Chemotherapy for Gastrointestinal Cancer: New Hopes or New Disappointments? J. A. WILS Dept. of Oncology, Laurentius Hospital, Roermond, The Netherlands

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

Wils JA. Chemotherapy for gastrointestinal cancer: new hopes or new disappointments? Scand J Gastroenterol 1992;27 Suppl 194237-94. Since the end of the eighties relevant progress has been made in the treatment of gastrointestinal tract cancer, as well in advanced disease as in the adjuvant setting. The neoadjuvant treatment of localized esophageal and gastric cancer is of high interest, and especially the adjuvant treatment of colorectal cancer provides a realistic hope for further progress in the years not too far ahead. Results of recent studies with implications for future trials are discussed. Key words: Chemotherapy; gastrointestinal tract cancer

J . A. Wils, M . D . , Dept. of Oncology, Laurentius Hospital, Mgr. Driessenstraat 6, 6043 CV, Roermond, The Netherlands

During the past 25 years a quite nihilistic approach has been prevalent among internists, surgeons, and gastroenterologists regarding chemotherapy in gastrointestinal tract cancer. 5-Fluorouracil (5-FU) for advanced colorectal cancer and combination chemotherapy with FAM (5-FU, adriamycin, and mitomycin) for gastric cancer have been the most used regimens. Irradiation has often been applied in locally advanced esophageal and rectal cancer. Until 1990, chemotherapy in the adjuvant situation was generally felt not to be of any benefit. In esophageal cancer the scene has changed with the advent of cisplatin-based regimens, and combined modality treatment with cytotoxic drugs, irradiation, and surgery is currently under intensive investigation. In gastric cancer ‘second-generation’ combination regimens have been developed with a higher response rate and a longer survival, and especially in locally advanced disease these protocols can lead to ‘downstaging’ in approximately 50% of the patients, resulting in an enhanced operability rate and probably in a longer survival. In advanced colon cancer an improved response rate as compared with 5-FU has been obtained with modulated 5FU, leading to better and longer palliation, and in the adjuvant setting 5-FU plus levamisole should now be considered standard treatment for Dukes C colon cancer, while in high-risk rectal cancer the combined modality approach with chemoradiotherapy is a good choice of treatment. ESOPHAGEAL CANCER Esophageal cancer is a virulent disease that is relatively uncommon in The Netherlands. There has been a sharp increase in the incidence of adenocarcinomas of the esophagus as opposed to epidermoid carcinoma; the etiology of this

change in histology is not clear. Adenocarcimas now make up 30-40% of all cases. Combined modality therapy for patients with locoregional disease includes chemotherapy followed by surgery, chemotherapy plus concurrent irradiation followed by surgery, or chemotherapy plus irradiation without surgery. Most chemotherapy protocols are cisplatin-based, but it is impossible to say whether one cisplatin-based protocol is superior to another. Randomized studies have demonstrated superior survival for chemotherapy plus irradiation versus irradiation alone (1,2). Intergroup studies in the USA are currently focusing on two major issues. In one study chemotherapy followed by surgery is compared with surgery alone, and in the second study concurrent chemoradiotherapy is compared with induction chemotherapy followed by concurrent chemoradiotherapy. In Europe the impact of neoadjuvant chemotherapy is being investigated simultaneously by the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal (GI) Tract Cooperative Group in a randomized trial that compares chemoradiotherapy followed by surgery with surgery alone. GASTRIC CANCER During the eighties new ‘second-generation’ combination chemotherapy protocols have been developed which appear to be more active than older regimens such as FAM. These protocols include EAP (etoposide, adriamycin, and cisplatin), ELF (etoposide, leucovorin, and 5-FU), continuousinfusion 5-FU plus cisplatin, and FAMTX (sequential highdose methotrexate (MTX) and 5-FU plus adriamycin). Phase-I1 results of these protocols have been reviewed elsewhere (3). The EORTC GI Group reported the results of a phase-

J . A . Wit5

88

Table I. Results of neoadjuvant chemotherapy for locally advanced gastric cancer (locally recurrent excluded) No. with

Resectable

of patients

Regimen

second look

(%)

Ref.

29 35 13 9 11 17 13 14

FU/cisplatin EAP EAP EAP FAMTX FMTX FAMTX FEMTX-P

25 21 5 2 3 14 7 5

21 (72) 19 (54) 1 (8) 2 (22) 1 (9) 8 (47) 3 (23) 5* (36) 60 (43j

8 9 10 6 6 11 4 12

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

Total no.

Total, 141

* One only at second attempt.

