CHAPTER 23 Radiotherapy and chemotherapy of GI tract malignancy
Introduction
There are several different parameters used to measure ‘benefit’ from chemotherapy or radiotherapy (Table 23.1). These terms are often used as endpoints in clinical trials assessing the efficacy of a treatment regimen.
Table 23.1 Definitions of outcome parameters used to measure efficacy of a treatment regimen
| Outcome parameter | Definition |
|---|---|
| Median survival1 | The time from either diagnosis or start of treatment at which half of the patients with a given disease are found to be, or expected to be, still alive |
| 5 year survival | Proportion of patients still alive 5 years after diagnosis or start of treatment |
| Cancer specific survival | Can be used as median survival or 5 year survival but includes patients who are still alive and those who died of causes not related to their cancer |
| Progression-free survival1 | The length of time from either diagnosis or start of treatment in which a patient is living with a disease that does not get worse |
| Time to progression1 | A measure of time after a disease is diagnosed (or treated) until the disease starts to get worse |
| Response rate1 | The percentage of patients whose cancer shrinks or disappears after treatment |
1 Definitions adapted from the National Cancer Institute, www.cancer.gov [accessed 4 June 2008]
Colorectal cancer (CRC)
Radiotherapy
The risk of local recurrence of rectal cancer following surgery correlates with the presence of microscopic tumor cells within 1 mm of the circumferential resection margin (CRM) (Quirke et al., 1986; Nagtegaal et al., 2002). External beam megavoltage radiotherapy can be administered to sterilize the surgical field and has therefore established a role in the treatment of rectal cancer as an adjunct to definitive surgery. There is no established role for adjuvant radiotherapy in the treatment of colon cancer.
The three adjuvant radiotherapy regimens in common practice are:
If a rectal cancer is considered operable at the outset, then a short course of radiotherapy may be given prior to surgery to reduce the risk of local recurrence. If a rectal cancer is considered to be inoperable or only potentially operable, then a long course of rectal radiotherapy, with or without chemotherapy, is given to downsize the tumor and increase the chance of a clear resection margin.
The ‘operability’ of a rectal cancer is determined by a pelvic magnetic resonance imaging (MRI) scan. A large European multicenter prospective study (MERCURY study) has demonstrated that MRI scans can accurately measure the depth of extramural tumor spread to within 0.5 mm (MERCURY, 2007). It is essential that each patient has a pelvic MRI scan which is discussed at a multidisciplinary meeting prior to commencing treatment to determine the optimal sequencing of the multimodality treatment. Patients are selected for long course preoperative radiotherapy (with or without chemotherapy) if there is felt to be a high chance that the surgeon will not be able to perform a curative (R0) resection based on the following findings on the pelvic MRI scan:
Short course preoperative radiotherapy
The Northwest Cancer Group published a randomized study evaluating a short course of preoperative radiotherapy for patients with tethered or fixed tumors (Marsh et al., 1994). A recurrence rate of 36.5% with surgery alone was significantly reduced to 12.8% by the addition of 20 Gy in 4 fractions (P = 0.0001). A survival advantage was demonstrated in the radiotherapy arm for patients that had a curative resection (53.3% versus 44.9% at 8 years, P = 0.033).
The well-quoted ‘Swedish’ study randomized 1168 patients planned for surgery to a short course preoperative radiotherapy regimen of 25 Gy in 5 fractions or surgery alone (Anonymous, 1997). An improvement in local recurrence rate (11% versus 27%; P < 0.001) and a 10% absolute improvement in 5-year survival (48% versus 58%; P = 0.004) was demonstrated.
The practice of total mesorectal excision (TME) has also led to improved local recurrence rates. The ‘Dutch’ study compared the benefits of TME with or without preoperative radiotherapy (Kapiteijn et al., 2001). A total of 1861 operable patients were randomized to receive preoperative radiotherapy (25 Gy in 5 fractions) followed by TME or TME alone. The local recurrence at 2 years was significantly lower in the radiotherapy arm (2.8% versus 8.2%; P < 0.001) but overall survival was the same (82% for both groups).
