This treatment strategy evolved since the beginning of our experience in 1991. Our accuracy in clinical assessment of tumor response has probably improved significantly with growing experience. At the begining, patients were more frequently followed without immediate surgery when a near-complete clinical response was considered with the hope that time would lead to a complete clinical response. More recently, these patients have been more readily assessed using full-thickness local excision as a diagnostic procedure, and according to the pathologic report they are then either managed by strict observation or referred to immediate radical surgery. Availability of surgical techniques such as Transanal Endoscopic Microsurgery has also lowered the trigger for a excisional biopsy (Full Thickness Transanal

Local Excision) in the presence of questionable residual lesions.

Fig. 3. Watch & Wait Algorithm

assessment.

An interesting strategy to increase the rates of tumor response is the delivery of chemotherapy during the waiting or resting period between radiation completion and tumor response assessment. Since February 2005, this approach has been adopted at our Institution.

Radiation therapy consists of 45 Gy of radiation delivered by a three-field approach with daily doses of 1.8 Gy on weekdays to the pelvis, followed by a 9-Gy boost to the primary tumor and perirectal tissue (54 Gy total). Concomitantly, patients receive three cycles of bolus 5FU (450 mg/m2) and a fixed dose of 50 mg of leucovorin for three consecutive days every three weeks. After completion of radiation, patients received three additional identical cycles of chemotherapy every three weeks (21 days) during nine weeks. Tumor response assessment is performed immediately at 10 weeks from radiation completion. (Fig 4)

In a preliminar report of our series including T2/T3 distal rectal cancers, the sustained complete clinical response rate (>12 months) was 65% with no significant increase in chemotherapy-related toxicity rates. After a recent update of this same cohort of patients, complete clinical response rate seems to be sustained after a median follow-up of more than 36 months at 65%.(Habr-Gama et al. 2009)

Fig. 4. The extended Chemoradiation regimen

#### **9. Long-term results**

At the beginning of our experience several patients were managed by radical surgery since residual cancer could not be confirmed or ruled out. This included patients with residual scars that were not candidates for local excision and those with partial narrowing of the rectum. In this context, many patients were operated and found to have ypT0 (absence of residual tumor). More recently, incorporation of TEM (Transanal Endoscopic Microsurgery) for diagnostic or staging purposes may lead to a significant decrease in the rates of pCR after radical TME.

In an attempt to understand the potential benefits of oncological surgery in terms of survival and local disease control, we performed a retrospective study where patients with complete

Nonoperative Management of Distal Rectal Cancer

still going on.(Habr-Gama et al. 2008a)

**12. Perspectives**

benefits.(Chua et al. 2010)

**13. References**

of tumor metabolism as function of time in these patients.

Radiat Oncol Biol Phys 2005;61(2):426–31.

After Chemoradiation: Experience with the "Watch & Wait" Protocol 331

procedures were performed at considerably long intervals after CRT completion (mean >50 months). In almost half of the cases an abdominoperineal resection (APR) was performed. Also, almost one third of these patients presented with low and superficial recurrences,

A significant subgroup of patients, presented early tumor regrowth (within 12 months from CRT completion). These patients were most commonly misdiagnosed as cCR and had their definitive surgical treatment postponed for a variable period of time. This raised the issue whether these patients could have been harmed from an oncologic standpoint, by delaying definitive surgical resection. However, long-term data revealed that they fared no worse than patients with incomplete clinical response and managed by radical surgery after 8 weeks from CRT completion. Noteworthy, final pathology in this group revealed significant tumor downstaging and even lower rates of lymph node metastases, further supporting the idea that downstaging is a time-dependent phenomenon. The fact that these patients were more frequently managed by APR, could reflect the motivation (by the surgeon and the patient) to delay final decision on radical resection, knowing that tumor regression could be

Several aspects in the management of complete clinical response after neoadjuvant CRT remain unresolved and should be a focus of future clinical and basic science research. Novel radiation therapy regimens including alternative radiation doses, delivery methods, and technical variants to maximize radiation-related tumor cell death and minimize side effects is an area of special interest. In addition, improved chemotherapy regimens might lead to an increase in the rate of complete clinical response and, possibly, improve survival rates. Some investigators have suggested the use of aggressive induction chemotherapy before the delivery of radiation to provide immediate treatment of undetected microscopic foci of metastatic tumor cells in addition to the primary tumor. These regimens are currently under investigation in controlled trials to provide data on safety and long-term

Another interesting and relevant topic in rectal cancer management is the optimal interval between CRT completion and assessment of tumor response, as already said. Ongoing prospective randomized trials comparing different intervals may provide additional information regarding this particular issue in rectal cancer management. Also, perhaps data from PET/CT imaging at different intervals from CRT completion may also indicate kinetics

Finally, development of next generation sequencing technology may allow further understanding of molecular genetic events relevant to sensitivity or resistance to neoadjuvant CRT. Perhaps identification of gene signatures will allow improvement of patient selection leading to true individualized management decisions. There is hope that studies using

Baxter NN, Morris AM, Rothenberger DA, et al. Impact of preoperative radiation for rectal

cancer on subsequent lymph node evaluation: a population-based analysis. Int J

RNAseq technology may provide more definitive information in the near future.

amenable to full thickness transanal excision.(Habr-Gama et al. 2006)

pathological response (pCR) were compared to patients with cCR managed nonoperatively.(Habr-Gama et al. 2004)

Patients managed by observation alone had similar outcomes to those managed by radical surgery in terms of long term survival. On the other hand, local recurrences were higher on the observation group, but noteworthy, all recurrences were within the rectal wall and amenable to surgical salvage. No pelvic relapses without endorectal component was observed.

Five-year overall and disease-free survival rates were associated to disease stage (clinical or pathological) and were 88% and 83%, respectively, in pCR group and 100% and 92% in cCR group respectively. These excellent survival rates in patients stage pCR and cCR were significantly better than those observed in patients ypII and ypIII. Curiously patients with stage ypI had intermediate results (Habr-Gama A, Perez RO, Nadalin W, et al. Long-term results of preoperative chemoradiation for distal rectal cancer correlation between final stage and survival. J Gastrointest Surg 2005;9:90-9; discussion 9-101.).

#### **10. Survival and recurrences**

Final TNM classification after neoadjuvant CRT remains the best predictor of survival in patients with rectal cancer. In a study of patients with similar baseline stages, final pathological classification distinguished those with worse and better outcomes.

Still, there is no prospective evidence favoring neoadjuvant RT over adjuvant CRT in terms of survival benefits. One explanation for this observation could be the detrimental effect of neoadjuvant CRT on host immunologic response against rectal cancer such as the potential blockade of peritumoral inflammatory as immunologic response.(Perez et al. 2007)

It has been suggested that adjuvant chemotherapy can improve survival only in highly selected patients with substantial tumor downstaging (ypT0-2).(Collette et al. 2007) These results may lead to a dramatical change in management of these patients who used to be considered for adjuvant treatment according to pretreatment staging.

An interesting observation is that in our series, systemic recurrences in cCR patients occurred considerably earlier than local recurrences. Besides intrinsic tumor behavior, this could be partly explained by the staging inaccuracy of the different available imaging modalities, which were probably not capable of detecting microscopic foci or metastasic disease at initial presentation. Also, local recurrences were observed in 10% of patients managed nonoperatively after a cCR. Interestingly, there were no extrarectal pelvic recurrences. Even though some recurrences may develop from the outer layers of the rectal wall, in all cases there was some luminal evidence of recurrence that could be detected by digital and rectoscopic examination.

Again, local recurrences developed considerably later during follow-up. This has also been observed in other series, where more than one third of patients who develop local recurrences after neoadjuvant CRT and radical surgery did so after 5 years of follow-up. In contrast, 75% of patients who develop local recurrences after radical surgery alone do so within 2 years of follow-up. This information may have implications when considering follow-up and surveillance strategies.( Habr-Gama et al. 2008a)

#### **11. Salvage therapy**

It has to be highlighted that up to now, all local recurrences in patients with cCR after neoadjuvant CRT were amenable to salvage therapy. These recurrences and their salvage procedures were performed at considerably long intervals after CRT completion (mean >50 months). In almost half of the cases an abdominoperineal resection (APR) was performed. Also, almost one third of these patients presented with low and superficial recurrences, amenable to full thickness transanal excision.(Habr-Gama et al. 2006)

A significant subgroup of patients, presented early tumor regrowth (within 12 months from CRT completion). These patients were most commonly misdiagnosed as cCR and had their definitive surgical treatment postponed for a variable period of time. This raised the issue whether these patients could have been harmed from an oncologic standpoint, by delaying definitive surgical resection. However, long-term data revealed that they fared no worse than patients with incomplete clinical response and managed by radical surgery after 8 weeks from CRT completion. Noteworthy, final pathology in this group revealed significant tumor downstaging and even lower rates of lymph node metastases, further supporting the idea that downstaging is a time-dependent phenomenon. The fact that these patients were more frequently managed by APR, could reflect the motivation (by the surgeon and the patient) to delay final decision on radical resection, knowing that tumor regression could be still going on.(Habr-Gama et al. 2008a)

#### **12. Perspectives**

330 Rectal Cancer – A Multidisciplinary Approach to Management

pathological response (pCR) were compared to patients with cCR managed non-

Patients managed by observation alone had similar outcomes to those managed by radical surgery in terms of long term survival. On the other hand, local recurrences were higher on the observation group, but noteworthy, all recurrences were within the rectal wall and amenable

Five-year overall and disease-free survival rates were associated to disease stage (clinical or pathological) and were 88% and 83%, respectively, in pCR group and 100% and 92% in cCR group respectively. These excellent survival rates in patients stage pCR and cCR were significantly better than those observed in patients ypII and ypIII. Curiously patients with stage ypI had intermediate results (Habr-Gama A, Perez RO, Nadalin W, et al. Long-term results of preoperative chemoradiation for distal rectal cancer correlation between final

Final TNM classification after neoadjuvant CRT remains the best predictor of survival in patients with rectal cancer. In a study of patients with similar baseline stages, final

Still, there is no prospective evidence favoring neoadjuvant RT over adjuvant CRT in terms of survival benefits. One explanation for this observation could be the detrimental effect of neoadjuvant CRT on host immunologic response against rectal cancer such as the potential

It has been suggested that adjuvant chemotherapy can improve survival only in highly selected patients with substantial tumor downstaging (ypT0-2).(Collette et al. 2007) These results may lead to a dramatical change in management of these patients who used to be

An interesting observation is that in our series, systemic recurrences in cCR patients occurred considerably earlier than local recurrences. Besides intrinsic tumor behavior, this could be partly explained by the staging inaccuracy of the different available imaging modalities, which were probably not capable of detecting microscopic foci or metastasic disease at initial presentation. Also, local recurrences were observed in 10% of patients managed nonoperatively after a cCR. Interestingly, there were no extrarectal pelvic recurrences. Even though some recurrences may develop from the outer layers of the rectal wall, in all cases there was some luminal evidence of recurrence that could be detected by

Again, local recurrences developed considerably later during follow-up. This has also been observed in other series, where more than one third of patients who develop local recurrences after neoadjuvant CRT and radical surgery did so after 5 years of follow-up. In contrast, 75% of patients who develop local recurrences after radical surgery alone do so within 2 years of follow-up. This information may have implications when considering

It has to be highlighted that up to now, all local recurrences in patients with cCR after neoadjuvant CRT were amenable to salvage therapy. These recurrences and their salvage

pathological classification distinguished those with worse and better outcomes.

blockade of peritumoral inflammatory as immunologic response.(Perez et al. 2007)

to surgical salvage. No pelvic relapses without endorectal component was observed.

stage and survival. J Gastrointest Surg 2005;9:90-9; discussion 9-101.).

considered for adjuvant treatment according to pretreatment staging.

follow-up and surveillance strategies.( Habr-Gama et al. 2008a)

operatively.(Habr-Gama et al. 2004)

**10. Survival and recurrences**

digital and rectoscopic examination.

