Neoadjuvant treatment for locally advanced rectal carcinoma

Critical Reviews in Oncology/Hematology 52 (2004) 61–71

Neoadjuvant treatment for locally advanced rectal carcinoma

Lara Maria Pasettoa,∗, Salvatore Pucciarellib, Marco Agostinib,Elena Rossia, Silvio Monfardinia

a Medical Oncology Division, Azienda Ospedale – Universit`a, Via Gattamelata 64, 35128 Padova, Italyb II Surgical Clinic, Azienda Ospedale – Universit`a, Via Giustiniani 2, 35128 Padova, Italy

Accepted 8 July 2004

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

2. Improvements in surgical technique. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

3. Radiotherapy alone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

4. Choice of chemoradiation regimen in locally advanced disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

A

s cancer isc patients canb cer has beena stoperativr tive radiation.N erall survivala al trials ofc advances ins rates and thee cted clinicalt ease.©

K

,000n the

1d

4.1. Chemoradiotherapy with 5-fluorouracil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634.2. Chemoradiotherapy with 5-fluorouracil and mitomycin C (MMC) or cisplatin (DDP). . . . . . . . . . . . . . . . . . . . . 644.3. Chemoradiotherapy with raltitrexed (Tomudex). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644.4. Chemoradiotherapy with oral fluorpyrimidines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654.5. Chemoradiotherapy with irinotecan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664.6. Chemoradiotherapy with oxaliplatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Biographies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

bstract

Rectal cancer is one of the most common neoplasms of Western Countries. Overall mortality at 5 years is about 40%. Thiommonly diagnosed at a precocious stage, but because of local relapse and/or metastatic disease, only half of radically resectede considered disease free. The value of adding radiotherapy to surgery in the treatment of patients with resectable rectal canssessed in trials using either preoperative or postoperative irradiation. Preoperative irradiation is more “dose-effective” than poeadiotherapy; that is, a higher dose is needed postoperatively to reduce rates of local recurrence to the same extent as preoperaevertheless, preoperative treatment has not been routinely recommended, mainly because it has not been shown to improve ovnd because in some trials it has been associated with increased postoperative mortality. This paper critically reviews clinichemoradiotherapy on whether an optimal combination exists for locally advanced rectal cancer. Even if in the latest years, recenturgery have improved the local control of disease, the next steps in rectal cancer care should aim at the improvement of local curenhancement of systemic control. New approaches to CT treatment are necessary. Patient enrolment into rigorous and well-condu

rials will generate new information regarding investigational therapies and it will offer improved therapies for patients with this dis2004 Elsevier Ireland Ltd. All rights reserved.

eywords:Chemoradiotherapy; Neoadjuvant; Rectal cancer; Review

∗ Corresponding author. Tel.: +39 049 8215931; fax: +39 049 8215932.E-mail address:[email protected] (L.M. Pasetto).

1. Introduction

The incidence of rectal cancer is approximately 35cases per year in the United States and 10,000 in Italy; i

040-8428/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.critrevonc.2004.07.001

62 L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71

European Union is about 15–25 cases/100,000/year[1]. Five-year overall mortality is about 40%. It is commonly diagnosedat a precocious stage, but only half of radically resected pa-tients (85–90% of cases) is considered disease free. Patientswith locally advanced disease and/or node involvement[2]have a high risk of relapse. Hence, their need of adjuvanttreatment and/or multidisciplinary therapeutic involvement(surgery, radiotherapy and oncology) [NIH Consensus Con-ference. Adjuvant therapy for patients with colon and rectalcancer. JAMA 1990;264:1444–1450]. Nowadays, no com-mon point of view about the standard adjuvant or neoadjuvanttreatment of the low-stage I (T1-2N0M0) to mid-low stageII-III (T3-4N0M0, T1-4N1-2M0) rectal cancer exists.

2. Improvements in surgical technique

Over the last few decades, the single most important fac-tor in local disease control has been the surgical techniquewith the introduction of a meticulous sharp mesorectum dis-section (TME). In patients with mobile rectal cancer, TMEhas so resulted in low local recurrence rate, especially forlesions at higher risk of recurrence (for example, low rectalcancer requiring abdominoperineal excision – APER)[4–9].Moreover, with the introduction of Quirke’s circumferentialr osti-c calr fp ob 7.6%C alrT esst fur-t encer ce ist afterp

3

Un-d skind aded s ac-c g tot ea-s l, thep des,t barl fifthl ram-i thep ch-n ose

is defined as that delivered at the intersection of the centralaxes of the three or four beams.

The first randomised trials[13,14] testing the addition ofshort course preoperative radiation (5 Gy daily for 5 days) re-ported a significantly improved local control with a decreas-ing local recurrence rate from 8.4% to 2.4%, if compared withsurgery alone, but they made no impact on survival (2-yeardeath of 15% in both arms).

The more recent administration of 45–50.4 Gy in 25–28fractions (1.8–2 Gy daily for 5 days/week) has reported betterresults than the short course irradiation schedule[15]. It sub-stantially decreased local failure rates as postoperative treat-ment and, unless counterbalanced by increased postoperativemortality seen in some trials[16], it slightly improved over-all survival (OS) (different to adjuvant radiotherapy)[15,17].According to these results which represent those achieved inthe general population, this approach has been adopted bymany[15,17–19]– but not all – European countries[20,21].

