A Case for More Intensive Systemic Therapy for Patients With Locally Advanced Rectal Cancer: Even in the Face of a Pathologic Complete Response

CASE REPORT

An otherwise healthy 54-year-old white woman was found to have a 2-cm friable sessile mass at 10–13 cm from the anal verge on a screening colonoscopy (Figure 1), with biopsies confirming high-grade, infiltrative adenocarcinoma (Figure 2). Her only symptoms included 2 years of fatigue, as well as occasional stool incontinence and urgency. She had a family history positive for colon disease; her father had colon cancer treated definitively with surgery alone at the age of 71, and a brother had colon polyps of unknown size.

Figure 1.

Colonoscopy showing 2-cm friable sessile mass at 10–13 cm from the anal verge.

Figure 2.

Biopsy from colonoscopy revealing high-grade infiltrative adenocarcinoma at high-power magnification. Courtesy of Guang-Yu Yang.

Her CEA at diagnosis was normal at 1.2 ng/mL, and her hemoglobin was also normal at 14 g/dL. She underwent computed tomography (CT) evaluation of her chest, abdomen, and pelvis, which revealed thickening of the rectosigmoid colon, some luminal narrowing, and a borderline prominent lymph node approximately 5 cm superior to the rectal mass (Figure 3). An endoscopic ultrasound revealed invasion into the muscularis propria (T2) as well as involved regional lymph nodes (N1) confirmed by fine needle aspiration.

Figure 3.

Computed tomography scan of chest, abdomen, and pelvis obtained prior to neoadjuvant chemoradiotherapy on 19 September 2009. The image reveals the rectal tumor and perirectal lymph nodes (both indicated by arrows) in coronal anteroposterior view.

After discussion with her oncologist, the patient opted for capecitabine with concurrent radiation treatment according to the ongoing Intergroup NSABP protocol R-04, despite not being enrolled in the study. She received capecitabine 825 mg/m² orally twice daily for 5 days per week taken concurrently with radiotherapy, which consisted of 4500 cGy in 25 fractions over 5 weeks with a 540 cGy boost for her nonfixed tumor (three fractions). She tolerated chemoradiotherapy with side effects including fatigue, enteritis, and proctitis, which resolved approximately 1 month after completing treatment.

Repeat CT scans of the chest, abdomen, and pelvis approximately 6 weeks after completion of neoadjuvant chemoradiotherapy revealed rectosigmoid wall thickening but no suspicious regional lymphadenopathy. She underwent a low anterior resection with a loop ileostomy that was eventually reversed 2 months later. Pathology revealed inflammatory tissue but no tumor as well as 12 lymph nodes without evidence of disease (T0N0), consistent with a pathologic complete response.

What is the most appropriate postoperative management for a patient with rectal cancer treated successfully in the neoadjuvant setting with chemoradiotherapy after a pathologic complete response?

DISCUSSION

Achieving a pathologic complete response following neoadjuvant 5-fluorouracil (5-FU) –based chemoradiotherapy has been reported to be in the range of 8–12%.^1,2 This outcome or, more generally, pathologic tumor downstaging seems to be an important predictor for outcome in locally advanced rectal cancer patients. In an M. D. Anderson Cancer Center report on 470 patients, the majority having T3N1–2 adenocarcinoma of the rectum, locoregional failure, metastatic disease, and overall survival were significantly predicted by the pathologic tumor T and N stages after neoadjuvant chemoradiotherapy, according to Cox proportional hazards analysis.³

Does this mean that patients with pathological tumor downstaging after neoadjuvant chemoradiotherapy have lower rates of recurrence and improved overall survival (OS) and therefore could be spared more intensive adjuvant approaches? Another study published out of M. D. Anderson retrospectively evaluated their experience with 117 patients, the majority having clinical T3N0–1 locally advanced rectal adenocarcinoma, treated between 1991 and 1995.⁴ Of 117 patients, 63% received adjuvant chemotherapy with a 5-FU–based regimen. Pathologic tumor downstaging was common, with a rate of 62%. At 46 months, they found that adjuvant chemotherapy improved disease-free survival (DFS) from 74% to 87% (P = .03) in patients who experienced pathologic tumor downstaging when compared with those who did not. Of the 74 patients who received adjuvant chemotherapy, approximately half experienced pathologic tumor downstaging and about half did not, though they were not matched for baseline characteristics.

In addition, a retrospective Canadian study in locally advanced clinical T3–4 rectal cancer patients also reported that responders to neoadjuvant chemoradiotherapy derived significant improvement in 5-year cause-specific survival and disease-free survival from 70% to 92% (P = .02) and 65% to 81% (P = .038), respectively, compared with nonresponders with adjuvant chemotherapy.⁵ Of note, though nonresponders did not have significant differences in 5-year cause-specific survival or disease-free survival based on adjuvant chemotherapy, there was a nonsignificant trend toward improvement in these outcomes with adjuvant chemotherapy.