The MRC CR07 trial randomly assigned 1350 patients with operable rectal cancer stage I to III to preoperative short-course radiotherapy (25 Gy in 5 fractions over 1 week) or surgery alone (Sebag-Montefiore et al., 2006). Patients in the surgery alone arm underwent postoperative chemoradiotherapy (45 Gy in 25 fractions with concomitant infusional 5-fluorouracil (5-FU)) if the resected specimen had positive circumferential margins. Compared to selective postoperative radiotherapy, preoperative radiotherapy reduced local recurrence from 11% to 5%. As expected, local recurrence rates were lower in the 596 patients who underwent optimal surgery with a total mesorectal excision (TME). In this group, local recurrence reduced from 6% with selective postoperative radiotherapy to 1% with preoperative radiotherapy. There was no difference in overall survival.
The benefits in local control demonstrated by these studies must be balanced against long-term toxicity from this hypofractionated regimen in the large numbers of patients with operable, good prognosis rectal cancer. Both the Dutch and Swedish studies have demonstrated increased incidence of bowel dysfunction in the irradiated group compared with surgery alone (Peeters et al., 2005; Birgisson et al., 2005). The Swedish group have also shown an increased incidence of second malignancies in the irradiated group (Birgisson et al., 2005). The early Northwest Cancer Group study demonstrated the benefit of using a lower dose regimen of 20 Gy in 4 fractions preoperatively (Marsh et al., 1994). A more recent retrospective audit from the Northwest group has suggested that delivering the lower dose regimen preoperatively to a smaller treatment volume than adopted in the Swedish and Dutch trials provides comparable local recurrence rates in patients with operable rectal cancer (Saunders et al., 2006).
Long-course radiotherapy
The MRC CR02 trial showed a 10% reduction in local recurrence when surgery was preceded by radiotherapy (40 Gy in 20 fractions) in potentially operable rectal cancers (5 year local recurrence 36% versus 46%, P = 0.04) (MRCRCWP, 1996). A more recent Cochrane meta-analysis assessing the role of preoperative radiotherapy in rectal cancer confirmed an improvement in local control with greater benefits in patients treated with a biologically equivalent dose (BED) of >30 Gy (Wong et al., 2007). The addition of chemotherapy to long-course radiotherapy has been shown to improve locoregional control. This was first demonstrated in the NSABP-02 trial randomizing patients with Dukes B or Dukes C rectal cancer to postoperative chemotherapy alone or concomitant long course postoperative CRT (Wolmark et al., 2000). A reduction in locoregional relapse from 13% in the chemotherapy arm to 8% in the CRT arm led to postoperative CRT becoming the standard adjuvant treatment of rectal cancer in North America (NIH, 1990). The EORTC 22921 trial randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive one of four regimens:
Radiotherapy consisted of 45 Gy in 5 weeks. Two courses of chemotherapy (5-FU 350 mg/m2 per day and leucovorin 20 mg/m2 per day for 5 days) were combined with preoperative radiotherapy and four courses were used for adjuvant postoperative chemotherapy. With a median follow-up of 5.4 years, overall survival was comparable in all four groups. The 5-year cumulative incidence rates for local recurrences were 8.7%, 9.6% and 7.6% in the groups that received chemotherapy preoperatively, postoperatively, or both, respectively, and 17.1% in the group that did not receive chemotherapy (P = 0.002) (Bosset et al., 2006).
The German Rectal Cancer Study Group directly compared preoperative long-course chemoradiotherapy to postoperative chemoradiotherapy. Preoperative chemoradiotherapy resulted in reduced 5-year local recurrence (6% versus 13%, P = 0.006) and fewer grade 3 or 4 acute toxicities (27% versus 40%, P = 0.001) and late toxicities (14% versus 24%, P = 0.01) compared to postoperative chemoradiotherapy (Sauer et al., 2004).
