Markus Moehler, Andreas Teufel, Peter R. Galle

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Markus Moehler, Andreas Teufel, Peter R. Galle

M. Moehler ( u)

Department of Internal Medicine, Johannes-Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany

e-mail: moehler@mail.uni-mainz.de

Abstract

Since colorectal cancer is the second most prevalent cancer worldwide, its treat- ment remains a major challenge for researchers, gastroenterologists and oncol- ogists. Despite curative resections, half of all patients diagnosed with colorectal cancer die because of their underlying disease. Integral chemotherapeutic com- ponents of standard regimens are 5-ﬂuorouracil (5-FU), its modulation by folinic acid and irinotecan or oxaliplatin. All these drugs sequentially given have results in terms of median overall survival of more than 20 months in the palliative treatment of advanced colorectal cancer. Oral ﬂuoropyrimidines, currently under clinical investigation, are likely to substitute continuous 5-FU. Inhibitors of growth factor receptors or their signaling may further prolong disease-free and overall survival rates. Preliminary evidence exists that improved adjuvant and neoadju- vant chemotherapy strategies may further improve the prognosis, mainly because more patients are able to go for primary or secondary surgery with curative intent.

Introduction

Colorectal cancer is the second most prevalent cancer and the third leading cause of cancer deaths worldwide [1]. Despite curative resections, many patients develop later recurrence or metachronic metastases. Many other patients already present with metastatic or surgically not resectable disease at the time of diagnosis. More than half of all colorectal cancer patients die as a result of its metastatic disease [2].

Therefore, there is an urgent need to improve the treatment options for colorectal cancer. This chapter ﬁrst reviews the established concepts of adjuvant and pallia- tive protocols. Second, it integrates the chemotherapeutic agents irinotecan and oxaliplatin into these treatment combinations. Third, we focus on the upcoming innovative strategies of oral ﬂuoropyrimidines and biological targeting to further increase the patients’ quality of life and the neoadjuvant protocols for a better likelihood of curative procedures (Fig. 1).

Recent Results in Cancer Research, Vol. 165

Springer-Verlag Berlin Heidelberg 2005c

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1960 1980 1990 2000 5-FU

irinotecan(CPT11)/oxaliplatin(OXA) oral fluoropyrimidines continuous infusion

biomodulation

(V)-EGF-antagonists Figure 1. Treatment strategies of colorectal cancer during the last 40 years

Established Concepts of Adjuvant and Palliative Treatment Protocols

For over 40 years, the antimetabolite 5-ﬂuoruracil (5-FU) and its modulation by folinic acid (FA) has been the standard of care [3]. Palliative chemotherapy has been shown to be more effective than best supportive care in prolonging survival and improving quality of life. In a north central cancer treatment group (NCCTG) trial, 429 patients were randomized to one of six regimens: 5-FU alone, 5-FU plus high-dose or low-dose FA, 5-FU plus high-dose or low-dose methotrexate or 5- FU plus cisplatin [4]. Herein, FA/5FU protocols were the superior regimens, with no signiﬁcant advantage over high-dose or low-dose FA regarding the response rates and the 1-year survival rate. In other studies, two major FA-modulated 5-FU regimens have been employed as standards at the end of the last century in western countries [5, 6]:

1. The Mayo Clinic protocol

5-FU 425 mg/qm daily and FA 20 mg/qm daily administered for 5 consecutive days, repeated every 4 weeks for two cycles and then every 5 weeks thereafter (6 months).

2. The Roswell Park regimen

5-FU 500 mg/qm and FA 500 mg/qm, administered once weekly, for 6 con- secutive weeks and repeated every 8 weeks.

