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Radiation Oncology Factoids > Anal > Flashcards

Anal Flashcards

1
Q

What is the incidence of anal cancer in the United States?

A

∼7,000 cases/yr in the United States.

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2
Q

Is there a sex predilection for anal cancer?

A

Yes. Anal cancer is more common in females than males (2:1).

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3
Q

What are some risk factors for anal cancer?

A

Hx of STDs/anal warts; multiple sexual partners (>10); anal-receptive intercourse; immunodeficiency (HIV, solid organ transplantation); smoking; Hx of Cx, vulvar, or vaginal cancer (HPV related malignancies).

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4
Q

Is anal cancer an AIDS-defining illness?

A

No. However, the demographically adjusted rate ratio for HIV-infected men and women relative to uninfected cohorts is 80 and 30, respectively. Cx cancer is an AIDS-defining illness.

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5
Q

What is the predominant histology of anal cancer?

A

SCC (75%–80%) is the predominant histology.

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6
Q

What virus strains are strongly associated (assoc) with anal cancer?

A

HPV strains 16, 18, 31, 33, and 35 are strongly assoc with anal cancer. Anal cancers are assoc. with HPV infection in 75%–90% of cases, with HPV16 the most common subtype.

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7
Q

How long is the anal canal, and where does it extend?

A

The anal canal is 4-cm long, extending distally from the anal verge (palpable junction b/t the internal sphincter and SQ part of the external sphincter, aka the intersphincteric groove) to the anorectal ring (where the rectum enters the puborectalis sling) proximally.

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8
Q

What is the histopathologic significance of the dentate line (aka pectinate line)?

A

The dentate line is the anatomic site where mucosa changes from nonkeratinized squamous epithelium distally to colorectal-type columnar mucosa proximally (dividing the upper from the lower anal canal).

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9
Q

Describe the anatomic location of the anal verge.

A

The anal verge is located at the junction of nonkeratinized squamous epithelium of the anal canal and keratinized squamous epithelium (true epidermis) of perianal skin

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10
Q

Which site carries a better prognosis: the anal margin or anal canal?

A

The anal margin carries a better prognosis.

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11
Q

Which pathology carries a higher risk for LR and distant recurrence in anal cancer?

A

Adenocarcinoma carries a higher risk.

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12
Q

What is the significance of the dentate line in terms of LN drainage?

A

Above dentate line: drains to pudendal/hypogastric /obturator/hemorrhoidal → internal iliac nodes
Below dentate line: drains to inguinal/femoral nodes → external iliacs

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13
Q

What % of anal cancer pts present with +LNs?

A

25%–35% of these pts present with +LNs

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14
Q

What are the 2 most common sites of DM?

A

Liver and lung

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15
Q

What is the occult positivity rate for inguinal nodes (i.e., if clinically–) in anal cancer?

A

For inguinal nodes, the occult positivity rate is 10%–15%.

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16
Q

What is the rate of extrapelvic visceral mets at presentation for anal cancer?

A

Extrapelvic visceral mets are present in 5%–10% of pts.

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17
Q

In anal cancer, what % of clinically palpable LNs are actually involved by cancer?

A

50% of clinically palpable LNs involve cancer, while the other 50% are usually reactive hyperplasia.

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18
Q

In anal cancers, what are the most important prognostic factors for LC and survival?

A

Tumor size and DOI predict for LC. The extent of inguinal or pelvic LN involvement predicts for survival

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19
Q

What are 4 common presenting Sx in anal cancer?

A

Bleeding, pain/sensation of mass, rectal urgency, and pruritus

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20
Q

What does the workup for anal cancer pts include?

A

Anal cancer workup: H&P (including gyn exam for women with Cx cancer screening), labs (HIV if risk factors), imaging, Bx of lesion, and FNA of suspicious LN

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21
Q

What imaging studies are typically done for anal cancer pts?

A

Chest/abdominal CT + pelvic CT or MRI with IV contrast. Consider PET/CT in same position as simulation for staging & planning guidance. (NCCN Guidelines 2018)

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22
Q

Is PET/CT more or less sensitive than diagnostic CT alone for detecting locoregional and met Dz?

A

Mistrangelo M et al. (IJROBP 2012) found PET/CT to be sup to CT in detecting the primary tumor (89% vs. 75%); Bhuva NJ et al. also found PET/CT diagnosed occult metastatic Dz following CT imaging in 5% of pts
and changed staging in 42% of pts, with the majority being upstaged. (Ann Oncol 2012)

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23
Q

What features of anal lesions need to be appreciated on physical exam? Why?