Chemotherapy
Meta-analyses have shown that chemotherapy for advanced CRC can slow progression and prolong disease survival compared with best supportive care (Simmonds, 2000, Anonymous, 2000). For nearly 50 years, 5-fluorouracil (5-FU) has been the mainstay of chemotherapy treatment for CRC and fluoropyrimidine-based chemotherapy remains a key component of the treatment algorithm for advanced disease. Indeed, until 10 years ago, 5-FU was the only chemotherapy option available to patients. 5-FU administered as a continuous infusion has superior efficacy when compared with 5-FU administered as an intravenous (IV) bolus (RR 22% versus 14%) (Anonymous, 1998a) and is associated with fewer World Health Organization grade 3 and 4 toxicities (Anonymous, 1998b).
Oral fluoropyrimidines, such as capecitabine and tegafur/uracil (UFT) are converted to 5-FU through various enzymatic conversions. Randomized trials (Hoff et al., 2001; Douillard et al., 2002; Carmichael et al., 2002; Van Cutsem et al., 2004a) have shown equivalence to bolus 5-FU/folinic acid (FA) but have not compared oral fluoropyrimidines to infusional 5-FU. Oral fluoropyrimidines now offer the patient a more convenient form of chemotherapy compared to single-agent infusional or bolus 5-FU.
The addition of irinotecan to 5-FU/FA, irrespective of regimen, conferred a significant clinical benefit, in terms of response rate (RR), progression-free survival (PFS) and overall survival (14.8 versus 12.6, 20.1 versus 16.9, 17.4 versus 14.1 months) compared with the corresponding 5-FU/FA regimen alone (respectively for Saltz et al., 2000; Douillard et al., 2000; Kohne et al., 2005), although it was associated with a higher incidence of grade 3 diarrhea.
Oxaliplatin is also effective first-line in the treatment of advanced CRC when combined with 5-FU (Giacchetti et al., 2000; de Gramont et al., 2007). RRs and median PFS times were longer in the oxaliplatin/5-FU/FA arms compared to the 5-FU/FA alone arms. However, median overall survival was not increased in the oxaliplatin arms. This may be attributable to cross-over from the 5-FU/FA to the oxaliplatin/5-FU/FA arms. The principal dose-limiting toxicities are neurotoxicity (which may be acute or chronic) and neutropenia (Grothey and Goldberg, 2004).
The relative efficacy of these two regimens was directly compared in the randomized Tournigand trial (Tournigand et al., 2004). Patients were randomized to one of two treatment arms. Those in arm A received FOLFIRI (irinotecan 180 mg/m2 and FA 200 mg/m2 on day 1, followed by bolus 5-FU 400 mg/m2 and continuous 5-FU, 2400–3000 mg/m2, by 46-hour infusion) until disease progression or unacceptable toxicity, at which time they crossed over to receive oxaliplatin (100 mg/m2 on day 1) in combination with the same modified de Gramont 5-FU/FA regimen (FOLFOX6). Conversely, the patients assigned to arm B received FOLFOX6 until disease progression, at which time they crossed over to receive FOLFIRI. The median overall survival was 21.5 months in arm A (FOLFIRI followed by FOLFOX6) and 20.6 months for patients assigned to arm B (FOLFOX6 followed by FOLFIRI), leading to the conclusion that the two regimens were essentially indistinguishable in terms of efficacy. However, it was noted that a significantly higher number of patients in arm B had their metastatic disease rendered resectable (P = 0.02). The most important observation from the Tournigand study was therefore that median survival was in excess of 20 months for both arms when the two combinations were used sequentially (i.e. the use of three active drugs during the course of the patient’s treatment).
