Анальный рак

Заболеваемость и смертность

It is expected that approximately 8,200 cases of anal cancer will be diagnosed in the United States in 2017 with an estimated 1,100 deaths. Of the 8,200 cases of anal cancer, 2,950 will be male and 5,250 will be female [1]. While it is an uncommon cancer accounting for <3% of all gastrointestinal malignancies, incidence increased almost twofold in men and 1.5-fold in women from the period 1973–1979 to 1994–2000 [2].

Скрининг факторов риска и предотвращение заболевания

Several well-known risk factors have been identified including various subtypes of the human papillomavirus (HPV), receptive anal intercourse, history of cervical, vulvar, or vaginal cancer, immunosuppression, and smoking [3–5]. High grade anal intraepithelial neoplasia (AIN) is a precursor to anal cancer and treatment of AIN may prevent the development of anal cancer. Screening of high-risk individuals like HIV-positive homosexual men with cytology, digital rectal examination, and HPV testing may significantly reduce the incidence of anal cancer. However, randomized studies are lacking [2,6–8].

Vaccination targeting the most common HPV types associated with cervical and anal cancer has been well studied. In a randomized trial of 4,065 males aged 16–26 years, use of a quadravalent vaccine compared to placebo showed a significant reduction in external genital lesions. In a planned subset analysis of this trial, it was shown that the incidence of AIN decreased by 50% with the quadravalent vaccine [2]. This led to FDA approval for the use of a quadravalent vaccine (Gardasil) to prevent anal cancer. Recently, in December 2014, the FDA approved the nine-valent HPV vaccine to cover five additional subtypes of HPV inclusive of 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by subtypes 6 or 11 preventing up to 90% of all HPV-associated malignancies [9]. The recommended routine HPV vaccination age ranges for girls and boys are 9–26 years and ages 9–15 years, respectively, to prevent HPV-associated cancers.

Клиническая картина

Rectal bleeding is the most common presenting sign of anal cancer, occurring in 45% of patients. However, this symptom is often attributed incorrectly to hemorrhoids since it is often associated with pain and/or discomfort, often resulting in prolonged delays in diagnosis. Rectal pain and/or fullness are reported by 30% of patients, and 20% of patients are asymptomatic at diagnosis. Other signs and symptoms include changes in bowel movements such as thin caliber stools and tenesmus. Condyloma are found in 50% of homosexual men with anal cancer. Pruritis is more common in tumors of the perianal skin, as well as anal Bowen disease and Paget disease. Most patients present with early-stage disease; only 10–20% present with American Joint Committee on Cancer (AJCC) stage IV [10].

Анатомия и гистология

The location of anal cancer is important because patients with cancers of the anal canal are treated differently from those with anal margin malignancies. The anal canal is the terminal part of the large intestine, and extends from the anorectal junction of the upper part of the pelvic floor to the anal verge (the hairbearing skin around the anus). This area includes the mucosal dentate line as well as the anorectal ring, a palpable ring that defines the level of the puborectalis muscle of the pelvic floor. Anal margin tumors are tumors of the perianal skin (defined as a zone of the skin with a 5 cm radius centered at the anal verge; these cancers have high cure rates with wide local excision alone, particularly when small (<3 cm in diameter) and well differentiated [11]). Local excision is only indicated for anal margin squamous cell cancer, and not for anal canal squamous cell cancer.

Squamous cell carcinoma (SCCA) is the most common histology of anal cancer, followed by adenocarcinoma and melanoma [12]. Rare histologic subtypes (representing, in aggregate, <3% of anal cancers), include carcinoid tumors, sarcomas, gastrointestinal stromal tumors, and lymphomas. Those SCCAs occurring above the dentate line are nonkeratinizing, whereas those at or below the dentate line are keratinizing.

Стадийность

Since radical surgery is no longer the first option in the primary treatment of anal SCCA, tumors are staged clinically by physical examination and radiographic imaging. SCCAs are currently staged according to the tumor, node, metastasis (TNM) staging system of the AJCC and the Union for International Cancer Control (UICC) 8th edition (Table 10.1) [13]. Tumor (T) category is determined by size and invasion of adjacent structures like vagina and prostate. Nodal (N) category is based on location of involved nodes including perirectal, pelvic, and inguinal lymph nodes. Tumors of the perianal skin are staged as skin cancers excluding melanoma.

