Anal Cancer: Background and Clinical Evidence


T1

≤ 2 cm

N1

Perirectal node(s)

M0

No distant metastasis

T2

2–5 cm

N2

Unilateral internal iliac and/or inguinal node(s)

M1

Distant metastasis

T3

> 5 cm

N3

Perirectal and inguinal nodes and/or bilateral internal iliac and inguinal nodes
  
T4

Invasion of nearby organs (vagina, urethra, bladder)
    

















Stage I
T1 N0 M0

Stage II
T2–T4 N0 or T1–T3 N1

Stage III
T4 N1 or any N2 or N3

Stage IV
Any M1





15.3 Prognostic Factors





  1. (a)


    Poor prognostic factors


    1. (i)


      Male gender: Male gender has been shown to be associated with poorer locoregional failure and OS at 5 years in multiple large randomized controlled trials (EORTC 22861, RTOG 98-11, ACT II) [11, 15–17].

       

    2. (ii)


      TN category: A retrospective analysis of RTOG 98-11 database showed poorer OS, DFS, local failure, and distant metastasis rate in patients with T3/T4 and node-positive disease [18]. Other retrospective studies using multivariate analyses have also shown poorer DFS, OS, and locoregional recurrence in patients with tumors greater than 5 cm (T3) and increased rates of distant metastasis in patients with more advanced N stages [15, 19].

       

    3. (iii)


      HPV negative: HPV-negative tumors are associated with poorer local control and overall survival than HPV-positive tumors [20, 21]. This may be, in part, due to high rates (80 %) of deleterious p53 mutations in HPV-negative tumors [22].

       

    4. (iv)


      Cigarette smoking: Current or former smokers have poorer OS compared to never smokers [23]. One hypothesis is that cigarette smoking affects the ability of the immune system to clear the HPV infection [11].

       

    5. (v)


      Anemia: Low baseline hemoglobin levels predict for poorer colostomy-free survival and DFS [16].

       

    6. (vi)


      HIV positive: In the era of highly active antiretroviral therapy (HAART), HIV-positive patients treated with chemoradiation appear to have similar rates of response and survival compared to HIV-negative patients [24, 25].

       

     


15.4 Molecular Biology





  1. (a)


    Human papillomavirus (HPV)


    1. (i)


      HPV is a DNA virus that is found in 80–90 % of anal tumors [5, 22, 26] and is associated with better survival outcomes [20, 21].

       

    2. (ii)


      ~100 different genotypes of this virus exist, but HPV-16 is the most high-risk subtype and is present in 70 % of anal tumors [5, 6, 26].


      1. 1.


        Other subtypes include HPV-18 (second most common high-risk subtype), HPV-6, HPV-11, and HPV-31 [3].

         

       

    3. (iii)


      HPV encodes two viral oncoproteins – E6 and E7 – which augment progression through the cell cycle. E6 binds p53, a critical tumor suppressor protein, and triggers its degradation via the ubiquitination pathway. E7 binds retinoblastoma-associated tumor suppressor proteins and facilitates transition from the G1 to S phase. Both of these actions result in abnormal cellular proliferation.

       

    4. (iv)


      Typically HPV is rapidly cleared by an individual’s immune system, but ~1 % of the general population is chronically infected. These chronic carriers present with anogenital warts [27].


      1. 1.


        Immunosuppression increases the risk of anal cancer by allowing reactivation of the virus in those with latent, persistent HPV infections [3, 5].

         

       

    5. (v)


      Premalignant lesions.


      1. 1.


        Similar to cervical cancer, anal cancer results from the progression of early premalignant lesions (SILs) to invasive carcinoma.


        1. (a)


          Low-grade squamous intraepithelial lesions (LSILs) [28] are typically self-limited in nature. These lesions are characterized by nuclear atypia or atypical mitoses that are limited to the basal layers of the epithelium. Anal intraepithelial neoplasia type 1 (AIN1) is a type of LSIL.

           

        2. (b)


          High-grade squamous intraepithelial lesion (HSIL) [28, 29] harbors the potential to progress to invasive carcinoma. Pathologic examination typically shows marked nuclear atypia or atypical mitoses throughout all epithelial layers, and tissue will stain positive for p16. AIN2 and AIN3 are types of HSIL.