Nowadays, systemically active chemotherapy syn-chronously with preoperative radiation has also been testedto improve OS.

4. Choice of chemoradiation regimen in locallyadvanced disease

e thee ng as houta urgi-ca im-p withsA rials[m tmentf da-t asp y andn oneo r tor rapyas er al int

rativec umorr dicalr ntc hasb fewr thusu n-c ned

esection margin (CRM), this concept has become prognally important – especially if negative (>1 mm), with a loecurrence in 16% of cases with CRM≤2 mm and in 5.8% oatients with CRM >2 mm[10–12]. CRM ≤ 1 mm has alsecome prognostic adverse for both distant metastasis (3RM+ versus 12.7% CRM−,P< 0.001) and 2-year surviv

ate (67.9% CRM+ versus 90.0% CRM−, P < 0.0001). AME with CRM− usually reduces local recurrence to l

han 10% at 2 years; the addition of radiation therapyher reduces it to less than 5%. Now that local recurrate is becoming low (2.4% of cases), distant recurrenhe major form of disease progression (15% of patientsreoperative radiation).

. Radiotherapy alone

Radiotherapy treatment is usually carefully planned.er a simulator taking X-rays the doctor marks patient’suring the planning session. Few pinprick tatoos are muring planning to make sure that the line-up process iurate. The clinical target volume, estimated accordinhe International Commission on Radiation Units and Murements report 50 (ICRU 50), includes the anal canarimary tumor, the mesorectal and presacral lymph no

he lymph nodes along the internal iliac vessels, the lumymph nodes up to the level of the upper border of theumbar vertebra, and the lymph nodes at the obturator fona. The plan is to deliver treatment with three beams withatient in a prone position or with a four-beam “box” teique with the patient lying either supine or prone. The d

At the beginning, chemotherapy was added to increasffect of postoperative radiotherapy – the only trial showiurvival benefit by postoperative chemotherapy alone witny radiotherapy was that conducted by the National Sal Adjuvant and Bowel Project (NSABP)[22]. Actually, thessociation of chemoradiotherapy had the objective torove OS and to decrease local failure rates if comparedurgery alone or surgery and adjuvant radiotherapy[23–26].ccording to the good results of three randomised t

24–26], in 1990 a US NIH Consensus Conference[3] recom-ended postoperative chemoradiation as standard trea

or rectal cancer in stages II and III but this recommenion was widely criticized. The obtained survival benefit wrobably ascribed to the systemic effect of chemotherapot to the improved local control of radiosensitization so,f the three trials[24] was severely underpowered in ordeeveal any benefit from either radiotherapy or chemothelone. Moreover, one of the other two studies[25] only in-ignificantly reduced local failure rate (P = 0.11). For theseasons, the role of radiotherapy concerning the survivhe postoperative radiochemotherapy was questioned.

Because these unresolved problems, preopehemoradiotherapy was administered to determine tegression of primarily unresectable cancer and its raemoving (T3-4 tumors)[27–31]. Whether neoadjuvahemoradiotherapy was superior to radiotherapy aloneeen the object of a lot of phase II trials but of only aandomised trials on a limited number of patients andnderpowered[32–34]. While one of these studies coluded that survival was slightly prolonged after combi

L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71 63

treatment[32], the others comparing radiotherapy alone andradiotherapy plus 5-fluorouracil (5FU) could not detect anystatistically significant differences in the antitumoral effects[33,34]. An increased toxicity was also observed; the useof a more appropriate radiation technique and improvedsupportive activities could have prevented it.

So, based only upon favourable treatment results in phaseII studies, preoperative radiochemotherapy has been regardedas “standard” therapy. Only three[35–37](two of which pre-maturely closed because of poor accrual and the third onestill ongoing) of multiple randomised trials[22–26,38–42]supported its superiority over postoperatory radiochemother-apy. In the German study[37], 805 patients with locallyadvanced operable rectal cancer were randomly assignedto pre or postoperative radiochemotherapy, a total dose of50.4 Gy (single dose 1.8 Gy) was applied to the tumor andthe pelvic lymph nodes. 5FU (1000 mg/m2/day) was admin-istered concomitantly in the first and fifth weeks of radi-ation as 120 h-continuous infusion. Four additional cyclesof 5FU-chemotherapy (500 mg/m2/day bolus) were applied.Radiochemotherapy was identical in both arms except fora small-volume boost of 5.4 Gy postoperatively. Acute tox-icity was low, with less than 15% of patients experiencinggrade 3 or higher toxicity. The principal toxicity was diar-rhea, with 12% in the postoperative arm and 11% in the pre-o vingg re then thera Post-o with1 f pa-t , 3%( top-e (pre-o vantr igherr

sserr y-

T5

A

G st 5

P and 4 5%

M TT)

5 9%

B rst 4

M ted 4

D ; NR = -LV= = patho tly withfi erapy sut

related efficacy, the downstaging of disease[44], the bestsphincter-saving not only for locally advanced disease buteven for low stage I rectal cancer, the precocious eliminationof micrometastases and the better compliance[43,45–51].The limits of this treatment were represented by possibleovertreatment because of undefined occult metastases at di-agnosis or because of uncorrected clinical radiological stadi-ation of disease.