Обследование

Suspected anal SCCA patients require a detailed history to assess for known risk factors. The degree of rectal bleeding and sphincter incontinence should be ascertained. A complete physical examination with a thorough digital rectal examination to assess for circumferential involvement, sphincter tone, and tumor size (and prostate involvement in men) is essential. In women, a pelvic examination should also be performed to rule out concurrent cervical cancer and to determine any vaginal involvement. Examination of the inguinal region should be completed in all patients. Anoscopy, proctoscopy, and/or flexible sigmoidoscopy are required to determine the extent of anorectal involvement. Laboratory studies should include a complete blood count, renal and hepatic function, hepatitis, and HIV status.

Radiographic imaging should include computed tomography (CT) of the abdomen and pelvis to assess for metastatic disease to the liver, retroperitoneal lymph nodes, pelvic, and inguinal lymph nodes. Magnetic resonance imaging of the pelvis will provide better anatomic detail to determine invasion of local structures, especially the sphincter-related musculature, and to evaluate mesorectal lymph nodes. Positron emission tomography (PET)/CT has provided utility in identifying the primary tumor, spread to inguinal lymph nodes, and response to therapy. HIV-positive patients had a higher incidence of PET-positive inguinal lymphadenopathy. All suspicious inguinal adenopathy should be biopsied as reactive lymph nodes are not unusual given the proximity of the tumor and would be informative for accuracy of staging and radiation simulation.

Прогноз и паттерны диссеминации

Anal SCCA can spread through direct extension and invasion of adjacent structures, lymphatic dissemination through perirectal, pelvic, and inguinal lymph nodes, and hematogenously to distant organs such as the liver and lungs. Tumors arising above the dentate line tend to spread to perirectal (N1) nodes and those at or below the dentate line spread to inguinofemoral (N2) nodes. The likelihood of spread to lymph nodes is directly related to the size and extent of invasion of the primary tumor. Nodal metastases are identified in 0–10% of T1–2 and 40–50% of T3–4 tumors [14,15]. Factors predicting worse overall and disease-free survival among subjects in the Radiation Therapy Oncology Group (RTOG) 9811 and the European Organisation for Research and Treatment of Cancer (EORTC) 22861 trials are male gender, larger tumor diameter, and positive lymph nodes [16,17].

Лечение

Рак краев анального отверстия

Пациенты с T1 раком краев анального отверстия должны подвергаться широкому локальному иссечению. В случае позитивных краев необходимо повторное иссечение. Если повторное иссечение не выполнимо, то рекомендуется только одна лучевая терапия в дозе 60 Gy. Пациенты с T2 или большими поражениями должны получать режимы химио-лучевой терапии, сходные с используемыми для рака анального канала.

Рак анального канала

Хирургия

Prior to development of sphincter-preservation treatments, abdominoperineal resection (APR) was the standard of care for the primary treatment of anal carcinoma, with 5-year overall survival in the range of 25–75% [18–20]. Locoregional and distant relapse occurred in up to 35% and 10%, respectively, with higher rates of relapse among patients with positive pelvic or inguinal lymph nodes. APR is reserved for salvage therapy for residual or recurrent disease. Transanal excision is only indicated for AIN without invasion.

Химиолучевая терапия

Nigro et al. established that complete response of anal SCCA was possible for patients treated with low dose radiotherapy (30 Gy) concurrent with 5-fluorouracil (5-FU) and mitomycin C (MMC) [21]. In a larger phase II study of patients treated preoperatively with the same chemoradiation regimen, 84% were rendered free of cancer. No recurrence of tumor was noted in those patients achieving a complete response. However, patients with residual cancer after preoperative therapy (15%) had recurrence at distant sites and died of disease [22]. Several randomized trials addressing the role of concurrent chemotherapy, induction chemotherapy, maintenance chemotherapy, and biologic therapy are summarized in Table 10.2.

Химиолучевая против лучевой терапии

While chemoradiation had been shown to be efficacious in patients with anal SCCA, some clinicians questioned the necessity of chemotherapy, as some early studies had demonstrated efficacy of high-dose radiation alone. Further, there was a concern about late toxicities with the radiation-potentiating effects of chemotherapy.

The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial (ACT I) addressed this question by randomizing 585 patients to either radiation monotherapy (45 Gy over 5 weeks) or the same radiation regimen combined with bolus 5-FU chemotherapy during the first and last week of radiation and MMC on day 1 [23]. Patients with a good response 6 weeks after treatment received a radiotherapy boost, and poor responders underwent salvage surgery. After a median follow-up of 42 months, the local failure occurred less often in the chemoradiation arm than to the radiation monotherapy arm (36% vs 59%; P <0.0001). Chemoradiation resulted in more early morbidity than radiation monotherapy (48% vs  39%, P = 0.03) but late morbidity rates (42% vs 38%, P = 0.39) were similar. Updated results after 13 years of follow-up showed median overall survival (OS) was 7.6 years for the chemoradiation arm and 5.4 years for the radiation alone arm. Although this difference was not statistically significant, the risk of dying from SCCA was significantly (P <0.004) lower (by 33%) with chemoradiation [24].