I11 study that compared FAMTX with FAM. A total of 213 patients were randomized. FAMTX yielded a 41% response rate versus 9% for FAM ( P < O.OOOl), while the updated survival was 44 weeks in FAMTX versus 29 weeks in FAM (log rank test: P = 0.002). There were no major differences in the toxicity, although mucositis was more pronounced in F A M X , and there was a cumulative thrombocytopenia in FAM (4). In a Spanish trial EEP has been compared with FEM (substituting epirubicin for adriamycin in EAP and FAM). In 98 fully evaluable patients the response to FEM was 13% and to EEP 30% ( P= 0.05), but EEP was significantly more toxic, with 3 treatment-related deaths, and the survival in the EEP arm was inferior to the FEM arm (5). A randomized study comparing EAP with FAMTX has been completed at Memorial Sloan Kettering Cancer Institute. A total of 60 patients were entered. The response in 30 patients who received FAMTX was 30%, including 10% complete responses, and in patients who were treated with EAP 20%, without complete responses. The toxicity of EAP was excessive, with four toxic deaths (6). In view of these data EAP does not appear suitable for routine treatment, and an editorial stated that EAP should no longer be used at all in gastric cancer (7). The EORTC GI Group has now initiated a phase-I11 study in advanced disease in which FAMTX is compared with ELF and with continuous infusion of 5-FU plus cisplatin. Several of the new regimens also yielded impressive results in locally advanced disease, leading to respectability in a significant percentage of patients (Table I), while 20-30% of these patients appear to enjoy long-term survival. This approach should be further investigated in large multicenter series, and the criteria for non-resectability (laparotomy or clinical staging?) should be clearly defined. Further studies should reveal whether the FAMTX protocol can be modified to achieve superior results. Therefore the International Cooperative Cancer Group (ICCG) is currently comparing FEMTX-P (MTX/S-FU plus epirubicin substituted for adriamycin, with the addition of cisplatin (P))

with FEMTX, to evaluate more precisely the role of cisplatin added to the high-dose MTX-based regimen. Although it is recognized that current active protocols result only in palliation and some prolongation of life in patients with metastatic disease, their main interest should be found in their application in the earlier stages of the disease. In the adjuvant setting the EORTC GI Group is now comparing FAMTX with no chemotherapy following curative surgery, while the ICCS compares FEMTX with controls. Both trials will be analyzed together. PANCREATIC CANCER No real progress has been made in the treatment of pancreatic cancer, and to date chemotherapy in advanced pancreatic cancer still remains experimental, without measurable impact on survival. An extensive review of available data has been published (13). In an effort to ameliorate the outlook for these patients all current treatment modalities must be improved and integrated in an optimal manner. It is possible that (neo?)adjuvant chemoirradiation may have an impact on the survival of resectable cases. For locally advanced disease, combined modality treatment with cytotoxic agents and irradiation so far offers the best palliation and should be further investigated. The role of intraoperative radiotherapy should be more clearly defined. More active drugs or more optimal treatment schedules must be continuously assessed, and the combination of cytotoxic agents with biologic agents should be explored. More importantly, future success lies in a better understanding of biologic mechanisms underlying malignant cell growth and.drug resistance. For instance, an overexpression of,P-glycoprotein might be present in pancreatic tumor cells, and ways of overcoming primary drug resistance must be found. COLORECTAL CANCER: ADVANCED DISEASE Extensive updated reviews of chemotherapy in advanced colorectal cancer have been published (14,15). 5-FU has been the principal cytotoxic agent for more than 30 years. Response rates in phase-I1 studies have widely ranged from zero to unreliably high percentages, but more recent phase111 studies have yielded 10-15% response rates, which is probably a fair estimation. The most frequently applied schedules have been bolus injections for 5 days every 4-5 weeks, or weekly bolus injections, sometimes after a single ‘loading’ dose for 5 consecutive days. Recently, more attention has been paid to continuous infusion schedules with which a higher dose intensity can be achieved without substantial toxicity. Continuous infusion and dose intensity of 5-FU will be discussed separately. Combination chemotherapy with other cytotoxic drugs added to 5-FU has a bleak history and has largely been

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

Chemotherapy for Gastrointestinal Cancer

abandoned. Interest has now switched to modulators of 5FU such as leucovorin (LV), MTX, N-(phosphonacety1)-Laspartate (PALA), levamisole, and interferon (IFN). It has been clearly demonstrated that with 5-FU/LV the response can be two to three times higher than with conventional bolus injections of 5-FU alone. With the exception of the Mayo-NCCTG study, a survival benefit has, however, not been obtained. Recently a meta-analysis has been carried out on nine randomized trials. Therapy with 5-FU/LV showed a highly significant benefit in response rate (23% versus 11%; response odds ratio = 0.45; P < lo-’). There was, however, no difference in overall survival (16). Data with MTXmodulated 5-FU have been more controversial, while the impact of PALA and of IFN is currently being explored in randomized studies. CONTINUOUS INFUSION 5-FU is a drug with very short plasma half-life of approximately 11 min. The drug has cytotoxic activity mainly against cells in S-phase; therefore with bolus injections only a small proportion of cells would be susceptible. Thus, there exists a sound rationale for the use of continuous infusion (CI) 5FU instead of bolus injections (17, 18). Furthermore, there is experimental evidence to suggest that infusional5-FU has a different mechanism of action than bolus 5-FU. Infusional 5-FU acts predominantly via interference with DNA metabolism, while bolus 5-FU has it cytotoxic effect mainly on RNA (19). In two randomized studies that compared CI with bolus injections of 5-FU, the response rate was higher in the CI group (20,21). Essentially the same results were obtained in a French study in which 155 patients were randomized between 5-FU, 750 mg/m2/day, CI for 7 days every 3 weeks, and bolus 5-FU, 500 mg/m2/day for 5 days every 4 weeks. The response rate was 19% versus 8% ( P < 0.02) with no difference in survival (22). Similar data were reported by the Eastern cooperative Oncology Group (ECOG). CI of 5-FU yielded a 27% response rate versus 19% with bolus injections ( P = 0.12) (23). A non-randomized study compared different schedules and doses of CI 5-FU. With a weekly 48-h CI in a dose of 60mg/kg, a response rate of 30% was obtained (24). A weekly 24-h infusion of 5-FU in escalating doses up to 3.4g/m2, with or without PALA, yielded a 40% response rate among a total of 30 patients with colorectal cancer. The maximum tolerated dose (MTD) for 5-FU in this schedule appeared to be 2.6 g/m2 (25). Other investigators used the same schedule of 5-FU (2.6 g/m2, weekly 21-h infusion) plus PALA and obtained a 43% response rate in 39 patient with advanced colorectal cancer (26). The authors themselves raised the question whether their results were obtained by the novel FU schedule or by the addition of PALA. Toxicity with CI of 5-FU is mild and consists of reversible mucositis which appears to be dependent on the length of