**11. Salvage therapy**

Several aspects in the management of complete clinical response after neoadjuvant CRT remain unresolved and should be a focus of future clinical and basic science research.

Novel radiation therapy regimens including alternative radiation doses, delivery methods, and technical variants to maximize radiation-related tumor cell death and minimize side effects is an area of special interest. In addition, improved chemotherapy regimens might lead to an increase in the rate of complete clinical response and, possibly, improve survival rates. Some investigators have suggested the use of aggressive induction chemotherapy before the delivery of radiation to provide immediate treatment of undetected microscopic foci of metastatic tumor cells in addition to the primary tumor. These regimens are currently under investigation in controlled trials to provide data on safety and long-term benefits.(Chua et al. 2010)

Another interesting and relevant topic in rectal cancer management is the optimal interval between CRT completion and assessment of tumor response, as already said. Ongoing prospective randomized trials comparing different intervals may provide additional information regarding this particular issue in rectal cancer management. Also, perhaps data from PET/CT imaging at different intervals from CRT completion may also indicate kinetics of tumor metabolism as function of time in these patients.

Finally, development of next generation sequencing technology may allow further understanding of molecular genetic events relevant to sensitivity or resistance to neoadjuvant CRT. Perhaps identification of gene signatures will allow improvement of patient selection leading to true individualized management decisions. There is hope that studies using RNAseq technology may provide more definitive information in the near future.

#### **13. References**

Baxter NN, Morris AM, Rothenberger DA, et al. Impact of preoperative radiation for rectal cancer on subsequent lymph node evaluation: a population-based analysis. Int J Radiat Oncol Biol Phys 2005;61(2):426–31.

Nonoperative Management of Distal Rectal Cancer

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**18**

*Canada*

**Systemic Treatment in Recurrent**

François-Xavier Otte, Mustapha Tehfe, Jean-Pierre Ayoub and Francine Aubin

*Université de Montréal*

**and Metastatic Unresectable Rectal Cancer**

Most patients with recurrent and metastatic rectal cancer cannot be cured. Selected patients with local recurrence or liver and/or lung-limited metastatic disease are sometimes curable with radiation therapy (RT) or surgery. However, for the majority of patients, treatment is palliative and systemic therapy remains the mainstay treatment. Over the last ten years, survival of patients with unresectable metastatic or recurrent rectal cancer has considerably improved. The median survival is about two years due to availability of new chemotherapy regimens and targeted therapies. For decades, 5-fluorouracil (5-FU) was the only active and available agent. Since the year 2000, irinotecan and oxaliplatin were approved. Access to all these three active agents strongly correlates with improved survival. More progress was achieved recently with the development of targeted therapies. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Cetuximab and panitumumab are two monoclonal antibodies targeting the epidermal growth factor

receptor (EGFR). Combinations of these different drugs are now commonly used.

treatment and specific treatment recommendations will also be discussed.

In non-curable patients, goals are improvement of survival and quality of life. The purpose of this chapter is to review data from clinical trials evaluating systemic therapy in unresectable recurrent or metastatic rectal cancer. Commonly used chemotherapy regimens and biologic agents will be described as well as their side effects. General principles of

Fluoropyrimidines have been used for the treatment of metastatic colorectal cancer (mCRC) for many years. 5-FU is a fluoropyrimidine that causes inhibition of thymidylate synthase and leads to impaired DNA synthesis. Adding folinic acid (leucovorin) intensifies the cytotoxic power of 5-FU stabilizing its bind to the enzyme. Different schedules of administration have shown clinical activity in different trials. Short-term infusional schedules have gained acceptance. A French study, compared a regimen of bolus 5-FU/LV day 1 to 5 every four weeks to bimonthly 5-FU/LV bolus over two hours followed by a 22 hours 5-FU infusion for two consecutive days. The infusional regimen showed better response rate (RR) and progression free survival (PFS). It was also associated with less

**1. Introduction**

**2. Chemotherapy 2.1 Fluoropyrimidines**

metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer. Ann. Surg. Oncol. 12:111–116.

### **Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer**

François-Xavier Otte, Mustapha Tehfe, Jean-Pierre Ayoub and Francine Aubin *Université de Montréal Canada*

#### **1. Introduction**

336 Rectal Cancer – A Multidisciplinary Approach to Management

Rimkus C, Friederichs J, Boulesteix A-L, Theisen J, Mages J, Becker K, Nekarda H,

Sanghera P, Wong DWY, McConkey CC, Geh JI, Hartley A. 2008. Chemoradiotherapy for

Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P,

Simunovic M, Sexton R, Rempel E, Moran BJ, Heald RJ. 2003. Optimal preoperative

Smith KD, Tan D, Das P, Chang GJ, Kattepogu K, Feig BW, Skibber JM, Rodriguez-Bigas

Stipa F, Zernecke A, Moore HG, Minsky BD, Wong WD, Weiser M, Paty PB, Shia J, Guillem

Suppiah A, Hunter IA, Cowley J, Garimella V, Cast J, Hartley JE, Monson JRT. 2009.

Tulchinsky H, Shmueli E, Figer A, Klausner JM, Rabau M. 2008. An interval >7 weeks

Wang H, Safar B, Wexner SD, Denoya P, Berho M. 2009. The clinical significance of fat

Weiss C, Arnold D, Dellas K, Liersch T, Hipp M, Fietkau R, Sauer R, Hinke A, Rödel C. 2010.

Withers HR, Haustermans K. 2004. Where next with preoperative radiation therapy for

Zmora O, Dasilva GM, Gurland B, Pfeffer R, Koller M, Nogueras JJ, Wexner SD. 2004. Does

chemoradiation in rectal cancer. Colorectal Dis 11:249–253.

neoadjuvant therapy. Dis. Colon Rectum 52:1767–1773.

phase I-II trials. Int. J. Radiat. Oncol. Biol. Phys. 78:472–478.

rectal cancer? Int. J. Radiat. Oncol. Biol. Phys. 58:597–602.

the operative strategy? Dis. Colon Rectum 47:1607–1612.

chemoradiotherapy for rectal cancer. N. Engl. J. Med. 351:1731–1740. Sermier A, Gervaz P, Egger JF, Dao M, Allal AS, Bonet M, Morel P. 2006. Lymph node

Ann. Surg. Oncol. 12:111–116.

Oncol (R Coll Radiol) 20:176–183.

radiotherapy. Br J Surg 90:999–1003.

World J Surg Oncol 4:29.

251:261–264.

11:187–191.

Oncol. 15:2661–2667.

rectal cancer. Clin. Gastroenterol. Hepatol. 6:53–61.

metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer.

Rosenberg R, Janssen K-P, Siewert JR. 2008. Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced

rectal cancer: an updated analysis of factors affecting pathological response. Clin

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retrieval in abdominoperineal surgical specimen is radiation time-dependent.

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MA. 2010. Clinical significance of acellular mucin in rectal adenocarcinoma patients with a pathologic complete response to preoperative chemoradiation. Ann. Surg.

JG. 2004. Residual mesorectal lymph node involvement following neoadjuvant combined-modality therapy: rationale for radical resection? Ann. Surg. Oncol.

Magnetic resonance imaging accuracy in assessing tumour down-staging following

between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann. Surg.

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Most patients with recurrent and metastatic rectal cancer cannot be cured. Selected patients with local recurrence or liver and/or lung-limited metastatic disease are sometimes curable with radiation therapy (RT) or surgery. However, for the majority of patients, treatment is palliative and systemic therapy remains the mainstay treatment. Over the last ten years, survival of patients with unresectable metastatic or recurrent rectal cancer has considerably improved. The median survival is about two years due to availability of new chemotherapy regimens and targeted therapies. For decades, 5-fluorouracil (5-FU) was the only active and available agent. Since the year 2000, irinotecan and oxaliplatin were approved. Access to all these three active agents strongly correlates with improved survival. More progress was achieved recently with the development of targeted therapies. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Cetuximab and panitumumab are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). Combinations of these different drugs are now commonly used.

In non-curable patients, goals are improvement of survival and quality of life. The purpose of this chapter is to review data from clinical trials evaluating systemic therapy in unresectable recurrent or metastatic rectal cancer. Commonly used chemotherapy regimens and biologic agents will be described as well as their side effects. General principles of treatment and specific treatment recommendations will also be discussed.

#### **2. Chemotherapy**

#### **2.1 Fluoropyrimidines**

Fluoropyrimidines have been used for the treatment of metastatic colorectal cancer (mCRC) for many years. 5-FU is a fluoropyrimidine that causes inhibition of thymidylate synthase and leads to impaired DNA synthesis. Adding folinic acid (leucovorin) intensifies the cytotoxic power of 5-FU stabilizing its bind to the enzyme. Different schedules of administration have shown clinical activity in different trials. Short-term infusional schedules have gained acceptance. A French study, compared a regimen of bolus 5-FU/LV day 1 to 5 every four weeks to bimonthly 5-FU/LV bolus over two hours followed by a 22 hours 5-FU infusion for two consecutive days. The infusional regimen showed better response rate (RR) and progression free survival (PFS). It was also associated with less

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 339

\*400 mg/m2 IV bolus day 1; 2400 mg/m2 IV continuous infusion over 46 h

\*500 mg/m2 IV

\*500 mg/m2 IV bolus on days 1

Capecitabine by mouth 1000mg/m2 twice a day on days 1 to 14

bolus

and 8

Every two weeks

Weekly for four weeks every six weeks

Every three weeks

Every three weeks

**Regimen Irinotecan Leucovorin 5-FU\*/capecitabine Schedule**

400 mg/m2 IV over 2 h day 1

20 mg/m2 IV

20 mg/m2 IV

on days 1 and 8

In 1998, the platinum derivative, oxaliplatin when given together with 5-FU was shown to have significant activity in mCRC (deBraud et al. 1998). The activity of oxaliplatin alone in mCRC is low (Rothenberg et al. 2003). In 2000, a study showed better PFS and RR with the addition of oxaliplatin to 5-FU/LV compared to 5-FU/LV infusional regimen alone as first-

The combination of oxaliplatin and oral capecitabine (XELOX or CAPOX) has also been studied and compared to other fluoropyrimidine/oxaliplatin combinations in multiple randomized studies. A pooled analysis of randomized trials comparing first-line CAPOX to oxaliplatin in combination to infusional 5-FU/LV showed that CAPOX resulted in lower RR, but this did not affect PFS and OS. The toxicity analysis showed thrombocytopenia and hand-foot syndrome were consistently more prominent with the CAPOX regimens (Arkenau et al. 2008). CAPOX may be considered in patients where ambulatory infusion is

In 2004, Tournigand and colleagues randomly assigned previously untreated patients to FOLFOX 6 or FOLFIRI. At progression, irinotecan was replaced by oxaliplatin or oxaliplatin by irinotecan. Both strategies showed equivalent RR (about 55%) and median survival (20.6 and 21.5 months). Nausea, mucositis and alopecia were more common with FOLFIRI while neutropenia and paresthesias were more common with FOLFOX (Tournigand et al. 2004).