Таблица 10.1. Стадийность анальной карциномы Американского Объединенного Комитета по Раку (AJCC) , 8-ая ред (за исключением меланомы, карциноида и сарком).

Определение первичной опухоли (T)

T категория T критерий
TX Первичная опухоль не может быть оценена
T0 Нет свидетельства первичной опухоли
Tis Высокозлокачественное сквамозное интраэпителиальное поражение (ранее называемая карцинома in situ, болезнь Боуэна (Bowen), анальная интраэпителиальная неоплазия II-III, высокозлокачественная анальная интраэпителиальная неоплазия)
T1 Опухоль ≤2 см
T2 Опухоль> 2 см, но ≤5 см
T3 Опухоль> 5 см
T4 Опухоль любого размера, инвазирующая в прилегающий орган(ы), такой как влагалище, уретра или мочевой пузырь

Определение региональных лимфатических узлов (N)

N категория N критерий
NX Региональные лимфатические узлы не могут быть оценены
N0 Нет метастазов в региональные лимфоузлы
N1 Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
N1a Metastasis in inguinal, mesorectal, or internal iliac lymph nodes
N1b Metastasis in external iliac lymph nodes
N1c Metastasis in external iliac with any N1a nodes

Определение отдаленного метастазирования (M)

M категория M критерий
M0 Нет отдаленных метастазов
M1 Отдаленный метастаз

AJCC прогностические стадийные группы

Когда T есть… И N есть… И M есть Тогда стадийная группа есть
Tis N0 M0 0
T1 N0 M0 I
T1 N1 M0 IIIA
T2 N0 M0 IIA
T2 N1 M0 IIIA
T3 N0 M0 IIB
T3 N1 M0 IIIC
T4 N0 M0 IIIB
T4 N1 M0 IIIC
Any T Any N M1 IV

Таблица 10.2. Рандомизированные исследования химио-лучевой терапии для анального рака.

 

CDDP, cisplatin; CFS, colostomy free survival; DFS, disease free survival; 5~FU, 5~fluorouracil; LC, local control; MMC, mitomycin C; OS, overall survival; PFS, progression free survival; RT, radiotherapy; *statistically significant; **not statistically significant.

The EORTC also conducted a phase III randomized trial of radiation versus chemoradiation in 110 patients with anal SCCA [25]. Surgical resection was performed if patients had not responded 6 weeks after 45 Gy or if palpable residual disease persisted after therapy completion. Subjects in the chemoradiation arm received bolus 5-FU chemotherapy during the first and last week of radiation and MMC on day 1. Patients in the chemoradiation arm had a higher complete response rate (80% vs 54%), as well as fewer locoregional recurrences and higher colostomy-free rates (P = 0.002). Unlike the results of ACT I, acute toxicities were not significantly different in the two groups. Late toxicities were also similar, with the exception of an increased incidence of anal canal ulcers in the combined modality group. The chemoradiation arm had an improved progression-free survival (PFS) (P= 0.05). There was no difference in OS between the two groups, although it should be noted that the median survival time had not been reached at the time of the study report.

ACT I and the EORTC trials confirmed the superiority of chemoradiation over radiation alone in the treatment of anal SCCA. Both trials showed an improvement in locoregional control and PFS with the addition of chemotherapy. The ACT I trial further showed that the addition of chemotherapy increased OS, but this benefit was evident only after long-term follow-up, possibly due to the increase in nonanal cancer deaths in the chemoradiation arm during the first 10 years.

  • Роль митомицина C

While ACT I and the EORTC study established the role of chemotherapy in combination with radiation in the treatment of SCCA, concern regarding the toxicity of MMC led to subsequent studies to determine the benefit of adding MMC to 5-FU. Although MMC is among the most active cytotoxic antineoplastic agents [26], its toxicity is significant and can include lifethreatening hemolytic uremic syndrome and thrombotic thrombocytopenic purpura [27–29]. The benefit of using MMC as part of a combined-modality approach for SCCA was initially reported before widespread recognition of the antitumor activity and radiosensitizing properties of cisplatin in the treatment of aerodigestive tract carcinomas [30].