The objectives of this kind of administration are the in-creased resectability rate in primarily inextirpable cancers(downsizing), sphincter saving in low-lying rectal cancers,also in T1-2N0M0 cases (with consequent quality of life im-provement), local failure rate reduction and OS and patho-logical complete remission (pCR) improvement.

In conclusion, even if radiotherapy alone is best docu-mented, many would now claim that chemoradiotherapy issuperior in most, if not all, situations[52–55]. Which is the“optimal” chemotherapy is still unknown, but probably it isthat which reaches the objectives with only minimal negativeconsequences.

4.1. Chemoradiotherapy with 5-fluorouracil

For many years 5FU (bolus, infusional or peroral, un-modulated or biochemically modulated) has been studiedm tmentf por-t ]( blec ced( rea-s ffi-c orer ds toe og-r andi en-e thec

perative arm having grade 3, and 1% in either arm harade 4-diarrhea. Erythema, nausea and leucopenia weext common toxicities, with less than 3% of patients in eirm suffering grade 3 or greater leucopenia or nausea.perative complication rates were similar in both arms,2% (postoperative arm) and 12% (preoperative arm) o

ients, respectively, suffering from anastomotic leakagepostoperative arm) and 3% (preoperative arm) from posrative bleeding, and 6% (postoperative arm) and 4%perative arm) from delayed wound healing. Neoadjuadiochemotherapy was well tolerated and beard no hisk for postoperative morbidity.

A strong rationale supporting it, was given by the leadiotherapy-related toxicity[43], the best radiotherap

able 1FU bolus regimens

uthors No. of patients CT regimen

rann et al.[46] 32 (T3 only) 5FU + LD-LV (firand fifth wks of RT)

ucciarelli et al.[49] 51 (locally advanced) 5FU + LV (firstfifth wks of RT)

insky et al.[56] 21 (unresectable, 7 ofwhich local relapses)

5FU + HD-LV (pre-Rand fourth wks of R

osset et al.[57] 85 (locally advanced) 5FU + LD-LV (fiand fifth wks of RT)

arsh et al.[58] 18 (locally advanced +unresectable)

5FU chronomodula(concomitant)

FS = disease-free survival; OS = overall survival; wks = weeks; y = yearshigh dose leucovorin; RT = radiotherapy; CT = chemotherapy; pCR

rst and fifth weeks of radiation therapy. The different doses of radiotho be analysed.

RT (Gy) Results DFS OS

0.4 Resectability: 85%, pCR: 9% 3-y, 60% NR

5 Resectability: 100%, pCR: 16% 5-y, 86% 5-y, 8

0.4 Resectability: 89%, pCR: 29% 3-y, 64% 3-y, 6

5 Resectability: 51%, pCR: 15% NR NR

5–55.8 Resectability: 94%, pCR: 28% NR NR

not reported; 5FU = 5-fluorouracil; LD-LV = low dose leucovorin; HDlogical complete remission. The first trials used 5FU bolus concurrenthe

employed and the different stages of treated disease made the trial relts difficult

ore because it represented the only efficacious treaor advanced rectal cancer but in phase II studies, the imance of the results has never been understood[36,41,56–58Table 1). The distinction between a primarily non-resectaancer (T4) and a clinically fixed/tethered/locally advanT3 and certain T4 cases) was difficult and this was theon why it was virtually impossible to draw conclusive eacy data from non-randomised comparisons. Only in mecent years, the improvement in endpoints and methovaluate tumor growth through the bowel wall (ultrasonaphy) has given better results. The relevance of in vitron vivo model data is however still unclear and it has not grally given any relevant information as how to schedulehemotherapy.

64 L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71

Table 25FU c.i. regimens

Authors No. of patients CT regimen RT (Gy) Results DFS OS

Rodel et al.[27] 31 (T4 only) 5FU c.i. (first and fifth wks of RT) 55.8 Resectability: 94%, pCR: 13% NR 5-y, 51%Schaffer et al.[62] 50 (locally advanced) 5FU c.i. (first and fifth wks of RT) 45 Resectability: 86%, pCR: 8% NR NVidetic et al.[28] 29 (T4 only) 5FU c.i. (concomitant) 54 Resectability: 79%, pCR: 13% 3-y, 83% 3-y, 94%Chen et al.[63] 31 (locally advanced) 5FU c.i. (concomitant) 55.8 Resectability: 100%, pCR: 10% NR 3-y, 68%Janjan et al.[64] 117 (locally advanced) 5FU c.i. (concomitant) 45 Resectability: 100%, pCR: 27% NR NRNgan et al.[65] 82 (locally advanced) 5FU c.i. (concomitant) 54 Resectability: 100%, pCR: 16% NR NRMehta et al.[66] 30 (locally advanced) 5FU c.i. (concomitant) 54 Resectability: 100%, pCR: 33% NR NR

DFS = disease-free survival; OS = overall survival; wks = weeks; y = years; NR = not reported; 5FU = 5-fluorouracil; c.i. = continuous infusion; RT =radiotherapy; CT = chemotherapy; pCR = pathological complete remission; 5FU c.i. significantly increases the time of cancer exposition since it is a drugphase-dependent and with a brief half-life. This has permitted the achievement of a maximum tolerated dose higher than that obtained with bolus administrationand it has modified the type of toxicity.