Thus, using FOLFOX or FOLFIRI in first-line treatment and then switching to the alternate regimen at progression or treatment intolerance is widely accepted. The decision of choosing one regimen over the other will be influenced by toxicity profile and patient

bolus

bolus

line treatment in advanced colorectal cancer (de Gramont et al. 2000).

An Italian study showed similar findings (Colucci et al. 2005).

 180 mg/m2 IV over 90 min day 1

125 mg/m2 IV

125 mg/m2 IV over 90 min

days 1 and 8

250 mg/m2 IV over 90 minutes day 1

bolus

on

Table 1. Irinotecan Regimens

**2.3 Oxaliplatin (table2)**

not possible or refused.

preference.

FOLFIRI *Fuchs et al. 2007*

IFL *Saltz et al.2000*

mIFL *Fuchs et al. 2007*

CapeIRI *Fuchs et al. 2007*

hematological and gastrointestinal (GI) toxicity. This "de Gramont regimen" is now a standard (de Gramont et al. 1997).

The widely used oral form of fluoropyrimidine is capecitabine. It is a prodrug that needs to be metabolized to 5-FU by multiple sequential enzymatic reactions. In 2001, a phase 3 randomized trial showed that use of oral capecitabine in first-line mCRC patients was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5- FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5- FU/LV in terms of tolerability although hand-foot syndrome was more common (Hoff et al. 2001). Similar results were observed in another identically designed randomized study (Van Cutsem et al. 2001).

Dihydropyrimidine dehydrogenase (DPD) is an important enzyme in the metabolism of fluoropyrimidines. It is the rate limiting enzyme in 5-FU catabolism. Patients who are deficient in DPD activity may have severe, even fatal toxicities such as severe diarrhea, mucositis and pancytopenia. For these patients, an alternative to 5-FU is raltitrexed which is a pure thymidylate synthase inhibitor. In a 2002 randomized study, raltitrexed showed similar RR and overall survival (OS) to the de Gramont regimen and was easier to administer, but resulted in greater toxicity (GI and hematological) and inferior quality of life (Maughan et al. 2002).

Fluoropyrimidines alone had been the standard first-line treatment of mCRC until the development of combination regimens with irinotecan or oxaliplatin. Fluoropyrimidine monotherapy remains a valid option for patients with contraindications to combined therapies. The infusional regimen (de Gramont) is the preferred fluoropyrimidine monotherapy. Capecitabine is a safe oral alternative to 5-FU.

#### **2.2 Irinotecan (table 1)**

Irinotecan is a topoisomerase I inhibitor and has demonstrated efficacy in mCRC as a single agent or in association with a fluoropyrimidine. Irinotecan in monotherapy showed superiority to best supportive care alone after 5-FU failure. A randomized trial showed that the OS was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. Quality of life was also better with less tumor related symptoms. In this trial, irinotecan was given every three weeks (Cunningham et al. 1998).

A randomized trial showed an advantage in RR, time to progression (TTP) and median survival for combined treatment with irinotecan/5-FU/LV over 5-FU/LV alone in first-line mCRC. An infusional regimen was used (the Douillard regimen). Treatment was given weekly or every two weeks. There were more toxicities in the irinotecan arm (diarrhea and neutropenia) but they were manageable (Douillard et al. 2000). Results of the BICC-C study suggest that the infusional regimen (FOLFIRI) is associated with better PFS and less toxicities compared to the bolus regimen (IFL).

The use of oral capecitabine associated with irinotecan (CapeIRI) was also assessed in the BICC-C study. It was compared to FOLFIRI and IFL. It was associated with more toxicities and less efficacy (Fuchs et al. 2007).

Late diarrhea and neutropenia are the main dose-limiting toxicities from irinotecan. UGT1A1 polymorphism predicts irinotecan toxicity. Irinotecan can also cause early-onset symptoms of cholinergic excess including diarrhea, abdominal cramping, lacrimation, rhinitis and salivation.

Table 1. Irinotecan Regimens

#### **2.3 Oxaliplatin (table2)**

338 Rectal Cancer – A Multidisciplinary Approach to Management

hematological and gastrointestinal (GI) toxicity. This "de Gramont regimen" is now a

The widely used oral form of fluoropyrimidine is capecitabine. It is a prodrug that needs to be metabolized to 5-FU by multiple sequential enzymatic reactions. In 2001, a phase 3 randomized trial showed that use of oral capecitabine in first-line mCRC patients was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5- FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5- FU/LV in terms of tolerability although hand-foot syndrome was more common (Hoff et al. 2001). Similar results were observed in another identically designed randomized study (Van

Dihydropyrimidine dehydrogenase (DPD) is an important enzyme in the metabolism of fluoropyrimidines. It is the rate limiting enzyme in 5-FU catabolism. Patients who are deficient in DPD activity may have severe, even fatal toxicities such as severe diarrhea, mucositis and pancytopenia. For these patients, an alternative to 5-FU is raltitrexed which is a pure thymidylate synthase inhibitor. In a 2002 randomized study, raltitrexed showed similar RR and overall survival (OS) to the de Gramont regimen and was easier to administer, but resulted in greater toxicity (GI and hematological) and inferior quality of life

Fluoropyrimidines alone had been the standard first-line treatment of mCRC until the development of combination regimens with irinotecan or oxaliplatin. Fluoropyrimidine monotherapy remains a valid option for patients with contraindications to combined therapies. The infusional regimen (de Gramont) is the preferred fluoropyrimidine

Irinotecan is a topoisomerase I inhibitor and has demonstrated efficacy in mCRC as a single agent or in association with a fluoropyrimidine. Irinotecan in monotherapy showed superiority to best supportive care alone after 5-FU failure. A randomized trial showed that the OS was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. Quality of life was also better with less tumor related symptoms. In this trial, irinotecan was given every

A randomized trial showed an advantage in RR, time to progression (TTP) and median survival for combined treatment with irinotecan/5-FU/LV over 5-FU/LV alone in first-line mCRC. An infusional regimen was used (the Douillard regimen). Treatment was given weekly or every two weeks. There were more toxicities in the irinotecan arm (diarrhea and neutropenia) but they were manageable (Douillard et al. 2000). Results of the BICC-C study suggest that the infusional regimen (FOLFIRI) is associated with better PFS and less

The use of oral capecitabine associated with irinotecan (CapeIRI) was also assessed in the BICC-C study. It was compared to FOLFIRI and IFL. It was associated with more toxicities

Late diarrhea and neutropenia are the main dose-limiting toxicities from irinotecan. UGT1A1 polymorphism predicts irinotecan toxicity. Irinotecan can also cause early-onset symptoms of cholinergic excess including diarrhea, abdominal cramping, lacrimation, rhinitis and

monotherapy. Capecitabine is a safe oral alternative to 5-FU.

standard (de Gramont et al. 1997).

Cutsem et al. 2001).

(Maughan et al. 2002).

**2.2 Irinotecan (table 1)**

three weeks (Cunningham et al. 1998).

and less efficacy (Fuchs et al. 2007).

salivation.

toxicities compared to the bolus regimen (IFL).

In 1998, the platinum derivative, oxaliplatin when given together with 5-FU was shown to have significant activity in mCRC (deBraud et al. 1998). The activity of oxaliplatin alone in mCRC is low (Rothenberg et al. 2003). In 2000, a study showed better PFS and RR with the addition of oxaliplatin to 5-FU/LV compared to 5-FU/LV infusional regimen alone as firstline treatment in advanced colorectal cancer (de Gramont et al. 2000).

The combination of oxaliplatin and oral capecitabine (XELOX or CAPOX) has also been studied and compared to other fluoropyrimidine/oxaliplatin combinations in multiple randomized studies. A pooled analysis of randomized trials comparing first-line CAPOX to oxaliplatin in combination to infusional 5-FU/LV showed that CAPOX resulted in lower RR, but this did not affect PFS and OS. The toxicity analysis showed thrombocytopenia and hand-foot syndrome were consistently more prominent with the CAPOX regimens (Arkenau et al. 2008). CAPOX may be considered in patients where ambulatory infusion is not possible or refused.

In 2004, Tournigand and colleagues randomly assigned previously untreated patients to FOLFOX 6 or FOLFIRI. At progression, irinotecan was replaced by oxaliplatin or oxaliplatin by irinotecan. Both strategies showed equivalent RR (about 55%) and median survival (20.6 and 21.5 months). Nausea, mucositis and alopecia were more common with FOLFIRI while neutropenia and paresthesias were more common with FOLFOX (Tournigand et al. 2004). An Italian study showed similar findings (Colucci et al. 2005).

Thus, using FOLFOX or FOLFIRI in first-line treatment and then switching to the alternate regimen at progression or treatment intolerance is widely accepted. The decision of choosing one regimen over the other will be influenced by toxicity profile and patient preference.

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 341

showed better RR (41 versus 66 percent), PFS (9.8 versus 6.9 months) and OS (22.6 versus 16.7 months) for FOLFOXIRI compared to FOLFIRI in the first-line setting. This was in a selected population of patients in good general condition and with favorable features. More toxicities were reported in the FOLFOXIRI arm especially in terms of neutropenia and neurotoxicity (Falcone et al.2007). This benefit and its cost in terms of toxicities were confirmed in a systematic review (Montagnani et al. 2010). In contrast, a Greek phase 3 randomized failed to show benefits to FOLFOXIRI when compared to FOLFIRI (Souglakos et al. 2006). However, compared to the Italian trial, lower doses of oxaliplatin, irinotecan and

**Regimen Oxaliplatin Irinotecan Leucovorin 5-FU/cape Schedule**

85mg/m2 200 mg/m2 Every

200 mg/m2 day 1

400 mg/m2 day 1

400 mg/m2 day 1

20 mg/m2 days 1, 8 and

400 mg/m2 day 1

400 mg/m2 day 1

200 mg/m2 day 1

15

capecitabine 1,000 mg/m2 orally twice daily on days 1 to 15

400 mg/m2 followed by FU 600 mg/m2 in 22-hour infusions on days 1 and 2

bolus FU 400mg/m2 followed by infusion 2400-3000 mg/m2 over 46 hours

bolus FU 400mg/m2 followed by infusion 2400 mg/m2 over 46

500 mg/m2 push days

infusion 2400 mg/m2 over 46 hours

infusion 3000 mg/m2 over 46 hours

Infusion 3200 mg/m2

over 48h

bolus FU

hours

1,8 and 15

Every three weeks

three weeks

Every two weeks

Every two weeks

Every two weeks

Every four weeks

Every two weeks

Every two weeks

Every two weeks

5-FU were used.

