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Chemotherapy of Upper GI Neoplasms:
Proven/Unproven
Niall C. Tebbutt and David Cunningham
Aims
To establish the role of chemotherapy for gastro-oesophageal tumours using cur- rently available evidence.
Introduction
In solid tumours, chemotherapy is frequently used both for palliation of advanced disease and also as an adjuvant therapy in order to improve the results of surgery in those patients with operable early stage disease. This chapter dis- cusses the role of chemotherapy in upper gas- trointestinal tract neoplasms, which comprise gastric and oesophageal cancers.
Advanced Disease
In the Western world, the majority of cases of oesophagogastric cancer present with advanced stage disease. Whilst loco-regional therapies such as surgery are the only treatments capable of achieving cure in early stage disease, they have an extremely limited role in advanced stage disease. Chemotherapy is used to control symptoms, maintain quality of life and prolong survival. Since advanced oesophagogastric cancer is incurable, it was important to ascer- tain the benefit attributable to the use of chemotherapy in this setting. Table 26.1 sum-
marises the results of trials comparing combi- nation chemotherapy regimens with best sup- portive care. Although these trials incorporate small numbers of patients, they have shown that chemotherapy achieves a statistically significant prolongation in median survival. It has also been demonstrated that the quality of life is also significantly improved in patients receiving chemotherapy, and financial analyses have shown that attainment of these benefits is cost effective [1]. It is now, therefore, accepted that patients with advanced oesophagogastric cancer who are sufficiently fit to receive chemotherapy should be considered for this treatment.
Single Agent Chemotherapy
A variety of chemotherapy agents have been evaluated using phase II studies in advanced
Table 26.1. Randomised trials comparing combination chemotherapy with best supportive case (BSC) in patients with advanced gastric cancer
Regimen Number of Median survival p patients (months)
ELF 10 10 <0.02
BSC 8 4
FAMTX 30 10 <0.001
BSC 10 3
FEMTX 17 12 <0.001
BSC 19 3
ELF, epirubicin, leucovorin, 5FU; FAMTX, 5FU, adriamycin, methotrexate; FEMTX, 5FU, epirubicin, methotrexate.
oesophagogastric cancer [2]. Results achieved in these studies are shown in Table 26.2.
Most studies include relatively small numbers of selected patients. Whilst it is difficult to compare the results between studies, it does provide an indication of which agents may have the greatest activity. The results demonstrate that relatively few agents can achieve response rates of greater than 25% in previously untreated patients.
Combination Chemotherapy Regimens
In an attempt to improve the results of chemotherapy, combination regimens consist- ing of those agents with the highest activity have been devised. Fluorouracil (5FU) has been a key component of many of these regimens because of its activity and its modest toxicity profile par- ticularly when administered by infusion sched- ules. An early combination regimen (FAM) consisted of 5FU, adriamycin and mitomycin-C (MMC). This combination regimen was estab- lished based on impressive response rates in phase II studies. The activity of this combina- tion regimen was confirmed in a randomised phase III study comparing treatment using FAM with adriamycin and MMC and 5FU, adri- amycin and methyl-CCNU in patients with advanced gastric cancer [3]. The FAM combi- nation regimen achieved the highest response rates (39%) and was also associated with the longest median survival (7.5 months).
Further chemotherapy regimens were devised in an attempt to improve on the FAM regimen.
The FAMTX regimen incorporated high dose methotrexate instead of MMC. A randomised study showed that FAMTX achieved superior response rates (41% versus 9%; p = 0.0001) and more prolonged median survival times (9.7 months versus 6.7 months; p = 0.004) than FAM [4]. More recently, two other combination regimens have been found to be equivalent to FAMTX in advanced gastric cancer. The response rates achieved using etoposide, leu- covorin and bolus 5FU (ELF), infused 5FU and cisplatin (FP) and FAMTX were 9%, 20% and 12% respectively and were not significantly different. The median survival times were 7.2 months with ELF, 7.2 months with FP and 6.7 months with FAMTX [5]. The authors con- cluded that all of these regimens had modest activity and that new strategies for advanced disease should be considered.
The combination of epirubicin 50 mg/m
2, cisplatin 60 mg/m
2and protracted venous infu- sion 5FU 300 mg/m
2/day was developed at the Royal Marsden Hospital, United Kingdom. This regimen also achieved an impressive response rate of 71% in a phase II study involving 128 patients [6]. This led to comparison of ECF with FAMTX in a randomised phase III study involv- ing 274 patients with advanced oesophagogas- tric cancer. The response rate in this study with ECF was superior to FAMTX (45% versus 21%;
p = 0.0002) and overall survival was also supe-
rior (8.9 months versus 5.7 months; p = 0.0009).