          1. (i)


            The progression of HSIL to an invasive cancer is influenced by various factors including infection with a high-risk HPV subtype and immunosuppression [29].

             

           

         

       

     


15.5 Patterns of Failure





  1. (a)


    Anal canal


    1. (i)


      Anatomy: The anal canal is the terminal portion of the large intestine. It measures roughly 4 cm and extends from the anorectal ring to the anal verge. The dentate line is located approximately 2 cm cranial from the anal verge and separates the anal canal into two segments – proximal (columnar/glandular epithelium) and distal (squamous epithelium). A zone of transitional epithelia (transitional zone) exists proximal to the dentate line.

       

    2. (ii)


      Patterns of spread.


      1. 1.


        Most patients (~50 %) present with disease localized to the anus [30].

         

      2. 2.


        Regional lymph node spread is seen in ~30 % of patients [11, 30]. The risk of lymphatic spread is correlated to primary tumor size [3]. The lymph nodes at risk depend on the location of the primary tumor. Tumors proximal to the dentate line drain to the perirectal nodes and along inferior/middle hemorrhoidal vessels to the internal iliac, obturator, and presacral nodes. Tumors distal to the dentate line drain to the superficial inguinal nodes.

         

      3. 3.


        Around 10 % of anal cancer patients have metastatic disease at the time of diagnosis [30]. The liver and lungs are the most common sites of metastatic spread.

         

       

    3. (iii)


      Patterns of failure.


      1. 1.


        Locoregional failure


        1. (a)


          Locoregional recurrence is the most common cause of failure following chemoradiation, occurring in approximately 10–30 % of patients [3]. Factors associated with increased risk of locoregional failure include higher T stage and N stage [19].

           

        2. (b)


          The vast majority (~90 %) of recurrences will develop within the first 2 years after treatment [31].

           

         

      2. 2.


        Distant failure


        1. (a)


          10–20 % of patients will develop metastatic disease after their primary treatment [32, 33]. The most common site of distant failure is the liver.

           

        2. (b)


          Retrospective studies have shown that higher N stage is correlated with increased risk of distant failure [19].

           

         

       

     

  2. (b)


    Anal margin


    1. (i)


      Anatomy: The anal margin is the region of perianal skin spanning 5 cm radially from the anal verge. The superficial inguinal lymph nodes are the first echelon of lymph node drainage.

       

    2. (ii)


      Patterns of spread: SCCs of the anal margin are typically well-differentiated tumors harboring a low potential for distant spread. Like anal canal tumors, the risk of lymphatic spread is directly correlated to the size of the primary tumor. Up to 67 % of patients with primary lesions greater than 5 cm have evidence of nodal involvement at diagnosis [34].

       

    3. (iii)


      Patterns of failure: Locoregional failure is most common in anal margin tumors.

       

     


15.6 Multidisciplinary Treatment of Anal Canal Tumors





  1. (a)


    History and physical


    1. (i)


      History: A detailed history focusing on presenting symptoms and risk factors should be obtained.


      1. 1.


        Presenting symptoms


        1. (a)


          Rectal bleeding – the most common presenting symptom

           

        2. (b)


          Pain

           

        3. (c)


          Pruritus

           

        4. (d)


          Tenesmus

           

        5. (e)


          Fecal incontinence or change in bowel habits

           

        6. (f)


          Anal mass

           

         

      2. 2.


        Risk factors

         

       

     

  2. (a)


    Sexual history (history of STDs or HIV, receptive anal intercourse)

     

  3. (b)


    History of immunosuppression, such as corticosteroid use or organ transplant

     

  4. (c)


    History of abnormal Pap smear


    1. (ii)


      Physical: A focused physical examination revolving around a thorough rectal and lymph node examination.


      1. 1.


        External examination and inspection of the anal margin.

         

      2. 2.


        Digital rectal examination (DRE) to assess location, size, and mobility of the tumor as well as functionality of the anal sphincter. During palpation, it is important to assess for involvement of other nearby structures including the vagina and prostate.

         

      3. 3.


        Anoscopy to visualize and assess the anal mucosa including the location of the mass relative to the anal verge. During anoscopy, the anal mass should be biopsied.

         

      4. 4.


        Inguinal lymph node examination.

         

      5. 5.


        Gynecologic exam including Pap smear for women to assess for vaginal involvement as well as screen for synchronous cervical cancer.