A

The degree of circumferential involvement and anal sphincter tone should be appreciated, b/c these may dictate Tx.

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24
Q

What is the approach to suspicious inguinal LNs in anal cancer pts?

A

FNA Bx should be considered for suspicious inguinal LNs.

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25
Q

On what is the T staging for anal cancer based? Define T1–T4.

A

T staging as per AJCC 8th edition for anal cancer is based on tumor size & invasion of adjacent organs.

TX: Primary tumor not assessed
T0: No evidence of primary tumor
Tis: High-grade squamous intraepithelial lesion
T1: ≤2 cm
T2: >2 but ≤5 cm
T3: >5 cm
T4: Invasion of adjacent organs (vagina, urethra, and bladder)

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26
Q

Does tumor invasion of sphincter muscle by anal cancer constitute a T4 lesion?

A

No. Direct invasion of the rectal wall, perirectal skin, SQ tissue, or sphincter muscle are not classified as T4.

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27
Q

Most pts with anal cancer present with what T stage?

A

Most anal cancer pts present at stage T2 or T3.

28
Q

What is the N staging for mets in inguinal, mesorectal, or internal iliac LNs?

A

Mets to inguinal, mesorectal, or internal iliac LNs is staged as N1a.

29
Q

What is the N staging for mets in external iliac LNs?

A

Mets to external iliac LNs is staged as N1b.

30
Q

What is the N staging for mets in external iliac LNs with concurrent mets in N1a nodes?

A

Mets to external iliac LNs with concurrent mets in N1a nodes is N1c.

31
Q

Is mets to common iliac nodes considered M1 Dz?

A

Yes. Mets to common iliac LNs is considered M1 Dz.

32
Q

What is the AJCC 8th edition (2017) stage grouping for anal cancer?

A 
Stage I: T1N0
Stage IIA: T2N0
Stage IIB: T3N0
Stage IIIA: T1–2N1
Stage IIIB: T4N0
Stage IIIC: T3N1 or T4N1
Stage IV: Any T Any N M1
33
Q

What are the 5-yr OS and DFS rates after surgical resection alone for anal cancer?

A

The 5-yr OS rate after complete surgical resection (APR) is ∼70%, and the DFS rate is ∼40%. (Mayo review of 118 pts: Boman BM et al., Cancer 1984)

34
Q

What % of pts who relapse develop local recurrent Dz as part of the total failure pattern?

A

∼80% develop local recurrent Dz. (Boman BM et al., Cancer 1984. Note: This was also a surgical series.)

35
Q

What are the OS and sphincter preservation rates for all-comers with anal cancer at 8 yrs after definitive CRT?

A

OS is ∼70% (RTOG 9811 & 0529) and sphincter preservation rate is ∼65% after CRT alone.

36
Q

What are the criteria for local excision alone in anal cancer? What are the LC rates in such carefully selected pts?

A

Small T1 lesion (<2 cm), well differentiated, –margins, <40% circumferential involvement, no sphincter involvement, compliant pts. For these well selected
pts, there is >90% LC. (Boman BM et al., Cancer 1984)

37
Q

Can radiotherapy alone be employed for early-stage anal cancer?

A

Yes. However, it can be employed only for T1N0 lesions. There were excellent LC rates of 100% and CR rates of 96% in 1 series. (Deniaud Alexandre E et al., IJROBP 2003)

38
Q

What was the standard surgical procedure for anal cancer before the advent of CRT? What was the disadvantage of this approach?

A

APR was the standard surgical procedure, but the disadvantage is that it requires permanent colostomy.

39
Q

Currently, when should Sg alone be considered sufficient for management of anal cancer?

A

Sg is sufficient with anal margin cancers in which the sphincter can be spared.

40
Q

Historically, what has been the sphincter preservation approach for the Tx of anal cancers?

A

Radiotherapy alone was employed in Europe since the early 1900s, whereas surgical resection was standard in the United States. Radiotherapy alone produced similar survival and control rates as Sg but allowed sphincter preservation. These results were better for less advanced tumors. Papillon J and Montbarbon JF (Dis Colon Rectum 1987) reported (in the largest series
of 159 pts with the use of EBRT and interstitial brachytherapy [30–42 Gy EBRT → implant 15–20 Gy]) a 5-yr OS of 65% and a sphincter preservation rate of 70%–82% (>4-cm tumor vs. ≤4-cm tumor).