This study also included patients with locally advanced inoperable disease as well as patients with metastatic disease. The response rate in patients with locally advanced disease was 58%
and a proportion of responding patients were able to proceed to surgery and subsequently underwent macroscopic and microscopic com- plete resection of the tumour (R0 resection).
A second randomised study has confirmed the activity of ECF. In this study ECF was com- pared with MCF, where MMC was combined with cisplatin and a larger dose of infused 5FU than is administered in ECF. In this study the response rates (42% versus 44%) and median survival time (9.4 months versus 8.7 months) for patients receiving both ECF and MCF were equivalent [7]. Whilst these measures of efficacy appeared equivalent, global quality of life was superior for patients receiving ECF. This is an
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Table 26.2. Response rates achieved in phase II studies ofvarious chemotherapy agents in advanced oesophagogastric cancer
Chemotherapy Number of Response
agent patients rate (%)
5FU (infusion) 13 31
5FU (bolus) 392 21
Mitomycin-C 211 30
Epirubicin 61 26
Doxorubicin 68 25
Docetaxel 37 24
Paclitaxel 33 17
Irinotecan 60 23
Cisplatin 129 19
Carboplatin 57 5
Methotrexate 28 11
important measure for a treatment that is given with palliative intent and this has led to the con- clusion that ECF is the superior regimen.
ECF is the Most Active Combination Chemotherapy Regimen in
Oesophagogastric Cancer
The evidence therefore indicates that the ECF regimen is the most active combination chemotherapy regimen for patients with advanced oesophagogastric cancer. Although this regimen is widely accepted as standard treatment, its acceptance has not been univer- sal. The reluctance to accept ECF has arisen for a number of reasons and various criticisms of the ECF versus FAMTX study have been raised to account for this reluctance. Firstly, there was a perception that the patients receiving FAMTX in the trial comparing FAMTX with ECF had fared badly. Further randomised studies using FAMTX now suggest that the median survival achieved using FAMTX of approxi- mately 6 months is comparable to other studies.
Secondly, more patients receiving ECF pro- ceeded to a potentially curative surgical resec- tion, which may have biased the results of this study. Whilst many would regard this result likely to be due to the superior activity of ECF, the role of neoadjuvant ECF in patients with locally advanced disease has never been for- mally assessed in a randomised study. Thirdly, the administration of ECF requires the insertion of long-term indwelling venous catheters and results in a relatively modest prolongation of median survival in comparison with regimens such as FAMTX.
ECF achieves a modest median survival dura- tion in patients with advanced oesophagogastric cancer, with a median survival time of approx- imately 9 months. The relatively short survival times highlight the need for ongoing improve- ment in the treatment of patients with advanced oesophagogastric cancer. This is particularly the case for elderly and less fit patients for whom the side effects of intensive combination chemotherapy may be significant.
Future Studies
In order to attempt to improve the results achieved using chemotherapy, several ran-
domised studies incorporating novel agents are currently in progress. A multicentre study coor- dinated by the Royal Marsden Hospital is using ECF as the standard arm and is comparing this with substitution of cisplatin by the third gen- eration platinum agent oxaliplatin and substi- tution of 5FU with the oral fluoropyrimidine capecitabine. The use of capecitabine in this fashion avoids the requirement for indwelling venous catheters.
Novel agents with activity in oesophagogas- tric cancer include the taxanes and the topoiso- merase I inhibitor irinotecan (CPT11). Phase II studies have suggested that CPT11 plus 5FU is an active regimen (response rate 42%) [8].
Similarly, the combination of docetaxel, cis- platin and 5FU appears active (response rate 44%) [9]. These regimens are now being com- pared to standard treatment in randomised phase III clinical trials.
Biological Therapies
Further strategies currently being evaluated in an effort to improve the results in patients with advanced oesophagogastric cancer include the use of biological therapies directed at pathways perceived to be important in the pathogenesis of gastric cancer. One of these approaches involves the use of marimastat, a matrix metalloproteinase (MMP) inhibitor. The MMP enzymes constitute a family of proteolytic enzymes. Elevated levels of MMP enzymes have been associated with a poor prognosis in gastric cancer. A randomised study comparing mari- mastat with placebo in patients with gastric cancer demonstrated prolongation of failure- free survival and after protracted follow-up an overall survival advantage, especially for those patients who had received prior chemotherapy.