At the beginning, for historical reasons, the first andfifth weeks of 5FU bolus chemotherapy concurrently withradiation therapy were employed but the different dosesof radiotherapy and the different stages of disease (alsoincluding patients with local relapses) made the trial resultsdifficult to be compared. Data reported pCR (no detectablesigns of residual cancer in the operative specimen) about20%; 3-year disease-free survival (DFS) and OS were about62% and 69%, and 5-year DFS and OS about 86% and85%. Haematological and gastrointestinal toxicities werelow.

In Mohiuddin’s randomised trial, subsequent changes in5FU schedule have shown that continuous infusion (c.i.) ad-ministration was associated to a response rate (RR), but notan OS, better than with bolus administration (pCR of 67%versus 10%), especially after high radiotherapy doses (pCRof 67% versus 0% after more than 50 Gy)[59–61].

5FU c.i. significantly increases the time of cancer ex-position since it is a drug phase-dependent and with abrief half-life. This permits the achievement of a maximumtolerated dose (MTD) higher than that obtained with bo-lus administration and it also modifies the type of toxic-ity (from neutropenia to palmar-plantar erythrodysesthesia).The MTD of 5FU administered as a 5-day c.i. and mod-ulated by a short infusion of folinic acid (FA) 100 mg/m2

t 2 .i.a etelye romea icity(

ekso seo eat-m yearD tox-i6

t isc hicha

4.2. Chemoradiotherapy with 5-fluorouracil andmitomycin C (MMC) or cisplatin (DDP)

The combination of 5FU c.i. and MMC[67] was based onthe in vitro synergy of two drugs and on their better resultsin terms of RR, DFS and quality of life (QOL) if comparedwith 5FU c.i. alone. In combination with radiotherapy, theregimen was associated with R0 resection in 82% of cases[24,29,68]and with haematological and gastrointestinal tox-icities similar to those observed after 5FU c.i. alone. pCR wasalso similar, but lower than that registered after 5FU c.i. andDDP combination in two randomised trials (FUMIR versusPLAFUR-4 versus PLAFUR-5, FUMIR-T3 versus FUMIR-T4 versus PLAFUR-4)[31,69](Tables 3 and 4). The results,similar to those obtained with 5FU c.i. monotherapy, sug-gested to stop these combinations and to continue with theadministration of 5FU alone.

4.3. Chemoradiotherapy with raltitrexed (Tomudex)

Raltitrexed, as 5FU, is a specific inhibitor of thymidy-late synthase (TS) and has radiosensitizing properties. It pre-dominantly enters the cell via the reduced folate carrier andthen undergoes polyglutamation. The polyglutamated formis more potent than the parent compound. It is retained int tor.I LV)b col-o rials,m %)w bo-l rt tlys eniaa lusr

om-b evelo /mw S

wice daily, is 750 mg/m, but the optimal dose of 5FU cnd whether the dose of FA could be reduced or complliminated are unresolved questions. Hand-foot syndnd severe mucositis represent the dose-limiting toxDLT).

Studies administering 5FU c.i. in the first and fifth wef radiotherapy[27,62] reported worse results than thobserved after administration during all radiotherapy trent (pCR of 10% versus 20%, respectively and 2-FS about 86%) but lower grade 3–4 haematological

cities than those observed after 5FU bolus (Table 2) [28,63–6].

Nowadays 5FU c.i. during all radiotherapy treatmenonventionally considered the standard treatment to wll other new drugs are compared.

he cell and prevents TS from binding to its folate cofact is a possible alternative to standard 5FU/leucovorin (ased regimens in the first line treatment of advancedrectal cancer. In three out four phase II randomised tedian survival time (MST) (9.7–10.9 m) and RR (15–20ere comparable to the results obtained with 5FU/LV

us or c.i. (10–12.7 m)[70–73]. However, in two of the fourials [71,73], time to progression (TTP) was significanhorter in the first group of patients and severe leucopnd mucositis were inferior if compared with 5FU/LV boegimens.

In two phase I/II dose-escalation trials of raltitrexed cined with preoperative pelvic radiotherapy, a tolerable lf toxicity and a pCR around 15–20% at the dose of 3 mg2

ere demonstrated[74,75] (Table 5). Data on DFS and O

L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71 65

Table 35FU c.i. combination regimens

Authors No. of patients CT regimen RT (Gy) Results DFS OS

Chan et al.[42] 27 (locally advanced) 5FU c.i. + MMC (concomitant)followed by 5FU

40 Resectability: 91%, pCR: 4% NR 2-y, 92%

Chan et al.[29] 156 (locally advanced) 5FU c.i. + MMC (concomitant)vs. 5FU c.i. + MMC (concomitantand adjuvant) vs. 5FU c.i. + MMC(concomitant) and 5FU + LV(adjuvant)

40 vs. 40 (+18 p.o.)vs. 50

Resectability: 91%, vs. 100%vs. 100%, pCR: 4% vs. 15%vs. 25%

5-y, 74% 5-y, 84%

Chan et al.[68] 46 (locally advanced) 5FU c.i. + MMC (concomitant) 40 Resectability: 89%, pCR: 4% NR 2-y, 73%

DFS = disease-free survival; OS = overall survival; wks = weeks; y = years; NR = not reported; 5FU = 5-fluorouracil; c.i. = continuous infusion; MMC =mitomycin C; RT = radiotherapy; CT = chemotherapy; pCR = pathological complete remission; p.o. = postoperative. The results, similar to those obtained with5FU c.i. monotherapy, suggested to stop these combinations and to continue with the administration of 5FU alone.