89

the infusion and the hand-foot syndrome. Myelosuppression is virtually absent. These data suggest a better therapeutic ratio for CI as opposed to bolus injections of 5-FU. DOSE INTENSITY It is possible that there exists a dose-response relationship for 5-FU in colorectal cancer. Data supporting this concept, however, are mainly derived from retrospective analysis of a single study or from a comparison of different trials. Retrospective analysis of a study may be misleading because a supposed dose-response relation can merely reflect the fact that patients with better prognostic factors can tolerate more chemotherapy. Comparison of different trials has even more flaws because of widely varying selection criteria, assessment of response, denominator of response, and so forth. With this in mind, collected data suggest that there exists a doseresponse relationship and emphasize the impact of dose intensity of 5-FU (27). This might be another reason why CI of 5-FU is potentially of great interest, because with CI a dose-intensity of at least 2.5g/m2/week can easily be achieved. HIGH-DOSE 5-FU To evaluate more properly the impact of adding modulating agents to 5-FU, the single agent 5-FU in the control arm should ideally be administered in the MTD. The question is, what is the MTD of 5-FU? It appears that the MTD with conventional bolus injections is different from the MTD with CI. Certainly, with conventional day 1 through 5 bolus injections every 4 weeks the MTD will not be much higher than 500 mg/m2 daily and for weekly bolus injections not much higher than 700-800 mg/m2, resulting in a dose intensity of 600-800 mg/m2/week. With weekly 24-hr infusions a dose-intensity of 2500 mg/m2/week can be obtained, and possibly higher doses are feasible. Recently a phase-study was performed in 18 patients, assessing 48-h CI of 5-FU weekly x6, at doses of 3.0 g/m’, 3.5 g/m2, and 4.0 g/m2. The MTD appeared to be 3.5 g/m2. Dose-limiting toxicities at higher doses were diarrhoea and myelosuppression. The response rate in the total population was 33%, but responses were only observed in non-pretreated patients, with a response rate of 43% (6 of 14) in this subgroup (28). In a consecutive trial the same authors treated 83 patients with a weekly 48-h CI of 5-FU, 3.5glm’. The response in 74 evaluable patients was 30% (29). These data are included in Table 11, which summarizes relevant data from studies using high-dose 5-FU. These response figures appear higher than with bolus injections and are not different from the response rates reported with 5-FU plus leucovorin. Therefore comparative studies of weekly CI of 5-FU in the MTD ( 2 . 6 3.5 g/m2, depending of the total number of weekly cycles?) versus ‘standard’ 5-FU plus leucovorin appear appropriate.

90

J . A. Wils

Table 11. Summary of phase-I1 and -111 studies with high-dose CI 5-FU No. of patients

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

177

Schedule 48 h/week ( 2 MTX)

155 139 485 30

7 days13 weeks

87 30

18

PCIS 24 h/week (* PALA) 24 h/week (plus PALA) 48 h/week

74 22

48 h/week 24 h/week

39

PCI PCI 48 h/week

Dose intensity, g/m2/week

Response, YO

Randomized

f1.66. (60 m g / W 1.36 2.1 2.1 22.5 (60mg/kg) 2.1 0.75-3.45

18

Yes

t

19 20 27 30

Yes Yes Yes No

22 30 23 24

30 40

Yes Yes

21 25

43

No

26

No

28

No No

29 35

No

37

2.6 3.0-4.0

33 (43% in non-

Ref.

pretreated patients) 3.5 2.6

(plus leucovorin) 29

24 h/week

30 45 (58% in non-

pretreated patients)

2.6

(plus leucovorin plus PALA)

48 (86% in non-

pretreated patients)

* Calculated over 12 weeks, after which period the response was evaluated, t Blijham G, et al. Unpublished data, 1991. t PCI = protracted continuous infusion. !iHigher response rate at higher dose intensity.