         

       

     

  5. (b)


    Laboratory work-up


    1. (i)


      Complete blood count with blood transfusion, if indicated

       

    2. (ii)


      Liver function tests

       

    3. (iii)


      Complete metabolic panel

       

    4. (iv)


      HIV serology and if positive CD4 count and viral load

       

     

  6. (c)


    Imaging


    1. (i)


      CT or MRI of the pelvis to assess local disease and pelvic or inguinal adenopathy.

       

    2. (ii)


      CT of the chest and abdomen to detect distant metastases.

       

    3. (iii)


      PET/CT is used in many centers for staging of anal cancer. PET/CT is more sensitive than CT scan in detecting the primary anal tumor, but more importantly has greater sensitivity in detecting occult nodes which can result in nodal upstaging and modifications to the radiation treatment plan [11, 35].

       

     

  7. (d)


    Treatment


    1. (i)


      Anal canal


      1. 1.


        M0: Patients with locoregionally confined disease should be treated with chemoradiation with concurrent mitomycin C (MMC) and 5-FU.


        1. (a)


          Chemotherapy: MMC is commonly delivered as a 10 mg/m2 IV bolus on days 1 and 29. 5-FU is given as a continuous infusion (100 mg/m2/day) in days 1–4 and days 29–32. Several studies suggest that capecitabine (825 mg/m2 oral bid, Monday through Friday) can be used in the place of 5-FU [36–38], but this has not been tested in a randomized phase III trial.

           

        2. (b)


          Radiation: The primary tumor and at-risk lymph nodes (perirectal, presacral, internal iliac, external iliac, and inguinal) should be covered [39]. At-risk nodal regions should receive at least 36 Gy (if conventional fractions are used), while the primary tumor and involved nodes should be treated to at least 45 Gy. An additional 9–14 Gy boost should be delivered to large primaries (T3-4) and bulky lymph nodes [40]. Radiation should be delivered using intensity-modulated radiation therapy (IMRT) to minimize treatment-associated toxicities [41]. There is no role for dose escalation in excess of 59 Gy [42, 43], and extended treatment breaks should be avoided [44].


          1. (i)


            Radiotherapy alone: Some institutions have reported excellent outcomes with radiation therapy alone, without concurrent chemotherapy, especially for T1 and N0 patients [45, 46]. Radiation therapy alone could therefore be considered as an acceptable treatment option for T1 N0 patients.

             

          2. (ii)


            Brachytherapy: Interstitial brachytherapy can be used to provide a boost (10–20 Gy) following EBRT, with acceptable toxicity and excellent local control [47, 48]. However, the use of brachytherapy remains limited to selected centers.

             

           

         

      2. 2.


        M1: Patients with metastatic disease should be treated with cisplatin-based chemotherapy [40]. An international trial is currently comparing 5-FU and cisplatin versus carboplatin and paclitaxel [49, 50]. Palliative radiation can be considered for bulky primary disease [40]. Definitive chemoradiation and surgical resection may be considered in patients with oligometastatic disease [49, 51].

         

      3. 3.


        Recurrent disease:


        1. (a)


          Local: Salvage APR is the standard of care [11]. If patients with local failure are eligible for salvage surgery, 5-year cancer-specific survival from the time of recurrence is 40–64 % [52, 53].

           

        2. (b)


          Inguinal nodes: Inguinal lymph node dissection [11].

           

        3. (c)


          Metastatic: Cisplatin-based chemotherapy.

           

         

      4. 4.


        HIV/AIDS patients: HIV-positive patients with CD4 counts greater than 200/mm3 should be treated according to the same approach as HIV-negative patients. Retrospective studies have shown equivalent survival outcomes for HIV-positive and HIV-negative individuals [24, 25]. However, toxicities including moist desquamation and severe diarrhea are significantly higher in patients with CD4 counts less than 200/mm3 [54]. Therefore, dose reduction or omission of MMC and smaller radiation fields should be considered in this population.

         

       

    2. (ii)


      Anal margin


      1. 1.


        Squamous cell carcinomas.


        1. (a)


          For small (T1 N0), well-differentiated tumors that do not involve the anal sphincter, the standard treatment is wide local excision with a goal of 1-cm radial margins [55, 56]. If the margin is positive, a re-excision should be attempted. Alternatively, the patient with a positive or close margin can be treated with adjuvant radiation (with or without 5-FU chemotherapy) to a dose of 60–66 Gy [3].