Continuous 5FU Is Superior to Bolus 5-FU

As 5-FU has a short plasma half-life and as its efﬁcacy and toxicity can be inﬂu-

enced by continuous infusions, prolonged or high-dose 5-FU protocols have been

thoroughly evaluated. In Europe, different 5-FU infusion protocols have been es-

tablished, with still widely used concepts on the part of the Spanish, the French or

the German study groups. A recent pooled metaanalysis of 1,219 patients compar-

ing continuous infusions with bolus administration of 5-FU reported a signiﬁcantly

higher response rate and modest improvement in survival (median, 12.1 months

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vs. 11.3 months; p=0.04) [7]. In infusional regimens, the toxicity proﬁle is to some extent altered with less hematological toxicity but more frequent hand-foot syndrome. In the US however, the European enthusiasm was tempered mainly because of concerns about catheter-associated complications and the possible pa- tient inconvenience. However, according to the data of Goldberg and Tournigand, American treatment strategies may also likely change to the more common use of 5-FU continuous infusions in oxaliplatin or irinotecan combinations [8, 9].

Adjuvant Chemotherapy Is of Benefit for UICC III (Dukes’ C) Patients

Many randomized trials have clearly demonstrated the benefits of adjuvant therapy in node-positive UICC III (Dukes’ C) colon cancer [10]. Standard of care is either the Mayo Clinic Protocol or the Roswell park regimen for 6 months in Western countries. However, the role of adjuvant chemotherapy following curative resection of node-negative colon cancer with large tumors (T3/T4; UICC II, Dukes’ B) is still in dispute [11]. The debate was stimulated by two conflicting meta-analyses, in which one of the NSABPs demonstrated similar treatment benefits for UICC II and III, although fewer recurrences were noted because of the improved prognosis at UICC II. The authors concluded that adjuvant chemotherapy should be considered since a significant proportional reduction in mortality was found [12]. However, the implication is still difficult because of the heterogeneity of the treatment arms.

In contrast, a separate meta-analysis showed no survival advantage for adjuvant therapy in UICC II patients, only a modest 2% absolute rest reduction in 5 years survival, concluding that adjuvant therapy should not be routinely offered to patients with UICC II disease [13]. Hopefully, prospective data will help to settle this ongoing controversy. Upcoming results of European trials are awaited with interest. Until then, patients with node-negative disease should be evaluated for discussion about the available data so that they may participate in the treatment decision.

State-of-the-Art in Colorectal Cancer

For Adjuvant Treatment in UICC III Colon Cancer, FA/5-FU Is Not Enough

Several ongoing, randomized studies in colon cancer are attempting to deﬁne

the role of new agents in adjuvant treatment. Recently reported data from the

adjuvant Mosaic study may therefore gain further clinical plausibility. In this

trial, oxaliplatin in the FOLFOX regimen induced an additional 23% relative risk

reduction in a 3-year relapse-free survival compared with infusional FA/5-FU alone

[14, 15]. However, the overall survival could not yet been shown to be signiﬁcantly

different (Fig. 2). Optimism also seems to be justiﬁed relative to the outcome of

the pan-European trial on adjuvant colon cancer (PETACC3/V-307) comparing

irinotecan with FA/5-FU (FOLFIRI) to infusional FA/5-FU alone. Other studies

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Figure 2. Disease-free survival by FOLFOX in adjuvant colon cancer

are the US/NCI Intergroup comparing weekly bolus FA/5-FU with or without irinotecan, while a French trial is comparing LV5FU2 alone and the same regimen plus irinotecan [16].

For Palliative Therapy, Irinotecan/Oxaliplatin with

Continuous FA/5FU Is the Standard of Care

FA/5-FU remained the most widely used chemotherapeutic agent for treatment of metastatic disease. However, in recent years there were at least six large phase III trials which changed deﬁnitely the common treatment praxis. Four main studies of irinotecan or oxaliplatin combined with FA/5-FU versus FA/5-FU alone showed the signiﬁcant superiority of the combination regimens in regard to progression- free survival (Table 1) [17–20]. Additionally, the overall survival was better for the irinotecan/FA/5-FU combinations [17, 18]. Very recently, Goldberg presented