RTOG 87-04/ECOG 1289 was a phase III intergroup study in which 310 patients with anal SCCA were randomized to chemoradiation with either 5-FU or 5-FU/MMC [31]. The MMC arm had a lower colostomy rate at 4 years (9% vs 23%, P = 0.002), and although the addition of MMC improved 4-year PFS (73% vs 51%, P = 0.0003), there was no statistically significant difference in 4-year OS. The addition of MMC did result in more acute toxicities (P <0.001). This trial confirmed the benefit of the adding MMC to 5-FU and radiation for SCCA but also suggested that it should not be used routinely in immunosuppressed individuals given the neutropenia rate and toxic deaths seen in the MMC arm.

  • Роль цисплатина

Based on the encouraging results of phase II studies incorporating cisplatin [32,33] compared to historical results of chemoradiation with 5-FU and MMC, RTOG 98-11 was designed to evaluate whether cisplatin was superior to MMC.

Индукционная или поддерживающая химиотерапия

RTOG 98-11 was an intergroup phase III trial that randomized 682 patients with SCCA to chemoradiation with either bolus 5-FU/MMC or induction cisplatin and 5-FU followed by chemoradiation with cisplatin and 5-FU during radiation. [34]. Chemoradiation with 5-FU/MMC resulted in superior 5-year disease-free survival (DFS) (67.8% vs 57.8%, P = 0.006) and 5year OS (78.3% vs 70.7%, P = 0.026) compared to chemoradiation with 5-FU and cisplatin [35]. Hence, chemoradiation with 5-FU/MMC remained the standard of care.

The cisplatin arm of RTOG 98-11 included two cycles of induction chemotherapy before chemoradiation was initiated, based on the hypothesis that induction chemotherapy could reduce the burden of disease and make the chemoradiation more effective, thereby improving DFS. As noted above, results for the cisplatin and 5-FU arm were inferior, suggesting no benefit for induction chemotherapy or for the use of cisplatin when MMC is an option.

The UNICANCER ACCORD 03 phase III trial sought to improve the efficacy of chemoradiation by either adding induction chemotherapy with 5-FU/cisplatin or dose escalation of the radiation boost [36]. Patients (n = 307) with SCCA >4 cm or <4 cm and N1-3 M0 were randomized to one of four treatment arms: (i) arm A: two cycles of induction chemotherapy with 5FU/cisplatin followed by chemoradiation with 45 Gy radiation over 5 weeks, plus standard dose boost (15 Gy); (ii) arm B: two cycles of induction chemotherapy with 5-FU/cisplatin followed by chemoradiation with 45 Gy radiation over 5 weeks plus high dose boost (20–25 Gy); (iii) arm C: chemoradiation with 45 Gy radiation over 5 weeks, 5-FU/cisplatin on weeks 1 and 5, and standard dose boost (15 Gy); and (iv) arm D: chemoradiation with 45 Gy radiation over 5 weeks, 5-FU/cisplatin on weeks 1 and 5, and high-dose boost (20–25 Gy). There was no statistically significant benefit in 5-year colostomy-free survival to either induction chemotherapy (P = 0.37) or high-dose radiation boost (P = 0.067). None of the secondary endpoints, including 5-year local control, 5-year disease-specific survival, and 5-year tumor-free survival, showed a statistically significant benefit with the addition of either induction chemotherapy or highdose radiation boost.

To date, ACT II is the only large phase III trial to be completed in the locally advanced patient population which also evaluated the role of cisplatin in the treatment of SCCA [37]. This 2Ч2 factorial trial randomly assigned 940 subjects to one of four groups to receive radiation (50.4 Gy) and bolus 5-FU on the first and last week of radiation with either MMC or cisplatin, with or without two cycles of maintenance chemotherapy (5FU/cisplatin). The primary endpoint was to establish superiority of 5-FU/cisplatin versus that of MMC for DFS. With regards to the cisplatin arm, there was no difference in complete response at 26 weeks (90.5% for MMC and 89.6% for cisplatin, P = NS) or toxicity (71% for MMC and 72% for cisplatin, P = NS). There was also no difference in 3-year PFS with regards to maintenance or no maintenance (74% vs 73% respectively, P = NS). As expected, addition of MMC resulted in nonhematologic toxicities. Given these equivocal results, chemoradiation with 5-FU and MMC remain the standard of care for the treatment of SCCA.

Регрессия опухоли

Anal SCCA may respond to chemoradiotherapy immediately or slowly, over several months. Cummings et al. demonstrated that the rate of regression over time is not a good measure of the effectiveness of treatment. [38]. In a French study, patients with T3 or T4 tumors who achieved a >80% response after the initial phase of radiotherapy had 5-year colostomy-free survival of 65%, versus 25% of patients who had <80% response (P = 0.002). The ACT-II trial showed a pivotal finding. In 29% of patients who did not achieve a complete response at 11 weeks, complete response may still be achieved at 26 weeks. Hence, these results suggest it may be appropriate to follow patients with persistent disease conservatively for up to 26 weeks as there is no evidence of disease progression [37].