           

        2. (b)


          For T1 N0 tumors or small T2 N0 tumors involving the anal sphincter, the primary tumor and inguinal lymph nodes can be treated with radiation alone [55].

           

        3. (c)


          For T3/T4 or N+ disease, the treatment paradigm is the same as that for anal canal tumors. Patients should receive definitive radiation including inguinal and pelvic radiation with concurrent 5-FU and mitomycin C-based chemotherapy.

           

         

      2. 2.


        Melanomas and basal cell carcinomas should be treated as skin cancers – surgery with wide local excision [31].

         

       

     


15.7 Key Clinical Studies


Historically, tumors of the anal canal were treated surgically. Seminal work by Dr. Nigro at Wayne State University in the 1970s suggested that neoadjuvant, concurrent chemoradiation therapy (CRT) to a low dose of 30 Gy with continuous-infusion 5-FU and MMC was sufficient to cure patients of their cancer, thereby enabling organ preservation and avoiding the need for up-front, radical surgical resection [57]. Since this early work, six randomized controlled trials (RCTs) have assessed the role and timing of chemotherapy and radiation in the treatment of anal carcinoma (Table 15.2). More recent studies have evaluated the role of IMRT.


  1. (a)


    Chemoradiation versus radiation alone: The first two, large anal cancer RCTs were both initiated in the late 1980s in Europe and compared local control following chemoradiation with 5-FU and mitomycin C versus radiation alone. Both trials showed improved local control, colostomy-free survival (CFS), and disease-free survival (DFS) in the chemoradiation arm. The radiation was delivered using split-course fractionation, which is no longer used.


    1. (i)


      United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial (ACT) I: ACT I is one of the larger anal cancer RCTs to date and has the longest median follow-up (13.1 years) [58]. 577 patients were randomized to either radiation alone or radiation with 5-FU/mitomycin C. The primary endpoint was local control. The trial involved a split course of radiation with the initial 45 Gy being delivered in 20–25 fractions, followed by a 6-week break and clinical reassessment. Depending on the degree of response (≥50 %, <50 %), the patient would receive either a boost or proceed to surgery. For those treated with CRT, there was a statistically significant improvement in 12-year local control (66 % vs 41 %), CFS (30 % vs 20 %), and DFS (30 % vs 18 %), resulting in a relative improvement of ~33 % in all of these endpoints. In addition, there was a trend toward improved overall survival in the CRT arm (median OS 7.6 years vs 5.4 years). While this did not reach statistical significance, there was a statistically significant reduction in the number of deaths from anal cancer (p=0.004) [58].

       

    2. (ii)


      European Organization for Research and Treatment of Cancer (EORTC): The EORTC trial is similar to ACT I in purpose and design, with only a few small differences. The EORTC study was considerably smaller (103 vs 577 patients) with a shorter median follow-up (3.5 years vs 13.1 years). A split course of radiation was also used in this trial with reassessment at 6 weeks following an initial dose of 45 Gy. Complete responders received an extra 15 Gy boost to the original tumor and involved nodes, partial responders received a 20 Gy boost, and nonresponders proceeded to surgery. The rate of side effects was comparable in the CRT and radiation arms. Despite the relatively small cohort and short follow-up, there was a significant improvement in 5-year local control (68 % vs 50 %) and CFS (72 % vs 40 %). No overall survival benefit was seen (5-year OS approximately 55 % in both arms) [32].

       

     

  2. (b)


    Alternate chemotherapy regimens: After ACT I and EORTC showed a clear benefit of CRT, subsequent studies have looked at whether less toxic chemotherapy regimens or the use of neoadjuvant or adjuvant chemotherapy could be used in the place of 5-FU/MMC. In summary, none of these trials have shown a benefit to alternative chemotherapy regimens, and concurrent CRT with 5-FU/MMC remains the standard of care.


