Anal Adenocarcinoma Treated in the Era of Total Neoadjuvant Therapy and Nonoperative Management

Abstract

BACKGROUND:

Anal adenocarcinoma bears a treatment strategy unique to other anal cancers.

OBJECTIVE:

To describe oncologic outcomes of total neoadjuvant therapy followed by watch and wait for anal adenocarcinoma.

DESIGN:

Retrospective analysis.

SETTING:

This study was conducted at a comprehensive cancer center.

PATIENTS:

Patients with anal adenocarcinoma treated between 2004 to 2019 were selected.

INTERVENTIONS:

Fifty-four patients received neoadjuvant therapy and were divided into two groups according to their treatment strategy: total neoadjuvant therapy versus single-neoadjuvant modality therapy.

MAIN OUTCOME MEASURES:

Organ preservation, tumor regrowth, local failure, distant metastasis rates, recurrence-free, and overall survival.

RESULTS:

The study included 70 patients with anal adenocarcinoma. Fifty-four patients (77%) received neoadjuvant therapy, of whom 30 (42%) received total neoadjuvant therapy and 24 (34%) received single neoadjuvant modality. Twenty-three (33%) patients achieved complete clinical response and were managed by watch-and-wait. The proportion of patients able to continue to watch-and-wait was higher after receiving total neoadjuvant therapy (60%) compared to single neoadjuvant modality therapy (20%) (p = 0.004). A tumor regrowth rate of 22% was observed in the total neoadjuvant therapy group. The 5-year overall survival rate was 70% (95% CI: 59%, 83%), including 61% (95% CI: 42%, 88%) for the total neoadjuvant therapy and 65% (95% CI: 48%, 88%) for single neoadjuvant modality groups. Colostomy was avoided in 50% of patients that received total neoadjuvant therapy and 83% watch and wait patients. Five-year recurrence-free survival rates of 55% (95% CI: 39%, 79%) and 30% (95% CI 15%, 58%) were observed in the total neoadjuvant therapy and single neoadjuvant modality groups, respectively.

LIMITATIONS:

Retrospective nature.

CONCLUSIONS:

This is the first report in the literature describing the safety and feasibility of non-operative management for anal adenocarcinoma. Anal adenocarcinoma treated with total neoadjuvant therapy and nonoperative management achieve comparable regrowth rates to those observed in rectal cancer, with similar oncologic outcomes to traditional treatment strategies. See Video Abstract.

INTRODUCTION

Anal canal adenocarcinoma (AAC) is a rare histological subtype of anal carcinoma, accounting for 5% - 17% of all anal cancers.^1–3 Compared to the most common subtype, squamous cell carcinoma (SCC), AAC appears to have more aggressive features and decreased survival.^3,4 In one historic series of 21 patients with anal adenocarcinoma both the crude 5- and 10-year survival rates were only 4.8%.¹ Although some previous studies advocated for definitive chemoradiotherapy (CRT), similar to the treatment of anal SCC,^5–7 the appropriate treatment for AAC, as advised by the current National Comprehensive Cancer Network (NCCN) guidelines, is management per the rectal adenocarcinoma treatment paradigm.⁸ In reality, many do not consider this an anal cancer and more a misclassified rectal cancer. The introduction of total neoadjuvant therapy (TNT) as a treatment approach to rectal adenocarcinoma has increased the rates of both clinical and pathologic complete response, resulting in excellent long term oncologic outcomes. The recently published OPRA trial⁹ showed that organ preservation is achievable in half of the rectal cancer patients treated with TNT, and that CRT combined with consolidative chemotherapy or induction chemotherapy, may be an appropriate strategy to maximize clinical complete response (cCR) rates.¹⁰ Controversy exists regarding the role of surgery in AAC, with a recent NCDB analysis suggesting improved overall survival with the incorporation of surgery into the management of anal adenocarcinoma.¹¹ Because AAC is such a rare occurrence, it is not feasible to perform large-scale prospective randomized controlled trials to study the nature of this disease. We sought to analyze the patterns of care and the oncologic outcomes of AAC in the era of the TNT and watch-and-watch (W&W) approach to better define the optimal treatment strategy of this rare cancer.