Интенсивность-модулируемая лучевая терапия

Intensity-modulated radiation therapy (IMRT) allows for safe tumor dose escalation while reducing dose to surrounding normal tissues like skin, small bowel, bladder, femoral heads, external genitalia, and bone marrow. IMRT has been evaluated in several dosimetric studies and shown to be superior compared to 3D conformal therapy planning [39–46]. Dermatologic and small bowel toxicity can necessitate treatment breaks which could potentially negatively affect outcomes. By reducing dose to surrounding normal tissues, acute toxicity will be minimized resulting in fewer treatment breaks and shorter overall treatment time [47–50]. Several small retrospective series with patient numbers ranging from 17 to 78 and median follow-up ranging from 16 to 24 months have demonstrated the safety and feasibility of IMRT chemoradiation (Table 10.3) [51–60]. Two to three year locoregional control, colostomy free survival, and overall survival range from 77 to 95%, 81 to 93%, and 87 to 100%, respectively. Acute grade 3 or greater gastrointestinal (GI) toxicity was reported in the range of 0–28%. Acute grade 3 or greater dermatologic toxicity was reported in the range of 0–38%. In RTOG 9811 where all patients were treated with conventional radiotherapy, acute grade 3+ GI and dermatologic toxicity were 36% and 49%, respectively [34,35]. RTOG 0529 is a completed prospective phase II trial to determine if dose-painted IMRT could reduce toxicity compared to RTOG 9811 [55]. The primary endpoint was a 15% reduction in combined grade 2+ genitourinary and gastrointestinal toxicity. Of 63 patients enrolled, 52 were evaluable. While the trial failed to meet its primary endpoint, there was a significant reduction in acute grade 2+ hematologic, grade 3+ dermatologic, and gastrointestinal toxicity. As such, IMRT has evolved as a de facto standard of care in the administration of radiotherapy for SCCA patients undergoing combined modality therapy [61].

Several retrospective studies comparing toxicity and outcomes of 3D conformal radiation to IMRT [47,49,50,62,63] are presented in Table 10.4. Four studies [47,49,50,63] report on toxicity with three studies showing significant reduction in acute grade 3+ GI and dermatologic toxicity [47,49,63] and one study by Chuong et al. showing a reduction in late grade 3+ GI toxicity in favor of IMRT (24.3% vs 5.8%; P = 0.012) [47]. All but one study [49] show equivalent outcomes with regard to locoregional control, colostomy-free survival, and overall survival. Bazan et al. do show that IMRT confers a survival and local control benefit over conventional radiation; however, the outcomes of their 3D conformal group are inferior to those reported in RTOG9811 and the other comparative studies.

Менеджмент паховых лимфатических узлов

Inguinal metastases are present at diagnosis in 0–33% of patients with anal SCCA; prevalence is even higher among those with AJCC T-categories T3–4 [64]. Prophylactic inguinal irradiation can reduce the inguinal recurrence rate among clinically node-negative patients from a range of 7.5–13% (without treatment), to approximately 1.3–3% [31,65–70]. Patients with T3–4 tumors and clinically uninvolved inguinal lymph nodes should have chemoradiation that includes inguinal irradiation [70,71]. The role of inguinal radiation in T1–2 tumors is still controversial. A phase II study by Matthews et al. revealed that the overall inguinal recurrence rate in 44 patients with T1–2 N0 tumors without inguinal radiation was 22.5% [72]. In a retrospective study from Zilli et al., they reported outcomes of T2N0 patients treated with chemoradiotherapy versus radiotherapy with or without inguinal radiation in 116 patients [73]. Overall 5-year inguinal relapse-free survival was 92.3%. Inguinal recurrence occurred in two patients (4.7%) treated without inguinal radiation. There were no groin relapses in patients treated with groin radiation. The 5-year locoregional control rates for patients treated with and without groin radiation and with radiotherapy alone versus chemoradiotherapy were 80.1% versus 77.8% (P= 0.967) and 71.0% versus 85.4% (P= 0.147), respectively. A trend toward a higher rate of grade 3+ acute toxicity was observed in patients treated with groin radiation (53% vs 31%, P= 0.076). Determination of who should be treated with groin radiation prophylactically will depend on increasing reliance of PET-CT. The study also showed that groin radiation was associated with increased grade toxicity [73]. However, lower doses of 36–42 Gy in 1.5–1.8 Gy fractions with IMRT to clinically uninvolved nodal regions has resulted in equivalent oncological outcomes with an associated decrease in dermal toxicity [47,51,52,54,55].

