multidrugresistant strains. In addition to microorganism contamination, larger particles, such as animal hair and dander, are spread through building ventilation systems.

Besides the above contaminants, building inhabitants are exposed to the biocides placed in the ventilation systems to control the spread of microorganisms. Many of these agents have been found to be extremely irritating to the upper respiratory system.

SICK BUILDING SYNDROME

A constellation of physical, chemical, and biological environmental factors found in the indoor working environment has been identified and is commonly referred to as the “sick building syndrome.” It has been reported to occur in 20 to 30% of all office workers, and it reportedly reduces their work productivity by up to 30%. Characteristic symptoms are often nonspecific: nasal irritation, rhinorrhea, nasal obstruction, chest tightness, dry and irritated eyes, dry and irritated throat, dry skin, rash, headaches, lethargy, and poor concentration. Several physical factors intensify the symptoms, including ambient temperature of more than 22°C, poor ventilation, and humidity greater than 70%. Artificial light also appears to play a role in this symptom complex. Environmental noise, negative ions, and inorganic dust have been associated with the syndrome. Chemical factors associated with sick building syndrome include exposure to secondhand smoking, formaldehyde vapors, volatile organic compounds (including office products such as photocopy ink), biocides, and other gases (e.g., carbon monoxide, carbon dioxide, nitrous

dioxide, ozone, sulfur dioxide). Chronic exposures to biological contaminants such as mites, molds, bacteria, and fungi all appear to pay significant roles in the symptom complex. The sick building syndrome takes on added importance in hospital settings, because lethargy and poor concentration on the part of hospital personnel can harm patients.

To conclude, there are numerous indoor environmental exposures that can damage components of the respiratory system. Of note, hospitals present a special set of exposure risks, related to the use of inhalational anesthetics, lasers, and certain laboratory chemicals. In addition, the use of central cooling and ventilation systems exposes inhabitants to potentially toxic microorganisms and biocides. More work is needed to protect workers from the effects of indoor inhalational agents. As health care leaders, physicians need to assume active roles as patient and employee advocates and educators.

SUGGESTED READINGS

Amdur RJ, Parsons JT, MendenhallWM, et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int Jradiat Oncol Biol Physiol 1989;16:25–36

Byers RM, Clayman GL, Guillamondequi OM, et al. Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract. Head Neck 1992;14:133–138

Fein, DA, Lee WR, Amos WR, et al. Oropharyngeal carcinoma treated with radiotherapy: a 30 year experience. Int J Radiat Biol Physiol 1996;34:289–296

Hall E. Radiobiology for the Radiologist. 4th ed. Philadelphia: JB Lippincott; 1993

Kahn F. The Physics of Radiation Therapy. Baltimore: Williams & Wilkins; 1993

Marcial VA, Gelber R, Kramer S, et al. Does preoperative irradiation increase the rate of surgical complications in carcinoma of the head and neck? A Radiation Therapy Oncology Group Report. Cancer 1982;49:1297–1301

MedenhallWM, Parson JT, Stringer SP, et al. Squamous cell carcinoma of the head and neck treated with irradiation: management of the neck. Semin Radiat Oncol 1992;2:163–170

Peters LJ, Ang KK. The role of altered fractionation in head and neck cancers. Sem Radiat Oncol 1992;2:180–194

Taylor JMF, Withers HR, Mendenhall WM. Dose time consideration of head and neck squamous cell carcinomas treated with irradiation. Radiother Oncol 1990;17:95–102

Tupchong L, Phil D, Scott CB, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG Study 73–03. Int J Radiat Oncol Biol Physiol 1991;20:21–28

Withers HR,Taylor JMF, Maciejewski B.The hazard of accelerated tumor clonogen repopulation during radiotheraphy. Acta Oncol 1988;27:131–146

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 715.

1.“Sick building syndrome” includes

A.Rhinorrhea and nasal obstruction

B.Headaches

C.Eye irritation

D.Lethargy

E.All of the above

2.Humidifiers have been associated with the spread of

A.Aspergillosis

B.Candidiasis

C.Tuberculosis

D.A and B

E.B and C

3.Particularly noxious environments in the hospital include

A.Operating rooms

B.Pathology laboratories

C.Photocopy centers

D.All of the above

E.None of the above

Scientific investigation is a process, the process of discovering the working of the natural world. Science answers the question, How? Science is a culture. It has its own language and etiquette, its own socialization and training routines, its own icons and articles of faith. Training to become a scientist is an indoctrination into this culture. Members learn certain ways of thinking, of posing questions, and of seeking their answers.

Clinical medicine is also a culture, albeit a different one from science. Imagine that you are a clinician, and a young scientist comes to see you. He has completed his doctorate and is nearing completion of his postdoctoral fellowship. He will be taking an academic position at a prestigious university within a year. He tells you that he has decided that his academic career will be more successful and fulfilling if he could have a clinical component in addition to his research activities. He would like to operate one afternoon a week. He also would like to spend 3 months with you in your practice to learn some surgery that he could do once he gets out of his fellowship. “Ludicrous,” you say.You have spent 4 years in medical school and 5 years in residency to learn your craft. Despite the fact that the young scientist is intelligent

and has excellent manual dexterity, there is no way he could master the art and science of clinical practice in 3 months, no way that he can become a member of the medical culture in that brief period of time.

Now imagine how it sounds to the senior scientist when a young resident, nearing completion of her training, comes requesting a few months of laboratory time so that she can “do science” one afternoon each week when she enters her academic job in a year or two. The scientist spent 7 years acquiring her PhD and 3 more years in her postdoctoral fellowship before she got her first grant support as an independent investigator. It is inconceivable that the resident, working part time in the laboratory for only a year or two, can learn how to pose a research question, develop a testable hypothesis, design an experiment, write a fundable research proposal, execute the experiment and analyze the results, and present or publish the findings. It is inconceivable that the resident could develop the kind of scientific intuition that only comes from years of experience, strong mentorship, and many frustrations and failures. It is also inconceivable that the resident could become a member of the science culture.