METHODS

Patient Population

Patients with rectal cancer treated at Memorial Sloan Kettering (MSK) between 2004 and 2019 were extracted from a prospectively maintained institutional database. Two investigators individually reviewed each case and identified a study population of patients with biopsy-proven, anal adenocarcinoma, defined as tumors with an epicenter located between the anal verge and ≤ 2 cm above the dentate line, and based on Memorial Sloan Kettering Cancer Center’s treating surgeon’s review and assessment.^1,12 Patients who were treated elsewhere (seen as second opinion at our institution) and those returning with recurrence after 2004 were excluded. A comprehensive chart review for clinical and tumor characteristics, including those related to preoperative imaging and endoscopy findings was performed. The locoregional staging was based on endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI). Clinical T stage (cT) was classified as Tis, cT1–4, according to preoperative imaging, and as cTx when these data were missing or the primary tumor was not visualized. The study was approved by the institutional review board of Memorial Sloan Kettering, and a waiver of informed consent was obtained.

Neoadjuvant and Adjuvant Therapy Regimens

Chemoradiotherapy (CRT) consisted of 25 to 28 fractions of 1.8 Gy with administration of concurrent, continuous infusion of fluorouracil or oral capecitabine. Patients generally received a radiation dose of 45 Gy with a sequential or integrated boost of 5–11 Gy to the tumor. Patients treated with CRT were recommended to receive additional chemotherapy as adjuvant treatment for a total of 3 to 4 months in accordance with the guidelines of the National Comprehensive Cancer Network.⁸ In the TNT group, induction chemotherapy,^13,14 consisting of 8 cycles of FOLFOX (folinic acid, fluorouracil, and oxaliplatin) administration was followed by long-course chemoradiation as described above. An alternative regimen was long-course chemoradiation followed by consolidation chemotherapy consisting of 8 cycles of FOLFOX. The third and least common neoadjuvant regimen was chemotherapy or chemoradiation only.

Surgical Technique

Patients with cCR at the completion of neoadjuvant therapy were given the option to enter a W&W protocol to preserve the rectum.¹⁵ Patients with cCR who chose surgery, patients without a cCR at restaging, and patients in whom the tumor regrew during W&W underwent total mesorectal excision (TME) surgery. Some of the patients underwent local excision or declined resection.

Pathologic Analysis

Pathology data were collected from analyses of resection specimens performed shortly after surgery. The NCCN guidelines recommend treatment of anal adenocarcinoma according to the paradigm established for rectal adenocarcinoma, despite substantial differences in their staging paradigms. In anal adenocarcinoma, T-stage was previously determined by either tumor diameter or by depth of invasion as per rectal adenocarcinoma. In our institution, each anal tumor was evaluated in accordance with standard protocols for rectal cancer pathology.¹⁶

Follow-up

Patients were seen within 1 month following resection, then every 3 to 4 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. Clinical examination was generally performed at each follow-up visit; serum carcinoembryonic antigen (CEA) was measured at each visit. CT scans were obtained based on individual follow-up regimens (generally every 6 –12 months). Positron emission tomography (PET) scans were selectively used when abnormalities on axial imaging raised the question of recurrence. Regrowth, the return of the tumor at the previous tumor site after achieving cCR, was possible in patients who underwent nonoperative management with W&W; for all other groups, local recurrence was defined as the first clinical, radiologic and/or pathologic evidence of the return of cancer of the same histologic type within the same location. Distant recurrence was defined as clinical, radiologic, and/or pathologic evidence of systemic disease outside the pelvis, at sites including but not limited to the liver, lungs, and para-aortic region. Local failure included an unresectable primary tumor following neoadjuvant treatment, local recurrence after a primary R0–1 resection, or positive margins in the primary tumor resection.

Statistical Analysis

We performed baseline demographic comparisons using analysis of variance (ANOVA) for continuous factors and two-sided χ² tests for categorical variables. Overall survival estimates for the sample population and treatment sub-groups were determined using the Kaplan–Meier method. Differences in survival across treatment subgroups were determined using the log-rank test. In all cases, a p value < 0.05 was considered statistically significant. The statistical analysis was performed using R software (version 4.2.1).