130mg/m2 IV on day 1

85 mg/m2 on day 1

100 mg/m2 day 1

85 mg/m2 day

85 mg/m2 on days 1 and 15

130 mg/m2 day 1

100 mg/m2 day 1

85 mg/m2 day

165 mg/m2 day 1

1

Table 2. Oxaliplatin Regimens

1

CAPOX *Hochster et al. 2008*

IROX *Goldberg et al.*

*2004*

*2004*

*2004*

*2008*

bFOL *Hochster et al.*

*2008*

*2006*

*2009*

FOLFOX 7 *Tournigand et al.*

FOLFOX 7 modified *Chibaudel et al.*

FOLFOXIRI *Falcone et al. 2007*

FOLFOX 4 *Goldberg et al.*

FOLFOX 6 *Tournigand et al.*

FOLFOX 6 modified *Hochster et al.*

One of the main concerns with the use of oxaliplatin is neurotoxicity. Acute neurotoxicity and cumulative sensory neuropathy are described. The acute neurotoxicity typical symptoms are dysesthesias of hands, feet and perioral region. More rarely, pharyngeal dysesthesias can be observed. These symptoms are generally triggered by cold, are associated with higher doses of oxaliplatin and are infusion-rate dependant. In 2008, Petrioli and colleagues suggested a prolonged infusion time to reduce the acute toxicity (Petrioli et al. 2008). This acute toxicity seems to be related to hyperexcitability of the peripheral nerves which has been attributed to disruption in cell membrane ion channels (Wilson et al. 2002; Park et al. 2009). In contrast, the cumulative neuropathy is generally sensory, symmetrical and without motor involvement. Oxaliplatin-induced cumulative sensory neuropathy occurs after several cycles of therapy (Cassidy et al. 2002). In about three fourths of patients, neurotoxicity is reversible with a median time to recovery of 13 weeks after treatment discontinuation. Strategies have been developed to prevent oxaliplatin-induced cumulative neurotoxicity. First, new schedules of administration were investigated. The Optimox-1 study randomly assigned patients to FOLFOX 4 (oxaliplatin 85 mg/m2) until progression or to six cycles of FOLFOX 7 (oxaliplatin 130mg/m2) followed by maintenance 5FU-LV for 12 cycles. FOLFOX 7 was then reintroduced for non progressive patients. RR, PFS and survival were similar in both arms. Grade 3 and 4 neuropathy was reduced in FOLFOX 7 arm after the sixth cycle even though it occurred earlier. The conclusion was that oxaliplatin can be safely stopped after six cycles in a FOLFOX 7 regimen (Tournigand et al. 2006). The Optimox-2 study compared a chemotherapy-free interval with maintenance 5-FU/LV after six cycles of modified FOLFOX 7 (mFOLFOX7) chemotherapy in the first-line treatment of mCRC. mFOLFOX 7 was reintroduced for patients with progressive disease in both arms. Duration of disease control (DDC) and PFS were better in the maintenance arm (Chibaudel et al. 2009). Thus oxaliplatin-free intervals are feasible but complete discontinuation of chemotherapy may be associated with inferior outcomes. Secondly, the benefit of use of IV calcium (Ca) and magnesium (Mg) in order to diminish neuropathy symptoms was suggested in randomized trials. In 2011, Grothey and colleagues showed that IV Ca/Mg is an effective neuroprotectant against oxaliplatin-induced cumulative neuropathy in adjuvant colon cancer. The incidence of grade 2 or greater cumulative sensory neurotoxicity was significantly reduced. The onset of grade 2 or greater sensory neurotoxicity was also delayed in patients receiving Ca/Mg (Grothey et al. 2011). This study had a low statistical power due to early closure of the trial because preliminary reports from another trial (CONcePT trial) that initially suggested decreased response rates for patients getting Ca/Mg (Hochster et al. 2007). This was later proven untrue by an independent radiologic review.

#### **2.4 Other chemotherapy combinations (table 2)**

The combination of oxaliplatin and irinotecan (IROX) has been assessed in first and second line setting. In the first-line setting, IROX was shown to be inferior and more toxic in elderly patients compared to FOLFOX (Sanoff et al. 2008) and equivalent to FOLFIRI (Fischer von Weikersthal et al.2011). In the second-line setting, IROX was compared to a triple regimen of 5FU/LV with alternating irinotecan and oxaliplatin. RR (23 versus 6 percent) and median survival (12.3 versus 9.8 months) were better with IROX but the doses of irinotecan and oxaliplatin were smaller in the triple therapy arm (Bécouarn et al. 2001). The efficacy of FOLFOXIRI regimen has been evaluated in two randomized studies. An Italian study

One of the main concerns with the use of oxaliplatin is neurotoxicity. Acute neurotoxicity and cumulative sensory neuropathy are described. The acute neurotoxicity typical symptoms are dysesthesias of hands, feet and perioral region. More rarely, pharyngeal dysesthesias can be observed. These symptoms are generally triggered by cold, are associated with higher doses of oxaliplatin and are infusion-rate dependant. In 2008, Petrioli and colleagues suggested a prolonged infusion time to reduce the acute toxicity (Petrioli et al. 2008). This acute toxicity seems to be related to hyperexcitability of the peripheral nerves which has been attributed to disruption in cell membrane ion channels (Wilson et al. 2002; Park et al. 2009). In contrast, the cumulative neuropathy is generally sensory, symmetrical and without motor involvement. Oxaliplatin-induced cumulative sensory neuropathy occurs after several cycles of therapy (Cassidy et al. 2002). In about three fourths of patients, neurotoxicity is reversible with a median time to recovery of 13 weeks after treatment discontinuation. Strategies have been developed to prevent oxaliplatin-induced cumulative neurotoxicity. First, new schedules of administration were investigated. The Optimox-1 study randomly assigned patients to FOLFOX 4 (oxaliplatin 85 mg/m2) until progression or to six cycles of FOLFOX 7 (oxaliplatin 130mg/m2) followed by maintenance 5FU-LV for 12 cycles. FOLFOX 7 was then reintroduced for non progressive patients. RR, PFS and survival were similar in both arms. Grade 3 and 4 neuropathy was reduced in FOLFOX 7 arm after the sixth cycle even though it occurred earlier. The conclusion was that oxaliplatin can be safely stopped after six cycles in a FOLFOX 7 regimen (Tournigand et al. 2006). The Optimox-2 study compared a chemotherapy-free interval with maintenance 5-FU/LV after six cycles of modified FOLFOX 7 (mFOLFOX7) chemotherapy in the first-line treatment of mCRC. mFOLFOX 7 was reintroduced for patients with progressive disease in both arms. Duration of disease control (DDC) and PFS were better in the maintenance arm (Chibaudel et al. 2009). Thus oxaliplatin-free intervals are feasible but complete discontinuation of chemotherapy may be associated with inferior outcomes. Secondly, the benefit of use of IV calcium (Ca) and magnesium (Mg) in order to diminish neuropathy symptoms was suggested in randomized trials. In 2011, Grothey and colleagues showed that IV Ca/Mg is an effective neuroprotectant against oxaliplatin-induced cumulative neuropathy in adjuvant colon cancer. The incidence of grade 2 or greater cumulative sensory neurotoxicity was significantly reduced. The onset of grade 2 or greater sensory neurotoxicity was also delayed in patients receiving Ca/Mg (Grothey et al. 2011). This study had a low statistical power due to early closure of the trial because preliminary reports from another trial (CONcePT trial) that initially suggested decreased response rates for patients getting Ca/Mg (Hochster et al. 2007). This was later

proven untrue by an independent radiologic review.

**2.4 Other chemotherapy combinations (table 2)**

The combination of oxaliplatin and irinotecan (IROX) has been assessed in first and second line setting. In the first-line setting, IROX was shown to be inferior and more toxic in elderly patients compared to FOLFOX (Sanoff et al. 2008) and equivalent to FOLFIRI (Fischer von Weikersthal et al.2011). In the second-line setting, IROX was compared to a triple regimen of 5FU/LV with alternating irinotecan and oxaliplatin. RR (23 versus 6 percent) and median survival (12.3 versus 9.8 months) were better with IROX but the doses of irinotecan and oxaliplatin were smaller in the triple therapy arm (Bécouarn et al. 2001). The efficacy of FOLFOXIRI regimen has been evaluated in two randomized studies. An Italian study showed better RR (41 versus 66 percent), PFS (9.8 versus 6.9 months) and OS (22.6 versus 16.7 months) for FOLFOXIRI compared to FOLFIRI in the first-line setting. This was in a selected population of patients in good general condition and with favorable features. More toxicities were reported in the FOLFOXIRI arm especially in terms of neutropenia and neurotoxicity (Falcone et al.2007). This benefit and its cost in terms of toxicities were confirmed in a systematic review (Montagnani et al. 2010). In contrast, a Greek phase 3 randomized failed to show benefits to FOLFOXIRI when compared to FOLFIRI (Souglakos et al. 2006). However, compared to the Italian trial, lower doses of oxaliplatin, irinotecan and 5-FU were used.

Table 2. Oxaliplatin Regimens

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 343

Bevacizumab is associated with several toxicities such as proteinuria, bleeding, HBP, arterial thromboembolic events (ATE) and gastrointestinal perforations (Kabbinavar et al. 2005). Thus high risk patients with comorbidities such as elderly patients and patients with historic of ATE or bleeding should be identified and carefully monitored if bevacizumab is administered. Also, because VEGF is involved in wound healing, bevacizumab should be

Cetuximab and panitumumab are monoclonal antibodies targeting the extracellular domain of the EGFR (epidermal growth factor receptor). *KRAS* mutations cause permanent activation of the downstream cascade and result in failure to respond to anti-EGFR monoclonal antibodies (Bardelli et al. 2010) (figure 1). *KRAS* mutations are detected in approximately 40% of mCRC. These mutations are mainly found in codons 12 and 13. Recent studies suggest however that not all mutations confer the same resistance to anti-EGFR therapy. Nevertheless, *KRAS* mutation is a predictive biomarker for anti-EGFR therapy and tumor *KRAS* status should be determined whenever anti-EGFR therapy is considered in the treatment of mCRC. According to ASCO's provisional clinical opinion, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for *KRAS* mutations in an accredited laboratory. If *KRAS* mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment (Allegra

Other mutations probably confer resistance to anti-EGFR therapy. *BRAF* mutation is found in 5 to 10 % of colorectal cancer tumors. *KRAS* and *BRAF* mutations are mutually exclusive. The *BRAF* mutation has been recognized as a negative prognostic marker but recent data does not confirm it as a negative predictive marker for anti-EGFR therapy. *PIK3CA* mutations/*PTEN* expression, amphiregulin and epiregulin are other potential predictive biomarkers but further supportive, preferably prospective, studies confirming their role as predictive biomarkers for anti-EGFR therapy would be necessary before considering their

stopped at least five weeks before any surgery.

**3.2 Anti-EGFR monoclonal antibodies**

use in routine clinical practice in this regard.

Fig. 1. EGFR Signal Transduction

et al. 2009).

#### **3. Targeted therapies**

Targeted cancer therapies are drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Bevacizumab, cetuximab and panitumumab are three monoclonal antibodies which have known efficacy in mCRC.

#### **3.1 Angiogenesis inhibitors**

#### **3.1.1 Bevacizumab**

Bevacizumab is a monoclonal humanized antibody targeting the VEGF. It is assumed that bevacizumab normalizes the vascular environment and improves the chemotherapy delivery to the tumor.