41
Q

What 2 seminal studies from the 1970s and 1980s in the United States demonstrated that surgical resection may not be needed after CRT, even after a short course of Tx?

A

The Wayne State experience (Nigro ND et al., Dis Colon Rectum 1974, 1983): preop regimen of 30 Gy/15 fx with continuous infusion 5-FU (1,000 mg/m2 × 4 days) and mitomycin-C (MMC) (single 15 mg/m2 bolus), with APR scheduled 6 wks after the regimen. 31 pts had completion Sg vs. 73 had definitive CRT alone. 71% pts had pCR in the surgical specimen. In the Sg
arm, the f/u NED rate was 79%. In the definitive CRT arm, the f/u NED rate was 82%.

Princess Margaret Hospital (Cummings BM et al., IJROBP 1991): prospective nonrandomized studies comparing RT alone, 5-FU + RT, or 5-FU/MMC + RT. OS was 70% in all groups, with LC best in the 5-FU/MMC arm of 93% c/w 60% in the RT-alone arm.

42
Q

What was the chemo regimen and RT dose delivered in the original anal cancer studies by Nigro ND et al.?

A

In Nigro ND et al., the regimen was 5-FU (1,000 mg/m2 × 4 days)/MMC (15 mg/m2 bolus) with an RT dose of 30 Gy (2 Gy per fx). (Dis Colon Rectum 1974, 1983)

43
Q

Anal margin tumors are treated like what other cancer?

A

Anal margin tumors are treated in the same manner as skin cancer.

44
Q

What is the current Tx paradigm for anal canal cancer?

A

Anal cancer Tx paradigm: definitive CRT

45
Q

What chemo doses are used in anal cancer, and what is the scheduling?

A

Anal cancer doses/scheduling: 5-FU 1,000 mg/m2/day intravenously on days 1–4 and 29–32; MMC 10 mg/m2 IV bolus on days 1 and 29 or 12 mg/m2 IV bolus on day 1 only

46
Q

What is the main radiobiologic advantage of MMC?

A

MMC is a hypoxic cell radiosensitizer

47
Q

For which pts is APR currently reserved?

A

APR is reserved as salvage for pts who recur post CRT or those who have had prior pelvic RT.

48
Q

Are there data directly comparing Sg with CRT in anal cancer?

A

No. There is no randomized evidence. However, 1 retrospective analysis from Sweden showed better 5-yr OS in pts who rcvd RT ± chemo, supporting
CRT as a better initial Tx option. (Goldman S et al., Int J Colorectal Dis 1989)

49
Q

What 2 major European randomized studies in anal cancer demonstrated the inferiority of definitive RT compared to combined CRT?

A

UKCCCR (ACT I) (Lancet 1996): 585 pts, any stage, randomized to RT vs. RT + 5-FU/MMC. RT was 45 Gy to the pelvis → 15–25 Gy with ≥50% response. If there was <50% response, then Sg was performed. Response was measured 6 wks after completion of induction therapy. The CR rate trended better in CRT (39% vs. 30%, p = 0.08), with 3-yr LC of 64% vs. 41% (p < 0.0001). The risk of death from anal cancer was also reduced in the CRT arm (HR 0.71, p = 0.02), but there was a nonsignificant benefit of 3-yr OS of 65% vs. 58% (p = 0.25).

13-yr update (Northover J et al., Br J Cancer 2010): The absolute risk of LRR was reduced by 25% and remained stable after 5 yrs. The risk of death was reduced by 12%, and absolute reduction in the colostomy rates remained at 10%, favoring CRT (all SS).

EORTC (Bartelink H et al., JCO 1997): 577 pts, T3–4 or N+, RT vs. RT + 5-FU/MMC. Boost was given based on the response assessed at 6 wks: 20 Gy to CR and 15 Gy to PR. The CR rate was measured after completion of
the entire course of therapy. The CR rate was sup in the CRT arm (80% vs. 54%, p = 0.02), as well as 3-yr LC (69% vs. 55%, p = 0.02), but not 3-yr OS (69% vs. 64%).

50
Q

What is 1 explanation why the United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) study had substantially inf rates of CR and LC c/w the EORTC study in anal cancer?