RESULTS

Baseline Patient and Tumor Characteristics

Within the 1446 patients with anal carcinoma treated at our institution between 2004 to 2019, 176 were diagnosed with anal adenocarcinoma. Patients with stage IV disease, a second primary cancer and extramammary Paget’s disease at the time of diagnosis were excluded. Seventy patients were included in the final analysis (Fig. 1). Thirty-four of these patients were staged using MRI, while 35 had an EUS and 1 had unreported imaging modality. The median distance from the anal verge was 0 cm (IQR: 0, 1.55). The anal tumor involved the anal sphincter complex in 39 patients, while 9 (patients did not have sphincter involvement and 22 patients had unreported sphincter invasion.

Figure 1.

Exclusion criteria and treatment groups.

Fifty-four patients (77%) who received neoadjuvant therapy were isolated and divided into two groups according to their treatment strategy: TNT (n = 30, 43%) and chemotherapy or CRT alone (single neoadjuvant modality [SNM] therapy, n = 24, 34%). Sixteen patients (23%) underwent upfront surgery. The distribution of clinical stages among the three cohorts was imbalanced (p = 0.010), namely, a majority of patients (n = 11) who underwent upfront surgery had clinical stage I disease (69% vs. 20% and 29% in the TNT and SNM group). Conversely, both groups that received neoadjuvant therapy had a greater proportion of patients with stage III disease than the upfront surgery group (Table 1). For this reason, patients in the upfront surgery group were analyzed and described separately from those who had neoadjuvant therapy.

Table 1:

Patient demographics and baseline tumor characteristics

Baseline Characteristics	TNT		SNM		Upfront surgery		p-value
N total	30	%	24	%	16	%
Baseline characteristics
Age, Median/IQR	63	53–71	66	48–75	62	53–80	0.78
Gender							0.41
Male	15	50.0	16	66.7	8	50
Female	15	50.0	8	33.3	8	50
Race/Ethnicity							0.57
White	26	86.7	17	70.8	12	75.0
Hispanic or Latino	3	10.0	2	8.3	1	6.3
Black or African American	1	3.3	4	16.7	2	12.5
Race other or ethnicity not reported	0	0.0	1	4.2	1	6.3
History of:
IBD	4	13.3	6	25.0	0	0.0	0.085
RT for Prostate Cancer	0	0.0	1	4.2	1	6.3	0.45
RT for Cervical Cancer	0	0.0	1	4.2	0	0.0	0.37
HIV	1	3.3	0	0.0	2	12.5	0.15
CRC	1	3.3	0	0.0	0	0.0	0.51
Diagnosis
Positive Baseline Inguinal Nodes	8	26.7	6	25.0	1	6.3	0.24
Clinical Stage							0.01
Stage I	6	20.0	7	29.2	11	68.8
Stage II	5	16.7	7	29.2	3	18.8
Stage III	17	56.7	10	41.7	1	6.3
Indeterminate	2	6.7	0	0.0	1	6.3
Differentiation							0.38
1-Well differentiated	1	3.3	3	12.5	0.0	0.0
2-Moderately differentiated	22	73.3	14	58.3	13	81.3
3-Poorly differentiated	7	23.3	6	25.0	2	12.5
Not reported	0	0.0	1	4.2	1	6.3
LVI							0.0015
Positive	6	20.0	2	8.3	8	50.0
Negative	10	33.3	15	62.5	8	50.0
Not reported	14	46.7	7	29.2	0	0.0
Signet ring morphology	0	0.0	5	20.8	0	0.0	0.0057
Mucinous histology	7	23.3	12	50.0	6	37.5	0.12
MMR							0.80
Proficient	12	40.0	8	33.3	5	31.3
Not reported	18	60.0	16	66.7	11	68.8

TNT= Total Neoadjuvant Therapy; W&W= watch and wait; SNM= Single Neoadjuvant Modality; IQR= interquartile range; IBD= inflammatory bowel disease; CRC= colorectal cancer; RT=radiation therapy; LVI= lymphovascular invasion; MMR= mismatch repair

In the TNT group, 21 (70%) patients received induction chemotherapy followed by CRT, and 9 (30%) had CRT followed by consolidative chemotherapy. Most of the patients in the SNM group received neoadjuvant CRT alone (n = 21, 88%) rather than chemotherapy alone (n = 3, 13%). Those who received chemotherapy alone were either not candidates for CRT due to previous pelvic RT or refused CRT.