Table 1. Main studies of irinotecan/oxaliplatin combined with FA/5-FU versus FA/5-FU alone

Regime RR PFS OS Author

Douillard/AIO 23% 4.4 14.1 Douillard

+ Irinotecan 35% 6.7 17.4 Lancet 2000

FL (Saltz) 21% 4.3 12.6 Saltz

+ Irinotecan 39% 7.0 14.8 NEJM 2000

LV5FU2 22% 6.6 14.7 De Gramont

+ Oxaliplatin 57% 9.0 16.2 JCO 2000

FUCM/LV 16% 6.1 19.9 Giacetti

+ Oxaliplatin 53% 8.7 19.4 JCO 2000

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Table 2. Infusion regimens and overall survival according to Tournigand [9]

Arm A Arm B

FOLFIRI FOLFOX FOLFOX FOLFIRI

n 109 89 111 69

RR 56% 15%^∗ 54% 4%

PFS 8.5 4.2^∗∗ 8.0 2.5 months

Total PFS 14.2 months 10.9 months

OS 21.5 months 20.6 months

∗p=0.05;^∗∗p=0.003.

PFS, progression-free survival; OS, overall survival.

data that oxaliplatin/continuous FA/5-FU was superior to irinotecan/bolus FA/5- FU (IFL) [8]. Merging these data, it is of utmost importance to treat all metastatic colorectal cancer patients with combinations of irinotecan or oxaliplatin combined with continuous FA/5-FU (FOLFIRI or FOLFOX). In second-line therapy, patients should receive oxaliplatin after irinotecan or vice versa [9].

Giving all three drugs as sequences resulted in a median survival of more than 20 months. This has been reached in the randomized phase III trial by Tournigand and colleagues (Table 2) [9]. They compared the sequence FOLFIRI followed by FOLFOX with the reverse sequence in advanced colorectal cancer. Thus this trial is extremely important, as patients with both sequences had comparable survival rates with 21.5 months for FOLFIRI and FOLFOX versus 20.6 months allocated to FOLFOX and then FOLFIRI. Response rates in first-line chemotherapy were about 56% and 54%, respectively. As other studies have revealed, patients refractory to first-line treatment should definitely receive a second-line therapy, which is oxaliplatin after irinotecan and irinotecan after oxaliplatin [9].

In addition to the agents discussed, several other drugs have shown activity in CRC. These include raltitrexed, trimetrexate, ethyniluracil, MTA and S1 [21].

However, it is also likely (at least in the near future) that applications of these drugs will be based on combination regimens with irinotecan or oxaliplatin.

Future Challenges in Colorectal Cancer

At present, there are three immediate challenges for the treatment of colorectal cancer:

• Do oral ﬂuoropyrimidines substitute 5-FU infusions without losing efﬁcacy in the combinations with irinotecan/oxaliplatin?

• How much will the combined use of chemotherapy with molecular targeted agents against growth factor receptors improve treatment options?

• Do local procedures (i.e., local resection, RFTA, PEI) additionally induce

a better long-term survival or even cure after downsizing with improved

neoadjuvant chemotherapy?

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Oral Fluoropyrimidines May Substitute Infusional 5-FU Regimens

Since the gastrointestinal mucosa contains dihydropyrimidine dehydrogenase (DPD) [22], one of the enzymes that catabolize 5-FU, it was questionable whether 5-FU can be given orally. It seemed that individuals who have greater concentra- tions of DPD in their intestinal mucosa inactivate more of 5-FU, which leads to lower plasma drug concentrations.

Strategies have been developed to improve the oral absorption of 5-FU including on the one hand the coadministration of drugs that inhibit the action of DPD [22] or on the other hand the oral administration of prodrugs of 5-FU that are absorbed intact and are activated metabolically after intestinal absorption. Three of these compounds have been compared individually with loading bolus FA/5- FU in prospectively randomized phase II and III trials as ﬁrst-line therapy for colorectal cancer [14, 23].