The UK MRC CR08 FOCUS trial was designed to assess the role of irinotecan or oxaliplatin combined with the modified de Gramont (MdG) infusional 5-FU/FA regimen, in the first- and second-line treatment of patients with advanced CRC. Patients with good performance status were randomly allocated to receive either single agent chemotherapy first line followed by combination chemotherapy at failure or combination chemotherapy upfront. Non-significant increases in overall survival were seen with each combination therapy over the staged single-agent arm (Seymour, 2005). This suggests that staged combination therapy may provide an alternative treatment strategy for those patients unable to tolerate first-line combinations. The optimum duration of treatment was assessed in the CR06 study (Maughan et al., 2003). After 12 weeks (6 cycles) of chemotherapy, patients with evidence of response or stable disease were randomized to stopping treatment, restarting with the same regimen on progression or continuing chemotherapy until progression. The study showed no benefit in continuing chemotherapy indefinitely and patients in the intermittent group had significantly fewer toxicities and adverse events.
Targeted agents
As our knowledge of tumor biology and genetics matures, a range of agents that interact with novel disease-associated targets are emerging into the clinical setting. Two drugs already approved for the treatment of CRC are the monoclonal antibodies cetuximab (Erbitux®), which binds to and inhibits activation of the epidermal growth factor receptor (EGFR) (Li et al., 2005), and bevacizumab (Avastin®), which binds vascular endothelial growth factor (VEGF-A) thereby interfering with signaling through the VEGF-1 and -2 receptors and inhibiting angiogenesis (Hicklin and Ellis, 2005).
Cetuximab has been approved in both Europe and the USA for use in combination with irinotecan, as second-line therapy in CRC patients who have failed prior irinotecan treatment. In the pivotal study, Cunningham and colleagues (Cunningham et al., 2004) randomized previously-treated patients who had progressed during or immediately following irinotecan-based therapy into two groups which received either cetuximab plus irinotecan or cetuximab alone. They demonstrated a higher RR (22.9% versus 10.8%) and an increase in the median time to progression (4.1 versus 1.5 months) for the combination-therapy group compared to the monotherapy group. More recently, single agent cetuximab has been shown to improve overall survival compared to best supportive care in patients with advanced colorectal cancer who had previously been treated with a fluoropyrimidine, irinotecan and oxaliplatin or had contraindications to treatment with these drugs (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.64 to 0.92; P = 0.005) (Jonker et al., 2007). The importance of determining the K-ras status of CRC prior to treatment with cetuximab has been demonstrated. Recent studies showed that patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit (Karapetis et al., 2008; Van Cutsem et al., 2009).
Cetuximab does not appear to increase the intensity or frequency of the characteristic side effects of cytotoxic chemotherapy. The most common cetuximab related adverse event reported is the development of an acne-like rash. This class effect of EGFR inhibitors is generally manageable (Segaert et al., 2005) and may be indicative of a response to cetuximab (Van Cutsem et al., 2004b).
Bevacizumab in combination with irinotecan/bolus 5-FU/FA has been approved for the first-line therapy of patients with advanced CRC based on the data from the Hurwitz trial (Hurwitz et al., 2004). Adding bevacizumab to a bolus irinotecan/5-FU regimen resulted in an improved median duration of survival (20.3 versus 15.6 months), an increased RR (44.8% versus 34.8%) and a longer median progression free survival (10.6 versus 6.2 months). Similarly, the second-line use of bevacizumab in combination with oxaliplatin/5-FU (FOLFOX) has shown a statistically significant survival advantage versus FOLFOX alone (12.5 versus 10.7 months) (Giantonio et al., 2005).
The use of bevacizumab has been associated with a low level of gastrointestinal perforation events (Kozloff et al., 2006) and some concern has been expressed as to whether anti-VEGF therapy might inhibit wound healing (Scappaticci et al., 2005). This concern led to the recommendation that a patient should not undergo elective hepatic resection during or within 8 weeks of bevacizumab treatment (Ellis et al., 2005).
Adjuvant treatment
Adjuvant treatment is aimed at preventing disease recurrence or increasing the time to relapse after a patient has undergone a curative resection of their tumor. Randomized trials from North America and Europe have demonstrated a 6–10% absolute improvement in overall survival for patients receiving adjuvant 5-FU based chemotherapy with Dukes C disease and a 2–5% benefit in Dukes B disease (Wolmark et al., 1988, 1993; Moertel et al., 1995; IMPACT, 1995; O’Connell et al., 1997; Gray et al., 2007). Common practice is to offer adjuvant chemotherapy postoperatively to all patients with Dukes C disease and ‘high-risk’ Dukes B disease (Dukes B tumors with evidence of tumor perforation, serosal involvement and/or vascular invasion, and patients who underwent non-elective emergency surgery).
