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2 Types and Frequency of Skin Reactions

2 Types and Frequency of Skin Reactions

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6



Thoracic Cancers



Stereotactic radiation therapy (SRT) is based on

the delivery of a small number of very high-dose

fractions (extreme hypofractionation). Typically

the patient will receive 1–5 fractions at a dosage

per fraction that might be 10–34 Gy. These high

doses per fraction produce a higher rate of acute

and late effects, as would be expected. One study

reported a rate of acute grade 2 or higher skin toxicity reaching 14 % following thoracic SRT [16].

Several reported series have documented new risks

for long-term chest wall injury or pain, not previously seen in patients receiving fractionated thoracic radiotherapy, especially in obese or diabetic

patients or when the intercostal nerves lie in close

proximity to the high-dose treatment field [17, 18].

Whole-brain radiation therapy (WBRT) is

given for any type of lung cancer that has spread

to the brain. For small cell cancers, prophylactic

cranial irradiation (PCI, essentially WBRT but

usually given to slightly lower doses) is part of

the standard of care for any limited stage patient

who achieves a complete response to chemoradiation or extensive stage patient who shows

response to chemotherapy [19, 20]. Temporary

alopecia should be expected after PCI with some

regrowth of hair in 2–3 months [21]. After

WBRT, hair regrowth will be less, and many

patients will experience regrowth of hair in a specific pattern called “reverse Mohawk,” meaning

that the vertex area of the scalp may receive the

highest doses and remain bald [22].



6.3



Impact of Technical Choices

on the Skin



For treatments using megavoltage photons treating lung parenchymal or mediastinal regions, the

skin reactions due to irradiation tend to be moderate in nature, because of the inherently skinsparing physical characteristics of megavoltage

energy beams and the central nature of these

areas within the chest cavity. However, the skinsparing effects can be negated if the overall field

size is very large, which creates a high buildup of

electrons at the surface, or if an excessive number

of devices such as blocking trays or multileaf collimation are introduced into the beam pathway

such as may be used in an attempt to make the



81



radiation doses very conformal to the tumor

shape, or, finally, if the entry of one highly

penetrating beam coincides with the exit point of

another [23]. Therefore, it is important that the

prescribing physician has familiarity with the

characteristics of the radiation to be employed

and inspect the arrangement of the beams that

comprise the total plan for the patient.

Even in relatively simple plans, the choices of

beam arrangement can have impact on the skin.

For example, the use of exclusively anteroposteriorly angled beams may increase the risk of a

local dermatitis because of the coincidence of

entry and exit of simultaneously delivered beams

in the same area. When planning a high-dose

treatment, it can be worth considering an arrangement of beam angles that do not all enter through

the same exact region of skin. With more complex and conformal treatments, whether given

using a 3D conformal or intensity-modulated

technique, consideration should be given to the

superficial effect of so-called glancing beams.

With an increasing number of beams that are

intended to produce a more conformal dose distribution around the target, there is a higher likelihood of employing beams that are obliquely

angled to the surface of the skin. Oblique beams

increase the surface dose and, when multiplied,

can create a local area of intense skin reaction

[24], especially because the beams are sometimes

extensively blocked and collimated for greater

conformality. This is seen more and more frequently with the advent of high-dose radiation

delivered with intensity-modulated techniques.

In particular, these effects can be more pronounced depending on the distance of the skin from

the targeted high-dose region. For instance, if areas

in the thoracic inlet or supraclavicular region are

included in the treatment field, especially in a thinner

patient, more severe reactions may be seen because

of the proximity of the skin to these relatively superficially located regions. This phenomenon of

increased reactions around and above the collar bone

has long been recognized and studied in breast cancer radiation treatment [25], although there is less of

a focus on the issue in thoracic oncology because of

the greater rarity of a clinical situation justifying

high-dose supraclavicular radiotherapy. In any case,

special care should be taken when radiation of any



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type is to be delivered to the supraclavicular or

mid-upper neck regions, as dermatitis in these areas

tends to be more severe and also more disabling and

painful to the patient than reactions on the skin of the

thorax proper. These neck treatments can result in

painful erythema and dry and wet desquamation, in

a manner similar to that seen when treatments are

given for breast or head and neck cancers (see related

chapters on these issues).

Conversely, in patients who are obese (the

standard definition would include patients with a

body mass index >30 kg/m2), more severe reactions may be observed in any part of the body due

to the quantifiably larger amount of body surface

area [26], the physical presence of skin folds, and

the excessive number of monitor units (actual

machine output) that must be delivered through

the surface to achieve the full amount of the dose

prescribed to the deeply located targeted regions.

Patients who are obese often have comorbid medical conditions that impede healing from acute tissue injury, and thus they may suffer from a longer

duration of skin-related or other severe effects.

Certain special clinical situations may incur an

increased risk of radiation-related skin or chest

wall reaction. For example, the use of superficially

directed electron therapy, which is occasionally

used to treat scars (sarcoma, mesothelioma), will

deliberately increase superficially located dermatitis in a dose-dependent manner [27, 28].