Пациенты с ослабленным иммунитетом

Chemoradiation therapy is not contraindicated for HIV-positive patients with anal SCCA. While acute treatment-related toxicity and relapse rates may be higher in patients with HIV-AIDS treated with chemoradiotherapy, their response to therapy and survival is comparable to those of HIV-negative patients [74–77]. However, dosage reduction of MMC may be necessary for patients with HIV-related complications given the high degree of myelosuppression that increases the chance of opportunistic infections [2].

Метастатическая болезнь

  • Химиотерапевтические режимы в лечении метастатической анальной SCCA

Several challenges remain in the treatment of metastatic anal SCCA. Most of the published evidence regarding metastatic anal canal cancer consists of small case series. Most chemotherapeutic regimens, mainly 5-FU and platinum-based therapy, have been adapted from studies of SCCA of other primary tumor sites. The optimal duration of chemotherapy remains unestablished. Based on our preliminary findings, systemic chemotherapy should be considered in any anal SCCA patients with good performance status and should be continued indefinitely for maximal outcome if tolerated well.

Table 10.3. Summary of studies evaluating intensity-modulated radiation therapy-based chemoradiation for anal cancer.

CFS, colostomy free survival; IMRT, intensity~modulated radiation therapy; LRC, locoregional control; NA, not available; OS, overall survival; RTOG, Radiation Therapy Oncology Group; 3DCRT, conventional radiation therapy.

 

Table 10.4. Retrospective studies comparing 3D conformal radiotherapy versus intensity-modulated radiation therapy for anal cancer.

1 Chronic grade 3+ gastrointestinal toxicity for 3DCRT versus IMRT is 24.3% vs 5.8% (P = 0.012); CFS, colostomy free survival; IMRT, intensity modulated radiation therapy; LRC, locoregional control; NA, not available; NS, not significant; OS, overall survival; RT, radiotherapy; 3DCRT, 3D conformal radiation therapy;

  • Золотой стандарт: 5-фторурацил (5-FU) и цисплатин

The most commonly reported regimen is continuous infusion of 5-FU (1 g/m2/day х 5 days) plus an infusion of cisplatin (100 mg/m2) on day 2, every 4 weeks which, in a series of 18 patients, demonstrated a partial response rate of up to 50% and a complete response rate of 15% [34,78–82]. All patients received a median of four cycles and all had acceptable toxicities. The most common toxicities included mucositis, nausea, vomiting, diarrhea, neutropenia, electrolyte imbalances, peripheral neuropathy, and tinnitus. Although typically providing some degree of response, long-term control or cure has not been reported in patients with metastatic SCCA receiving this regimen.

  • Карбоплатин/паклитаксел/продолжительная инфузия 5-FU (TPF)

Hainsworth et al. conducted a phase II study of 60 patients with metastatic SCCA of any nonpulmonary primary site of which only four patients had SCCA of the anal canal. The chemotherapy regimen consisted of paclitaxel 200 mg/m2, 1-h intravenous infusion, days 1 and 22; carboplatin (AUC = 6, days 1 and 22); 5-FU 225 mg/m2/day, by 24-h continuous intravenous infusion, days 1–36; repeated every 6 weeks. In this study, all patients received a maximum of four cycles of therapy, which caused a high incidence of grade 3/4 toxicities including myelosuppression (48%), diarrhea (17%), and mucositis (28%). The overall and complete response rates were 65% and 25%, respectively. Two patients with a primary anal SCCA had complete responses. The median duration of response for the anal SCCA patients was 26 months [83].

Новые подходы

Treatment-naпve patients: the InterAACT trial (EA 2133; NCT02560298) is the first randomized phase II of 5-FU/cisplatin versus carboplatin/paclitaxel in newly diagnosed metastatic patients. This international trial has completed enrollment with final results pending.

Previously treated patients: a phase I expanded cohort study of the single agent immune checkpoint kinase inhibitor LY2606368 was conducted in heavily pretreated patients (n= 26) [84]. Single agent LY260636 resulted in a response rate of 16% (one complete response; three partial response as per RECIST criteria 1.1).

The role of immune checkpoint (PD-1) inhibitors against the programmed death ligand have also been evaluated. A phase IB expanded cohort study of pembrolizumab was conducted in previously treated SCCA tumors overexpressing PD-1 resulting in a response rate of 13% [85,86]. NCI9673 was the first phase II study completed to evaluate the role of immune checkpoint inhibitors of single agent nivolumab resulting in a response rate of 24% (two complete responses; seven partial responses) [87]. NCI9673 is undergoing an amendment to allow additional patient enrollment. Additional studies are currently being proposed to evaluate the role of immune checkpoint inhibitors in locally advanced anal cancer.