Notably, a randomized trial that compared protracted CI of 5-FU with bolus S-FU/LV in 139 patients showed no differences in the response rate or survival (response, 20% versus 16%; survival, 9 months). The calculated dose intensity in this trial was 2100 mg versus 462 mg/m*/week (30). The question whether modulators of 5-FU can further enhance the response rate that can be achieved with CI of high-dose 5-FU alone requires further studies. Murine studies suggest that leucovorin does not confer enhanced selectivity to 5-FU when the drug is administered in MTD on its own (31), and preclinical data suggest that the intracellular targets for 5-FU cytotocity are different for FU/ leucovorin and for high-dose 5-FU (32). It is of interest that the only two randomized studies that did not show superiority of 5-FU/leucovorin utilized 5-FU in intensified doses (33,34). Three pilot studies that assessed potential modulation of high-dose 5-FU have been reported. In the first trial leucovorin, 500 mg/m2, was infused simultaneously with weekly 24-h CI with 5-FU, 2.6g/m2. The overall response rate among 22 patients with colorectal cancer was 45% and among 12 non-pretreated patients 58%. The median survival in the non-pretreated patient population was more than 22 months (35). In the second trial PALA, 250mg/m2, plus leucovorin, 500 mg/m2, were added to weekly 24-h CI of 5FU, 2.1-2.6 g/m*, with little toxicity and response rates of interest even in pretreated patients (36). In a subsequent

phase-I1 trial by these authors 29 patients, for the greater part pretreated, were entered. The response rate was 48%, with six responses in seven non-pretreated patients (37). We are assessing potential modulation of high-dose 5-FU in our current trial that compares low-dose MTX plus highdose 5-FU versus the same plus PALA. Current US largescale randomized trials conducted by ECOG and SWOG compare high-dose 5-FU (2.6 g/mZ, weekly) plus or minus PALA with different S-FU/leucovorin schedules. It remains important to realize that we are treating patients in a palliative setting with a median survival of 1-2 years. Effective regimens with a low-toxicity profile are of particular interest in an effort to maintain the quality of life as high as possible. COLORECTAL CANCER: ADJUVANT TREATMENT

Colon cancer Until 1988 the advantage of adjuvant chemotherapy for colorectal cancer was felt by the vast majority of oncologists to be essentially non-existent. Results of 5 randomized studies, with a total of 2450 patients included, assessing chemotherapy with 5-FU plus semustine, failed to demonstrate any therapeutic benefit (38-42). In contrast to these studies, in 1988and in 1989 two large cooperative group trials resulted in a significant benefit for adjuvant chemotherapy in colon cancer.

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

Chemotherapy for Gastrointestinal Cancer

The National Surgical Adjuvant Breast and Bowel Project (NSABP) entered 1116 eligible patients in a trial comparing MOF (methyl-CCNU, vincristine, and 5-FU) versus BCG immunotherapy versus control. The 5-year survival in the MOF group was 67% versus 59% in controls ( P = 0.05). Patients who received BCG, however, also benefited: 5year survival was 67% versus 59%. However, when deaths without evidence of recurrent tumor were excluded, the differences between BCG treatment and controls disappeared (43). The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic initiated a clinical trial in 1978 in which they randomly assigned 401 eligible patients with stage-B? or -C colon cancer to either levamisole or levamisole +5FU or to control. The combination of 5-FU + levamisole produced a highly significant reduction in tumor recurrence ( P= 0.003). An overall survival benefit was not clearly demonstrated ( P = 0.09), although there was a significant survival improvement in a retrospective subset analysis in Dukes C cancer ( P = 0.03) (44). Keeping in mind the potential flaws of retrospective subset analyses, these results were considered of sufficient interest to justify a large-scale cooperative study conducted by the NCCTG plus Mayo Clinic, ECOG and SWOG, in which patients were prospectively stratified for Dukes C and B cancer. In this trial 1296 patients were entered; 318 eligible patients with stage Bz and 929 eligible patients with stage C received either treatment for 1 year with 5-FU plus levamisole or levamisole alone or no treatment. After a median follow-up of 3 years there was a very significant reduced hsk of cancer recurrence of 41% and a death reduction of 33% in the combined treatment group with stage C. There was no benefit from levamisole alone. The results of adjuvant treatment in the patients with stage B2 were equivocal and too preliminary to enable firm conclusions. Toxic effects of levamisole and 5-FU were essentially the same as those of 5-FU alone and usually not severe (45). In an update of this study after 5 years of follow-up, these data did not change

(46). These results of the NSABP, the NCCTG, and the Intergroup trials, corroborated by a meta-analysis of all controlled trials of systemic, prolonged 5-FU-containing chemotherapy, which yields an overall reduction in mortality of 14% (47), firmly support the use of adjuvant therapy especially in patients with Dukes C colon cancer. This has led the National Cancer Institute (NCI) in the USA to adopt a very strong point of view with regard to the adjuvant treatment of Dukes C colon cancer. In fact, in ongoing trials in the USA untreated control arms are abolished because a no-treatment arm is no longer considered acceptable (48). In addition, a consensus meeting in April 1990, held by the National Institute of Health, concluded that 5-FU + levamisole is to be standard therapy for Dukes C colon cancer. Where do we stand in Europe? Should we adapt our