Ten patients had a history of inflammatory bowel disease (IBD), including 7 patients who had fistula-associated AAC due to Crohn’s disease, and underwent neoadjuvant therapy. Half of these patients presented with clinical stage III disease, followed by 3 patients with stage II and 2 patients with stage I disease. Four patients had TNT and none of them were offered W&W. Two patients underwent TNT followed by pelvic exenteration. Six patients received neoadjuvant CRT (n = 5) or chemotherapy (n = 1) alone followed by surgery. Five patients received adjuvant chemotherapy as well.

None of the patients with an available mismatch repair (MMR) status were MMR deficient (MSI-high). Intact MMR status (MSI-low) was identified in 12 (40%) TNT patients, and 8 (33%) SNM patients. More patients in the SNM cohort expressed signet ring morphology in their tumors than the other two groups, but mucinous histology was similarly observed in all three groups. An apparent difference in lymphovascular invasion (LVI) existed among the three cohorts (p = 0.002), with the upfront surgery cohort having a greater proportion of patients with LVI positivity than the SNM cohort. Further details about the baseline disease characteristics are provided in Table 1.

Treatment Outcomes

The median length of follow-up was 58.1 months (IQR: 35.9 – 89.2 months) from the time of diagnosis. Eighteen (60%) patients in the TNT group achieved cCR and were able to enter W&W (Fig. 1). Four (22%) patients who continued to W&W after receiving TNT, had completion APR for tumor regrowth. Within the TNT group, 1 (3%) patient underwent multiple LEs, and 11 (37%) underwent APR (Table 2). Two patients with clinical stage III disease attained pCR. Seven (23%) of the patients that underwent TNT and surgery, received adjuvant chemotherapy for reasons including R1 resection, incomplete neoadjuvant treatment or extensive disease at the time of surgery (usually prior to 2010).

Table 2:

Most definitive treatment outcomes

Treatment Outcome	TNT		SNM		p-value
N Total
	30	%	24	%
Initial surgery					0.0088
LE	1	3.3	2	8.3
APR	9	30.0	17	70.8
Pelvic exenteration	2	6.7	0	0.0
Salvage surgery					0.51
LE	1	3.3	1	4.2
APR	4	13.3	1	4.2
Final Pathologic Stage					0.22
pCR	2	6.7	4	16.7
is	1	3.3	0	0.0
I	5	16.7	5	20.8
II	4	13.3	5	20.8
III	4	13.3	5	20.8
IV	0	0.0	1	4.2
Indeterminate or W&W	14	46.7	4	16.7
Tumor Regression Grade					0.18
<10% tumor remaining	5	16.7	8	33.3
10–50% tumor remaining	5	16.7	4	16.7
>50% tumor remaining	3	10.0	5	20.8
W&W	14	46.7	4	16.7
Not reported	3	10.0	3	12.5
Oncologic Events (Total)	13	43.3	14	58.3	0.41
Local regrowth	4	13.3	1	4.2	0.50
Locoregional recurrence	5	16.7	5	20.8	0.70
Distant metastasis	6	20.0	11	45.8	0.083
Progression of disease	0	0.0	1	4.2	0.91

TNT= total neoadjuvant therapy; W&W= watch and wait; SNM= Single neoadjuvant modality; LE= local excision; APR= abdominal perineal resection; pCR= pathologic complete response

The SNM group included 5 patients that achieved cCR after CRT (n = 4) or chemotherapy (n = 1) alone and continued to W&W. One (20%) of these patients had tumor regrowth and underwent LE. Nineteen patients in the SNM cohort underwent either LE (n = 2, 11%) or APR (n = 17, 89%). Four patients (17%) presented with clinical stage I (n = 2) or stage II (n = 2) tumors had APRs with pCR on final pathology. One LE patient further developed local recurrence and required a completion APR. Fourteen (58%) patients continued to receive adjuvant CRT (n = 1) or chemotherapy (n = 13).