Capecitabine represents a member of the prodrug group which is absorbed intact through the mucosa. In the liver, it is subsequently metabolized to doxi- fluridine. The enzyme thymidine phosphorylase, which is selectively expressed in tumor tissue, leads to the final conversion of doxifluridine into 5-FU, exploit- ing a higher 5-FU activity at the tumor site [24]. In clinical trials, capecitabine monotherapy has been demonstrated to have a favorable safety profile that is typ- ical of infused 5-FU [24]. Given its toxicity profile (i.e. hand and foot syndrome), capecitabine acts biologically similarly to continuous 5-FU infusion [24, 26]. The majority of adverse events were mild to moderate, with a low incidence of alopecia and myelosuppression. With a dosage of 1,250 mg/qm twice daily, for 2 weeks of treatment followed by 1 week of rest, capecitabine has been approved by the FDA and most European nations as monotherapy of metastatic colorectal cancer [24].

Currently, combination protocols with oxaliplatin or irinotecan are under inves- tigation in phase II and III trails to determine whether they can substitute their 5-FU combinations, like FOLFOX or FOLFIRI [14, 25–27].

Inhibition of Growth Factor Receptors and Their Signaling Will Be Integrated into the Chemotherapeutic Concepts

The regulation and expression of growth factors and/or their receptors have been extensively studied in the development and prognosis of colorectal cancer [28, 29].

The epidermal growth factor receptor (EGFr) is a commonly expressed transmem- brane glycoprotein which signals pathways affecting mainly cellular proliferation.

Similar to EGFR, the vascular endothelial growth factor (VEGF) receptor is local-

ized in the cell membrane and consists of two transmembrane proteins [30]. After

binding the ligands, receptor dimerization activates intracellular tyrosine kinases,

triggering further signaling reactions regulating cell growth and survival. Tumor

cells overexpressing EGFR or VEGFR may in addition produce endogenous recep-

tor ligands, leading to an autocrine-stimulated proliferation. Thus, the blockade

of growth factors and its signaling pathways are of mutual interest as targets for

anticancer therapy.

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Table 3. Response rates and overall survival by cetuximab plus irinotecan (CPT) in irinotecan-refractory colorectal cancer patients

Cetux/Iri Cetux

CR/PR 22.9% 10.8%

Tumor control 55.5% 32.4%

Survival

Progression-free 4.1 months 1.5 months

Overall 8.6 months 6.9 months

In the laboratory, monoclonal antibodies to EGFR inhibited proliferation of cells that simultaneously produce both EGFR and its activating ligand. The Cetuximab (C225, Erbitux) is an immunoglobulin G1 chimeric antibody antagonizing the EGF receptor [31]. Based on its first scientific background, a phase II study evaluated the activity and safety of cetuximab plus irinotecan in irinotecan-refractory colorectal cancer patients, with a major response rate of 22.5%. Subsequently, Cunningham confirmed in the same patient population during a later randomized phase II trial that both cetuximab alone and cetuximab plus irinotecan had response rates of 10.8% for cetuximab alone and 22.9% for cetuximab plus irinotecan (Table 3) [32, 33]. Additionally, preliminary phase II data for the combination of cetuximab with oxalipaltin or irinotecan plus infusional FA/5-FU in first-line treatment in EGFR- positive metastatic colorectal cancer patients showed response rates and tumor control rates of up to 70% and 90%, respectively [34, 35]. In this study, secondary resections of liver metastases were possible in three patients and had been planned in another two [34]. Comparably, cetuximab combined with irinotecan/biweekly FA/5-FU achieved a tumor control in 89% in EGFR-positive colorectal cancer patients [35].

The most common toxicity of cetuximab was an acne-like rash, which occurrs in approximately 75% for patients. A recent meta-analysis investigated the rela- tionship between the presence and severity of the rash and survival [33]. Here, skin rash could be identiﬁed as an important clinical gate marker of efﬁcacy. Therefore, further prospective trials are initiated to evaluate skin rash and other biological markers for the dosing and response of such EGF antagonists.