    1. (i)


      Radiation Therapy Oncology Group (RTOG) 87-04/Eastern Cooperative Oncology Group (ECOG) 1289: In an attempt to drop the more toxic MMC from the chemotherapy regimen, this trial compared concurrent CRT with 5-FU/MMC versus 5-FU alone. A split-course radiation regimen was used to treat all patients, this time with a “post-induction” biopsy obtained 4–6 weeks after delivery of the initial 45–50.4 Gy. If the post-induction biopsy was positive, an additional 9 Gy boost was delivered, and the patient was considered to have a local failure. The primary endpoint was local control. The rate of negative post-induction biopsies (i.e., immediate local control) was 92 % in the 5-FU/MMC arm and 86 % in the 5-FU arm (p = 0.135), and the 4-year CFS was significantly lower in the 5-FU/MMC arm (71 % vs 59 %). The prevention of colostomies with MMC was driven primarily by patients with bulky (T3/T4) disease (p = 0.019). The 4-year DFS was also significantly improved (73 % vs 51 %, p = 0.0003). While the 5-FU/MMC regimen was superior, it did lead to greater acute hematologic complications (18 % vs 3 %, p < 0.001). Chronic side effects were similar [59].

       

    2. (ii)


      RTOG 98-11: Since RTOG 87-04 showed that MMC could not simply be excluded from the chemotherapy regimen, RTOG 98-11 investigated whether the addition of neoadjuvant chemotherapy and replacement of MMC with a less toxic drug (cisplatin) could improve outcomes compared to the standard 5-FU/MMC. Cisplatin was an appealing alternative drug as it had been shown to be successful for anal cancer in phase II studies and was also effective in other HPV tumors including cervical cancer and oropharyngeal cancer [44, 60]. RTOG 98-11 accrued from 1998 to 2005 and randomized 649 patients to the standard arm (CRT with 5-FU/MMC) or the experimental arm (neoadjuvant chemotherapy with 5-FU/cisplatin for two cycles, followed by concurrent CRT with 5-FU/cisplatin). This trial was, therefore, not a direct comparison of 5-FU/MMC versus 5-FU/cisplatin. All patients received an initial 45 Gy in 25 fractions followed by a 10–14 Gy boost for patients with T3/T4 disease, positive nodes, or T2 tumors with residual disease after 45 Gy. Radiation was not delivered with a split course as in earlier trials. The 5-year DFS (primary endpoint) (68 % vs 58 %, p = 0.006) and OS (78 % vs 71 %, p = 0.026) were significantly improved in the 5-FU/MMC arm. The 5-year CFS was also better for patients receiving 5-FU/MMC (72 % vs 65 %, p = 0.05). It is difficult to conclude from this trial whether the inferior outcomes in the cisplatin arm were due to the use of induction chemotherapy or due to the difference in the concurrent chemotherapy regimens. Delaying the initiation of definitive CRT with neoadjuvant chemotherapy may have resulted in poorer outcomes in the cisplatin arm, or resulted in platinum-based radio resistance [17, 61]. Nevertheless, based on this trial, concurrent CRT with 5-FU and mitomycin remains the standard of care.

       

    3. (iii)


      UKCCCR ACT II: ACT II was a 2 × 2 study that compared CRT with 5-FU/MMC versus 5-FU/cisplatin and also examined the impact of maintenance chemotherapy with 5-FU/cisplatin. A total of 940 patients were randomized to one of four arms: (1) CRT with 5-FU/MMC, (2) CRT with 5-FU/cisplatin, (3) CRT with 5-FU/MMC followed by maintenance 5-FU/cisplatin, and (4) CRT with 5-FU/cisplatin followed by maintenance 5-FU/cisplatin. For radiation, all patients were treated to 50.4 Gy in 28 fractions. The primary endpoints of the study were complete response at 6 months and progression-free survival. Neither of these were significantly different in any of the four arms. Additionally, none of the other survival endpoints (OS, CFS) were different. Hence, this trial indicates that concurrent 5-FU/cisplatin leads to equivalent outcomes as concurrent 5-FU/MMC. Further, the cisplatin arms had significantly lower grade 3+ hematologic side effects (16 % vs 26 %, p < 0.001); however, the authors cited increased resources needed for the administration of cisplatin infusions compared to mitomycin. This study also indicates that there was no benefit to maintenance chemotherapy, though only 44 % of patients randomized to the maintenance arms completed both cycles of maintenance chemotherapy.

