Introduction

Anal canal cancer is a distinct entity from the most common colorectal neoplasms. The etiology, risk factors, clinical progression; staging and treatment related features are different.¹ Anal cancer is a rare malignancy, but in past two decades the incidence has increased probably due to an increased prevalence of multiple sex partners, smoking, human papilloma virus (HPV) and human immunodeficiency virus (HIV) infection.²

Anal cancer is typically a squamous cell carcinoma that arises near the squamocolumnar junction. Local control and sphincter preservation are the two major challenges of treatment. Anal cancer is most effectively treated with surgery and in early stage surgery is often curative. The difficulty with surgery has been the necessity of removing the normal anal canal passage and leaving the patient with a life long colostomy bag. Since Nigro et al. in 1974 reported complete regression in 3 patients after radiochemotherapy approach; it brought a huge paradigm shift since then in the management of anal cancers.³ Combination strategy including external radiation with concurrent chemotherapy to reduce the necessity of debilitating surgery has become the standard of care. This “combined modality” approach has led to the increased preservation of an intact anal sphincter and therefore improved the quality of life.⁴ Survival and cure rates are excellent and many patients are left with a functional sphincter. Total radiation dose, overall duration of radiation therapy, duration of the gap and indications of additional boost are not clear, but it is demonstrated that overall duration of treatment should be as short as possible to improve the therapeutic ratio.

Patients and Methods

Population based historical cohort with confirmed histological diagnosis of anal canal or anal margin cancer treated with organ preservation approach such as chemo radiation from 1970- 2006 and registered with provincial Saskatchewan Cancer Registry was evaluated.

We studied 152 patients who had confirmed pathological diagnosis of anal carcinoma. However 102 patients were ineligible as they did not received organ preservation chemo radiotherapy. Out of these, forty eight patients had abdominal perineal resection upfront, 6 patients had palliative radiation for symptom control, 5 patients had local excision requiring no further adjuvant treatment, 2 patients had cesium/radium interstitial implant, 8 patients had radical radiation alone, 28 patients had best supportive care and on 5 patients information was missing. In the end only 50 patients received radiation and chemotherapy as an organ preservation approach. Median age was 58 years (range 31-79 years).Thirty patients (60%) were under 60 years of age and 20 (40%) were above the age of 60 years. Patient’s baseline characteristics are outlined in Table 1. Mean follow-up was 4.2 years (range 8-21 years). Primary end points were colostomy free survival, disease free survival and overall survival. The influence of tumor stage,nodal stage, age, radiation dose, interruption during treatment on primary end points were also evaluated. Acute skin, gastrointestinal and hematological toxicity was scored according to RTOG and late by LENT/SOMA scale.

Therapy

All patients received combined radiochemotherapy with intention to conserve anal canal. The recommended dose for radiation to primary tumor was 48-58 Gray (Gy), negative inguinal nodes 30-36 Gray and grossly involved nodes 50-55 Gray. The patients were treated by shrinking radiation field technique. Inguinal nodes were treated in the exit beam of the PA (posterior) field in supine position and boosted with anterior electron field in the same position. The whole pelvis was treated by two parallel opposed fields with wider anterior and small posterior field with the 6 MV photon machine. The majority of the patients were treated with a full bladder in order to reduce small bowel toxicity. In the first phase the prescription was 30.6 Gy in 17 fractions (180 cGy per fraction) to the whole pelvis with the superior border at L5/S1 and the inferior border at 2.5cm below the tumor or anal margin. The lateral margin in the anterior beam included lateral inguinal nodes usually to the greater trochanter of the femur, while as the lateral edge in the posterior field was 2cm beyond the true pelvis. Supplementary radiation to the inguinal nodes was delivered with anterior electron fields matched with exit from the posterior field.

In the second phase the superior border was dropped to the bottom of sacroiliac joints and 14.4 Gy in 7 fractions to a total of 45 Gy was delivered. Additional radiation was delivered to gross tumor disease with a 2 to 2.5 cm margin to total of 54-59 Gy depending on clinical presentation. Involved inguinal nodes were boosted with a 2cm margin to total a of 55–59 Gy. This was achieved by photons and additional electrons. Most of the patients were treated as per RTOG 9811.All patients received mitomycin and 5FU (fluorouracil) based chemotherapy concurrent with radiation. 5 FU was 1000mg/m² /day continuous infusion, day 1-4 week 1 and week 5, mitomycin C 10mg/ m² /day intravenous, day 1 only week 1 and week 5.

