Keywords

Cancers of the gastrointestinal tract include those arising in the esophagus, stomach, pancreas, gallbladder, biliary tree, liver, small and large bowel, and anus. There are an estimated 291,150 gastrointestinal cancers in the United States in 2015 with 163,050 cases in men and 128,100 in women [1]. Many of these cancers employ dual or trimodality therapy, integrating chemotherapy, radiation, and surgery. Chemotherapy, when combined with radiation, is used as a radiation sensitizer amplifying both the therapeutic effect and, unfortunately, the toxicity. While hematologic and gastrointestinal toxicities are notable in this group, of particular importance is the management of the skin toxicity, since the locations of some of the tumors require radiation to the perianal skin . There are 7,270 and 39,610 annual cases of anal and rectal cancer, respectively, diagnosed in the United States. Therefore, this chapter focuses on these two disease entities and the management of the associated skin toxicity. Nonetheless, these methods can be extended to other areas in the management of gastrointestinal malignancies where skin reactions may occur, such as the neck in cervical esophageal tumors.

1 Anal Cancer

Anal cancer is a relatively rare entity, with an expected incidence of 7270 cases and 1010 deaths in 2015 [2, 3]. Almost 90 % of cases are attributed to human papillomavirus (HPV) [4], and similar to cervical cancer, anal cancer often begins as high-grade anal dysplasia. Patients who are immunocompromised are particularly susceptible. HIV-positive patients represent a special category of anal cancer patients, and anal cancer is twice as common in these patients as compared to HIV-negative patients. Anal-receptive intercourse is a risk factor in males.

Despite multiple attempts to modify and improve treatment, the fundamental treatment paradigm dates to 1980. Prior to this, the standard of care was an abdominal perineal resection (APR) , resulting in a permanent colostomy. Dr. Nigro [5] at Wayne State University pioneered the use of neoadjuvant chemotherapy with radiation followed by surgery. The majority of patients treated with chemotherapy and radiation had no residual tumor at the time of surgery, and subsequently surgery was reserved for salvage. Overall 24 of 28 patients had a clinical complete response to chemoradiation, and thus was born the era of definitive chemoradiation for anal cancer. Since that time, the use of 5-fluorouracil (5-FU) and mitomycin C (MMC) has remained unchanged. This regimen can cause significant skin toxicity (in addition to hematologic toxicity). While multiple trials have endeavored to eliminate or replace MMC, the colostomy-free survivals without MMC have been inferior to combination regimens that include it.

1.1 Frequency of Acute Dermatologic Toxicity and Factors Affecting Acute Toxicity

Table 8.1 [6–11] presents the frequency of acute grade 3 or greater skin toxicity in patients with anal cancer. The high rate of skin toxicity is due to both radiation and concurrent chemotherapy. Therefore, in an effort to mitigate toxicity, studies focusing both on the modification of chemotherapy (both eliminating the components of the regimen, as well as replacing them) and radiotherapy were done.

Table 8.1 Acute toxicity
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The benefit of adding chemotherapy to radiation was evaluated in the UKCCCR Anal Cancer Trial (ACT 1) [6, 12] where 585 patients were randomized to radiation with or without MMC and 5-FU chemotherapy. Severe acute dermatologic toxicity was 14 % with radiation and 17 % with radiation and chemotherapy, but local control was compromised with radiation alone. An EORTC trial randomized 110 patients with anal cancer to radiation or chemoradiation with 5-FU a nd MMC [7]. Grade 3–4 dermatologic toxicity was reported in 50 % of the radiation patients compared to 57 % of the chemoradiation patients. However, an increased incidence of anal canal ulcers was observed in the chemoradiation arm. The addition of MMC to 5-FU did not increase the frequency of acute skin toxicity in the RTOG 87–04 trial [8]. With the evidence for increased local control with the inclusion of chemotherapy, subsequent studies investigated whether the chemotherapy regimen could be modified for an improved therapeutic ratio. A landmark trial, RTOG 9811 [9, 13], addressed two questions: can cisplatin replace MMC, with the hopes of reducing toxicity, and does adding neoadjuvant chemotherapy to chemoradiation improve outcomes? In this trial, where the standard arm of 5-FU and MMC with radiation was compared against induction 5-FU and cisplatin, followed by 5-FU, cisplatin, and radiation, combined grade 3 and 4 skin toxicity was 48 and 41 % by the treatment arm, respectively. The UNICANCER ACCORD 03 phase 3 trial evaluated induction chemotherapy with 5-FU and cisplatin and dose escalation of the radiation boost. Grade 3–4 non-hematologic toxicity was similar among the treatment arms.

Anti-EGFR-1 targeted therapies have been evaluated in the treatment of anal cancer. Olivatto et al. [14] reported 52 % grade 3–4 acute radiation dermatitis in a phase 1 study of 23 patients treated with 5-FU, cisplatin, and cetuximab. A phase 2 trial evaluating concurrent chemoradiation with cetuximab was closed due to excessive toxicity [15].

HIV-positive patients require special attention. Patients with CD4 counts above 200 can be considered for treatment according to standard therapy on a case-by-case basis, and their outcomes with ongoing antiretroviral therapy can be on par with HIV-negative patients [16–21]. However, patients with CD4 counts approaching and below 200 must be managed with extreme caution. The low CD4 counts make them particularly susceptible to skin toxicity, infection, and poor healing. A study from UCSF [20] reported that of eight patients with CD4 < 200, four required hospitalization for the management of toxicities including moist desquamation. At our institution we consider radiotherapy alone or a less intensive chemotherapy regimen for these patients, depending on their comorbidities.