However, the prolongation in survival was modest at approximately 1 month and overall quality of life was not improved [10]. Therefore further evaluation of the role of marimastat is likely to be required in order to define a role for this drug in patients with advanced gastric cancer.
Other possible approaches include agents tar- geted to the epidermal growth factor receptor (EGFR). Antibodies to EGFR and drugs inhibit- ing the EGFR kinase domain are currently being evaluated in oesophagogastric cancer as well as other tumour types.
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Adjuvant Therapy
Although a proportion of patients may be cured by surgical resection of primary oesophageal or gastric tumours, 70% or more of patients will subsequently develop recurrent disease. This is due to the presence of unresected micrometas- tasis. Adjuvant treatment aims to eliminate residual tumour cells and increase the propor- tion of patients achieving long-term disease- free intervals and overall survival benefit.
Instituting treatment soon after surgery may have a number of advantages. The tumour burden is low and the likelihood of development of chemotherapy-resistant cell clones smaller.
The knowledge of the range of agents with activ- ity in advanced disease raises the possibility of utilisation of these agents in the adjuvant setting.
Gastric Cancer
The majority of studies of adjuvant therapy after resection of gastric cancers have failed to demonstrate any benefit for this treatment. A number of meta-analyses have also failed to indicate any benefit for adjuvant therapy, although a more recent analysis has suggested that there may be a small benefit [11]. An important caveat in interpretation of the data is that many of the studies used suboptimal adju- vant chemotherapy regimens, with many involving treatment using single chemotherapy agent regimens. In addition, many of the studies included relatively small numbers of patients and therefore there would need to be substan- tial differences in outcome for these to be sta- tistically significant. Adjuvant chemotherapy is therefore regarded as an unproven treatment after surgical resection of gastric cancer and eli- gible patients should be considered for adjuvant chemotherapy trials.
Oesophageal Cancer
Adjuvant chemotherapy after surgical resection of squamous cell carcinoma of the oesophagus has been evaluated in two randomised studies using the combinations of cisplatin with vindesine and cisplatin with 5FU given for two cycles [12–14]. In each study, there was no impact on overall survival for the group receiv- ing chemotherapy. Like the results of the gastric
cancer trials, relatively small numbers of patients have been studied and the chemo- therapy regimens are not necessarily optimal.
For example, it is unlikely that two cycles of chemotherapy would have a dramatic impact on micrometastatic disease. However, at this stage it must be concluded that postoperative adju- vant chemotherapy remains an unproven treat- ment for oesophageal carcinoma.
Adjuvant
Chemoradiotherapy
Gastric Cancer
Since both local as well as systemic recurrence represents a common problem after gastric cancer resection, a North American Intergroup trial evaluated a combined modality adjuvant regimen compared with observation. This incorporated postoperative chemotherapy involving one cycle of 5FU and leucovorin (LV) followed by two cycles of 5FU/LV administered concurrently with radiotherapy followed by two further cycles of 5FU/LV. The schema of treat- ment is outlined in Figure 26.1 [15]. The results of this adjuvant treatment showed that this therapy led to a 10% survival advantage after 3 years (52% versus 41%; p = 0.03). Failure-free survival was 49% for the treatment arm com- pared with 32% for no adjuvant therapy (p = 0.001). Whilst this treatment is now regarded as standard therapy in North America, it has not yet been widely accepted in Europe because of concerns about toxicity with abdom- inal chemoradiation and the adequacy of surgery. In the trial 41% and 32% of patients suffered grade 3 and 4 toxicities respectively and 54% of patients received less than a D1 resec- tion.
Neoadjuvant Treatment
Neoadjuvant therapy involves the administra- tion of systemic treatment before loco-regional therapy such as surgery. This approach to the treatment of oesophagogastric cancer offers a number of potential advantages. It allows systemic treatment to be delivered as early as possible, which may have advantages from the
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perspective of treatment of micrometastatic disease. In addition, it allows the possibility that inoperable locally advanced tumours may be downstaged, thereby rendering these tumours amenable to potentially curative surgical resec- tion. It also provides prognostic information, with tumour response to neoadjuvant chemotherapy representing the most important prognostic factor for prolonged survival in gastric cancer [16]. The principal disadvantage of neoadjuvant chemotherapy is the possibility that tumour progression may occur during the course of treatment, thereby rendering the tumour inoperable and allowing the risk of dis- semination of disease.