When evaluating the total number of patients who were managed by W&W (n = 23, 33%) in the 70-patient cohort, 19 of them avoided an APR, yielding an organ preservation rate of 83%. Furthermore, the local regrowth and local failure rates in all the patients that ultimately proceeded to W&W were 22% (n = 5) and 13% (n = 3), respectively.

The 10 patients with a history of IBD did not achieve cCR and underwent either a LE (n = 1) or APR (n = 9). On final pathology, 3 patients obtained a pCR, 1 of whom received TNT. Of note, half of the IBD patients were treated prior to the era of W&W, therefore the time between neoadjuvant therapy and restaging was shortened and they proceeded to surgery. Half (n = 5) of the IBD patients developed a local (n = 3) or distant (n = 3) recurrence.

Oncologic Outcomes

Compared to the SNM cohort, patients who underwent TNT were more likely to be managed by W&W (p = 0.009). The patients who received TNT had a higher rate of organ preservation (n = 15, 50%) than those who underwent SNM (n = 6, 25%), although the difference was not statistically significant (p = 0.11). The local failure rates in the TNT and SNM cohort were similar, at 17% (n = 5) and 29% (n = 7), respectively.

The 5-year survival rate for the overall population was 71% (95% CI: 60%, 83%), including 61% (95% CI: 42%, 88%) for TNT patients and 65% (95% CI: 48%, 88%) for SNM patients (Fig. 2). The TNT group showed no significant difference in overall and recurrence-free survival when compared to the SNM group (Fig. 3). The patients who underwent TNT had a 5-year recurrence-free survival of 55% (95% CI: 39%, 79%) compared to 30% (95% CI: 15%, 58%) in the SNM patients. There was no significant difference in time to recurrence (p = 0.200). Distant metastasis occurred in 20% (n = 6) of TNT patients, and 49% (n = 11) of SNM patients, while distant-metastasis-free survival at 5 years was 51% (95% CI: 33%, 79%), and 40% (95% CI: 24%, 68%), respectively (Fig. 4). The total sample of patients who entered W&W (n = 23), had a 5-year recurrence-free survival of 52% (95% CI: 32%, 84%) and a 5-year distant metastasis-free survival of 71% (95% CI: 54%, 94%).

Figure 2.

Overall survival of patients who underwent total neoadjuvant therapy (TNT) versus single neoadjuvant modality therapy.

Figure 3.

Recurrence-free survival in patients who received total neoadjuvant therapy (TNT) versus single neoadjuvant modality therapy.

Figure 4.

Distant recurrence-free survival of patients who received TNT versus single neoadjuvant modality therapy.

Upfront Surgery Patients

A subset of 16 (23%) patients within the total cohort underwent surgery prior to receiving chemotherapy or radiation. Three (19%) patients initially had APRs, while 13 (81%) had LEs, 6 of whom required completion APR. Five (31%) patients had local recurrences and 2 (13%) developed distant metastases. The 5-year recurrence-free survival was 56% (95% CI: 37%, 87%) while distant metastasis-free survival was 83% (95% CI: 65%, 100%). The overall survival for the upfront surgery patients was 88% (95% CI: 73%,100%) at 5 years.

DISCUSSION

In this retrospective series, almost a third of patients with anal adenocarcinoma treated with neoadjuvant therapy achieved a clinical complete response. The proportion of clinical complete response was higher after receiving TNT (60%), compared to single-neoadjuvant modality therapy (20%). All patients with IBD-associated anal adenocarcinoma required surgery. Tumor regrowth in patients who achieved a clinical complete response was 22%, comparable to historical figures for rectal adenocarcinoma.

Anal adenocarcinoma is rare and experience from previous series is limited. While practice-pattern heterogeneity exists as the treatment of anal adenocarcinoma evolves, most data support an aggressive treatment approach including trimodal therapy.¹ Nonoperative management is well established for rectal adenocarcinoma, and by extrapolation, the same treatment goal is often implemented at our institution for patients with AAC who have a cCR after TNT. This study examined the oncologic outcomes of a cohort of patients with AAC that received different treatment modalities, including nonoperative management, over a 15-year period. The results of this study suggest that TNT and nonoperative management, like in rectal cancer, can be considered in AAC patients, with acceptable regrowth rates, organ preservation rates, overall and recurrence-free survival.