Even as many VEGF or VEGFR antagonists (e.g., Iressa, PTK787, SU5416, SU6668) are currently under investigation [36], the VEGF antibody bevacizumab (rhuMab against VEGF-A), presented the most promising results in a randomized phase II study with three arms: bolus FA/5-FU (Roswell-Park schedule) without rhuMab VEGF, with 5 or 10 mg/kg rhuMab VEGF-A biweekly in metastatic col- orectal cancer [37]. With FA/5-FU plus 5 mg/kg bevacizumab, the response rate was 40%, progression-free survival was 9.0 months, and median survival was 21.5 months, both higher than with FA/5-FU alone or with FA/5-FU combined with the high dose of 10 mg/kg rhuMab VEGF [37].

Recently, impressive results of the ﬁrst phase III trial in 813 chemonaive

metastatic colorectal cancer patients randomized to irinotecan/bolus FA/5-FU

(IFL) versus IFL plus bevacizumab were reported (Table 4) [38]. The response

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Table 4. Irinotecan/bolusFA/5-FU (IFL) versus IFL plus bevacizumab (BV) in chemonaive metastatic colorectal cancer patients

IFL/placebo (n=412) IFL/BV (n=403)

Overall survival 15.6 months 20.3 months

Progression-free survival 6.2 months 10.6 months

Response rate 35% 45%

Hypertension 2.3% 11%

rate (35% vs. 45%), progression-free survival (6.2 vs. 10.6 months) and overall survival (15.6 vs. 20.3 months) were all in favor of the combination. There were no additional significant toxicities, except of grade III hypertension with beva- cizumab (10.9% vs. 2.3%), but no significant increase in bleeding or thrombotic events. Thus, the concept of anti-angiogenic treatment has been proven for the first time in a phase III study [38].

Neoadjuvant Chemotherapy May Additionally Improve Individual and Overall Survival Increasing numbers of liver metastases may now be considered surgically re- sectable [28]. Various factors explain this trend [39]: progress in surgical tech- niques, better knowledge of the functional anatomy of the liver, detection of metastases at an earlier stage, introduction of new therapeutic approaches (e.g., cryosurgery, radiofrequency ablation) and use of improved chemotherapy before resection [40–43]. This neoadjuvant chemotherapy approach with FA/5-FU plus oxaliplatin or irinotecan [44] reduced the size of metastases, so that additional 50%–60% of metastases that previously seemed unresectable could be resected [39, 44, 45]. After complete surgery of (liver) metastasis, approximately 30% of patients can be expected to survive 5 years or longer [46]. Thus, the advantage of better downsizing may also have an effect on the outcome of the patient population itself. Randomized prospective trials testing this neoadjuvant chemotherapy ap- proach further with FA/5-FU plus irinotecan or oxaliplatin are currently ongoing [47].

A recent study showed that neoadjuvant chemotherapy with oxaliplatin-based

therapy may induce sinusoidal obstructions in the liver, associated with sinusoidal

ﬁbrosis and veno-occlusive lesions, occasionally with nodular or regenerative hy-

perplasia [48]. To our knowledge, these changes after oxaliplatin have not been sys-

tematically investigated in other chemotherapeutic protocols. As no targeted liver

biopsy studies have yet been performed in patients who received oxaliplatin-based

chemotherapy, it is difﬁcult to justify the role of these new-found abnormalities. To

date, oxaliplatin has proven to be safe and its side effects have been easy to manage

with appropriate awareness from the patient and care providers. However, as at

least three-quarters of patients had speciﬁc liver lesions after oxaliplatin, the clin-

ical consequences of these sinusoidal lesions need to be reevaluated with respect

to the potential impairment of liver regeneration after extended resections [48].

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