Other novel approaches include a live attenuated Listeria monocytogenes (Lm-)-based immunotherapy (ADXS11-001) which was developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16/E7. A pilot trial led by Safran et al. (NCT02399813) suggests there may be a role for ADXS11-001 in early stage anal cancer [88]. FAWCETT (NCT02399813) is a phase II single agent trial that is currently ongoing in previously treated metastatic anal cancer.

Спасительная терапия

Локорегиональный рецидив

Locoregional recurrence occurs after chemoradiation in approximately 10–30% of patients with anal SCCA [89,90]. Patients with recurrence after chemoradiation who undergo salvage APR surgery have a 5-year survival of 40–60% compared to a 3-year overall survival of 5% for patients who are unsuitable for surgery [91]. In a study from MD Anderson Cancer Center of 31 patients with locoregional recurrence [89], the 5-year survival rate following salvage APR was 64%; the most significant prognostic factor was a negative resection margin [92]. Median survival for patients with negative and positive margins after salvage surgery was 33.0 versus 14.3 months, respectively.

Patients with inguinal recurrence who did not receive groin radiation were salvaged with chemoradiation. However, if there is inguinal recurrence after groin radiation, an inguinal lymph node dissection should be performed. APR can be avoided if there is no recurrence in the anus in patients with inguinal recurrence.

Радиационная техника

Таргетируемый объем и дизайн области облучения

With the increased utilization of multifield techniques for 3D conformal radiotherapy (3DCRT) and IMRT, proper delineation of tumor and nodal volumes is required. The gross tumor volume (GTV) is representative of the tumor and grossly involved lymph nodes. The extent of GTV can be determined by information from physical examination and endoscopic findings. In addition, GTV can be more accurately delineated by fusion of the treatment planning CT scan to a treatment planning magnetic resonance image or PET-CT scan obtained at the time of simulation. The clinical target volume (CTV) includes microscopic extension of the GTV in addition to the high-risk nodal areas including perirectal and mesorectal nodes, pelvic lymph nodes including bilateral internal and external iliac chains, bilateral inguinal lymphatics, and presacral nodes. The superior extent of the CTV is at the level of the sacral promontory or the iliac bifurcation. The inferior extent of the CTV is 3 cm below the GTV of the anal canal.

NCCN recommends following the multifield technique per RTOG 9811 [34], although IMRT-based treatment is being more commonly used [61]. PET-CT should be performed for treatment planning purposes for accurate delineation of the GTV and involved lymphatics. For node-negative patients, field reduction off the superior border and groins is recommended after 30.6 and 36 Gy, respectively. Attempts should be made to reduce dose to the femoral heads. In patients treated with an AP (anteroposterior)–PA (posteroanterior) approach, lateral inguinal lymphatics should be brought to a minimum dose of 36 Gy using an anterior en face electron boost matched to the PA field exit dose. IMRT can be used in place of 3DCRT but requires precise contouring of normal tissues, GTV, and CTV to reduce marginal miss. In RTOG 0529, 81% of patients required IMRT replanning with three cases of major deviations of normal tissues [55]. Atlases for precise contouring of SCCA targets and normal tissues are available at the RTOG (http://atc.wustl.edu/ protocols/rtog-closed/0529/ANAL_Ca_CTVs_5-21-07_Final. pdf, accessed 28 September 2017) and from the Australasian Gastrointestinal Trials Group [93].

Перерывы в лечении

ECOG 4292, a phase II trial of chemoradiation with 5-FU and cisplatin in SCCA, enrolled 33 subjects [32]. This trial prescribed a radiation dose of 59.4 Gy in 33 fractions over 60 days. There were two cohorts. Cohort 1 (n = 19) had a planned 2 week break in the radiation after 36 Gy was given and cohort 2 (n = 13) had no planned break. The 5-year overall survival for cohorts 1 and 2 was 58% and 84%, respectively. A comparison of outcomes of patients treated on RTOG 8704 (50.4 Gy) versus RTOG 9208 (59.4 Gy split course) revealed that overall, disease-free, and colostomy-free survival were inferior in patients treated with split course radiation [94]. In a recent analysis of pooled data from RTOG 9811 and RTOG 8704, it was shown that total treatment time but not total RT duration was significantly associated with colostomy failure and local failure on univariate analysis [95]. It was suggested that induction chemotherapy may contribute to local failure by increasing total treatment time. Finally, the results of the ACT II randomized trial showed a high complete response and 3-year relapse-free survival of 74% with 50.4 Gy chemoradiation [37]. The good results were attributed to the lack of a treatment break. Treatment breaks in general should be avoided whenever possible. However, this may be unavoidable due to treatmentrelated toxicity like skin desquamation and diarrhea [96]. IMRT has been shown to reduce toxicity and RT duration compared with 3DCRT. However, no differences in locoregional control, overall, and colostomy-free survival were noted (Tables 10.3 and 10.4).