A

The CR rate was measured 6 wks after induction therapy in the UKCCCR, whereas it was measured 6 wks after completion of all therapy in the EORTC
study (which had a longer course of Tx b/c boost was not delivered until after 6 wks of initial therapy). The definition of LC is different b/t the 2 studies. In the UKCCCR study, the definition was more strict, with failure defined as <50% tumor reduction after just 6 wks of 45 Gy to the pelvis.

51
Q

Can MMC be removed from the standard regimen of 5-FU/MMC for the Tx of anal cancer? What major study addressed this question?

A

No. MMC cannot be deleted from the standard regimen. RTOG 87-04 (Flam M et al., JCO 1996): 291 pts, MMC/5-FU + RT vs. 5-FU + RT. RT was 45–50.4 Gy. The difference in OS was not SS (76% vs. 67%, p = 0.31), but MMC improved the DFS rate (73% vs. 51%, p = 0.0003) and 4-yr colostomy free survival (CFS) rate (71% vs. 59%, p = 0.014). Grade 4 or 5 heme toxicity was worse (26% vs. 7%).

52
Q

Can cisplatin (CIS) be substituted for MMC in the Tx of anal cancer? What 2 major studies addressed this question?

A

2 RCTs suggest that substituting CIS for MMC does not improve and possibly worsens outcomes:

RTOG 98-11 (Gunderson LL et al., JCO 2012): 649 pts, all stages except T1 or M1; excluded AIDS or prior cancers; randomized to standard MMCbased therapy vs. 2 cycles of CIS/5-FU → CIS/5-FU × 2 with RT. RT was
45 Gy to the pelvis, with boost for T2 residual to 10–14 Gy. DFS and OS were significantly sup in MMC-arm. 5-yr DFS: 67.8% vs. 57.8%, p = 0.006; 5-yr OS: 78.3% vs. 70.7%, p = 0.026. There was a trend toward statistical superiority of MMC arm for CFS, LRF, and colostomy failure. Acute grade 3–4 severe heme toxicity was significantly worse in the MMC arm (61.8% vs. 42.0%, p < 0.001) but not in long-term toxicities (13.1% vs. 10.7%). Major criticism: Neoadj chemo on the experimental arm may have confounded the results.

ACTII (James R et al., Lancet Oncol 2013): 2 × 2 design, 940 pts (T1–2 (50%), T3–4 (43%), 30% N+, 85% anal canal, 15% anal margin) treated with 5-FU (1,000 mg/m2/day, days 1–4, days 29–32) and RT (50.4 Gy) and randomized to concurrent MMC (12 mg/m2, day 1) or CIS) (60 mg/m2, days 1 and 29). 2nd randomization involved adding maintenance therapy (4 wks after CRT) to 2 cycles 5-FU/CIS or no maintenance. Median f/u was 5.1 yrs. Results: No. difference in CR rate at 26 wks (90.5% MMC vs. 89.6% CIS). Hematologic grade 3–4 side effects occurred in 26% MMC vs. 16% CIS. 3-yr PFS, OS, and CFS did not differ significantly b/t groups. The authors concluded that 5-FU/MMC/RT without maintenance chemo remains the standard of care.

53
Q

What is the role of brachytherapy in anal cancer?

A

Brachytherapy is generally not done in the United States d/t poor LC (<30% for large lesions) and higher complication rates. An older French experience
showed favorable results with combined interstitial (Ir-192) and EBRT. (Papillon J & Montbarbon JF, Dis Colon Rectum 1987)

54
Q

Is there a role for dose escalation in anal cancer?

A

No. A phase III trial from France randomized pts with tumors ≥4 cm, or <4 cm and N1–3M0 to 1 of 4 Tx arms (2 × 2 factorial design). The 1st randomization was plus or minus induction chemo (2 cycles 5-FU and CIS).
All pts then rcvd 45 Gy with 5-FU and CIS. 3 wks after completion of CRT, pts were then randomized to 1 of 2 boost doses: the standard-boost dose (15 Gy) or the high-boost dose (20 Gy for complete responders and 25 Gy for partial responders). The endpoint was CFS. There was no difference in CFS at 5 yrs. (Peiffert D et al., JCO 2012)

55
Q

What is the recurrence rate after definitive CRT for anal cancer, and what are the salvage rates at 5 yrs?

A

The recurrence rate is stage dependent (Gunderson LL et al., IJROBP 2013) but overall is ∼30%, and the salvage rate at 5 yrs following LR is ∼40%–50%.

56
Q

Per RTOG 98-11, which anal cancer pts need to rcv a boost beyond 45 Gy?