Gastric Cancer
Phase II studies have demonstrated that neoad- juvant chemotherapy is an effective strategy in selected patients with gastric cancer. A current Medical Research Council (MRC) study is com- paring the results after three cycles of ECF neoadjuvant chemotherapy followed by surgical resection followed by a further three cycles of ECF adjuvant chemotherapy with surgical resection alone for patients with cancers of the stomach or oesophagogastric junction. The design of this trial is illustrated in Figure 26.2.
This study is close to completing accrual and should provide valuable information about the role of neoadjuvant chemotherapy in gastric cancer.
Oesophageal Cancer
In the case of oesophageal cancer, preopera- tive approaches have included neoadjuvant chemotherapy or neoadjuvant chemoradiation.
The neoadjuvant chemotherapy studies have often included relatively small numbers of patients receiving a variety of chemotherapy regimens. However, two large studies have recently been reported, one of which has shown a significant benefit for this approach. The results of all these studies are summarised in Table 26.3. A recent MRC study involving 800 randomised patients compared preoperative chemotherapy using two cycles of cisplatin 80 mg/m
2and 5FU 1000 mg/m
2d1–4 with no preoperative treatment [17]. The trial design is illustrated in Figure 26.3. Preoperative chemotherapy was feasible and resulted in a higher rate of macroscopic complete resection (84% versus 71%). The R0 resection rate was 60% in the chemotherapy arm compared with 55% in the surgery arm. This constitutes an important outcome, as only patients who achieve an R0 resection would be anticipated to be able to achieve long-term survival. Impor- tantly, there was no increase in perioperative complications or deaths after preoperative chemotherapy. There was a statistically signifi- cant improvement in both progression-free and overall survival, with 2-year survival being 45%
in the combined modality arm compared with 35% in the surgery alone arm.
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Figure 26.1. Outline of trial comparing postoperative chemoradiotherapy with observation after resection of gastric cancer.
A similar schedule of preoperative treatment has also been evaluated in a large American study [18]. This trial compared the results of surgery after preoperative chemotherapy using three cycles of cisplatin and fluorouracil with surgery alone. Preoperative chemotherapy achieved a small although not statistically sig- nificant improvement in the R0 resection rate.
However, this did not result in any impact on overall survival.
It is difficult to explain the different results from these two studies. Nevertheless, the large number of patients enrolled in the MRC study makes the results of this trial quite compelling.
It is likely that there are subgroups of patients who derive most benefit from such a neoadju- vant treatment approach. These may be identi- fied based on more accurate staging techniques such as endoscopic ultrasound or based on the molecular genotype of the tumour. However,
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Table 26.3. Results of randomised studies of neoadjuvant chemotherapy in oesophageal carcinomaMedian overall survival (months)
Trial Number of Histology Chemotherapy Chemotherapy Surgery
patients
Roth et al 39 Squamous Cisplatin, vindesine, bleomycin 8 9
Nygaard et al 91 Squamous Cisplatin, bleomycin 8 8
Schlag et al 77 Squamous Cisplatin, 5FU 3 cycles 10 10
Kok et al 160 Squamous Cisplatin, etoposide 2–4 cycles 18.5* 11
Kelsen et al 440 Squamous/ Cisplatin, 5FU 3 cycles 14.9 16.1
adenocarcionma
MRC OEO2 802 Squamous/ Cisplatin, 5FU 17.6* 13.6
adenocarcinoma
*p< 0.01.
Figure 26.2. Outline of MRC study evaluating neoadjuvant chemotherapy in operable gastric cancer.
until these groups are identified it would be rea- sonable to consider neoadjuvant chemotherapy in patients who were being considered for radical resection of oesophageal carcinoma.
Neoadjuvant
Chemoradiotherapy
Oesophageal Cancer
A randomised study has compared chemora- diotherapy with radical radiotherapy as defini-
tive treatment for oesophageal carcinoma.
This study compared two cycles of cisplatin 75 mg/m
2and 5FU 1000 mg/m
2d1–4 given con- currently in weeks 1 and 5 with 50 Gy radio- therapy followed by two further cycles of the same chemotherapy with 64 Gy radiotherapy alone (Figure 26.4) [19]. The majority of cases were squamous cell carcinomas, but adenocar- cinomas were included. Median survival was 14 months in the combined modality arm compared with 9 months in the radiotherapy arm. The 5-year survival rate was 27% for the combined modality therapy versus 0% for radiotherapy.
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Figure 26.3. Outline of MRC study evaluating neoadjuvant chemotherapy in operable oesophageal cancer.
Figure 26.4. Outline of trial comparing radical radiotherapy with chemoradiotherapy as definitive treatment for oesophageal cancer.