Follow-up

The follow up examination was done approximately 8 weeks after completion of chemo radiotherapy. It included physical examination, computed tomography of pelvis including inguinal area if available and anoscopy. Patients were examined every 3 months for first 2 years, followed by visits every 6 months for 5 years. Local failure was defined as the presence of disease after 90 days post completion of local treatment. This was biopsied and if histology was reported positive for malignancy, patients were sent for surgical opinion.

Statistical Analysis

The overall survival, disease free survival and colostomy free survival were estimated according to the Kaplan Meier test.

Results

Figure 1

The median follow-up was 3.1 years ( 8-21years). The baseline characteristics are outlined in Table 1.

Figure 2

Table 1 Baseline demographics

The majority of patients had stage II (60%) as per AJCC (American joint cancer committee) Staging Manual. All patients had squamous cell carcinoma on histology with 34% moderately differentiated, 26% poorly differentiated, 20% well differentiated and 20% undifferentiated variety. The majority of patients (75%) had a CT scan of the abdomen/pelvis and a chest X-ray as routine staging investigations before commencing treatment. All patients in this data set received external beam radiation. The median dose was 53 Gray, delivered in 48 days. Twenty seven patients (54%) had treatment interruption ranging from 2-12 days secondary to severe skin reactions. The majority of patients (48%) received mitomycin and 5 FU based chemotherapy .Only 2 patients (4%) received cisplatinum instead of mitomycin. Twenty patients (40%) had grade II skin reactions, 4 had grade III and 1 patient had grade IV skin reaction in inguinal folds. Grade I rectal toxicity was documented in 40 patients, grade II in 5 patients. One patient had severe rectal toxicity which required surgical intervention. Grade I bladder toxicity was seen in 2 patients.

Out of 50 patients treated with combined modality treatment 7 patients (14%) had local recurrence. Median time from completion of treatment to recurrence was 13 months

( range 2-129 months).Distant metastasis was seen in 12 patients ( 24%).The median time to develop distant disease was 3.1 years (range 8-21 years).Majority of local recurrences were seen in or near local site except 1 who failed in the inguinal area. Distant metastases were seen in the iliac area, peritoneum, liver and lung. In patients who received a radiation boost to gross tumor site only 11% failed locally compared to 25% who did not receive a radiation boost. The majority of patients who failed either at the primary or at a distant site had poorly differentiated disease on initial biopsy. Those patients who received a higher radiation dose (> 50 Gray) had a greater proportion of patients with no disease recurrence when compared to those who received a lower dosage (≤ 50Gy) 67% vs.74% respectively (Figure 1)

Figure 3

Figure 1; Bar diagram showing recurrence vs. radiation dose.

Patients with higher stage III and IV disease had the highest proportion of recurrent disease 30% and 67% respectively. Complete data about acute toxicity was available. Late effects were documented only in 30 patients. The majority of patients, 48 (96%) had treatment related toxicity mostly skin, rectal and bladder respectively. The higher the radiation doses, the worse the reactions. Seven patients required admission in hospital secondary to severe skin toxicity. Eighteen patients had acute hematological toxicity and 2 patients had leucopenia sepsis. Twenty patients required regular skin care by a health care professional another thirty patients were given instructions by a Radiation Oncology trained nurse. Colostomy for therapy related sphincter insufficiency was necessary on only 1 patient. Overall late side effects were moderate, only 2 patients had grade III concerning sphincter control issues. However because of the context of a retrospective study and the diffuse treatment parameters, it was difficult to analyze the true incidence of late toxicity. Late toxicity did not correlate with dose fractionation or field size. However the trend noted fewer late complications if the dose was less than 50 Gray.

Overall survival (OS) at 5 years estimated by Kaplan Meier curves was 53% ( Figure 2).

Figure 4

Figure 2; Overall survival (OS) at 5 years.