91

treatment attitude or should we first seek to confirm the data that have come from the USA? We feel that the evidence that adjuvant therapy works in colon cancer is convincing enough (49), and the EORTC GI Group has abandoned a control arm. Currently, a meta-analysis is being performed on updated results of completed trials with adjuvant intraportal chemotherapy, and preliminary data show a significant survival benefit of therapy (survival odds ratio = 0.77) but, somewhat surprisingly, no effect on the incidence of liver metastases (M. Buyse, personal communication, 1991). These data clearly need to be confirmed, but they suggest a systemic effect of intraportal infusion which might be due to the timing of chemotherapy. Therefore ’early’ perioperative chemotherapy, either locally directed by intraportal or intraperitoneal route, or by intravenous route, is of great interest in both colon and rectal cancer. Consequently, the main question of the new study of the EORTC GI Group is whether ‘early’ locally directed perioperative treatment has an additional benefit added to ‘late’ systemic chemotherapy. Late systemic chemotherapy will be either ‘standard’ 5-FU/ levamisole or 5-FU plus/l-leucovorin.

Rectal cancer In a Clinical Announcement published in March 1991 the NCI sought to bring to the attention of clinicians the benefits that may be achieved with adjuvant therapy of rectal cancer. It was stated that combined modality treatment with a sequential regimen of 5-FU-based chemotherapy and irradiation concurrently with 5-FU may be recommended as therapy for individuals with resected TNM stage-I1 and -111 cancer (50). Are the data generated so far convincing enough for adoption of this practice? High-risk rectal cancer has been defined as TNM stage I1 (Dukes B, modified Astler Coller BZ-3)and stage 111 (Dukes C, modified Astler Coller CI-3). The high local recurrence rate in this stage of disease has led clinicians to assess the role of preoperative or postoperative adjuvant radiotherapy. Some randomized studies have yielded a positive result on the incidence of local recurrence, while others have not. None have resulted in an overall survival benefit. It might be argued, however, that at least some palliation is obtained by a decrease in the local recurrence rate and that pelvic irradiation is therefore justifiable. The role of adjuvant chemotherapy was addressed by a study conducted by the NSABP, in which chemotherapy with 5-FU, vincristine, and methyl-CCNU was compared with radiotherapy or observation after surgery (51). Congruent with their results in colon cancer, chemotherapy led to a survival advantage ( P = 0.05) over radiotherapy or control. It should be noted, however, that this study did not include a combined treatment arm and that there was no improvement in local tumor control. The combined application of chemotherapy (methylCCNU plus 5-FU) with irradiation concurrently with 5-FU