Until recently, the standard therapy most widely used in the UK was a weekly bolus 5-FU/FA regimen, as pioneered in the QUASAR trial (Gray et al., 2007). The X-ACT study comparing capecitabine to bolus 5-FU/FA in patients with resected stage III CRC (Twelves et al., 2005) showed equivalent disease-free survival. The MOSAIC study aimed to show that the addition of oxaliplatin to a conventional 5-FU/FA regimen was beneficial to patients in the adjuvant setting (Andre et al., 2004). Patients who had undergone curative resection for stage II or III CRC were randomized to an infusional 5-FU/FA regimen with or without oxaliplatin (FOLFOX). The DFS at three years was 78.2% in the oxaliplatin group, compared to 72.9% for 5-FU/FA group (P = 0.002). A recent update has shown a significant benefit in overall survival (OS) for stage III patients at 6 years (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.66 to 0.98) (de Gramont et al., 2007). However, there was not OS benefit for patients with stage II disease. A recent phase III study showed no advantage of adding bevacizumab to adjuvant FOLFOX chemotherapy in stage II or III CRC (3 year DFS 75.5% for FOLFOX vs 77.4% for FOLFOX and bevacizumab, hazard ratio, 0.89; 95% CI, 0.76–1.04) (Wolmark et al., 2009).
Anal cancer
In 1987, a multicenter anal cancer trial (ACT I) was set up by the UK Coordinating Committee on Cancer Research (UKCCR) to compare the most promising regimens of radiotherapy alone with combined modality therapy. Five hundred and eighty-five patients were randomized to receive either 45 Gy radiotherapy (RT) over 4–5 weeks (n = 290) or the same RT combined with mitomycin (MMC)/5-FU. Patients who had a good response after 6 weeks underwent a further radiotherapy boost; patients who had not responded after 6 weeks underwent salvage surgery. Combined chemoradiotherapy showed a 46% reduction in local failure after a median survival of 42 months, although there was increased early morbidity and no survival advantage (58% with RT versus 65% with chemoradiotherapy after 3 years, P = 0.25) (UKCCCR, 1996). The EORTC conducted a similar trial also demonstrating a significant increase in locoregional control (18% improvement at 5 years) and colostomy free survival (32% improvement at 5 years) with chemoradiotherapy compared to radiotherapy alone (Bartelink et al., 1997).
The ACT II trial randomized patients to RT totalling 50.4 Gy in 28 fractions together with either 5-FU/MMC or 5-FU/cisplatin during the first and fifth weeks of RT. Patients are also further randomized to two courses of chemotherapy or just follow up after CMT. There was no difference in the complete response rate between concurrent 5-FU/MMC or 5-FU/cisplatin (94% vs 95%, P = 0.53) and no difference in recurrence free survival (HR 0.89, 95% CI 0.68 to 1.18; P = 0.42) or overall survival (HR 0.79, 95% CI 0.56 to 1.12; P = 0.19) with the addition of maintenance chemotherapy (James et al., 2009).
The recently published RTOG 98-11 study has questioned the efficacy of RT and 5-FU/CDDP in the treatment of anal cancer (Ajani et al., 2008). This multicenter phase III study randomized patients to either 5-FU (1000 mg/m2 on days 1–4 and 29–32) plus MMC (10 mg/m2 on days 1 and 29) and RT (45–59 Gy starting on day 1) or 5-FU (1000 mg/m2 on days 1–4, 29–32, 57–60 and 85–88) plus cisplatin (75 mg/m2 on days 1, 29, 57 and 85) and RT (45-59 Gy starting on day 57). There was no difference between the two arms in disease-free survival, overall survival, locoregional control and distant metastasis rates. The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% versus 19%; P = 0.02). However, this was not a direct comparison of mitomycin/5-FU versus cisplatin/5-FU as the cisplatin arm incorporated two cycles of induction chemotherapy prior to starting RT. Induction chemotherapy may have resulted in accelerated repopulation and an increase in the number of clonogens at the onset of radiation in the cisplatin arm. The ACT II study does not incorporate induction chemotherapy in either arm and the results of ACT II should help clarify the optimum chemo-RT regimen for anal carcinomas.