Bolus IFL (irinotecan/5-FU/LV) plus bevacizumab (5mg/kg) was compared to IFL plus placebo in previously untreated patients with mCRC. They observed statistically better RR, PFS and OS (20.3 versus 15.6 months). This was the pivotal study which led to the approval of bevacizumab in the treatment of mCRC. Grade 3-4 high blood pressure (HBP) was significantly increased in the bevacizumab arm (Hurwitz et al. 2004). FOLFIRI regimen has however gained acceptance over the bolus IFL regimen due to a more favorable toxicity profile. The BICC-C trial showed a significant advantage in terms of median survival with FOLFIRI plus bevacizumab compared to mIFL plus bevacizumab (28 versus 19 months, p=0.037) (Fuchs et al. 2007). Several trials have also addressed the benefit of adding bevacizumab to an oxaliplatin-based regimen. In a phase 2 cohort study (TREE-2), three oxaliplatin-containing regimens (FOLFOX, bolus 5FU and oxaliplatin-bFOL, CAPOX) were investigated in association with bevacizumab. Median survivals were respectively 26.1, 20.4 and 24.6 months (Hochster et al. 2008). Median OS was 23.7 months for the combined group treated with bevacizumab compared to 18.2 months for patients who did not received bevacizumab.The benefit of adding bevacizumab to oxaliplatin-containing chemotherapy appeared however to be more modest in the NO16966 trial. The addition of bevacizumab to FOLFOX4 or XELOX resulted in an increase of PFS of 1.4 months but the superiority of bevacizumab was statistically evident only in the XELOX subgroup (p=0.0026). Additionally, the OS significance did not reach statistical difference (21.3 months vs. 19.9 months) and the RR was similar in both groups (47% vs. 49%) (Saltz et al. 2008). The use of bevacizumab in first line is nevertheless widely accepted with either FOLFOX or FOLFIRI. In a phase 2 randomized study 5-FU/LV plus placebo was compared to 5-FU/LV plus bevacizumab. The bevacizumab-based treatment showed significant better PFS and non significant better OS (Kabbinavar et al. 2005). Thus, 5-FU/LV plus bevacizumab remains an option for patients with contraindications to other regimens.

The addition of bevacizumab in second-line treatment was assessed in the ECOG 3200 trial. Patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to receive FOLFOX4 in combination with bevacizumab (at 10 mg/kg), FOLFOX4 or bevacizumab alone. This study showed better PFS and OS in the FOLFOX4 plus bevacizumab arm. No activity was shown with bevacizumab alone (Giantonio et al. 2007). In contrast, there is no strong enough evidence to continue bevacizumab beyond progression in first-line treatment although favorable data is suggested by the BRITE study. This cohort study showed encouraging survival rates in patients who received postprogression chemotherapy with continued bevacizumab (Grothey et al. 2008).

Bevacizumab is associated with several toxicities such as proteinuria, bleeding, HBP, arterial thromboembolic events (ATE) and gastrointestinal perforations (Kabbinavar et al. 2005). Thus high risk patients with comorbidities such as elderly patients and patients with historic of ATE or bleeding should be identified and carefully monitored if bevacizumab is administered. Also, because VEGF is involved in wound healing, bevacizumab should be stopped at least five weeks before any surgery.

#### **3.2 Anti-EGFR monoclonal antibodies**

342 Rectal Cancer – A Multidisciplinary Approach to Management

Targeted cancer therapies are drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Bevacizumab, cetuximab and panitumumab are three monoclonal antibodies which have

Bevacizumab is a monoclonal humanized antibody targeting the VEGF. It is assumed that bevacizumab normalizes the vascular environment and improves the chemotherapy

Bolus IFL (irinotecan/5-FU/LV) plus bevacizumab (5mg/kg) was compared to IFL plus placebo in previously untreated patients with mCRC. They observed statistically better RR, PFS and OS (20.3 versus 15.6 months). This was the pivotal study which led to the approval of bevacizumab in the treatment of mCRC. Grade 3-4 high blood pressure (HBP) was significantly increased in the bevacizumab arm (Hurwitz et al. 2004). FOLFIRI regimen has however gained acceptance over the bolus IFL regimen due to a more favorable toxicity profile. The BICC-C trial showed a significant advantage in terms of median survival with FOLFIRI plus bevacizumab compared to mIFL plus bevacizumab (28 versus 19 months, p=0.037) (Fuchs et al. 2007). Several trials have also addressed the benefit of adding bevacizumab to an oxaliplatin-based regimen. In a phase 2 cohort study (TREE-2), three oxaliplatin-containing regimens (FOLFOX, bolus 5FU and oxaliplatin-bFOL, CAPOX) were investigated in association with bevacizumab. Median survivals were respectively 26.1, 20.4 and 24.6 months (Hochster et al. 2008). Median OS was 23.7 months for the combined group treated with bevacizumab compared to 18.2 months for patients who did not received bevacizumab.The benefit of adding bevacizumab to oxaliplatin-containing chemotherapy appeared however to be more modest in the NO16966 trial. The addition of bevacizumab to FOLFOX4 or XELOX resulted in an increase of PFS of 1.4 months but the superiority of bevacizumab was statistically evident only in the XELOX subgroup (p=0.0026). Additionally, the OS significance did not reach statistical difference (21.3 months vs. 19.9 months) and the RR was similar in both groups (47% vs. 49%) (Saltz et al. 2008). The use of bevacizumab in first line is nevertheless widely accepted with either FOLFOX or FOLFIRI. In a phase 2 randomized study 5-FU/LV plus placebo was compared to 5-FU/LV plus bevacizumab. The bevacizumab-based treatment showed significant better PFS and non significant better OS (Kabbinavar et al. 2005). Thus, 5-FU/LV plus bevacizumab remains an

The addition of bevacizumab in second-line treatment was assessed in the ECOG 3200 trial. Patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to receive FOLFOX4 in combination with bevacizumab (at 10 mg/kg), FOLFOX4 or bevacizumab alone. This study showed better PFS and OS in the FOLFOX4 plus bevacizumab arm. No activity was shown with bevacizumab alone (Giantonio et al. 2007). In contrast, there is no strong enough evidence to continue bevacizumab beyond progression in first-line treatment although favorable data is suggested by the BRITE study. This cohort study showed encouraging survival rates in patients who received post-

progression chemotherapy with continued bevacizumab (Grothey et al. 2008).

option for patients with contraindications to other regimens.

**3. Targeted therapies**

known efficacy in mCRC.

**3.1.1 Bevacizumab**

delivery to the tumor.

**3.1 Angiogenesis inhibitors**

Cetuximab and panitumumab are monoclonal antibodies targeting the extracellular domain of the EGFR (epidermal growth factor receptor). *KRAS* mutations cause permanent activation of the downstream cascade and result in failure to respond to anti-EGFR monoclonal antibodies (Bardelli et al. 2010) (figure 1). *KRAS* mutations are detected in approximately 40% of mCRC. These mutations are mainly found in codons 12 and 13. Recent studies suggest however that not all mutations confer the same resistance to anti-EGFR therapy. Nevertheless, *KRAS* mutation is a predictive biomarker for anti-EGFR therapy and tumor *KRAS* status should be determined whenever anti-EGFR therapy is considered in the treatment of mCRC. According to ASCO's provisional clinical opinion, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for *KRAS* mutations in an accredited laboratory. If *KRAS* mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment (Allegra et al. 2009).

Other mutations probably confer resistance to anti-EGFR therapy. *BRAF* mutation is found in 5 to 10 % of colorectal cancer tumors. *KRAS* and *BRAF* mutations are mutually exclusive. The *BRAF* mutation has been recognized as a negative prognostic marker but recent data does not confirm it as a negative predictive marker for anti-EGFR therapy. *PIK3CA* mutations/*PTEN* expression, amphiregulin and epiregulin are other potential predictive biomarkers but further supportive, preferably prospective, studies confirming their role as predictive biomarkers for anti-EGFR therapy would be necessary before considering their use in routine clinical practice in this regard.

Fig. 1. EGFR Signal Transduction

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 345

*KRAS* tumors did not benefit, and may actually have been harmed, with the addition of cetuximab (RR of 33% vs. 49% in the FOLFOX4 alone group (p=0.106)). The phase III COIN trial is another important study which has evaluated the effect of addition of cetuximab to first-line oxaliplatin-based regimens treatment for advanced colorectal cancer. The choice of fluoropyrimidine (either 5-FU or capecitabine) was decided by the treating physician prior randomization (66% of the patients received oxaliplatin plus capecitabine). In patients with wt-*KRAS* tumor, the addition of cetuximab to oxaliplatin- based chemotherapy was associated with a small increase in best overall response (64% vs. 57%, P=0.049). In contrast to CRYSTAL and OPUS studies, however, the addition of cetuximab was not associated with any significant improvement in OS or PFS. (Maughan et al. 2011). Discrepancy between

Panitumumab is a fully human monoclonal antibody targeting the extracellular domain of EGFR. Similarly to cetuximab, panitumumab has shown efficacy in previously mCRC

In patients refractory to 5-FU, irinotecan and oxaliplatin, panitumumab monotherapy showed significantly improved PFS from 7.3 to 8 weeks (p<0.001) and RR (10 percent versus 0 percent) compared to BSC alone. There was no OS benefit, likely due to panitumumab use after crossover in the BSC alone. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed (Van Cutsem et al. 2007). In this study, the effect on PFS in the wt-*KRAS* group was significantly higher than in the mutant group. Median PFS in the wt-*KRAS* group was 12.3 for panitumumab versus 7.3 weeks for BSC. RR was 17 percent for wt-*KRAS* versus 0 percent for patients with mutant *KRAS* tumors. This showed that panitumumab monotherapy efficacy is confined to wt-*KRAS* tumors and that this status should be considered in selecting patients for panitumumab monotherapy (Amado et al. 2008). In 2010, the FOLFIRI/panitumumab combination was compared to FOLFIRI alone in second-line treatment. In the *KRAS*-wt patients, when panitumumab was added to FOLFIRI median PFS was 5.9 months versus 3.9 months for FOLFIRI alone (p=0.004)(Peeters

Panitumumab, in conjunction with chemotherapy regimen, has also been evaluated in firstline therapy for mCRC. In 2010, Douillard and colleagues compared FOLFOX 4 and panitumumab versus FOLFOX 4 alone as first-line chemotherapy for previously untreated mCRC (PRIME study). In the *KRAS*-wt patients, panitumumab-FOLFOX4 combination significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; p=0.02). In the *KRAS*-mutant patients, outcome was significantly worse with panitumumab underscoring the importance of *KRAS* screening (Douillard et al. 2010). Several studies have assessed the use of a dual antibody modality. The PACCE study evaluated the addition of panitumumab to bevacizumab and chemotherapy (oxaliplatinand irinotecan-based) as first-line treatment for mCRC (Hecht et al. 2009). This study was stopped due to an interim analysis showing inferior PFS and more toxicities in the panitumumab arm. The CAIRO 2 study assigned untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab or the same regimen plus weekly cetuximab. PFS was worse in dual antibody therapy (Tol et al. 2009).These results suggest that dual

antibody therapy should not be considered outside further clinical trials.

these studies remains difficult to explain.

treated patients as well as in first-line therapy.

**3.2.2 Panitumumab (table 3)**

et al. 2009).