Univariate risk factor sub-analysis using Kaplan Meier and log rank tests revealed that stage at presentation and T score showed a statistically significant impact on survival with p <0.05. Stage I and II had better overall survival. A higher T component in AJCC staging had the worst overall survival. The rest of the parameters such as treatment time, radiation dose, age, gender and radiation boost did not affect overall survival. Stage I and II had OS of 64.7% while as stage III or higher had only 30.8%.

Figure 5

Figure 3; Disease specific survival at 5 years.

Disease specific survival at 5 years was 67% (Figure 3).

Univariate risk factor sub-analysis using Kaplan Meier and log rank test revealed that stage at presentation was the only risk factor which had an inverse impact on local or distant failure. Stage I and II had a better outcome as compared to stage III and IV 78% vs. 36% respectively. Overall, local recurrence free survival was 72% at 5 years. Stage I had 75%, stage II 80%, stage III 70% and stage IV only 33% respectively (Figure 4).

Figure 6

Figure 4; Local recurrence free survival as per Stage at 5 years.

Tumor site influenced local control. Anal canal had a higher risk of relapse than anal margin. Other factors such as N stage, age, gender and radiation treatment dose reached no statistical significance for evaluating end points. Multivariate analysis (Cox Proportional Hazards Model) was attempted, however due to small numbers, this analysis was inconclusive.

Colostomy free 5 year survival was 83%. Stage I and II had 86% and stage III or higher had only 66%. None of the risk factors showed statistically significant differences on colostomy free survival as all p values were greater than 0.05. Sphincter preservation was retained in 40 patients and 10 required salvage abdominoperineal resection. One patient had APR secondary to radiation toxicity and rest of 9 patients had disease recurrence. The anorectal function of patients treated with radiation that had the anus conserved was optimal. Full continence was recorded in 28 patients, 5 patients had some rectal urgency, another 5 had minor incontinence and 2 patients had moderately impaired anorectal function. Twelve patients had anal stenosis recorded secondary to radiation requiring regular dilatation.

Discussion

Until few decades ago the standard of practice in managing anal cancer patients was abdominoperineal surgery. This practice was challenged in 1974 when Nigro et al published their experience with 3 patients with squamous cell carcinoma of the anal canal who after preoperative treatment with radiation and chemotherapy had achieved a pathological complete response at the primary site. The dose of external radiation was only 30 Gray and chemotherapy used was mitomycine C and 5 FU.⁵Since then an organ preservation approach with a combined modality of treatment has been the standard of practice.

Accordingly the number of patients treated with a combined approach has steadily increased in our province especially between 2000- 2007. Patients in the latter part of the 1990’s were younger and this may be due to the increased prevalence of HPV and HIV infections. Since our study is retrospective, the data on HPV and HIV was available only in 20 patients. Regarding effectiveness of this approach Nigro et al and other available data in literature confirmed the efficacy of treatment in achieving local control and saving the sphincter. In the literature the local control and colostomy free survival is 65-80%.⁶ Colostomy free survival (CFS) of 83% and disease free survival (DFS) of 67% in our study is similar to what has been reported in the literature but the 5 year overall survival of 53% is bit lower. Although direct comparisons of the data cannot be done as we have no information if these patients received a full dose of chemotherapy, comorbidities and fewer cases of early stage which can confound the data and affect OS. Peiffert et al evaluated different prognostic factors from 9 studies and found that only the T stage was quoted as a prognostic factor in 8 studies and the rest of the parameters such as nodal status, age and gender did not represent any statistical significance.⁷

In our study, advanced T stage and overall stage affected colostomy free survival and overall survival respectively. The rest of the parameters did not reach statistical significance. RTOG long term data suggested 20-30% local failure, particularly for advanced T stage⁸ Nigh et al found the local control rate by radiation dose with chemotherapy to be 64% < 45 Gray, 72% for 45-50 Gray and 92% for doses more than 55 Gray.⁹At Mass General Hospital patients treated with radiation doses lower than 54Gray had lower local control as compared to patients who received ≥ 54 Gray.¹⁰ Similarly data from M. D. Anderson showed local control of 32% for 45-49 Gray, 71% for 50-55 Gray and 80% for 55-60 Gray.¹¹