Upper GI malignancy
Esophageal cancer
Carcinoma of the esophagus can be treated with definitive surgery, CRT or radiotherapy alone. For patients with operable tumors, standard practice in the UK is to offer two cycles of neoadjuvant cisplatin/5-FU chemotherapy based on the OE02 trial. Eight hundred and two patients with operable esophageal cancer were randomly assigned to resection alone or resection preceded by two courses of cisplatin (80 mg/m2 on day 1) and 5-FU (1000 mg/m2 by continuous infusion days 1 to 4) given three weeks apart. Preoperative chemotherapy was associated with significantly greater overall survival (hazard ratio for mortality 0.79, 95% confidence interval, 0.67 to 0.93), two-year survival (43% versus 34% percent) and median survival (16.8 versus 13.3 months) (OE02, 2002). The current MRC OE05 phase III study is comparing four cycles of neoadjuvant epirubicin, cisplatin and capecitabine to the standard OE02 regimen preoperatively. In the United States Intergroup trial 0113, 467 patients with potentially resectable esophageal or gastro-esophageal (GOJ) junction cancer were randomly assigned to surgery alone or three cycles of preoperative cisplatin/5-FU chemotherapy followed by surgery (Kelsen et al., 1998). There was no difference between the groups in survival at one, two or three years (59%, 35% and 23% versus 60%, 37% and 26% percent, respectively). The OE02 and Intergroup trials had populations with very similar pretreatment characteristics. The different outcomes may partly be explained by the difference in dose intensities and time to definitive surgery between the studies. The Intergroup trial used three cycles of cisplatin/5-FU compared to two cycles in the OE02 study. In using a less demanding regimen than the Intergroup trial, more patients completed the full course of preoperative chemotherapy in the OE02 study (80% versus 71%) and the time to surgery after completion of the chemotherapy was shorter (median 63 days versus 93 days).
There is evidence to suggest that a concurrent trimodality approach (concomitant CRT followed by surgery) provides a survival benefit compared to surgery alone. An Irish trial randomly assigned patients with esophageal or GOJ adenocarcinoma to surgery alone or preceded by CRT (Walsh et al., 1996). Preoperative treatment consisted of radiotherapy (40 Gy in 15 fractions over three weeks) and two courses of cisplatin/5-FU starting on day one of the radiotherapy regimen. CRT was associated with significantly longer median survival (16 versus 11 months, P = 0.01) and three-year survival (32% versus 6%, P = 0.01). These results were criticized because of the lower than expected survival with surgery alone.
The only trial directly to compare induction chemoradiotherapy to chemotherapy alone was the multicenter German POET (Preoperative chemotherapy or radiochemotherapy in esophagogastric adenocarcinoma trial), which focused exclusively on GOJ adenocarcinomas. Patients were randomly assigned to 16 weeks of cisplatin/5-FU chemotherapy alone or 12 weeks of the same chemotherapy regimen followed by radiotherapy (30 Gy over three weeks) concurrent with cisplatin (50 mg/m2 on days 2 and 8) and etoposide (80 mg/m2 on days 3 to 5) (Stahl et al., 2007). The trial was closed early because of poor accrual. In a preliminary report with a median follow-up of 46 months, patients undergoing CRT had better median survival (33 versus 21 months) and three-year survival (47% versus 28%, P = 0.07), but these potentially clinically meaningful differences were not statistically significant.