In stereotactically directed treatments, the

proximal chest wall may need to be defined as a

dosimetrically defined avoidance structure due to

the risks of long-term toxicity to the chest wall

musculature, ribs, and intercostal nerves.

Creating a formal chest wall avoidance structure

in this manner is usually considered a standard

practice only for tumors that are to be treated to

high doses in close proximity to the chest wall

[29–31]. However, there may be a role for

increased attention to superficial skin toxicity as

a more general practice. In regard specifically to

acute skin reaction, SRT-related acute toxicity

was reported by one group as most accentuated

by the same technical factors widely recognized

as risks in traditionally fractionated external

beam therapy; identified factors associated with

Common Terminology Criteria for Adverse

Event (CTCAE)-defined grade 2 or higher acute



S.S. Yom and F. Yuen



skin toxicity included using only three beams

(due to the convergence of their exit and entry

points in one area), distance from the tumor to the

posterior chest wall skin of less than 5 cm (due to

superficial location of the high-dose region near

the skin surface and the added bolus effect of a

stabilizing immobilization cradle in which the

patient lies down), and a maximum skin dose of

50 % or higher of the prescribed dose [16].

Furthermore, dosimetric precautions to the

external skin surface or chest wall, while they

mostly apply to the superficial tissues in close

proximity to the target of a stereotactic or highdose treatment, should be kept in mind as potentially useful to evaluate all subcutaneous tissues

where beams enter or exit. For example, in one

clinical trial of SRT given for liver metastases, the

investigators reported a grade 3 severe reaction

with overlying skin breakdown in the subcutaneous

tissue of an area remote from the posteriorly located

target [32]. As a result, some SRT lung cancer trials, such as RTOG 0618, have mandated contouring of a 5 mm ring at the entire external surface of

the body to check for high-dose regions that may

be unintentionally delivered to focal spots remote

from the areas of highest interest [33].

There is a substantial body of evidence that individual patient-related factors also play a role in chest

wall toxicities and should be considered in anticipating a severe reaction. Patients with conditions predisposing to poor healing, such as diabetes, obesity,

vascular compromise, or osteoporosis, are at highest

risk for nerve damage, rib fracture, long-term inflammation, fibrosis, or pain [17, 18, 34]. In these patients,

consideration may be given to treatment courses lasting 4–5 fractions as opposed to 3 fractions or less, to

try to reduce toxicity [35]. This patient population

represents an area of ongoing clinical investigations

to develop medical or technical strategies to reduce

the potential for high-grade effects.

Not just unique to lung cancer but also in other

areas of focal radiotherapy, the study of hypofractionated treatments is a very rapidly growing area

of medicine; as these practices becomes more

widespread for all stages of lung cancer treatments, the immediate effect of their dissemination

will likely be some increase in both acute and late

toxicity incidence. Strategies to prevent and manage these toxicities are likely to be an area of



6



Thoracic Cancers



greater interest as these approaches become

widespread. Hypofractionated approaches are not

isolated to lung cancer but are being used in all

areas of medicine including palliation [36].

Proton therapy is beginning to be used for

patients with intrathoracic conditions such as lymphoma, sarcoma, and lung cancer. Proton therapy

poses a special risk of skin toxicity due to a typical

arrangement utilizing fewer beams and the relatively higher percentage of dose deposited at the

entry point of each beam. Especially if the number

of entry beams is limited and/or if the treatment is

hypofractionated, the expected reaction can be

notably higher than what is seen with megavoltage

photon-based treatments. One small case report

anecdotally noted a higher incidence of grade 2–3

skin reactions being observed with the use of thoracic proton therapy and proposed the use of a

transparent film which seemed to decrease effects

to the surface via an unclear mechanism [37]. Other

forms of particle therapy, such as neutron or carbon

ion therapy, are less well known but have also been

associated with higher rates of skin toxicity.



6.4



Other Factors Affecting

Acute Skin Toxicity



6.4.1



Concurrent Chemotherapy



Concurrent use of systemic chemotherapy in combination with radiation therapy is very common in

treating lung cancers. Concurrent chemotherapy

does increase the incidence of other acute toxicities, such as esophagitis, although whether there is

an effect on acute dermatitis is unknown [38].

Taxanes, which are frequently used in concurrent

chemoradiation regimens, result in hair loss [39].

In the advanced stage population, where traditionally fractionated 3D conformal and intensity-modulated

radiation therapy treatments are often combined with

concurrent chemotherapy, there has been a relatively

low incidence of severe dermatitis because of the usual

deep-seated nature of these tumors, so this has not usually been an area of focused concern. However, with

newer developments such as hypofractionation or proton therapy, the effects of concurrent systemic therapy

will require closer evaluation.



83



In metastatic patients who start with radiation

but later receive chemotherapy at some point in

their course, recall phenomena may be seen with

certain chemotherapy agents if they are given

prior to radiation. Gemcitabine is the best-known

systemic agent in producing these recall phenomena, but erlotinib and pemetrexed, both very

commonly used in metastatic lung cancer, have

also been reported in this context [40, 41].