Cetuximab is associated with severe infusion reaction in three percent of patients. Ninety percent occur during the first infusion and generally in the three first hours. Premedication with anti H1 antagonist and/or glucocorticoid is recommended (Wilke et al. 2008). Panitumumab is generally associated with less infusion reaction because of its 100% human origin. Cetuximab and panitumumab may be also associated with a magnesium-wasting syndrome. Serum levels of this electrolyte should be carefully monitored during treatment. Acneiform eruption occurs in two third of patients treated anti-EGFR molecules. Some studies suggest benefit from using prophylactic antibiotics such as minocyline or doxycycline and topical application of hydrocortisone-based cream (Scope et al. 2007; Lacouture et al. 2010).

#### **3.2.1 Cetuximab (table 3)**

Cetuximab is a chimeric (mouse/human) monoclonal antibody against the EGFR. In mCRC, cetuximab has shown efficacy in monotherapy as well as in combination with chemotherapy. It can be used in previously mCRC treated patients or in first-line therapy. In 2007, cetuximab alone was compared to best supportive care (BSC) in the CO-17 trial. Patients had immunohistochemically detectable EGFR, previously been treated with fluoropyrymidines, irinotecan and oxaliplatin or had contraindications to treatment with these drugs. Survival was significantly better in the cetuximab arm (6.1 vs. 4.6 months). Quality of life was better preserved in the cetuximab group. Cetuximab was associated with a skin rash; grade 2 or higher grade rashes were strongly associated with improved survival (Jonker et al. 2007). In a subsequent analysis, in patients with mutated *KRAS* tumors, there was no significant difference between those who were treated with cetuximab and those who were treated with best supportive care. For wild-type (wt) *KRAS* patients, PFS (3.7 versus 1.9 months) and median OS (9.5 versus 4.8 months) were significantly improved by treatment with cetuximab as compared with best supportive care alone (Karapetis et al. 2008).

In the BOND study, a randomized phase 2 trial, irinotecan plus cetuximab was compared to cetuximab alone for patients refractory to irinotecan. RR and TTP were significantly better in the irinotecan plus cetuximab arm (22.9% vs. 10.8% and 4.1 vs. 1.5 months). There was a trend for better survival also in this arm as well (Cunningham et al. 2004).

In the EPIC trial, adding cetuximab to irinotecan after first-line fluoropyrimidine and oxaliplatin treatment failure, improved RR (16.4 percent versus 4.2 percent), PFS (4.0 versus 2.6 months) and quality of life compared with irinotecan alone (Sobrero et al. 2008; table 3).

Trials have also evaluated the efficacy of cetuximab in combination with chemotherapy in first-line treatment of mCRC. In the phase III CRYSTAL trial, the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) was investigated as first-line treatment for metastatic colorectal cancer. There was a significant advantage in RR, PFS and OS for the cetuximab group, but this benefit was limited to *KRAS*-wt patients (Van Cutsem et al. 2010).

In the randomized phase II multicenter OPUS trial, the addition of cetuximab to FOLFOX4 was associated with improved outcomes compared to FOLFOX4 alone in first-line treatment. A statistically significant better chance of response and PFS was shown in patients with *KRAS* wild-type tumors (Bokemeyer et al. 2009; table 3). Patients with mutant *KRAS* tumors did not benefit, and may actually have been harmed, with the addition of cetuximab (RR of 33% vs. 49% in the FOLFOX4 alone group (p=0.106)). The phase III COIN trial is another important study which has evaluated the effect of addition of cetuximab to first-line oxaliplatin-based regimens treatment for advanced colorectal cancer. The choice of fluoropyrimidine (either 5-FU or capecitabine) was decided by the treating physician prior randomization (66% of the patients received oxaliplatin plus capecitabine). In patients with wt-*KRAS* tumor, the addition of cetuximab to oxaliplatin- based chemotherapy was associated with a small increase in best overall response (64% vs. 57%, P=0.049). In contrast to CRYSTAL and OPUS studies, however, the addition of cetuximab was not associated with any significant improvement in OS or PFS. (Maughan et al. 2011). Discrepancy between these studies remains difficult to explain.

#### **3.2.2 Panitumumab (table 3)**

344 Rectal Cancer – A Multidisciplinary Approach to Management

Cetuximab is associated with severe infusion reaction in three percent of patients. Ninety percent occur during the first infusion and generally in the three first hours. Premedication with anti H1 antagonist and/or glucocorticoid is recommended (Wilke et al. 2008). Panitumumab is generally associated with less infusion reaction because of its 100% human origin. Cetuximab and panitumumab may be also associated with a magnesium-wasting syndrome. Serum levels of this electrolyte should be carefully monitored during treatment. Acneiform eruption occurs in two third of patients treated anti-EGFR molecules. Some studies suggest benefit from using prophylactic antibiotics such as minocyline or doxycycline and topical application of hydrocortisone-based cream (Scope et al. 2007;

Cetuximab is a chimeric (mouse/human) monoclonal antibody against the EGFR. In mCRC, cetuximab has shown efficacy in monotherapy as well as in combination with chemotherapy. It can be used in previously mCRC treated patients or in first-line therapy. In 2007, cetuximab alone was compared to best supportive care (BSC) in the CO-17 trial. Patients had immunohistochemically detectable EGFR, previously been treated with fluoropyrymidines, irinotecan and oxaliplatin or had contraindications to treatment with these drugs. Survival was significantly better in the cetuximab arm (6.1 vs. 4.6 months). Quality of life was better preserved in the cetuximab group. Cetuximab was associated with a skin rash; grade 2 or higher grade rashes were strongly associated with improved survival (Jonker et al. 2007). In a subsequent analysis, in patients with mutated *KRAS* tumors, there was no significant difference between those who were treated with cetuximab and those who were treated with best supportive care. For wild-type (wt) *KRAS* patients, PFS (3.7 versus 1.9 months) and median OS (9.5 versus 4.8 months) were significantly improved by treatment with cetuximab as compared with best supportive care alone (Karapetis et al.

In the BOND study, a randomized phase 2 trial, irinotecan plus cetuximab was compared to cetuximab alone for patients refractory to irinotecan. RR and TTP were significantly better in the irinotecan plus cetuximab arm (22.9% vs. 10.8% and 4.1 vs. 1.5 months). There was a

In the EPIC trial, adding cetuximab to irinotecan after first-line fluoropyrimidine and oxaliplatin treatment failure, improved RR (16.4 percent versus 4.2 percent), PFS (4.0 versus 2.6 months) and quality of life compared with irinotecan alone (Sobrero et al.

Trials have also evaluated the efficacy of cetuximab in combination with chemotherapy in first-line treatment of mCRC. In the phase III CRYSTAL trial, the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) was investigated as first-line treatment for metastatic colorectal cancer. There was a significant advantage in RR, PFS and OS for the cetuximab group, but this benefit was limited to *KRAS*-wt patients (Van

In the randomized phase II multicenter OPUS trial, the addition of cetuximab to FOLFOX4 was associated with improved outcomes compared to FOLFOX4 alone in first-line treatment. A statistically significant better chance of response and PFS was shown in patients with *KRAS* wild-type tumors (Bokemeyer et al. 2009; table 3). Patients with mutant

trend for better survival also in this arm as well (Cunningham et al. 2004).

Lacouture et al. 2010).

2008).

2008; table 3).

Cutsem et al. 2010).

**3.2.1 Cetuximab (table 3)**

Panitumumab is a fully human monoclonal antibody targeting the extracellular domain of EGFR. Similarly to cetuximab, panitumumab has shown efficacy in previously mCRC treated patients as well as in first-line therapy.

In patients refractory to 5-FU, irinotecan and oxaliplatin, panitumumab monotherapy showed significantly improved PFS from 7.3 to 8 weeks (p<0.001) and RR (10 percent versus 0 percent) compared to BSC alone. There was no OS benefit, likely due to panitumumab use after crossover in the BSC alone. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed (Van Cutsem et al. 2007). In this study, the effect on PFS in the wt-*KRAS* group was significantly higher than in the mutant group. Median PFS in the wt-*KRAS* group was 12.3 for panitumumab versus 7.3 weeks for BSC. RR was 17 percent for wt-*KRAS* versus 0 percent for patients with mutant *KRAS* tumors. This showed that panitumumab monotherapy efficacy is confined to wt-*KRAS* tumors and that this status should be considered in selecting patients for panitumumab monotherapy (Amado et al. 2008). In 2010, the FOLFIRI/panitumumab combination was compared to FOLFIRI alone in second-line treatment. In the *KRAS*-wt patients, when panitumumab was added to FOLFIRI median PFS was 5.9 months versus 3.9 months for FOLFIRI alone (p=0.004)(Peeters et al. 2009).

Panitumumab, in conjunction with chemotherapy regimen, has also been evaluated in firstline therapy for mCRC. In 2010, Douillard and colleagues compared FOLFOX 4 and panitumumab versus FOLFOX 4 alone as first-line chemotherapy for previously untreated mCRC (PRIME study). In the *KRAS*-wt patients, panitumumab-FOLFOX4 combination significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; p=0.02). In the *KRAS*-mutant patients, outcome was significantly worse with panitumumab underscoring the importance of *KRAS* screening (Douillard et al. 2010).

Several studies have assessed the use of a dual antibody modality. The PACCE study evaluated the addition of panitumumab to bevacizumab and chemotherapy (oxaliplatinand irinotecan-based) as first-line treatment for mCRC (Hecht et al. 2009). This study was stopped due to an interim analysis showing inferior PFS and more toxicities in the panitumumab arm. The CAIRO 2 study assigned untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab or the same regimen plus weekly cetuximab. PFS was worse in dual antibody therapy (Tol et al. 2009).These results suggest that dual antibody therapy should not be considered outside further clinical trials.

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 347

in advanced CRC. Their conclusion was that the three active drugs in mCRC (5-FU/LV, irinotecan and oxaliplatin) should be available to all patients in order to maximize the OS (Grothey et al. 2004). For patients with good performance status, combination therapy (FOLFOX or FOLFIRI) should be preferred as first-line chemotherapy. The choice of regimen should be based on the different toxicity profile of these two regimens. Fragile patients are not candidates for combination therapy but can benefit from treatment with fluoropyrimidine monotherapy. Infusion regimens are associated with less toxicity and should be used in any regimen. The use of oral capecitabine in regimens such as CAPOX is also a valid option for patients for whom infusion is not possible or refused. Different strategies can be used in an attempt to prevent oxaliplatin-induced neuropathy. It remains unclear if a combination regimen such as FOLFOXIRI is superior to FOLFOX or FOLFIRI combined with bevacizumab or an anti-EGFR monoclonal antibody. FOLFOXIRI is associated with significant toxicity and its use is not yet standard in first-line treatment of mCRC. The addition of bevacizumab, a monoclonal antibody targeting the VEGF, is now widely recommended with FOLFIRI, FOLFOX or fluoropyrimidine monotherapy in firstline therapy of mCRC for patients without contraindications to this agent. The use of bevacizumab in second-line setting is also recommended in patients who did not receive this agent in first-line treatment. The benefit of its use beyond progression remains controversial and is not presently recommended. Bevacizumab is associated with potentially serious toxicities so careful attention and monitoring of expected side effects is mandatory. Anti-EGFR monoclonal antibodies, cetuximab and panitumumab, are associated with improved outcomes when used as single agents as salvage therapy in patients with chemotherapy-refractory mCRC and when used for first-line and second-line therapy of mCRC in conjunction with chemotherapy regimens. However, their benefit is restrained to patients whose tumor does not harbour *KRAS* mutation. It is unknown whether adding EGFR inhibitors to initial therapy or using it in a sequential approach as a component of second or third –line therapy gives better results. Also, for now, it is not clear whether bevacizumab or anti-EGFR inhibitor should be preferentially added to first-line therapy. Indeed, chemotherapy plus bevacizumab currently represents the most widely accepted standard for first-line treatment of mCRC. Results from the current North American CALGB/SWOG cooperative group trial of best chemotherapy plus either bevacizumab or cetuximab in untreated *KRAS-*wt metastatic colorectal patients will help in guiding this decision. Although there are no trials directly comparing panitumumab to cetuximab, these agents appear to have comparable efficacy and they are probably interchangeable. Treatment must be individualized as always, taking into account goals of therapy, *KRAS* mutation status, and the toxicity profiles of each agent. Inclusion of patients in clinical trials

Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology

provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. *J Clin Oncol.* Apr 20 2009;27(12):2091-2096. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy

in patients with metastatic colorectal cancer. *J Clin Oncol.* Apr 1 2008;26(10):1626-

should always be encouraged if possible.