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

92

J . A. WiLF

has been compared with irradiation alone, with chemo- are sufficient. Furthermore, the late radiotherapy-related therapy, and with no postoperative treatment in a study serious toxicity is of concern, and the percentage of patients conducted by the Gastrointestinal Tumor Study Group suffering from these sequelae should be weighted against (GITSG), which resulted in a 24% improvement in 7-year the percentage that enjoys potential survival benefit. Where do we stand in Europe? Radiotherapy is considered survival in the combined modality approach compared with control ( P = 0.005). The number of approximately 50 by many to be the adjuvant treatment of choice, at least in patients in each arm of the trial, however, was relatively patients at very high risk for local recurrence (Astler Coller small, and 15% of the patientsdid not receive chemotherapy. CZ-3), while combined treatment is hardly a choice at There was no significant survival advantage for the combined all. Preoperative radiotherapy is of interest and in fact is modality over irradiation alone (52). The second study to advocated by some but is hampered by the lack of more favor the combined approach was conducted by the Mayo specific methods to identify patients at high risk preClinic and the NCCTG. This trial, in which chemotherapy operatively. also consisted of methyl-CCNU plus 5-FU, yielded a signifiIt appears too early to advocate combined modality as cant survival benefit for combined modality treatment over ‘reasonable’-that is, routine treatment, outside clinical irradiation alone. In this study 204 patients were trials-as is done by the NCI. We feel that the available data randomized, and with a median follow-up of more than 7 do not persuasively prove that chemo- plus radio-therapy is years the combined modality arm was found to produce a superior to one of the individual treatment modalities (57). 34% reduction in the overall cancer relapse rate ( P = When planning new trials, it is relevant to know what 0.0016), while the cancer-related death rate was reduced studies are underway in the USA. Currently, NSABP invesby 36% ( P = 0.0071) (53). It is important to note that tigators are comparing chemotherapy programs with chemoradiotherapy in this study led to serious late abdominal therapy plus irradiation. The chemotherapy programs complications in 6.7% of patients, with 2% treatment- consist of 5-FU plus leucovorin or 5-FU, vincristine, and related deaths. It should be realized that this trial contained methyl-CCNU. The Intergroup (Mayo Clinic’s NCCTG, neither a chemotherapy alone arm nor a control arm. ECOG and South West Oncology Group (SWOG)) inIn contrast with these results, a preliminary report from corporates irradiation in all their protocol arms and comthe ECOG showed no significant differences in patients with pares different chemotherapy protocols. The current rectal cancer randomized to chemotherapy with methylIntergroup trial (INT 0114) utilizes sequential single-agent CCNU plus 5-FU, radiotherapy, or sequential radio- plus 5-FU and high-dose pelvic irradiation plus concurrent bolus chemotherapy. It may be relevant that in this study chemoinj6ctions of 5-FU as the control group, while the expertherapy was not administered concomitantly with radioimental groups employ combinations of 5-FU, levamisole, therapy (54). Mature data from this trial are awaited. and leucovorin plus radiotherapy. These ongoing studies will Chemotherapy in the successor NCCTG study (NCCTG provide important information about more optimal treat864751), which was closed after accrual of 680 patients in ment. half the time projected, consisted of different schedules of What kind of studies should we perform? For those who 5-FU concurrent with irradiation and 5-FU plus or minus feel that the role of radiotherapy is still not obvious, trials methyl-CCNU before and after radiotherapy. Tumor comparing chemotherapy programs (similar to those for relapses have actually been somewhat more numerous in colon cancer) or a chemotherapy program plus or minus patients receiving methyl-CCNU (55). These data are corradiotherapy could be initiated. For those for whom the role roborated by the results of a subsequent GITSG adjuvant of irradiation is sufficiently well established, trials comparing study protocol which showed no improvement for combined modality therapy that included methyl-CCNU as part of the different chemotherapy protocols in addition to radiotherapy systemic treatment when compared with treatment with 5- would be more appropriate. Because the update of the Intergroup study concerning FU alone (56). Are these data sufficiently conclusive? The first GITSG the effectiveness of systemic 5-FU plus levamisole in colon study is the only one that has demonstrated a superiority cancer showed the same beneficial effect after 5 years as with combined modality over surgery alone. With regard to after 3.5 years, it will be difficult to achieve superior results this trial it is difficult to accept that a substantial benefit can with any schedule or currently available drugs. Therefore, derive from a chemotherapy protocol that is deferred for this regimen should probably be one of the chemotherapy more than 2 months after surgery, that is not even received arms in future trials in rectal cancer. Other potentially important issues for future research by 15% of patients, and that contains a drug subsequently include the incorporation of biologic therapy in the therashown to be of no therapeutic value or even to be detripeutic program, the optimal timing and route of chemomental. Undoubtedly, the Mayo-NCCTG trial that showed therapy, more effective radiosensitization by the addition of benefit for chemoirradiation over a significant survival biochemical or biologic modulators to 5-FU, and optimal irradiation was well conducted, but one can question whether fractionation of radiotherapy. the data obtained in one study with 100 patients in each arm