       

     

  3. (c)


    Dose escalation:


    1. (i)


      Intergroup ACCORD 03: ACCORD 03 was another 2×2 study that investigated the potential role of dose escalation as well as neoadjuvant chemotherapy. ACCORD 03 was a smaller study than ACT II (only 307 patients) and randomized patients to four arms: (1) CRT with 5-FU/cisplatin + standard boost, (2) CRT with 5-FU/cisplatin + high-dose boost, (3) induction 5-FU/cisplatin × two cycles followed by CRT + standard boost, and (4) induction 5-FU/cisplatin × two cycles followed by CRT + high-dose boost. Unlike RTOG 98-11 and ACT II, radiation was again delivered in a split-course fashion with a 3-week break after the initial 45 Gy, at which time patients were reassessed for clinical response. If patients had some degree of response, they proceeded on to receive either a standard boost (15 Gy) or high-dose boost (20–25 Gy). There was no significant difference across the four arms in terms of CFS (primary endpoint) or other survival endpoints. In addition, even when combining the two induction chemotherapy arms or the two high-dose boost arms, there was no significant difference in colostomy-free survival (3-year CFS 79 % vs 76 %, p = 0.37 and 3-year CFS 79 % vs 76 %, p = 0.067, respectively). In summary, this trial suggests that there is no clear role for induction chemotherapy or boosting gross disease to doses in excess of 60 Gy.

       

     

  4. (d)


    Induction chemotherapy: The RTOG 98-11 and ACCORD 03 trials discussed above both failed to show any benefit from induction chemotherapy.

     

  5. (e)


    Maintenance chemotherapy: As discussed above, the ACT II trial showed no benefit from maintenance chemotherapy.

     

  6. (f)


    IMRT: In order to decrease the acute and long-term toxicities associated with high-dose radiation to the anal canal, recent retrospective and prospective studies have investigated the role of intensity-modulated radiation therapy (IMRT) in reducing dose to normal tissues during radiation treatment. Overall these studies show excellent survival outcomes and lower rates of severe side effects compared to the historic RCTs (Table 15.3) [62–70]. A few of the larger retrospective studies and RTOG 05-29 are highlighted below.


    1. (i)


      Retrospective:


      1. 1.


        Salama, 2007 [62]: This multicenter retrospective study was the largest early study assessing outcomes with IMRT-based chemoradiotherapy in anal cancer. It looked at the outcomes of 53 patients treated from 2000 to 2006, but had relatively short median follow-up (14.5 months) and only reported 18-month survival outcomes. While the rate of acute toxicities was high compared to some of the more recent retrospective studies (59 % of patients suffering acute grade 3+ hematologic toxicities, 38 % of patients with grade 3 dermatitis), they were considerably lower than the earlier randomized controlled trials, including RTOG 98-11.

         

      2. 2.


        Kachnic, 2012 [63]: This retrospective series of 43 patients was the first to analyze the results from “dose-painting IMRT” (DP-IMRT). Prior studies had utilized the technology of IMRT and multiple beams to precisely shape the radiation and avoid critical structures; however, dose was ultimately delivered with sequential boosts as opposed to utilizing a simultaneous integrated boost, or DP-IMRT. DP-IMRT allows radiation to be delivered using a single plan. In this study, patients with T2 N0 disease had the primary tumor treated to 50.4 Gy and the elective nodal CTV treated to 42 Gy in 28 fractions, while patients with more advanced disease received two extra fractions with the primary tumor treated to 54 Gy and the nodal CTV treated to 45 Gy in 30 fractions. This study showed comparable survival outcomes compared to earlier studies and very low non-hematologic acute toxicities (grade 3+ skin 10 % and grade 3+ GI 7 %).

         

      3. 3.


        Mitchell, 2014 [64]: A more recent study from MD Anderson Cancer Center incorporated a simultaneous integrated boost technique that treated the GTV in 2 Gy fractions (as opposed to 1.8 Gy fractions in RTOG 05-29 and Kachnic, et al.). A total of 65 patients were analyzed, and outcomes from this study were excellent with a 2-year local control rate of 91 % and 2-year overall survival of 96 %. Acute complication rates were very low (3 % hematologic, 17 % skin, 9 % gastrointestinal). The low rate of hematologic side effects compared to other series was due, in part, to the use of concurrent 5-FU and cisplatin in the majority of patients, as opposed to 5-FU and mitomycin C. Additionally, the utilization of vaginal dilators for female patients may have decreased the rate of acute vulvar and skin toxicities.

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Oct 18, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Anal Cancer: Background and Clinical Evidence

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