**6. References**

1634.

Table 3. Randomized Trials of Anti-EGFR-chemotherapy Association

#### **4. Local recurrence**

The treatment of locally recurrent disease largely depends on prior treatments. Whether the patient had prior surgery and/or radiation will determine the therapeutic approach. Surgery alone may be an option if negative surgical margins can be achieved. Extensive surgery is generally required. Combined therapies including chemotherapy and radiation (if prior radiation was not administered) are favored. In this setting the addition of chemotherapy to radiation before surgery improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in a Norwegian phase 3 randomized study (Braendengen et al. 2008). Still this data has to be considered carefully because the patients in this study had primary unresectable tumors as well as local recurrences and that prior radiation was not allowed. Patients with local recurrence were more likely to be unresectable after preoperative treatment. Trends to improved local control were seen in a retrospective study from the Mayo clinic with the addition of 5-FU to external beam radiotherapy, intraoperative electron beam and surgery (Gunderson et al. 1996).

#### **5. Summary and recommendations**

Striking advances have been made in the treatment of metastatic colorectal cancer in the past fifteen years. In 2004, Grothey and colleagues reviewed seven published phase III trials in advanced CRC. Their conclusion was that the three active drugs in mCRC (5-FU/LV, irinotecan and oxaliplatin) should be available to all patients in order to maximize the OS (Grothey et al. 2004). For patients with good performance status, combination therapy (FOLFOX or FOLFIRI) should be preferred as first-line chemotherapy. The choice of regimen should be based on the different toxicity profile of these two regimens. Fragile patients are not candidates for combination therapy but can benefit from treatment with fluoropyrimidine monotherapy. Infusion regimens are associated with less toxicity and should be used in any regimen. The use of oral capecitabine in regimens such as CAPOX is also a valid option for patients for whom infusion is not possible or refused. Different strategies can be used in an attempt to prevent oxaliplatin-induced neuropathy. It remains unclear if a combination regimen such as FOLFOXIRI is superior to FOLFOX or FOLFIRI combined with bevacizumab or an anti-EGFR monoclonal antibody. FOLFOXIRI is associated with significant toxicity and its use is not yet standard in first-line treatment of mCRC. The addition of bevacizumab, a monoclonal antibody targeting the VEGF, is now widely recommended with FOLFIRI, FOLFOX or fluoropyrimidine monotherapy in firstline therapy of mCRC for patients without contraindications to this agent. The use of bevacizumab in second-line setting is also recommended in patients who did not receive this agent in first-line treatment. The benefit of its use beyond progression remains controversial and is not presently recommended. Bevacizumab is associated with potentially serious toxicities so careful attention and monitoring of expected side effects is mandatory. Anti-EGFR monoclonal antibodies, cetuximab and panitumumab, are associated with improved outcomes when used as single agents as salvage therapy in patients with chemotherapy-refractory mCRC and when used for first-line and second-line therapy of mCRC in conjunction with chemotherapy regimens. However, their benefit is restrained to patients whose tumor does not harbour *KRAS* mutation. It is unknown whether adding EGFR inhibitors to initial therapy or using it in a sequential approach as a component of second or third –line therapy gives better results. Also, for now, it is not clear whether bevacizumab or anti-EGFR inhibitor should be preferentially added to first-line therapy. Indeed, chemotherapy plus bevacizumab currently represents the most widely accepted standard for first-line treatment of mCRC. Results from the current North American CALGB/SWOG cooperative group trial of best chemotherapy plus either bevacizumab or cetuximab in untreated *KRAS-*wt metastatic colorectal patients will help in guiding this decision. Although there are no trials directly comparing panitumumab to cetuximab, these agents appear to have comparable efficacy and they are probably interchangeable. Treatment must be individualized as always, taking into account goals of therapy, *KRAS* mutation status, and the toxicity profiles of each agent. Inclusion of patients in clinical trials should always be encouraged if possible.

#### **6. References**

346 Rectal Cancer – A Multidisciplinary Approach to Management

Cetuximab First FOLFIRI Median PFS\*: 9.9 vs. 8.4 months

Cetuximab First FOLFOX 4 Overall RR\*: 61% vs. 37%

5FU or capecitabine

Panitumumab First FOLFOX 4 Median PFS\*: 9.6 vs. 8 months

Cetuximab Second Irinotecan PFS: 4 vs. 2.6 months (p<0.0001)

Panitumumab Second FOLFIRI Median PFS\*: 5.9 vs. 3.9 months

The treatment of locally recurrent disease largely depends on prior treatments. Whether the patient had prior surgery and/or radiation will determine the therapeutic approach. Surgery alone may be an option if negative surgical margins can be achieved. Extensive surgery is generally required. Combined therapies including chemotherapy and radiation (if prior radiation was not administered) are favored. In this setting the addition of chemotherapy to radiation before surgery improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in a Norwegian phase 3 randomized study (Braendengen et al. 2008). Still this data has to be considered carefully because the patients in this study had primary unresectable tumors as well as local recurrences and that prior radiation was not allowed. Patients with local recurrence were more likely to be unresectable after preoperative treatment. Trends to improved local control were seen in a retrospective study from the Mayo clinic with the addition of 5-FU to external beam

radiotherapy, intraoperative electron beam and surgery (Gunderson et al. 1996).

Striking advances have been made in the treatment of metastatic colorectal cancer in the past fifteen years. In 2004, Grothey and colleagues reviewed seven published phase III trials

HR 0.696 (p=0.0012)

HR 0.796 (p=0.0093)

(p=0.011)

(p=0.0163)

cetuximab

(p=0.02)

(p=0.004)

Median OS\*: 23.5 vs. 20.0 months

Median PFS\*: 7.7 vs. 7.2 months

ORR\*: 64% vs. 57% (p=0.049) No significant improvement in OS or PFS with the addition of

RR: 16.4% vs. 4.2% (p<0.0001) OS: 10.7 vs. 10.0 months (p=0.71) but 46.9% of the patients in the irinotecan group received cetuximab after trial. *(KRAS* unselected)

**Trial Agent Line Chemotherapy Results (\****KRAS-***wt patients)**

Cetuximab First Oxaliplatin with

Table 3. Randomized Trials of Anti-EGFR-chemotherapy Association

CRYSTAL *Van Cutsem et al. 2011*

OPUS *Bokemeyer et al. 2009*

COIN *Maughan et al. 2011*

PRIME *Douillard et al. 2010*

EPIC *Sobrero et al.2008*

STUDY 181 *Peeters et al*. 2010

**4. Local recurrence**

**5. Summary and recommendations**

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer 349

Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with

Fischer von Weikersthal L, Schalhorn A, Stauch M, et al. Phase III trial of irinotecan plus

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**19**

*1Germany 2Spain*

**Side Effects of Neoadjuvant Treatment**

*2Division of Colon & Rectal Surgery, University Hospital HUVN Granada*

Neoadjuvant treatment of locally advanced rectal cancer patients provides undisputable advantages regarding local control (1; 2), and it seems to afford the benefit of survival in patients with preoperative complete regression (3; 4). Furthermore, local control is an important feature in life quality of rectal cancer patients. However, due to the perspicuous interests in oncological effects, the acute and moreover late side effects tend to be neglected. The consequence is that especially late side effects have probably been underestimated until

Many patients would perceive a permanent stoma and loss of the anal sphincter as a stigma that lowers their self-esteem (5). Hence, sphincter preservation is a major request of the patients and developed to an important surgical concern. In fact, patients are willing to trade a considerable amount of survival to avoid a colostomy (6). And more than this, they

Though, with regard to oncological and surgical outcome control late results are important. For all patients quality of life matters are fundamental. This particularly counts for those patients who show an incomplete regression or none and therefore do have only limited

The TME trial was the first large study that compared additional preoperative radiation therapy to TME (Total Mesorectal Excision) surgery alone (1). To register the acute side effects the RTOG (Radiation Therapy Oncology Group) classification 0-5 was used. In general, RTOG 0 represents no complaints and RTOG 5 is a toxicity leading to death. Mild toxic effects are grade 1 and 2; ≥ grade 3 counts as severe toxic effect. The trial showed acute side effects in 26% of the patients within three months of the start of short course radiation therapy (7). It is noticeable in the precise description of the side effects that the most frequent complications were gastrointestinal followed by neurological. 13% of the patients showed gastrointestinal symptoms, most of them grade I or II; only one patient suffered from grade III and none of grade IV (7). It is interesting to know that the scoring system for neurological symptoms was additionally implemented one year after the beginning of the

are also disposed to trade survival in order to avoid chemotherapy (6).

**1. Introduction**

benefit from the treatment.

**2. Acute side effects**

now.

**in Locally Advanced Rectal Cancer**

Karoline Horisberger1 and Pablo Palma2

*1Department of Surgery, University Hospital Mannheim*

Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL. Acute oxaliplatininduced peripheral nerve hyperexcitability. *J Clin Oncol.* Apr 1 2002;20(7):1767- 1774.

### **Side Effects of Neoadjuvant Treatment in Locally Advanced Rectal Cancer**

Karoline Horisberger1 and Pablo Palma2 *1Department of Surgery, University Hospital Mannheim 2Division of Colon & Rectal Surgery, University Hospital HUVN Granada 1Germany 2Spain*

#### **1. Introduction**

352 Rectal Cancer – A Multidisciplinary Approach to Management

Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL. Acute oxaliplatin-

1774.

induced peripheral nerve hyperexcitability. *J Clin Oncol.* Apr 1 2002;20(7):1767-

Neoadjuvant treatment of locally advanced rectal cancer patients provides undisputable advantages regarding local control (1; 2), and it seems to afford the benefit of survival in patients with preoperative complete regression (3; 4). Furthermore, local control is an important feature in life quality of rectal cancer patients. However, due to the perspicuous interests in oncological effects, the acute and moreover late side effects tend to be neglected. The consequence is that especially late side effects have probably been underestimated until now.