Качество жизни пациентов, перенесших лечение анального рака

The majority of patients with anal SCCA who are treated with chemotherapy and radiation have excellent outcomes [34]. However, immediate side effects and toxicity may adversely affect the quality of life (QoL). The immediate and late effects include sexual dysfunction, urological/GI complaints, financial difficulties, fatigue, and a reduction in emotional and social well-being [97].

Acute effects of chemoradiation for anal carcinomas include diarrhea, mucositis, skin erythema, and myelosupression. Late complications include anal ulcers, stricture, stenosis, fistulae, and necrosis.

Allal et al. evaluated the QoL of 41 patients with anal SCCA (35 female and six male), after radiation alone or combined chemoradiation. Patients treated with radiation with or without chemotherapy rated their QoL to be similar to that of the general population with the exception of noting more frequent diarrhea [98]. Although 50% of these patients reported suboptimal anal function, 71% reported that they were satisfied with their current function. Of note, however, the sexual functioning score in this study was very low, with only 35% of patients reporting some sexual activity. Moreover, the extent of this activity varied greatly among patients and never reached the maximum level of functioning in any patient. Because genital organs are in close proximity to the high-dose treatment volume, this high degree of sexual dysfunction is consistent with the studies of women with gynecological cancers [99] and men with prostate cancers [100], in whom loss of sexual desire and/ or orgasm, dyspareunia, and loss of potency are frequent.

Das et al. also evaluated long-term QoL of 32 patients with anal SCCA who were treated with radiotherapy or chemoradiation. These patients had acceptable overall QoL scores, but poor sexual functioning scores. Of note, younger patients were found to have lower QoL and sexual functioning scores [101].

Проактивные подходы к лечению побочных эффектов

Половые побочные эффекты

Proactive care and prompt responses to onset of side effects can help minimize immediate and long-term effects. For women receiving pelvic radiation, the early and ongoing use of dilators, moisturizers, and lubricants should be encouraged, with clear information given about its importance. Vaginal foreshortening due to fibrosis is a significant subacute and late side effect of pelvic irradiation. Cullen et al. suggest eight care recommendations that address the concerns of women treated with pelvic radiation: (i) introducing the dilator in a light and straightforward manner; (ii) enhance dilator accessibility; (iii) introduce the dilator early in treatment; (iv) emphasize health maintenance over intercourse as a benefit of dilator use; (v) explore and acknowledge women’s values and views on sexuality; (vi) increased awareness and sensitivity to emotional reactions; (vii) enhance psychoeducational resources for supporting vaginal dilator use; (viii) ensure consistent institutional practice when introducing the dilator. Early involvement of support services, including physical therapists, pelvic rehab specialists, dieticians, and psychosocial support can be very helpful. Also, topical estrogen, vaginal moisturizers, lubricants, and vaginal dilators can help improve sexual function in women. Minimizing radiotherapy dose to a portion of the anterior wall of the vaginal vault may also be helpful. Phosphodiesterase inhibitors, such as sildenafil, can help improve sexual function in men after anal cancer treatment.

Mirabeau-Beale et al. evaluated 95 consecutive women who were treated for locally advanced anal cancer between 2003 and 2012 [102]. Sixty-four percent of patients developed grade 2 and 3 vaginal stenosis. The development of vaginal stenosis was more common in younger patients, with a higher dose of radiation, and associated with years of radiation therapy provided.

Сохранение фертильности

It is essential that all disciplines discuss fertility preservation and refer patients of child-bearing age to a reproductive endocrinologist [103,104].

Гастроинтестинальные побочные эффекты

Articles have reviewed the appropriate management of GI and sexual dysfunction after pelvic radiotherapy [105–107]. Opiate agonists such as loperamide, bulking agents, and a low-fiber diet can help decrease GI symptoms, like diarrhea. Sacral nerve stimulation may be a possible treatment for fecal and urinary incontinence [108].

Заключение

Concurrent chemoradiation for curative intent remains the standard of care for locally advanced anal cancer. Although the role of chemotherapy as a radiation sensitization has largely remained unchanged, the multidisciplinary management is now focused on prolonging the duration of surveillance before making a critical decision regarding salvage surgery as well as acute and chronic toxicities. Novel approaches will likely include the role immunotherapy as a potential treatment option for both early and late stage disease.

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