6.4.2



Concurrent Targeted Therapy



Targeted therapies have not been used concurrently

with radiation except in a few circumstances. The

most substantial concurrent uses of targeted therapies (cetuximab, erlotinib) have occurred as addons to the basic chemoradiation platform for stage

III disease. For example, in the large randomized

trial RTOG 0617, there were four arms arranged in

a two-by-two design including 74 Gy versus 60 Gy,

with or without cetuximab [42]. Across the four

arms, there was no clearly noticeable pattern of

increased general dermatologic effects or specific

effects such as dermatitis, dryness, and pruritus.

The rate of dermatitis across the four arms ranged

from 18 to 26 % for grade 1, 6 to 12 % for grade 2,

and 1 to 3 % for grade 3, which was the highest

grade attained. However, the two cetuximab-containing arms did have higher rates of dry skin,

approximately 25–27 % and 11–12 % for grades 1

and 2, compared to the non-cetuximab-containing

arms, which had rates of 7–9 % and 2–3 %, respectively, as well as pruritus, which was counted at

rates of 10–12 % and 0–1 % for grades 1 and 2 in

the non-cetuximab-containing arms, versus

17–26 % and 6–8 % in the cetuximab-containing

arms. It is unclear how rigorously these effects

were graded, and it is likely that there may have

been some underreporting of these somewhat more

subtle and less clinically significant effects. The

largest level of difference between the non-cetuximab and cetuximab arms was seen in the rates of

desquamating rash, perhaps because of its more

clinically evident nature. The cetuximab arms had

rates of 14–15 %, 12–13 %, and 4 % for grades 1, 2,

and 3, respectively, versus rates of 4–7 %, 2–3 %,

and 0–1 % in the non-cetuximab-containing arms.



S.S. Yom and F. Yuen



84



Targeted therapies (such as erlotinib) have

been very rarely used with SRT. The one

prospective trial that has been published did not

report dermatologic or chest wall toxicity [43].



6.4.3



Reirradiation



For patients being reirradiated to the chest for palliative purposes, skin reaction has not been reported

as a dose-limiting toxicity [44]. However, patients

who have been previously radiated to the thorax

and are treated again with curative intent can be at

higher risk for radiation skin toxicity, especially if

the second treatment is given with stereotactic

technique. One study of this specific clinical scenario reported an incidence of grade 2 or higher

chest wall pain in 18 % and skin toxicity in 5 %

[45]. For these patients, the original plan should be

reviewed, and consideration should be given to

avoid excessive skin and chest wall dosages to

areas treated previously. Particular attention should

be paid if the reirradiation will include the supraclavicular region or neck. For these cases, thermoluminescent dosimetry is advised to gauge the

delivered dose to the areas at highest risk.



6.5



Management of Skin

Reaction



Most thoracic radiation patients will not require

very extensive management. Ongoing self-care

activities should be encouraged to minimize the

reaction and not allow it to progress. Most of the

time, the program will require relatively simple

interventions such as moisturization to relieve dryness as well as consideration of light cotton clothing

or dressings (Mepilex Lite) to reduce friction and

sun exposure to the area. Itching is an issue that

should be very actively managed; if the patient

scratches the area, there is increased irritation and

exacerbation of the reaction, with risk for dry desquamation as well as infection. These patients

should be given soothing emollients, 1 % topical

hydrocortisone lotion, and if the reaction is truly

very severe, antipruritic medication can be prescribed or intermediate potency steroid creams may

be required. All patients should be generally coun-



seled to avoid sun exposure to the chest area, and, if

swimming is desired, moisturization is advised after

completion of activity (a partner may be needed to

help apply the moisturizer over the back, where tanning is typically the most pronounced).

For patients who experience severe brisk erythema, cooling hydrogels should be used to increase

comfort. The rare patients who demonstrate a very

intense level of this reaction are at high risk for wet

desquamation and should be monitored closely. For

severe wet desquamation, control of potential skin

infection may be required. In our clinic, we will

consider the use of silver-containing amorphous

hydrogel (Silvasorb) or, in very severe cases, silverimpregnated hydrofiber or alginate dressings.



6.6



Photographs

and Recommendations



Below are general skin care recommendations

(Table 6.1), week-by-week treatment instructions,

and photographs that demonstrate typical skin reactions over time for patients undergoing external

beam radiation to the thorax (Table 6.2). Photographs

of special reactions and instructions on how to treat

these more uncommon cases are also provided

(Table 6.3). Figure 6.1 is a general suggested treatment algorithm for skin care for patients undergoing external beam radiation to the thorax.

Table 6.1 General principles of skin care for patients

with skin reactions involving the thorax

Patient should:

• Cleanse daily with mild soap and water

• Use lotions and creams recommended by your

provider

• Continue to wear soft under garments that

provide support and control moisture

Patient should not:

• Rub, put pressure on, or scratch radiated area

• Take hot water showers, hot baths, use wash

cloths, or use loofahs

• Apply any lotion, cream, or ointment within the

3 hours prior to radiation treatment

• Wash off lotion, cream, or ointments if applied

three or more hours before radiation treatment

• Apply drying agents to the skin unless instructed

to do so

• Use any tape or adhesives on the radiated skin



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