The positive results of this study have led to acceptance of chemoradiotherapy as a possible treatment option for those patients who are not surgical candidates. This may apply for those patients who are not candidates for surgical resection on the grounds of concurrent medical disorders or because the anatomical location of the primary tumour renders surgery technically difficult, such as tumours arising in the cervical oesophagus. Nevertheless, the local failure rate with such an approach is significant (47%).
This has stimulated trials which incorporate chemoradiotherapy in addition to surgery.
Whilst a variety of regimens have been studied, most randomised studies evaluating these regimens have been negative. These results are summarised in Table 26.4. Whilst the study by Walsh et al has reported improved sur- vival with neoadjuvant chemoradiotherapy prior to surgery compared with surgery alone, this study has been criticised because of the relatively poor outcomes achieved in the surgery alone control arm [20]. A limitation of chemoradiotherapy is toxicity, which is increased with such therapy. For instance, in the trial reported by Urba et al, neutropenic sepsis occurred in 39% of patients and 63% of patients required feeding tubes in order to maintain nutrition because of radiation oesophagitis [21].
Therefore, in the absence of any significant benefit attributable to this approach, neoadju- vant chemoradiation prior to surgery for oesophageal carcinoma is currently regarded as an unproven treatment.
Improvements in Adjuvant and Neoadjuvant
Therapies
As new agents are evaluated further in the advanced setting, it is likely that those agents with the highest activity will be used in the adju- vant and neoadjuvant setting. However, even the use of these agents is unlikely to benefit all patients. It is likely that only selected patients will derive benefit from adjuvant or neoadju- vant therapy. These are patients who only have micrometastatic disease and whose tumours are responsive to chemotherapy.
Exclusion of Patients with Metastatic Disease
Conventional staging procedures do not exclude a number of patients with metastatic disease. However, the use of positron emission tomography (PET) scans has been shown to provide a useful adjunct to conventional staging using CT scans and endoscopic ultrasound examination [22]. The inclusion of PET scans could allow radical surgery and chemotherapy to be targeted at those patients who are most likely to benefit.
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Table 26.4. Results of randomised studies of neoadjuvant chemoradiotherapy in oesophageal carcinomaTrial Number Histology Chemotherapy Radiotherapy Chemotherapy Surgery
of patients dose
Le Prise et al 86 Squamous Cisplatin, 5FU 20 Gy, 10 10 10.5
fractions
Nygaard et al 88 Squamous Cisplatin, bleomycin 35 Gy in 20 9 8
fractions
Bosset et al 282 Squamous Cisplatin, 2 cycles 37 Gy in 10 18.6 fractions
Walsh et al 113 Adenocarcinoma Cisplatin, 5FU 2 cycles 40 Gy in 15 16*
fractions
Urba et al 100 Squamous/ Cisplatin, 45 Gy in 30 16.9
adenocarcinoma vinblastine, 5FU 2 cycles fractions
*p< 0.01.
Prediction of Tumour Response Using Molecular Markers
There has been considerable interest in the use of molecular markers to identify tumours which are most likely to respond to chemotherapy.
This has not been extensively evaluated in oesophagogastric cancers. However, studies involving small numbers of patients with gastric cancer showed that patients whose tumours had elevated levels of the enzyme thymidylate syn- thase (TS) were resistant to 5FU. Similarly, tumours with elevated levels of mRNA encod- ing the DNA repair gene ERCC1 were more likely to be resistant to cisplatin [23]. Further evaluation of the role of molecular markers may allow the identification of patients who are most likely to benefit from chemotherapy, and who could potentially be targeted to receive adjuvant or neoadjuvant chemotherapy. This type of strategy is advantageous as it ensures that only those patients who are likely to derive benefit from chemotherapy actually receive that treat- ment, thereby sparing toxicity in those who do not derive benefit.
Conclusions
Combination chemotherapy is proven to benefit patients with advanced oesophagogastric cancer. It is hoped that improvements in the treatment of advanced stage disease together with careful case selection will allow more patients with early stage disease to benefit from adjuvant or neoadjuvant chemotherapy or chemoradiotherapy.
Questions
1. What are the goals of palliative chemotherapy in advanced oesopha- gogastric cancer?
2. Which combination chemotherapy regimen is considered most active in advanced oesophagogastric cancer?
3. Which adjuvant therapy has shown a survival advantage after resection of gastric cancer?
4. What are the potential advantages and disadvantages of neoadjuvant chemo- therapy in oesophageal cancer?
5. Which neoadjuvant chemotherapy regi- men has achieved a survival advantage in operable oesophageal cancer?
References
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