Chemotherapy for Gastrointestinal Cancer

19. Aschele C, Sobrero AF, Guglielmi A, et al. Schedule dependent mechanisms of resistance to 5-fluorouracil in HCT-8 cells [abstract]. Proc Am SOCCancer Res 1991;32:353. T h e adjuvant treatment of colorectal cancer is indeed a 20. Seifert P, Baker LH, Reed MOL, et al. Comparison of conpromising field of research with a realistic hope for further tinuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 1975;36: improvement in the year not t o o far ahead. Because the 12H. magnitude of the effects may be small, but relevant, we can 21. Lokich JJ, Ahlgren JD, Gullo JJ, et al. Prospective randomized more efficiently contribute to further progress by large-scale comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a trials on an international basis. Mid-Atlantic Oncology Program study. J Clin Oncol 1989;7: 425-32. 22. Rougier Ph, Paillot B, Laplanche A, et al. End results of a REFERENCES multicentric randomized trial comparing 5 FU in continuous systemic infusion (CI) to bolus administration (B) in measurable I . Herskovic A, Martz K, Al-Sarraf M, et al. Intergroup esophametastatic colorectal cancer (MCC)) [abstract]. Proc Am SOC geal study: comparison of radiotherapy (RT) to radio-chemoClin Oncol 1992;11:163. therapy combination: a phase 111 trial [abstract]. Proc Am SOC 23. Hansen R, Ryan L, Anderson T, et al. A phase 111 trial of bolus Clin Oncol 1991;10:135. 5FlJ versus protracted infusion 5FU+/- cisplatin in metastatic 2.Sischy B, et al. Interim report of EST 1282 phase Ill protocol colorectal cancer. An Eastern Cooperative Oncology Group for the evaluation of combined modalities in the treatment of study (EST 2286) [abstract]. Proc Am SOCClin Oncol 1992; patients with carcinoma of the esophagus, stage I & I1 [abstract). 11:171. Proc Am Soc Clin Oncol 1990;9:105. 3. Wils J. Perspectives in the treatment of advanced gastric cancer. 24. Shah A, MacDonald W, Goldie J, et al. 5-FU infusion in advanced colorectal cancer: a comparison of three dose schedAnti-Cancer Drugs 1991;2:133-7. ules. Cancer Treat Rep 1985;69:739-42. 4. Wils J, Klein HO, Wagener DJTh, et al. Sequential high dose methotrexate and 5-fluorouracil combined with doxorubicin: a 25. Ardalan B, Singh G, Silberman H. A randomized phase I and 11 study of short term infusion of high-dose fluorouracil with or step ahead in the treatment of advanced gastric cancer. A trial without N- (phosphonacety1)-L-aspartic acid in patients with of the EORTC gastro-intestinal (GI) Tract Cooperative Group. advanced pancreatic and colorectal cancer. J Clin Oncol 1988; J Clin Oncol 1991;9:827-31. 6:1053-8. 5. Cruz-Hernandes J, Cervantes A, Belon J, et al. Treatment of stage IV gastric cancer (GC) with a second or third generation 26. O’Dwyer PJ, Paul AR, Walczak J, et al. Phase I1 study of biochemical modulation of fluorouracil by low-dose PALA in chemotherapy [abstract ECCO-61. Eur J Cancer 1991; Suppl 2: patients with colorectal cancer. J Clin Oncol 1990;9:1497-1503. S80. 6. Kelsen D, Atiq OT, Saltz L, et al. FAMTX versus etoposide, 27. Hryniuk WM, Figueredo A, Goodyear M. Applications of dose intensitv to oroblems in chemotheraov of breast and colorectal doxorubicin, and cisplatin: a random assignment trial in gastric cancer.’Semin Oncol 1987;14 Supply:3-1 I . cancer. J Clin Oncol 1992;10:541-8. 7. O’Connell M. Etoposide, doxorubicin. and cisplatin chemo- 28. Diaz-Rubio E, Aranda E, Martin M, et al. Weekly high-dose therapy for advanced gastric cancer: an old lesson revisited. J infusion of 5-fluorouracil in advanced colorectal cancer. Eur J Clin Oncol 1992;lO:SlS-6. Cancer 1990;26:727-9. 8. Lasser Ph, Rougier Ph, Mahjoubi M, et al. Neoadjuvant chemo- 29. Diaz-Rubio E, Jimeno J, Aranda E, et al. Weekly high-dose therapy (NCT) in locally advanced gastric cancer (LAGC) infusion of 5-Ruorouracil (5-FU) in advanced colorectal cancer [abstract ECCO-61. Eur J Cancer 1991; Suppl 2: S71. [abstract]. Abstracts of International Conference on Biology and 9. Wilke H, Preusser P, Fink U, et al. New developments in the Treatment of Gastrointestinal Malignancies, Frankfurt, 1992:82. treatment of gastric carcinoma. Semin Oncol 1990;17 Suppl 30. Conroy T , Adenis A, Brucker P, et al. A prospective ran2:61-70. domized trial of protracted infusional 5 FU with allopurinol 10. Lerner A, Gonin R, Steele GD, Mayer RJ. Etoposide, doxoruversus bolus 5 FU and high-dose leucovorin in metastatic colobicin, and cisplatin chemotherapy for advanced gastric adenorectal cancers [abstract]. Proc Am SOCClin Oncol 1992;11:162. carcinoma results of a phase I1 trial. J. Clin Oncol 1922;10:536 31. Martin DS, Stolfi RL, Colofiore JR. Failure of high dose leu40. covorin to improve therapy with the maximally tolerated dose 1 1 . Plukker JTh, Mulder NH, Yerschueren RCJ. Combined of 5-fluorouracil: a murine study with clinical relevance? J Natl chemotherapeutic/surgical approach of locally advanced cancer Cancer Inst 1988;80:496-501. of the cardia and gastric fundus [abstract]. Abstracts of EORTC 32. Martin DS, Nord LD, Stolfi RL, et al. Biochemical modulation Symposium on Advances in Gastrointestinal Tract Cancer of 5-fluorouracil (FU): a different biochemical emphasis, (FU) Research and Treatment 1989:41. RNA, can produce greater in vivo anticancer efficacy than 12. Conroy Th, Wils J, Wagener DJTh, et al. Phase I1 trial with leucovorin (LV)-FU [abstract]. Proc Am SOCClin Oncol 1991; FEMTX-P in advanced gastriccancer. Abstractsof International 10:97. Conference on Biology and Treatment of Gastrointestinal Valone FH, Friedman MA, Wittlinger PS, et al. Treatment of 33. Malignancies, 1992, Feb 4-7;72; Frankfurt/Main. patients with advanced colorectal carcinomas with fluorouracil 13. Wils J. Chemotherapy in pancreatic cancer: a rational pursuit? alone, high-dose leucovorin plus fluorouracil, or sequential Anti-Cancer Drugs 1991 ;2:3- 10. methotrexate, fluorouracil, and leucovorin: a randomized trial 14. Blijham GH. Chemotherapy of colorectal cancer. Anti-Cancer of the Northern California Oncology Group. J Clin Oncoll989; Drugs 1991;2:233-45. 7: 1427-36. 15. Bruckner HW, Motwani BT. Chemotherapy of advanced cancer 34. Di Constanzo F, Bartolucci R, Calabresi F, et al. Fluorouracilof the colon and rectum. Semin Oncol 1991;18:443-61. alone versus high-dose folinic acid and fluorouracil in advanced 16. Advanced Colorectal Cancer Meta-analysis Project. Modulation colorectal cancer: a randomized trial of the Italian Oncology of 5-fluorouracil by leucovorin in patients with advanced coloGroup for Clinical Research (GOIRC). Ann Oncol 1992;3:371rectal cancer: evidence in terms of response rate. J Clin Oncol 6. 1992;10:89&903. 35. Ardalan B, Chua L, Tian E, et al. A phase I1 study of weekly 17. Lokich JJ. Optimal schedule for 5-fluorouracil chemotherapy. 24-hour infusion with high-dose fluorouracil with leucovorin in Intermittent bolus or continous infusion? Am J CIin Oncol colorectal carcinoma. J Clin Oncol 1991 ;9:625-30. 1985;8:445-8. 18. Carlson RW, Sikic BI. Continuous infusion or bolus injection 36. Ardalan B, Sridhar KS, Benedetto P, et al. A phase I, I1 study in cancer chemotherapy. Ann Intern Med 1983;99:823-33. of high-dose 5-fluorouracil and high-dose leucovorin with low-