In landmark RTOG 87-04 study the data established the important role of mitomycin (MMC).The patients who received RT+5FU+MMC had local failure of 19% vs. 30% in patients in whom MMC was omitted.¹² In our analysis the advanced T stage influenced the overall survival which has been seen in the literature as well. Concerning the radiation dose at the primary tumor site, patients who received more than 50 Gray had higher local control than those who received less than 50 Gray. We, however did not calculate the local control if 55 Gray was the cohort value. In the literature however, data suggests that the optimal radiation dose when combined with external radiation is approximately 55 Gray. ^{A boost with interstitial brachytherapy can potentially and radio biologically improve the therapeutic index but brachytherapy is not frequently used in North America due to the risk of necrosis.}

Regarding breaks during radiation there is sufficient information that they decrease the chance of local control. In a dose escalation phase II study by RTOG 9208, a two week break was allowed which unfortunately increased higher colostomy rates at 2 years around 30%.Similarly an EORTC study by Bartelink, showed that a break during radiation yielded poorer results. So, interruptions are not routinely encouraged and if needed they should be minimal.¹³The publication of the Radiation Therapy Oncology Group (RTOG) ^{98-11 Intergroup study in late April 2008, which randomly assigned patients to receive neoadjuvant fluorouracil (FU)/cisplatinum followed by chemo radiotherapy (CRT) or to receive standard concomitant FU and mitomycin, provides an opportunity to examine the role of neoadjuvant chemotherapy (NACT) in the management of anal cancer.14In this trial, no benefit was seen for the neoadjuvant approach, despite the obvious attraction and rationale for using cisplatinum in this setting. Notably, although neoadjuvant FU/cisplatinum chemotherapy was piloted before this study, the studies justifying the neoadjuvant approach in RTOG 98-11—one using FU and mitomycin as the CRT component—were not reported until 2001 and 2005, well into the accrual for this trial.15This important study accrued a total of 682 patients between 1998 and 2005. Patients were randomly assigned between the standard arm of concurrent CRT with FU and mitomycin (341 patients), and the novel arm of neoadjuvant FU and cisplatinum for two cycles before CRT with concurrent FU and cisplatinum (341 patients). The majority of patients had T2 tumors, but 35% had stage T3/T4 and 26% had clinically involved lymph nodes. Of these 682 patients, 644 were deemed eligible for the trial. The results demonstrated that NACT with cisplatinum/FU followed by FU/cisplatinum–based CRT failed to improve overall survival, disease-free survival (DFS), loco-regional control and distant relapse when compared to the standard treatment arm of FU/mitomycin C CRT. In fact, trends favored the FU/mitomycin C CRT arm.}

The analysis of the pattern of recurrence shows that after this aggressive chemoradiation approach the patients failed in the primary site but not necessarily in the same location and rarely in the inguinal area. The median time for recurrence was 28 months. No statistical significance was found between the radiation technique and local failure. In literature the reported median time to local failure is 18 months. The reason for this delay could be that anal canal cancers are multifocal in nature and related to infectious precancerous lesions as seen in cervical malignancies. Late failures could be related to HPV infection which unfortunately is on the rise in today’s society. There is still the big question about radiation volume to be treated and this is still unresolved. The normal lymphatic drainage of the anal canal is perirectal, the internal iliac and the inguinal lymph nodes. The perirectal and inguinal nodal recurrences are quite rare in the literature. Whether we should treat smaller volume with radiation and thereby decrease skin toxicity seems very attractive but not accepted universally yet. The acute toxicity of combined approach is on the higher side. The risk is outweighed by the benefit achieved in local control and colostomy free survival and possible reduction in deaths from the disease.

In our study colostomy was performed secondary to radiation toxicity in one patient. Continence was reasonably good. In the literature around 65% of patients achieved complete continence .The quality of life (QOL) data in the anal canal is sparse but two studies which looked into it found it to be acceptable. In our data this aspect was not covered so we don’t have information on QOL; however it should be addressed in future trials.

Conclusion

Combined radiochemotherapy for anal canal malignancies is very effective therapy with acceptable but high acute and minimal late side effects. T stage seems to be consistently reported in the literature as a bad prognostic factor affecting outcome. The role of HPV and HIV infection needs to be investigated thoroughly as we will be facing more and more patients in our practice that will fall in this subgroup in near future.