Most patients in this study were treated with neoadjuvant therapy. The proportion of patients that were able to continue to W&W was significantly higher after receiving TNT compared to CRT or chemotherapy alone. Patients treated with the contemporary TNT protocol who achieved cCR and were managed with W&W, yielded a regrowth rate (22%) consistent with the tumor regrowth rate of 27– 40% in rectal cancer patients that were treated nonoperatively in the OPRA Trial.⁹ Differences in 5-year overall and recurrence-free survival rates between the TNT or SNM approaches, were not statistically significant however, an APR was avoided in 50% of patients that received TNT and 83% of the total number of patients who continued to W&W. While earlier studies described local failure rates approaching 50% in patients with AAC who received multimodal therapy, including CRT and either APR or LE,^3,5,17–20 our cohort rendered a lower rate of local failure. These results may suggest the oncological safety of the W&W protocol in patients with AAC.

Surgery has been considered imperative in the management of AAC, leading to an improvement in median survival from 42 – 45 months to 79 – 87 months, as published by 2 National Cancer Database studies in 2019.^11,21 However, information pertaining to the intent of treatment, salvage therapy outcomes, or specific treatment regimens in these studies was lacking. The disease-free survival reported in recent studies varied from 21 to 58% according to the treatment modality.² Moreover, Lukovic et al. previously reported a 5-year cumulative incidence of distant metastasis reaching 30% in patients treated with multimodal treatment.¹² While metastasis is common in this subtype of anal cancer, our results included acceptable 5-year distant metastasis-free and recurrence-free survival among the TNT cohort and patients who entered W&W.

Examples of nonoperative management of patients with IBD associated AAC are almost nonexistent. In the current study, half of the patients with IBD associated AAC were treated in the era of TNT. However, none of whom were offered to be included in the W&W approach. Nonetheless, one third of the patients achieved pCR. In a recent, retrospective, single-center analysis of anal fistula associated adenocarcinoma all patients received an APR in combination with CRT. The results of this study demonstrated poor clinical outcomes.²² The oncological safety of non-operative management in this rare subgroup of patients remains unanswered.

Although promising, it is important to emphasize that no series, including the present, has an adequate sample size to make definitive recommendations regarding the ideal treatment strategy. The retrospective nature of this study creates a space for selection bias and heterogeneity of the treatment approaches. Selection factors, physician preferences, and patients treated over long time intervals further limit the analysis. Both the long time period of the present study and the multidisciplinary approach to each patient resulted in numerous different treating physicians. This resulted in a heterogeneous management approach to this cohort of patients, which further limits possible conclusions regarding treatment approaches. Moreover, the definition of anal cancer remains a controversial topic. Some experts will argue that anal adenocarcinoma is simply a misclassified distal rectal adenocarcinoma. Although our institution uses the rectal cancer staging system for anal adenocarcinoma, others may have used the anal carcinoma staging system. Still, this study clarifies the existing confusion regarding the staging and treatment of anal adenocarcinoma and specifies that the evolving treatments for rectal cancer are safe in this patient population.

As advancements in genetic and molecular profiling techniques ensue, further research into these biologic differences should be performed. When it comes to the management of a single patient, multidisciplinary treatment planning by a team that includes a surgeon, medical oncologist, and radiation oncologist as well as a frank and open discussion with the patient regarding treatment outcomes should be performed to optimize patient-centered care.

These findings were originally presented at the annual meeting of the American Society of Colon and Rectal Surgeons.²³

CONCLUSIONS

The optimal treatment strategy for anal adenocarcinoma is evolving. This is the first report to describe the safety and feasibility of W&W in AAC patients who achieved a clinical complete response after neoadjuvant treatment. Our results suggest that for locally advanced anal adenocarcinoma, TNT with attempt at W&W can be considered in patients who achieve a clinical complete response, with acceptable oncological outcomes.