Table 45FU c.i. combination regimens

Authors No. of patients CT regimen RT (Gy) Results DFS OS

Valentini et al.[31] 163 + 83 + 40 FUMIR (5FU c.i. + MMC) vs.PLAFUR-4 (5FU c.i. + DDP) vs.PLAFUR-5 (5FU c.i. + DDP)

37.8 vs. 50.4 vs. 50.4 pCR: 9% vs.23% vs. 20%

NR NR

Chau et al.[67] 36 (locally advanced) 5FU c.i. + MMC (concomitant)and 5FU c.i. + MMC (adjuvant)

50.4–54 pCR: 3% 1-y, 81% 1-y, 96%

Valentini et al.[69] 82 + 40 + 42 FUMIR-T3 (5FU c.i. + MMC)vs. FUMIR-T4 (5FU c.i. + MMC(first and fifth wks of RT) vs.PLAFUR-4 (5FU c.i. + DDP)

37.8 vs. 45 vs. 50.4 pCR: 9% vs.8% vs. 21%

NR 5-y, 66% (forT3 cases)

DFS = disease-free survival; OS = overall survival; wks = weeks; y = years; NR = not reported; 5FU = 5-fluorouracil; c.i. = continuous infusion; MMC =mitomycin C; DDP = cisplatin; RT = radiotherapy; CT = chemotherapy; pCR = pathological complete remission. The results, similar to those obtained with5FU c.i. monotherapy, suggested to stop these combinations and to continue with the administration of 5FU alone.

Table 5Raltitrexed monotherapy regimens

Authors No. of patients CT regimen RT (Gy) Results

Valentini et al.[74] 15 (locally advanced) Tomudex (every 19 days of RT) 50.4 pCR: 15%Gambacorta et al.[75] 67 (locally advanced) Tomudex (every 19 days of RT) 50.4 pCR: 20%

RT = radiotherapy; CT = chemotherapy; pCR = pathological complete remission. Data on DFS and OS are still not evaluable. There are no phase III trialsongoing to confirm these results.

are still not evaluable. Two phase II studies with neoadju-vant raltitrexed in the unresectable or relapsed disease areongoing.

There are no phase III trials ongoing to confirm good re-sults.

4.4. Chemoradiotherapy with oral fluorpyrimidines

Oral fluoropyrimidine are metabolized in the liver and inthe tumoral cells to 5FU permitting prolonged tumoral cellexposure to 5FU with lower plasmatic concentrations andlower toxicity (hand-foot syndrome, diarrhea, vomiting, andmucositis) than with 5FU alone. Tegafur is an oral fluoropy-rimidine commonly metabolized to 5FU in the microsomialliver system. In combination with uracil, which inhibits theprincipal enzyme of the catabolic via of 5FU with 5FU in-crease, it gives origin to UFT. The only few phase II studiesof UFT with radiotherapy (45 Gy) report a pCR of 16% and3-year DFS and OS of 83% and 90%, respectively[76–80].Diarrhea represents the DLT (Table 6). In these trials the dose

of radiotherapy is lower than that usually reached and the re-sults are not too satisfactory.

The general availability of capecitabine (Xeloda), theother oral fluoropyrimidine, has provided a much more con-venient alternative to 5FU c.i. and has been demonstrated inrandomised trials to be at least as effective as 5FU bolus butwith less toxicity. Capecitabine mimics 5FU c.i. action withthe advantage of the oral administration.

Three dose-finding studies have been performed with oralcapecitabine added to a fixed dose of radiation[81–83]. Onestudy used a continuous schedule of capecitabine[81] and theother two a 5 days per week regimen[82,83]. The first studyidentified a MTD of continuous capecitabine 1000 mg/m2

twice daily every day[81]; the recommended dose for phaseII studies was capecitabine 825 mg/m2 twice daily every dayplus standard radiotherapy[84] – phase III randomised trialsbetween capecitabine continuous schedule and 5Fu c.i. areongoing. In the other two trials the recommended dose forphase II studies was 900 mg/m2 twice daily with pCR up to31%[84–87].