For bulky and borderline unresectable tumors, chemotherapy alone may not achieve sufficient downstaging. Definitive radiotherapy alone has been reported to give 5-year survivals of less than 10% and median survivals ranging from 6 to 12 months (Sun, 1989; Okawa et al., 1989; Araujo et al., 1991; Wan et al., 1991; Sykes et al., 1998). The Radiation Therapy Oncology Group (RTOG) 85-01 trial was the landmark trial that established the superiority of chemoradiation over radiation alone (Herskovic et al., 1992). Patients were randomized to receive either CRT with 50 Gy in 25 fractions, 5 days per week and concurrent adjuvant cisplatin/5-FU or 64 Gy in 32 fractions of radiotherapy without chemotherapy. The 5-year survival rate was 27% in the combined therapy arm compared with 0% in the control arm (P < 0.0001). In the Intergroup Study 0123, all 236 patients received concurrent chemotherapy with cisplatin and 5-FU (as in RTOG 85-01), but they were randomly assigned to one of two different RT doses: 50.4 Gy (28 fractions of 1.8 Gy each, 5 fractions per week) or 64.8 Gy (36 fractions of 1.8 Gy each, 5 fractions per week). Higher radiotherapy doses were not associated with a higher median survival (13 months [95% confidence interval, 10.5 to 19.1 months] versus 18 months [95% confidence interval, 15.4 to 23.1 months]). High-dose radiotherapy was associated with significantly more toxicity (Minsky et al., 2002). The UK SCOPE trial is currently recruiting patients to determine the role of the EGFR inhibitor cetuximab in combination with definitive, RTOG 85-01 type CRT for inoperable esophageal cancer.
Stomach cancer
Surgery remains the definitive treatment for gastric cancer. The standard adjuvant approaches vary between Europe and North America. Practice in the UK has been influenced by the MAGIC trial. Five hundred and three patients with potentially resectable gastric, distal esophageal or GOJ adenocarcinomas were randomly assigned to surgery alone or surgery plus perioperative chemotherapy (three preoperative and three postoperative cycles of epirubicin, cisplatin and infusional 5-fluorouracil (ECF)). Only 42% of patients were able to complete protocol treatment, including surgery and all three cycles of the postoperative chemotherapy. Nevertheless, with median four-year follow-up, progression-free survival was significantly worse in the surgery alone group (hazard ratio [HR] for progression 0.66, 95 percent confidence interval, 0.53 to 0.81; P < 0.001) as was overall survival (HR for death 0.75, 95% confidence interval, 0.60 to 0.93, P = 0.009). The 25% reduction in the risk of death favoring chemotherapy translated into an improvement in five-year survival from 23% to 36% (P = 0.009) (Cunningham et al., 2006). The US Intergroup study INT-0116 randomly assigned 556 patients following potentially curative resection of gastric cancer to observation alone or adjuvant combined CRT (Macdonald et al., 2001). Treatment consisted of one cycle of 5-FU and leucovorin daily for five days, followed one month later by 45 Gy (1.8 Gy/day) radiotherapy given with 5-FU and leucovorin on days 1 to 4 and on the last three days of radiotherapy. Two more five-day cycles of chemotherapy were given at monthly intervals beginning one month after completion of radiotherapy. Three-year disease-free (48% versus 31%, P < 0.001) and overall survival rates (50% versus 41%) were significantly better with combined modality therapy and median survival was significantly longer (36 versus 27 months, P = 0.005). Grade 3 and 4 toxic effects occurred in 41% and 32% of the CRT group, respectively, while three patients (1%) died from treatment-related toxic effects. These results changed the standard of care in the USA following potentially curative resection of gastric cancer from observation alone to surgery followed by adjuvant combined CRT.