CONCLUSION

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

93

Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/18/14 For personal use only.

94

J . A. Wils

dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies. Cancer 1991;68:1242-6. 37. Ardalan B, Donofrio K, Sridnar KS, et al. Is there hope after 5-FU bolus? A phase I1 study of short term protracted infusion of high dose 5-fluorouracil (5-FU) with leucovorin (LV), and low dose phosphoacetyl-1-asparcticacid (PALA) in colorectal carcinoma (abstract]. Proc Am SOCClin Oncol 1992;11:186. 38. Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer-results of a prospectively randomized trial. N Engl J Med 1985;312:1465-72. 39. Mansour E, Ryan L, Lerner H, et al. Lack of effectiveness of 5-FU t methyl CCNU as compared to 5-FU for adjuvant therapy in colon cancer [abstract]. Proc Am SOCClin Oncol 1989;8:115. 40. Panettierre FJ, Goodman PJ, Constanzi JJ et al. Adjuvant therapy in large bowel adenocarcioma: long-term results of a Southwest Oncology Group study. J Clin Oncol 1988;6:947-54. 41. Higgins GA Jr, Amadeo JH, McElhinney J , et al. Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. Cancer 1984;53:1-8. 42. Abdi EA, Harbora D, Hanson J, et al. Adjuvant chemoimmuno and immunotherapy in stage B2 and C colorectal cancer. Proc Am SOCClin Oncol 1987;6:93. 43. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Nat Cancer Inst 1988;80:30-6. 44. Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large bowel carcinoma: an evaluation of levamisole and the combination of levamisole and 5-fluorouracil. A study of the North Central Cancer Treatment Group (NCCTG) and the Mayo Clinic. J Clin Oncol 1989;7:1447-56. 45. Moertel CG, Fleming TH, Macdonald JS, et a. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. 46. Moertel C, Fleming T, MacDonald J, et al. The Intergroup study of fluorouracil (5-FU) plus levamisole (LEV) and levamisole alone as adjuvant therapy for stage C colon cancer. A final report [abstract]. Proc Am SOCClin Oncol 1992;11:161.

47. Buyse M. Current status of adjuvant therapy of colon carcinoma [abstract]. Abstract of International Conference on Biology and Treatment of Gastrointestinal Malignancies 1992, Feb 4-7; 55; Frankfurt/Main. 48. The efficacy and the group C status of levamisole plus 5-fluorouracil for patients with Dukes’ C colon cancer. National Cancer Institute (NCI) press release on levamisole Bethesda, Maryland 20892 (U.S.A.). September 26, 1989. 49. Wils JA, Wagener DJTh. Adjuvant treatment of colon cancer. Where to go from here? Ann Oncol 1990;1:329-31. 50. National Cancer Institute Clinical Announcement. Adjuvant Therapy of Rectal Cancer, March 14, 1991. 51. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Nat Cancer Inst 1988;80:21-9. 52. Douglass H O Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986;315:1294-5. 53. Krook JE, Moertel CG. Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal cancer. New Engl J Med 1991;324:709-15. 54. Mansour EG, Lefkopoulou M, Johnson R, Douglass H Jr. A comparison of post-operative adjuvant chemotherapy, radiotherapy or combination therapy in potentially curable resectable rectal carcinoma. An ECOG study EST 4276 [abstract]. Proc Am SOCClin Oncol 1991;10:154. 55. O’Connell M, Wieand H, Krook J , et al. Lack of value for methyl-CCNU(MeCCNU) as a component of effective rectal cancer surgical adjuvant treatment: interim analysis of intergroup protocol 86-47-51 [abstract]. Proc Am SOCClin Oncol 1991;10:134. 56. Gastrointestinal Tumor Study Group. Radiation therapy and 5fluorouracil(5-FU) with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 1992;10:549-57. 57. Wils J , Wagener DJTh. Combined modality adjuvant treatment of high-risk rectal cancer: a treatment of choice or a choice of treatment? Ann Oncol 1992;3:197-9.