66 L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71

Table 6Oral fluoropyrimidine regimens: tegafur and tegafur-uracil (UFT) monotherapy

Authors No. of patients Ctregimen RT (Gy) Results

Calvo et al.[76] 120 (locally advanced) Tegafur (concomitant) vs.5FU c.i. (first and lastweeks of RT)

45–50 Resectability: 100%, pCR: 23% vs. 14%

de la Torre et al.[77] 35 (locally advancedand unresectable)

UFT + LV (concomitant) 45 Resectability: 88%, pCR: 18%

Hoff et al. [78] 15 (locally advanced) UFT + LV (concomitant) 45 Resectability: 93%, pCR: 21%Feliu et al.[79] 41 (locally advanced) UFT + LV (first and last 2

wks of RT)45 Resectability: 100%, pCR: 15%

Uzcudun et al.[80] 38 (locally advanced) UFT + LV (first and last 2wks of RT)

45 Resectability: 98%, pCR: 10%

wks = weeks; y = years; 5FU = 5-fluorouracil; c.i. = continuous infusion; LV = leucovorin; RT = radiotherapy; CT = chemotherapy; pCR = pathologicalcomplete remission; In these trials the dose of radiotherapy is lower than that usually used. Results are not too satisfactory.

Table 7Oral fluoropyrimidine regimens: capecitabine monotherapy

Authors No. of patients CT regimen RT (Gy) Results

Yoon et al.[82] 32 vs. 44 (locally advanced) Capecitabine + LV (first and last 2wks of RT) vs. 5FU + LV (first andlast weeks of RT)

45 pCR: 31% vs. 5%

Kim et al. [85] 45 (locally advanced) Capecitabine + LV (first and last 2wks of RT)

50.4 pCR: 31%

wks = weeks; LV = leucovorin; RT = radiotherapy; CT = chemotherapy; pCR = pathological complete remission. Even if preliminary data report good resultsin term of pCR, it is still impossible to define the results in term of DFS and OS.

In a retrospective review of 32 patients treated withcapecitabine and concurrent radiation Vaishampayan et al.[88] found that the median dose of capecitabine delivered onMonday through Friday of each week of radiation (45–64 Gyover a 4–6-week period) was 1600 mg/m2/daily. The excel-lent tolerability of this regimen suggested that this dose ofcapecitabine had a similar tolerability as 5FU 200 mg/m2 asprotracted infusion (Table 7).

Even if preliminary data report good results in term ofpCR, it is still impossible to define the results of DFS andOS.

4.5. Chemoradiotherapy with irinotecan

Irinotecan (Campto or CPT11), a topoisomerasi I in-hibitor, sensitises tumor cells to radiation and in combinationwith 5FU results in an enhanced cytotoxicity to metastaticcolorectal cancer. Even if the frequent acute gastroenterictoxicity (grade 3 diarrhoea of 9%, mucositis of 7%, abdomi-nal cramping of 4%), the association also gives a significanttumor downstaging, but it has not been studied long enough.

In one of the few trials with concomitant CPT11, 5FU c.i.and radiotherapy (50.4 Gy), Mehta et al.[89] reported 37%

Table 8C

A n

M CPT11 : 37%N CPT11 20%

5 an; RT ission.T additio

pCR. Similar results were not confirmed by Navarro’s study[90] in which pCR achieved 20% (Table 8).

Some other phase II trials with additional patients andlonger follow-up are still necessary to confirm the good re-sults obtained in Mehta’s study, to reach DFS and OS data andto value new schedules with lower toxicity in the neoadjuvantsetting.

4.6. Chemoradiotherapy with oxaliplatin

Oxaliplatin (Eloxatin) is a diaminocyclohexane (DACH)– platinum compound, active in several solid tumor types,including some cisplatin/carboplatin refractory diseases. Themain mechanism of action of oxaliplatin, like cisplatin, ismediated through the formation of DNA-adducts, which arebulkier and more hydrophobic than platin adducts.

Oxaliplatin is an excellent candidate to incorporate withneoadjuvant “downsizing” regimens due to its rapid cytore-ductive capacity in colorectal cancer and its relative lack ofacute dose-limiting side effects. The DLT of oxaliplatin aloneis a cumulative neuropathy which does not become a treat-ment issue until after 4–6 months of treatment. Acute neuro-toxicity manifests one hour after the infusion and ends 2 or

PT11 regimens

uthors No. of patients CT regime

ehta et al.[89] 32 (locally advanced) 5FU c.i. +avarro et al.[90] 34 (locally advanced) 5FU c.i. +

FU = 5-fluorouracil; c.i. = continuous infusion; CPT11 = campto or irinotechese good results need to be confirmed by other phase II trials with

RT (Gy) Results

(concomitant) 50.4 Resectability: 100%, pCR(concomitant) 45 Resectability: 44%, pCR:

= radiotherapy; CT = chemotherapy; pCR = pathological complete remnal patients and longer follow-up.

L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71 67

Table 9Oxaliplatin regimens with 5FU

Authors No. of patients CT regimen RT (Gy) Results

Carraro et al.[93] 22 (unresectable) 5FU/LV + oxaliplatin (first and last wks of RT) 50.4 Resectability: 54%, pCR: 25%Gerard et al.[94] 40 (locally advanced) 5FU/LV + oxaliplatin (first and last wks of RT) 50 Resectability: 100%, pCR:

15%Aschele et al.[96] 46 (locally advanced) 5FU c.i. + oxaliplatin (concomitant) 50.4 Resectability: 97%, pCR:

26% (65% if T1-2 N0 wereenclosed)

wks = weeks; 5FU = 5-fluorouracil; c.i. = continuous infusion; LV = leucovorin; RT = radiotherapy; CT = chemotherapy; pCR = pathological completeremission. The results need to be confirmed by other phase II-III trials with additional patients and longer follow-up.