Palliative chemotherapy improves survival in advanced gastric cancers (Murad et al., 1993; Pyrhonen et al., 1995; Glimelius et al., 1997). Two randomized studies and a meta-analysis support the use of the epirubicin, cisplatin and infusional 5-FU regimen (ECF) often used first line for advanced gastric cancer (Webb et al., 1997; Ross et al., 2002; Wagner et al., 2006). A recent study has shown a regimen using epirubicin, oxaliplatin and oral capecitabine (EOX) is as effective as ECF (Cunningham et al., 2008). The authors suggest that EOX is a more convenient regimen for the patient as the oral capecitabine is at least as effective as the infusional 5-FU and the oxaliplatin (which does not require hydration) is at least as effective as cisplatin (which does require hydration).
Pancreatic cancer
Systemic chemotherapy, RT or a combination of chemotherapy and RT have all been applied following surgery in an effort to improve outcome in patients undergoing potentially curative (R0) resection of exocrine pancreatic cancers. The European Study Group for Pancreatic Cancer 1 Trial (ESPAC 1) was a 2×2 factorial design trial with four groups: adjuvant CRT, adjuvant chemotherapy, adjuvant CRT followed by chemotherapy, or surgery alone. Chemoradiotherapy consisted of 20 Gy radiotherapy plus three days of concomitant 5-FU, repeated after a planned break of two weeks. Adjuvant chemotherapy consisted of bolus leucovorin-modulated 5-FU (leucovorin 20 mg/m2, 5-FU 425 mg/m2), administered daily for five days, every 28 days, for six months. Adjuvant chemotherapy demonstrated a survival benefit compared to surgery alone (5-year survival 21% versus 8%, P = 0.009). Postoperative CRT was found to be detrimental with an estimated five-year survival rate of 10% among patients assigned to receive CRT and 20% among patients who did not receive CRT (P = 0.05) (Neoptolemos et al., 2004). The ESPAC 3 trial is currently randomizing patients to surgery alone or surgery followed by gemcitabine chemotherapy or surgery followed by 5-FU chemotherapy. Results are awaited.
The guidelines on ‘good practice’ in the UK from the NHS Executive recommends that chemoradiotherapy and not radiation alone may be considered for ‘fit’ patients with inoperable locally advanced pancreatic cancer (Department of Health, 2001). The evidence of benefit for CRT over radiation alone in the treatment of locally advanced pancreatic cancer was provided by the gastrointestinal tumor study group (GITSG.) They demonstrated a small advantage in survival of 3–4 months with chemoradiotherapy compared to radiotherapy alone. One-year survival was 40% with CRT and 10% with RT alone (Moertel et al., 1981). Current practice is to use radiotherapy in combination with 5-FU or capecitabine. Several phase II trials recruiting in the UK are assessing the role of targeted agents in combination with radiotherapy for treating inoperable pancreatic cancer.
Palliative chemotherapy is the treatment of choice for metastatic pancreatic cancers. This approach is also used for locally advanced disease not suitable for CRT. Single agent gemcitabine (1000 mg/m2 weekly for seven weeks followed by a week of rest, then weekly for three out of every four weeks) has shown improved 1-year survival over 5-FU (600 mg/m2 weekly) (18% versus 2%) (Burris et al., 1997). A multinational phase III trial comparing gemcitabine alone to gemcitabine and capecitabine showed no significant benefit in overall survival (7.2 versus 8.4 months, P = 0.234). Unplanned subgroup analysis did show a significant benefit in overall survival (10.1 versus 7.4, P = 0.014) with gemcitabine/capecitabine versus gemcitabine alone in patients with a good performance score (Karnofsky performance score 90 to 100) (Herrmann et al., 2007). In contrast, gemcitabine in combination with cisplatin has been shown to improve overall survival in advanced or metastatic biliary tract cancer (ABC) compared to gemcitabine alone (median OS 11.7 vs 8.2 months, P = 0.002) (Valle et al., 2009).
Future directions
The future treatment of GI malignancies will be influenced by further developments in targeted molecular therapies. As an alternative to cytotoxic chemotherapy, the novel agents have a different and often less severe toxicity profile. When combined with conventional cytotoxic chemotherapy and/or radiotherapy, there is often only limited increase in the overall toxicity of a treatment. The targeted therapies are currently being investigated in large, phase III multicenter studies for both upper and lower GI malignancies.
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