This makes sense if we assume that neoadjuvant chemoradiotherapy is a type of stress test to check the biology of the tumor and its sensitivity to antineoplastic therapy. It would then stand to reason that patients experiencing pathologic tumor downstaging after neoadjuvant chemoradiotherapy are exactly the subgroup who could benefit most from adjuvant chemotherapy. The only large prospective data currently available, EORTC 22,921, revealed a trend toward improved DFS and OS benefit (P = .15 and .12, respectively) for adjuvant chemotherapy following neoadjuvant treatment. This trial randomly assigned 1011 patients with T3–4 resectable rectal cancers in a two-by-two design to receive (1) neoadjuvant radiotherapy, (2) 5-FU–based neoadjuvant chemoradiotherapy, (3) 5-FU–based neoadjuvant chemoradiotherapy followed by 5-FU–based adjuvant chemotherapy, or (4) neoadjuvant chemoradiotherapy followed by adjuvant 5-FU–based adjuvant chemoradiotherapy.⁶

Interestingly, Collette et al performed a subset analysis on patients with M0 disease at the time of curative surgery including 785 of the original 1011 patients. They found that patients achieving pathologic tumor downstaging to T0–2 had improved 5-year DFS when treated with adjuvant chemotherapy (76.7% vs. 65.6%; P = .013). No benefit to adjuvant chemotherapy was found in the patients without pathologic tumor downstaging after neoadjuvant chemoradiation (45.1% vs. 48.9%; P = .224). There was an OS benefit with adjuvant chemotherapy as well in patients who were downstaged, but this was seen only in patients with tumors >5 cm from the anal verge and in those not undergoing an abdominoperitoneal resection.⁷ Table 1 summarizes the outcomes with adjuvant chemotherapy based on the patients' tumor downstaging.⁸

Table 1.

Effect on disease-free and overall survival of adding adjuvant chemotherapy based on downstaging after neoadju vant chemoradiotherapy^*

Study	Patients (N)	Benefit on DFS	Benefit on OS
Collette et al (7)	785	5 year	5 year
		ypT0-2 HR 0.64 (95% CI, 0.45–0.91)	ypT0-2 HR 0.64 (95% CI, 0.42–0.96)
		ypT3-4 HR 1.18 (95% CI, 0.89–1.57)	ypT3-4 HR 1.19 (95% CI, 0.84–1.68)
Janjan et al (4)	117	46 months	Data not available
		Downstaged 87% vs. 74% (P < .03)	—
		Not downstaged 47% vs. 92% (P < .03)	—
Das et al (3)	470	5 year	5 year
		ypT0-2 89%, dependent on CT	ypT0-2 89%, dependent on CT
		ypT3-4 52%–67%, independent of CT	ypT3-4 63%–68%, independent of CT
Chan et al (5)	156	5 year	5 year
		Downstaged 81% vs. 65% (P = .038)	Downstaged 92% vs. 70% (P = .02)
		Not downstaged 55% vs. 37% (P = .07)	Not downstaged 74% vs. 41% (P = .07)

Abbreviations: CI = confidence interval; CT = chemotherapy; DFS = disease-free survival; HR = hazard ratio; OS = overall survival.

^*Adapted with permission from Springer Verlag.

For the case under discussion, an oncologist may have chosen to observe the patient clinically and forego adjuvant chemotherapy because the response to neoadjuvant therapy was so robust, but this approach does not give enough weight to the presenting clinical stage. If we are to improve survival in this disease, it is unlikely to be achieved by sparing people adjuvant chemotherapy following neoadjuvant chemoradiotherapy. Because pathologic tumor downstaging is such an important predictor of improved disease-free and overall survival as well as response to adjuvant chemotherapy in locally advanced rectal cancer, we need to focus on strategies that improve this response.

The addition of oxaliplatin was successful in adjuvant treatment of stage III colon cancer,⁹ and early-phase studies have demonstrated pathologic complete responses as high as 30% in locally advanced rectal cancer with the addition of neoadjuvant oxaliplatin.^10,11 Although a prospective large phase III study comparing capecitabine with capecitabine plus weekly oxaliplatin combined with radiation found more grade 3–4 toxicity but no improvement in pathologic complete responses, there were significant improvements in radial margin positivity and pathologic minimal residual disease.¹² Important clinical outcomes including local and distant disease control are not yet available. NSABP R-04 should provide a more definitive answer to the optimal neoadjuvant chemotherapy regimen in locally advanced rectal cancer because the trial compares capecitabine versus 5-FU, each with or without the addition of oxaliplatin.

Again, because pathologic tumor downstaging and complete responses are signatures of tumor sensitivity and the addition of oxaliplatin to 5-FU appears to improve that rate, we would predict that more aggressive neoadjuvant chemotherapy has the potential to improve disease-free and overall survival. ECOG 3204 and 5204 both include adjuvant chemotherapy and will provide additional information on DFS for patients receiving adjuvant FOLFOX (folinic acid/5-FU/oxaliplatin) with or without bevacizumab for stage II/III rectal cancer.

Adjuvant chemotherapy was discussed with this patient, and she favored being treated. She was concerned about her quality of life while carrying a pump for the 5-fluorouracil infusion. Therefore, she was offered the combination of capecitabine and oxaliplatin. Treatment initiation was delayed because of her ileostomy reversal and then recurrent clostridia difficile colitis, but she began adjuvant therapy at 3 months after surgery and tolerated two cycles well.