3 days later; chronic toxicity is dose-cumulative related andranges from 12% at 900 mg/m2 to 75% at 1500 mg/m2.

Many treatment regimens have been described as attemptsto add chemotherapy to radiation therapy for the treatmentof rectal cancer. Most have employed the first and fifthchemotherapy week schedule concurrently with radiationtherapy with or without 5FU[91–94]. The studies demon-strated the feasibility of this association with a high delivereddose intensity (DI), acceptable low gastrointestinal toxicity,low risk of neutropenia or early postoperative complicationsand encouraging evidence of activity (pCR about 20%)[95](Table 9).

In Aschele’s study[96], oxaliplatin 60 mg/m2/week com-bined with 5FU 225 mg/m2 as a protracted c.i. in 46 patientswith locally advanced or recurrent disease, was associatedwith pT0-2N0 of 65% and pCR of 26%. The toxicity of theregimen was acceptable, with only two patients (4%) experi-encing grade 4 diarrhoea and five patients (11%) grade 3.

In two other similar studies, TS level decreased in 92%endoscopic biopsies performed on day 8 after a single doseof oxaliplatin. TS downregulation represents a pharmacody-namic explanation of the clinical synergism observed withoxaliplatin and fluoropyrimidines[97].

Nowadays in new ongoing trials these regimens have beenmodified adding oral fluoropyrimidine or changing the sched-u ble.I ofo ine8 Gyi tox-i . Apa e2 tiveR ithcc der-a es.

in5 tions1 cteds per-f pa-

tients with tumors≤2 cm from the dentate line had sphincter-saving surgery. Dose-limiting grade 3 gastrointestinal toxic-ity was observed in two of six patients treated with 60 mg/m2

of oxaliplatin. Thus, 50 mg/m2 was the recommended dosefor the phase II study. There were only two cases of short-lived grade 3 diarrhoea. Myelosuppression, mainly leucope-nia, was restricted to grade 2 in 19% of patients.

Valentini et al.[101] confirmed the feasibility of the com-bination of oxaliplatin and raltitrexed reporting pCR of 37%and grade 3 toxicity in 20% of cases.

Few data of phase II trials are not yet available to concludethe actual efficacy of oxaliplatin and radiotherapy combina-tion in the neoadjuvant setting. Only randomised trials willreveal future developments.

5. Conclusion

In locally advanced or in low stage I rectal cancer tu-mor downstaging (pT0-2N0) and pCR are good endpointsof neoadjuvant chemoradiation therapy and they range from4% to 44% of cases (0% after radiotherapy alone), but only asmall number of trials analyzes the importance of sphincter-preservation in low T1-2N0M0 cases; mostly they treat stagesII–III of disease. Whether pCR may have an impact ont clear[ entc hichi blyi ini-m lt tod n theo d tri-a llow-u

nt( redt ouldb

fort eenro Ii li-

le of administration. Preliminary data are still not availan a phase I study[98] on 14 patients, the associationxaliplatin 50 mg/m2 (days 1, 8, 22 and 29), capecitab25 mg/m2 (days 1–14 and 22–35) and radiotherapy (50.4

n 1.8 Gy per fraction) provoked grade 3 gastrointestinalcity in 12% of cases and grade 2 leucopenia in 50%hase II study is ongoing. In another phase I–II trial[99], thessociation oxaliplatin 130 mg/m2 (day 1) and capecitabin000 mg/m2 (days 1–14 every 21) resulted in an objecR of 55%. Toxicity was similar to that observed wapecitabine as single agent at a dose of 2500 mg/m2/daily,onsistently with the observation that oxaliplatin only motely increases the expected toxicities of fluoropyrimidin

In another study [100], the association oxaliplat0 mg/m2 on days 1, 8, 22, and 29 with planned escalateps of 10 mg/m2 and capecitabine 825 mg/m2 bid on days–14 and 22–35 resulted in a pCR in 19% of the resepecimens. Radical surgery with free margins could beormed in 79% of patients with T4 disease, and 36% of

he outcome (OS and DFS) of these cases is still un102,103]; some studies have shown that the pre-treatmlinical stage and not the pathological stage affects it. Ws the “optimal” chemotherapy is still unknown, but probat is that which reaches the better results with only m

al negative consequences. Nowadays, it is still difficuemonstrate that a specific regimen is more efficient thather because of the small number of phase III randomisels and the lack of standardized treatment or adequate fop.

At now 5FU c.i. during all radiotherapy treatme45–50.4 Gy in 25–28 fractions) is conventionally considehe standard treatment to which all other new drugs she compared[15,27,28,62–66].

Interesting interactions in vitro or in vivo model datahe human clinical situation have also more recently beported with the TS inhibitor raltitrexed[74,75], peroral flu-ropyrimidines like capecitabine[85,86], the topoisomerase

nhibitor irinotecan[89,90]and the platinum analogue oxa

68 L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71

platin[90,94,96]. The trials are still ongoing and no phase IIIrandomised trials are available for comparison to the “stan-dard” and for defining DFS and OS yet. Phase III trials willsoon be needed to define the best approach taking into con-sideration local control, sphincter preservation, survival andquality of life.

