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Neoadjuvant Chemotherapy for Disseminated Colorectal Cancer: Changing the Paradigm

Gastrointestinal Research Program, Aptium Oncology, Palm Springs, CA

Theoretical arguments for neoadjuvant systemic therapy before definitive surgery or radiation are well known and frequently articulated. The most compelling of these include treating undetected distant microscopic metastases as early as possible and downstaging tumors to allow for less radical, even organ-sparing, surgery without sacrificing overall survival (OS) or cure. Proofs of efficacy for neoadjuvant therapy include hard end points such as improved OS and increased cure rates. Because determination of cure rates and OS may take years, surrogate end points have been sought. In the clinic, the first measurement of efficacy is usually radiographic response. However, radiographic responses of solid tumors are poor surrogates for prognosis, whereas pathologic response, especially pathologic complete response (pCR), has been far more valuable in determining OS and cure after neoadjuvant therapy.¹

To date, most neoadjuvant solid tumor therapy has concentrated on the response of the primary tumor in relation to long-term outcome for patients with breast, esophageal, head and neck, gastric, and rectal cancers. The impact of systemic neoadjuvant chemotherapy on metastatic disease before surgery has received far less investigative attention. Nevertheless, as more effective systemic therapy in disseminated colorectal cancer² has been married to improved techniques in liver surgery,³ many clinicians and investigators consider neoadjuvant systemic therapy to be appropriate for patients with metastases to the liver.^4,5 The popularity of this practice, in the absence of class I clinical evidence, apparently triggered a recent cautionary note by experts in this field.⁶

In this issue, Benoist et al⁷ report a prospective clinical trial designed to "determine the significance" (their words) of increasingly important surgical and biologic questions after "seemingly effective" (my words) neoadjuvant chemotherapy in colorectal cancer patients with isolated liver metastases. They used radiographic response of specific liver lesions to define which patients were included in this study. Their questions included what percentage of predetermined surgically resectable liver metastases with complete radiographic response (cRR) actually have no cancer in the resected specimen (pCR), were these patients cured, and can a cRR in a surgically inaccessible lesion convert an inoperable patient to one who may be operable for cure if the cRR lesion remains in the liver.⁷

From 1998 to 2004, Benoist et al⁷ prospectively evaluated 586 consecutive patients treated at their institution for liver metastases from colorectal cancer and identified a cohort of 38 patients (6%) with liver-only metastatic colorectal cancer who also had no previous surgical or ablative intervention and fewer than 10 liver metastases. The cRRs for the 38 patients were initially identified using computed tomography scans and external abdominal ultrasonography (US). Patients were prospectively separated into the following two categories: 16 patients with liver lesions potentially curable by R0 liver resection without preoperative or neoadjuvant chemotherapy, and 22 patients whose number and location of the liver lesions precluded consideration of curative operation. For the 22 patients who did not meet their criteria for curative resection, the authors did not resect or remove the lesions designated as cRR after chemotherapy. Instead, at operation, these lesions were left in situ while they resected or ablated other visible lesions.

At the time of surgery, the investigators confirmed cRR in patients with intra-abdominal US (IUS). IUS upstaged 20 (30%) of 66 lesions in nine patients thought to have cRR by external computed tomography and US. After IUS, 15 lesions were still designated cRR in the group who were considered operable for cure before chemotherapy. After resecting these areas of cRR, microscopic examination revealed 12 (80%) with microscopically identifiable or viable cancer cells. Thus, systemic chemotherapy produced a pCR in only three (20%) of 15 cRR lesions. After IUS, 31 lesions were still designated cRR in the group designated inoperable for cure before chemotherapy. These lesions were not resected. At 1 year, 23 patients (73%) developed recurrences at the site of the unresected lesions. Is this disappointing? Certainly. Is it useful information? Certainly.

Although the clinical lessons of this trial presently apply to only a small percentage of colorectal cancer patients with metastatic liver lesions, this qualitative study has much to commend it and leaves much to comment on. With diligence, expertise, and great cooperation among specialists, the investigators who designed and reported this trial achieved their objectives. Moreover, their results should serve to alter practice for those interested in improving cure rates for patients with disseminated colorectal cancer. Can lesions exhibiting a cRR be left in the liver? No. The planned curative resection should not be altered by radiographic responses. Can a cRR in a lesion that cannot be resected because of its anatomic position alter the potential for surgical cure? No. Unfortunately, this is not yet the case. Unless an R0 resection can encompass all lesions, a curative surgical procedure is not a realistic option. A pCR for all visible tumors, and not a cRR for a few, remains the Holy Grail for neoadjuvant treatments.

As more complicated liver resections become safer for patients with disseminated colorectal cancer, a working group must develop internationally acceptable criteria to define patients amenable for curative surgery. Although these criteria will be a moving target, without them, prospective phase III trials cannot be successfully designed and executed. Likewise, criteria for patients who are not surgically resectable for cure must be agreed on. Indeed, the results of Benoist et al⁷ should not be a signal to discontinue efforts at surgery for the group designated unresectable for cure. Instead, it should provide further impetus to design clinical trials for these patients to test new systemic or local agents, new targets, and new surgical techniques.

Currently, neoadjuvant systemic therapy for patients with liver lesions secondary to colorectal cancer cannot be considered standard. There is no proof that such treatment increases cure rates or extends survival over surgery alone. Furthermore, we should be a bit skeptical of the reasoning that suggests that a response to neoadjuvant therapy mandates the continuation of the same therapy after surgery. If several cycles of neoadjuvant systemic chemotherapy eradicate some lesions entirely but leave visible resistant clones, it is unlikely that continuing the same therapy in the postoperative setting will produce a prolonged survival or cure. Here, again, is another hypothesis begging for proof.

Perhaps the most immediately relevant message in this article is the importance of a strong, interactive multidisciplinary team to plan the care and cure for patients with disseminated colorectal cancer. The treatment of disseminated colorectal cancer is no longer the domain of one group. This is the real paradigm shift.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Kaufmann M, Hortobagyi GN, Goldhirsch S: Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: An update. J Clin Oncol 24: 1940-1949, 2006[Abstract/Free Full Text]

2. Goldberg RM: Advances in the treatment of metastatic colorectal cancer. Oncologist 10: 40-48, 2005[Abstract/Free Full Text]

3. Khatri VP, Petrelli NJ, Belghiti J: Extending the frontiers of surgical therapy for hepatic colorectal metastases: Is there a limit? J Clin Oncol 23: 8490-8499, 2005[Abstract/Free Full Text]

4. Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23: 2038-2048, 2005[Abstract/Free Full Text]

5. Pozzo C, Basso A, Cassano M, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15: 933-939, 2004[Abstract/Free Full Text]

6. Bilchik AJ, Poston G, Curley SA, et al: Neoadjuvant chemotherapy for metastatic colon cancer: A cautionary note. J Clin Oncol 23: 9073-9078, 2005[Free Full Text]

7. Benoist S, Brouquet A, Penna C, et al: Complete response of colorectal liver metastases after chemotherapy: Does it mean cure? J Clin Oncol 24: 3939-3945, 2006[Abstract/Free Full Text]

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