Many patients would perceive a permanent stoma and loss of the anal sphincter as a stigma that lowers their self-esteem (5). Hence, sphincter preservation is a major request of the patients and developed to an important surgical concern. In fact, patients are willing to trade a considerable amount of survival to avoid a colostomy (6). And more than this, they are also disposed to trade survival in order to avoid chemotherapy (6).

Though, with regard to oncological and surgical outcome control late results are important. For all patients quality of life matters are fundamental. This particularly counts for those patients who show an incomplete regression or none and therefore do have only limited benefit from the treatment.

#### **2. Acute side effects**

The TME trial was the first large study that compared additional preoperative radiation therapy to TME (Total Mesorectal Excision) surgery alone (1). To register the acute side effects the RTOG (Radiation Therapy Oncology Group) classification 0-5 was used. In general, RTOG 0 represents no complaints and RTOG 5 is a toxicity leading to death. Mild toxic effects are grade 1 and 2; ≥ grade 3 counts as severe toxic effect. The trial showed acute side effects in 26% of the patients within three months of the start of short course radiation therapy (7). It is noticeable in the precise description of the side effects that the most frequent complications were gastrointestinal followed by neurological. 13% of the patients showed gastrointestinal symptoms, most of them grade I or II; only one patient suffered from grade III and none of grade IV (7). It is interesting to know that the scoring system for neurological symptoms was additionally implemented one year after the beginning of the

Side Effects of Neoadjuvant Treatment in Locally Advanced Rectal Cancer 355

leukopenia (25 vs. 35%) (12). Gastrointestinal and skin complications were no different

The addition of oxaliplatin to neoadjuvant treatment, either with 5-FU treatment or capecitabine, significantly increased the acute toxicity (particularly diarrhoea) three-fold and 2.5-fold, respectively (13; 14). However, toxicity could be interpreted as feasible as particular grade III toxicities were recorded in not more than 15% of the patients. It was disappointing, however, that the rates of complete response did not change in both trials (13; 14). Unfortunately, there are no other randomised phase III trials that have compared different

A pooled analysis of three phase I/II trials of patients treated with or without additional

Looking at the postoperative complications one can notice that reporting of them is performed on an irregular basis concerning the definition of some complications as well as whether they are reported at all. Few randomised studies (2; 7; 14) report in detail on perioperative complications while others outline the overall rate of complications (Tables 2/3). However, the interpretation of surgical and other complications is complex, even in the case of detailed reports. By way of example, the TME trial meticulously reports a significantly higher rate of postoperative complications in irradiated patients (7). Nevertheless, the rate of all surgical complications is the same for irradiated and nonirradiated patients, although it differs for those with abdominoperineal resection. This is caused by the rate of perineal wound dehiscence that is increased following neoadjuvant radiation, while the rate of anastomotic leakages is no different between the groups. In addition, cardiac and psychological complications that are significantly more frequent in

With regard to the risk of perineal wound dehiscence, the results of the different studies are inconsistent. While it is significantly increased for short-course radiation and

The early anastomotic leakage rate has been reported as 8-18% after neoadjuvant treatment and is thereby no different from rates in non-irradiated patients (Table 3) (2; 7; 10; 17; 18). A correlation between neoadjuvant treatment and anastomotic leakage rate cannot be seen in a single study (2; 7; 9; 10; 17). However, in a population-based study from Sweden, the multivariate analysis of 432 out of 6833 patients revealed preoperative radiation to be an independent risk factor for anastomotic leakage (19). The restriction of this publication, however, is the fact that the large majority of these operations were performed without

Besides this, two single-centre studies report a positive correlation between the preoperative

One main problem of anastomotic leakage reporting is the fact that there is no definition of leakage that has to be reported (Fig. 2/3). While some studies report all clinical apparent leakages as well as the abscess around the anastomosis as leakage (7; 21), others do differ between clinical and radiological leakage (20). Some do not define what they count as

Until now, the influence of intensified chemoradiation using oxaliplatin is described by only one phase III trial (14). In this single trial, the rate of anastomotic leakage is no different between patients who received capecitabine and those with additional oxaliplatin (14).

leakage (2), others just allude to those complications that require reintervention (9).

irradiated patients aggravate the higher postoperative complication rate (7).

chemoradiation in some trials (7; 16), others rule out an influence (2).

TME. Though, the influence of this fact is in this regard not known.

regression grade and the risk of anastomotic leakage (Fig. 1) (20; 21).

cetuximab saw no difference in question of acute toxicity (15).

between the arms.

CRT regimens.

**3. Postoperative complications**

trial because observations of acute plexopathy in the antecedent Swedish Rectal Cancer Trial were published in 1996 (8). During the first full year of the 4-year trial, no neurological symptoms were recorded in any of the patients (7). In fact, the Swedish Rectal Cancer Trial also compared neoadjuvant short-course radiation with surgery alone; however, this trial was conducted in the era before TME. It has to be noticed that during the recruitment phase of the Swedish Rectal Cancer Trial, the radiation technique changed from three-beam to four-beam (8). The authors explicitly report that no plexopathy was observed after conventional fractionation of the radiotherapy (2Gy/d) but only after short-course hypofractionated 5x5Gy radiation (8).

Neoadjuvant chemoradiation correlates more closely with higher acute toxicity than shortcourse radiation (9); in fact, it seems to be less harmful than postoperative chemoradiation with regard to acute toxicity (2). Comparing preoperative chemoradiation and long-course radiation with 45 Gy it seems to be obvious that radiation is more tolerable in the acute phase (10; 11). Actually, in most studies only grade 3 and grade 4 toxicities are listed, though the higher rates of grade 1 and 2 toxicities are not mentioned.

Cap: capecitabine; CapOx: capecitabine and oxaliplatin

Table 1. Acute toxicity ≥ grade III (\*toxicities ≥ grade II) in randomised trials.

An impression of the difference is given in the publication of the EORTC 22921 study that listed all toxicities ≥ grade 2 and which thereby obtained a toxicity rate of 37.7 resp. 54% comparing 45 Gy with chemoradiation (11). The exclusive subsumption of grade 3 and 4 toxicities of neoadjuvant treatment obtains a toxicity rate below 20% (Table 1). It should be noted that in a direct comparison of 5-FU versus capecitabine in a phase III trial, capecitabine showed to constitute significantly more hand-footsyndrome (31 vs. 2%) but less leukopenia (25 vs. 35%) (12). Gastrointestinal and skin complications were no different between the arms.

The addition of oxaliplatin to neoadjuvant treatment, either with 5-FU treatment or capecitabine, significantly increased the acute toxicity (particularly diarrhoea) three-fold and 2.5-fold, respectively (13; 14). However, toxicity could be interpreted as feasible as particular grade III toxicities were recorded in not more than 15% of the patients. It was disappointing, however, that the rates of complete response did not change in both trials (13; 14). Unfortunately, there are no other randomised phase III trials that have compared different CRT regimens.

A pooled analysis of three phase I/II trials of patients treated with or without additional cetuximab saw no difference in question of acute toxicity (15).

#### **3. Postoperative complications**

354 Rectal Cancer – A Multidisciplinary Approach to Management

trial because observations of acute plexopathy in the antecedent Swedish Rectal Cancer Trial were published in 1996 (8). During the first full year of the 4-year trial, no neurological symptoms were recorded in any of the patients (7). In fact, the Swedish Rectal Cancer Trial also compared neoadjuvant short-course radiation with surgery alone; however, this trial was conducted in the era before TME. It has to be noticed that during the recruitment phase of the Swedish Rectal Cancer Trial, the radiation technique changed from three-beam to four-beam (8). The authors explicitly report that no plexopathy was observed after conventional fractionation of the radiotherapy (2Gy/d) but only after short-course

Neoadjuvant chemoradiation correlates more closely with higher acute toxicity than shortcourse radiation (9); in fact, it seems to be less harmful than postoperative chemoradiation with regard to acute toxicity (2). Comparing preoperative chemoradiation and long-course radiation with 45 Gy it seems to be obvious that radiation is more tolerable in the acute phase (10; 11). Actually, in most studies only grade 3 and grade 4 toxicities are listed, though

**Therapy strategy Toxicity**

695 vs. 719 5x5 Gy versus TME 2.4 vs. 0 n.s.

**grade III-IV**

3 vs. 18 0.001

37.7 vs. 54 \* <0.005

2.7 vs. 14.6 <0.005

27 vs. 40 0.001

10.9 vs. 25.4 <0.001

**P value**

**(%)**

hypofractionated 5x5Gy radiation (8).

**Reference No. of**

Marijnen 2002

Bujko 2004

Bosset 2004

Gérard 2006

Sauer 2004

Gérard 2010

the higher rates of grade 1 and 2 toxicities are not mentioned.

155 vs. 157 5x5 Gy versus

398 vs. 400 45 Gy versus

367 vs. 375 45 Gy versus

404 vs. 394 Pre- versus

293 vs. 291 Cap vs. CapOx

Table 1. Acute toxicity ≥ grade III (\*toxicities ≥ grade II) in randomised trials.

preoperative

preoperative

preoperative

postoperative

preoperative chemoradiation

chemoradiation (5-FU)

chemoradiation (5-FU)

chemoradiation (5-FU)

chemoradiation (5-FU)

An impression of the difference is given in the publication of the EORTC 22921 study that listed all toxicities ≥ grade 2 and which thereby obtained a toxicity rate of 37.7 resp. 54% comparing 45 Gy with chemoradiation (11). The exclusive subsumption of grade 3 and 4 toxicities of neoadjuvant treatment obtains a toxicity rate below 20% (Table 1). It should be noted that in a direct comparison of 5-FU versus capecitabine in a phase III trial, capecitabine showed to constitute significantly more hand-footsyndrome (31 vs. 2%) but less

**patients**

Cap: capecitabine; CapOx: capecitabine and oxaliplatin

Looking at the postoperative complications one can notice that reporting of them is performed on an irregular basis concerning the definition of some complications as well as whether they are reported at all. Few randomised studies (2; 7; 14) report in detail on perioperative complications while others outline the overall rate of complications (Tables 2/3). However, the interpretation of surgical and other complications is complex, even in the case of detailed reports. By way of example, the TME trial meticulously reports a significantly higher rate of postoperative complications in irradiated patients (7). Nevertheless, the rate of all surgical complications is the same for irradiated and nonirradiated patients, although it differs for those with abdominoperineal resection. This is caused by the rate of perineal wound dehiscence that is increased following neoadjuvant radiation, while the rate of anastomotic leakages is no different between the groups. In addition, cardiac and psychological complications that are significantly more frequent in irradiated patients aggravate the higher postoperative complication rate (7).

With regard to the risk of perineal wound dehiscence, the results of the different studies are inconsistent. While it is significantly increased for short-course radiation and chemoradiation in some trials (7; 16), others rule out an influence (2).

The early anastomotic leakage rate has been reported as 8-18% after neoadjuvant treatment and is thereby no different from rates in non-irradiated patients (Table 3) (2; 7; 10; 17; 18). A correlation between neoadjuvant treatment and anastomotic leakage rate cannot be seen in a single study (2; 7; 9; 10; 17). However, in a population-based study from Sweden, the multivariate analysis of 432 out of 6833 patients revealed preoperative radiation to be an independent risk factor for anastomotic leakage (19). The restriction of this publication, however, is the fact that the large majority of these operations were performed without TME. Though, the influence of this fact is in this regard not known.