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iographies

Lara Maria Pasettowas born on 5 January 1969licante (Spain). Since 11 February 2000 she hasorking as a Medical Doctor at the Medical Oncoloepartment of Padova University Hospital (Chief Profonfardini). On 3 March 1994, she graduated in medit the University of Padova with score 110/110.btained a diploma for practicing as doctor in Padova oay 1994. She attended – first as a student and then

isiting doctor – the Second Surgery Clinic (Clinica Chirica II) in Padova (Department of Oncologic and Surgciences), Chief Prof. M. Lise, from 15 September 1

o 14 June 1999. On 15 December 1998, she specian Oncology at the University of Padova (score: 70/70aude). Then she attended the Medical Oncology Divi

L.M. Pasetto et al. / Critical Reviews in Oncology/Hematology 52 (2004) 61–71 71

of Padova (Chief Prof. S. Monfardini) as visiting doctor(since 15 June 1999). She obtained a scholarship from 1August 1999 to 1 February 2000 at the Medical OncologyDepartment of Padova, where she is presently an M.D. Shehas participated to the writing of 80 articles (with abstractsand acts of Congresses).

Salvatore Pucciarelliwas born on 7 February 1954 atSavoia di Lucania (Potenza) (Italy). In 1988 Pucciarelli spe-cialised in gastroenterology and digestive endoscopy (marks48/50), in 1987 attended an 8-week ‘Winter Course’ oncolonproctology at St. Mark’s Hospital, London, and alsoattended a 4-day ‘St. Mark’s Hospital Lecture Course’ onColonproctology. In 1986 Pucciarelli qualified as Head ingeneral surgery (marks 93/100), in 1984 specialised in gen-eral surgery (marks 70/70 cum laude). In 1978 Puccia-relli graduated in medicine at Padova University (marks110/110). In 1992 Pucciarelli was a senior assistant at theInstitute “Clinica Chirurgica II”, University of Padova. In1980 Pucciarelli was a permanent researcher at the Insti-tute “Clinica Chirurgica II”, University of Padova. Puc-ciarelli was the author or co-author of 54 articles innational\international journals or congress proceedings, 32abstracts of papers presented at national\international con-gresses, three chapters for books.

inP theD dovaU ru-a logya d theG andi h.D.)i ofP witht col-o co-l forr also

attends to some research programs of the Second SurgeryClinic (Clinica Chirurgica II) in Padova Chief Prof. M. Lise,as molecular biologist. He participated in the writing of 15articles (with abstracts and acts of Congresses).

Elena Rossiwas born on 17 February 1977 in Padova(Italy). On 18 March 2003 she graduated in medicine at theUniversity of Padova with score 106/110. She obtained adiploma for practicing as doctor in Padova on 9 December2003. She is attending the Medical Oncology Division ofPadova (Chief Prof. S. Monfardini) as visiting doctor (since15 June 1999). She has participated to the writing of ninearticles.

Silvio Monfardini is presently the Chief of the Divisionof Medical Oncology. Azienda Ospedaliera – Universita,Padova (Italy). He was the Scientific Director of the Na-tional Cancer Institutes – Naples (Italy), Scientific Directorof the National Cancer Institutes – Aviano (Italy). He (age64) is the author of 427 publications, >220 of which werepublished in indexed journals. In the last 25 years he hascontributed at the National Cancer Institute in Milan andsubsequently at the Centro di Riferimento Oncologico– Aviano in designing, conduction and evaluating manyclinical trial protocols. He has periodically held histeachinga zedb int eanS rna-t oralc d inE tureri cial-i l. Hei In-t s inc Eu-r As-s dento y).

Marco Agostiniwas born on 27 November, 1973adova (Italy). He has been working as a Biologist atepartment of Oncologic and Surgical Sciences of Paniversity Hospital (Chief: Prof. M. Lise) since 2 Febry 2000. On 13 November 2000 he graduated in Biot the University of Padova. In January 2002 he entereenetic Medical School of the University of Padova

n December 2003 he won the Research Doctorate (Pn Oncologic and Surgical Sciences of the Universityadova. As a molecular biologist he has collaborated

he hereditary colon study group of First Sperimental Ongy (Oncologia Sperimentale I) in Aviano (Regional On

ogic Center – CRO), Chief A. Viel, since June 2001esearch studies on genetics of colorectal cancer. He

ctivity mainly in national and regional courses organiy the Italian Association for Medical Oncology and

hose in Medical Oncology organized by the Europchool of Oncology. He has been the director of the Inte

ional Union against Cancer project for teaching antitumhemotherapy. Within this project has was the organizeurope and outside Europe. He is presently teaching lec

n the medical oncology courses of the Oncology Spezation courses at the Padova University Medical Schoos the author of the Manual of Medical Oncology by theernational Union Against Cancer and of other textbooklinical oncology. He has formerly been President of theopean Society for Medical Oncology and of the Italianociation of Medical Oncology. Presently he is the Presif the SIOG (International Society of Geriatric Oncolog