In an effort to mitigate toxicity, more modern techniques of radiation delivery, targeting the tumor while sparing normal tissue, have been extensively investigated. Radiation was traditionally done with two opposing anterior–posterior and posterior–anterior fields. While this was effective in targeting the tumor at areas of at-risk disease, it also encompassed significant amounts of normal tissue, including the skin not at risk for tumor involvement. The effects of this can be seen in studies reporting grade 3 or greater toxicity ranging from 32 to 65 % of patients receiving conventional or 3D conformal radiation.

The ability to conformally shape radiation therapy has significantly improved over the last two decades, and the use of intensity-modulated radiation therapy (IMRT) has been incorporated into many cancer subsites, including GI tumors. The use of IMRT allows for the reduction of dose to normal tissues including the skin.

Due to the toxicity associated with anal cancer treatments , incorporation of IMRT into the treatment of this disease was investigated by several institutions. Table 8.2 [22–24] shows the results of IMRT series and includes a single-arm prospective trial, RTOG 0529, testing the hypothesis that delivery of radiation with IMRT could preserve historical outcomes in terms of overall survival and colostomy-free survival, but reduce skin toxicity [25]. As expected, the rates of grade 3 or higher skin toxicity, in comparison with the control arm of RTOG 9811, demonstrated improved outcomes with less skin toxicity using IMRT. Therefore, IMRT with 5-FU and MMC now represent the standard of care.

Table 8.2 IMRT for anal cancer
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2 Rectal Cancer

Rectal cancer patients also undergo chemoradiation, but the location of the tumor is often deeper within the pelvis, reducing the radiation dose to the perianal area, where toxicity is the greatest. The treatment paradigm for rectal cancer consists of preoperative radiation and chemotherapy, with radiation to the whole pelvis and concurrent 5-FU. Unlike anal cancer patients, rectal cancer patients undergo resection with a total mesorectal excision (TME), often followed by adjuvant chemotherapy. Several factors contribute to lower toxicity in rectal cancer patients compared to anal cancer patients: (1) chemotherapy is single-agent 5-FU, and MMC is not used, (2), the radiation dose is lower since patients will be getting surgery after to remove the tumor, and (3) due to the location within the deep pelvis, radiation fields do not typically extend to the skin. Nonetheless, these patients can also exhibit skin toxicities, and management of these skin toxicities is similar.

The incorporation of IMRT into rectal cancer treatment has also been investigated. RTOG 0822 was designed in a similar fashion to RTOG 0529 discussed above: a single-arm trial using IMRT, with toxicity outcomes to be compared with historical controls. This study did not show a reduction in toxicity with IMRT, but utilized a nonstandard regimen of capecitabine and oxaliplatin , as opposed to the standard of care, capecitabine alone. Therefore, it is difficult to say if IMRT will result in a significantly lower toxicity if used with the standard of care regimen. A retrospective study [26] at the Mayo Clinic (Arizona) showed improved grade 2 and greater toxicity outcomes with IMRT compared to conventional techniques, but the reported toxicity outcomes did not include skin toxicity and were mainly attributed to the reduction in GI toxicity.

3 Long-Term Toxicity

Long-term toxicities can be significant and patients must be adequately counseled. The rates of long-term grade 3 and greater skin toxicity is low, as shown in Table 8.3 [13, 27]. Common long-term side effects include sterility, as well as rectal and urinary urgency. The function of the anal sphincter can be compromised, resulting in less control over bowel movements. Less common long-term toxicities include erectile dysfunction, decreased vaginal secretions, menopause, and vaginal stenosis (requiring vaginal dilators). Damage to the bones of the hip and pelvis makes patients more susceptible to fracture. Rarely, bowel complications such as ulcers, small bowel obstruction (SBO), or perforation require surgical intervention. As with all diseases treated with radiation, there is a small risk of secondary malignancies.

Table 8.3 Long-term toxicity
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4 Management Strategies

Due to the high rates of skin toxicity, anticipation and planning for skin toxicity must be incorporated into treatment at each phase. In the treatment planning stage, particularly when IMRT is used, we recommend examining the skin dose closely and placing film dosimeters at first treatment. Doses should not exceed the anticipated dosage by more than 10 %. Patients should be extensively counseled both prior to treatment and on treatment for skin toxicity. Strategies for skin management as a function of time on treatment are listed below. Furthermore, management of gastrointestinal toxicity is also important as diarrhea can cause significant irritation of the skin (in addition to dehydration). We recommend instituting antidiarrheal medications when the patient exceeds three loose bowel movements per day. All patients also undergo nutrition consult prior to starting therapy, both to ensure adequate oral intake and to learn which foods can mitigate diarrhea.

Below are general skin care recommendations (Table 8.4), week by week treatment instructions with examples of acute and late skin reactions for anal cancer patients undergoing IMRT (Table 8.5), and photographs that demonstrate how skin reactions in anal cancer patients may vary by ethnicity (Table 8.6). Photographs of special reactions and instructions on how to treat these more uncommon cases are also provided (Table 8.7). Figure 8.1 is a general suggested treatment algorithm for skin care for gastrointestinal cancer patients.

Table 8.4 General principles of skin care for gastrointestinal cancer patients
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Table 8.5 Examples of acute and late skin reactions for anal cancer patients undergoing IMRT
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Table 8.6 How skin reactions in anal cancer patients may vary by ethnicity
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Table 8.7 Special cases and skin reactions
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Fig. 8.1
figure 1

Suggested treatment algorithm for skin care

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