A

Pts with T3, T4, or N+ lesions or T2 lesions with residual Dz after 45 Gy needed a boost >45 Gy

57
Q

What is the dose per fx for anal cancer per RTOG 98-11?

A

Per RTOG 98-11, the dose per fx for anal cancer is 1.8 Gy/fx to 45 Gy initially, then 2 Gy/fx to 55–59 Gy total for the CD portion

58
Q

How far caudally should inguinal nodes be covered in anal cancer?

A

Inguinal nodes should be covered to the inf border of the lesser trochanter.

59
Q

What is the standard CRT regimen for anal cancer pts who are HIV+?

A

HIV+ pts can typically be treated with the same RT + 5-FU/MMC regimen as HIV– pts. HIV+ pts with CD4 counts <200/mm3 or other complications of
HIV may require chemo (e.g., CIS instead of MMC or 1 dose of MMC) and/or RT dose adjustments

60
Q

What is the role/evidence for IMRT in anal cancer?

A

RTOG 0529, a phase II single arm study, assessed the utility of 5-FU/MMC and dose-painted IMRT in reducing grade 2+ GI/GU toxicities compared with the conventional arm from RTOG 9811. Of 52 evaluable pts, a significant reduction was noted in acute grade 2+ hematologic (73% vs. 85%, p = 0.03), grade 3+ GI (21% vs. 36%, p = 0.008) and grade 3+ dermatologic adverse events (23% vs. 49%, p < 0.0001). Of note, 81%
required dose-painted IMRT replanning on central review (Kachnic LA et al., IJROBP 2013). Cancer control outcomes appear similar vs. RTOG 9811, with 8-yr OS, DFS, and CFS of 68% vs. 69%, 62% vs. 57%, and 66% vs. 63%, respectively (Kachnic LA et al. ASTRO 2017. Abstract only). In addition, numerous retrospective studies suggest decreased toxicity and comparable efficacy. (Milano MT et al., IJROBP 2000; Menkarios C et al., Radiat Oncol 2007) (Anorectal contouring atlases: Myerson RJ et al., IJROBP 2009; Ng M et al., IJROBP 2012; Muirhead R et al., Clin Oncol 2014)

61
Q

When treating with IMRT, how might you simulate a pt in order to minimize toxicity?

A

To minimize skin toxicity in the groin, simulate supine in the frog leg position. In larger pts, however, consider treating prone on a belly board to decrease bowel dose (smaller pts do not benefit as much) (Olsen J et al., IJROBP 2017), as this appears well tolerated with respect to dermatitis d/t IMRT decreasing skin dose & toxicity vs. 3D-CRT

62
Q

What RT dose guidelines exist for small bowel in anal cancer pts?

A

Findings from RTOG 0529 showed: small bowel volumes of 186.0 cc, 155.0 cc, 41.0 cc, and 30.4 cc receiving more than 25, 30, 35, and 40 Gy,
respectively, correlated with increased risk of acute grade ≥2 GI adverse events. (Olsen J et al., IJROBP 2017)

63
Q

What is the main toxicity of MMC?

A

MMC has acute hematologic toxicities but does not contribute to late toxicities.

64
Q

Most anal cancer recurrences are within what timeframe?

A

Most anal cancers recur within 2 yrs.

65
Q

According to the NCCN guidelines (2018), what is the post-Tx f/u for anal cancer?

A

Post-Tx anal cancer f/u: Evaluate in 8–12 wks after Tx with DRE. Bx only if there is progressive Dz. If there is complete remission, perform exam with inguinal nodal evaluation & DRE q3–6 mos for 5 yrs, and anoscopy q6–12 mo × 3 yrs. Consider C/A/P CT with contrast annually × 3 yrs (e.g., if T3–4 or N+).

66
Q

What is the mean time to tumor regression after CRT?

A

The mean time to tumor regression after CRT is 3 mos (but can be up to 12 mos); therefore, there is no benefit to routine post-Tx Bx. (Cummings BJ et al., IJROBP 1991)

67
Q

If a pt has Bx-proven persistent Dz 3 mos after completing Tx, should the pt be referred immediately for salvage Sg?

A

No. Pts may be re-evaluated again after 4 wks. If there is still no regression, or if there is progression, consider Bx again and restage if necessary. If there
is evidence of regression, continue observation and evaluation in 3 mos.

Radiation Oncology Factoids (44 decks)

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