24 Induction Therapy for Resectable Esophageal Cancer

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200

24

Induction Therapy for Resectable Esophageal Cancer

Sarah E. Greer, Philip P. Goodney, and John E. Sutton

of the treatment. Deﬁ nitive local control is also delayed, which may be an important clinical consideration in patients who are symptomatic with dysphagia and poor preoperative nutritional status.

24.1. Published Evidence

24.1.1. Preoperative Radiotherapy

While preoperative radiation (without chemotherapy) has been studied in the past, it failed to show a beneﬁ t for overall survival, and in many cases^6–8 proved to increase the morbidity and mortality associated with treatment. For these reasons, more recent trials have evaluated preoperative radiation only in combination with chemotherapy.

24.1.1.1. Randomized, Controlled Trials

At least six randomized trials comparing preoperative radiotherapy and surgery with surgery alone for esophageal carcinoma have been performed.^6–11 Radiotherapy regimens varied, with low-to-moderate doses ranging from 20Gy to 53Gy over a period of 1 to 4 weeks prior to surgery.

Accrual of patients in randomized, controlled trials of preoperative radiotherapy took place prior to 1989 (Table 24.1).

No statistically signiﬁ cant survival beneﬁ t for groups receiving preoperative radiotherapy was seen. In fact, some studies found a small reduc- tion in overall survival following preoperative radiotherapy, which may have been due in part to Despite advances in treatment regimens, overall

5-year survival rates for esophageal cancer remain low, averaging less than 30%.^1–5 Although surgery remains the standard treatment and the only hope for cure, there is growing support for multimodality therapy.

While there has been little signiﬁ cant progress in improving overall survival in esophageal cancer despite new chemotherapeutics and surgical techniques, induction chemotherapy and/or radiotherapy followed by surgery offers several potential advantages over surgery with or without adjuvant treatment.

First, up-front chemotherapy and radiation may be better tolerated than therapy following extensive surgery. Second, a preoperative strat- egy allows those with occult distant disease to declare themselves, avoiding delay in systemic treatment for micrometastases as well as avoiding major surgical procedures which may not be curative. Third, preoperative therapy allows delivery of chemotherapy or radiation to a rela- tively well-perfused tumor bed, thus improving its efﬁ cacy. It may also cause sufﬁ cient tumor destruction, particularly at the periphery, to improve resectability. By increasing the likeli- hood of a margin-negative resection, induction therapy may improve local control.

However, there are disadvantages to induction therapy. Preoperative treatment is associated with signiﬁ cant morbidity and mortality. In attempts to minimize this toxicity, especially in preoperative combination therapy with chemotherapy and radiation, dose reductions may be necessary, potentially compromising the efﬁ cacy

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TABLE 24.1. Single modality induction therapy – randomized, controlled trails of preoperative chemotherapy or radiation versus surgery alone. Median Author andStudyLevel ofPatients survivalOverall survival (percentage) Statistical yeartype Type of cancerAccrualevidenceTreatment groupsenrolled (months) 1 year2 year3 year4 year5 yearsignificance Launois et al.6 RCT Squamous 1973–1976 1+ 40-Gy 67 4.5 4620 151410p = ns 1981 Surgery Surgery alone578.2 (mean) 5035252012 Gignoux et al.7 RCT Squamous 1976–1982 1+ 33-Gy 115 12.3552420 1710p = 0.94 1987 Surgery Surgery alone 114 12 (mean) 57 30 14119 Wang et al.9 RCT 1977–1985 1+ 40-Gy 104 35p = ns 1989Surgery Surgery alone 102 30 Nygaard et al.11 RCT Squamous 1983–1988 1− 35-Gy 58 10442521p = 0.08 1992 Surgery Surgery alone 50 7 34139 Arnott et al.12 RCT Squamous 1979–1983 1+ 20-Gy 908 402213 9 9 p = 0.4 1992 Adenocarcinoma Surgery Surgery alone 868 4028 232117 Fok et al.8 RCT Squamous 1968–1981 1+* 24–53-Gy 40 114234241010p = ns 1994Surgery Surgery alone39225836241616 Nygaard et al.11 RCT Squamous 1983–1988 1−Cisplatin, bleomycin56 7 31 6 3 p = ns 1992 Surgery Surgery alone 50 7 34139 Schlag et al.17 RCT Squamous1+ Cisplatin, 5-FU 227.5 20 p = ns 1992 Surgery Surgery alone 245 32 Maipang et al.18 RCT Squamous 1988–1990 1+ Cisplatin, vinblastin,2417583131p = ns 1994 bleomycin Surgery Surgery alone2217854036 Law et al.22 RCT Squamous 1989–1995 1+ Cisplatin, 5-FU 7416.8604438 28 28 p = ns 1997 Surgery Surgery alone 731350311414 Ancona et al.19 RCT Squamous 1992–1997 1+ Cisplatin, 5-FU47257555444234p = 0.55 2001 Surgery Surgery alone47247555413822 MRC 2002RCT Squamous 1992–1998 1++ Cisplatin, 5-FU 400 16.859433528 26p = 0.004 Adenocarcinoma Surgery HR = 0.79 Surgery alone402 13.35434272015(95% CI, 0.67–0.93) Abbreviations: 5-FU, 5 fluoro uracil; ns, not significant; RCT, randomized controlled trial; MRC = Medical Research Council.

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treatment related mortality that exceeded 20% in some trials.^6–8

24.1.1.2. Meta-analyses

Because the number of patients treated in clinical trials was small, a Cochrane Review meta- analysis was performed using individual patient data to determine conclusively whether there is any effect for preoperative radiotherapy.¹² This study included 1147 patients with updated survival data and a median follow-up of 9 years. The overall hazard ratio was 0.89 [χ²(1) = 3.48, p = 0.06], suggesting a trend towards a modest beneﬁ t for preoperative radiotherapy, but with a small abso- lute improvement in survival of 4% at 5 years.

A second meta-analysis was performed by Malthaner and colleagues.¹³ Again, no statistically signiﬁ cant difference in the risk of mortality with preoperative radiotherapy compared with surgery alone was detected [relative risk (RR) = 1.01; 95% conﬁ dence interval (95% CI), 0.88–1.16; p = 0.87), but overall survival was evaluated only at 1 year.

24.1.1.3. Systematic Reviews

A number of systematic reviews also address the clinical question of the efﬁ cacy of preoperative radiotherapy in resectable esophageal cancer.^13–16 These reviews uniformly conclude that there is no beneﬁ t from preoperative radiotherapy with respect to resectability, treatment-related mortality, or overall survival as demonstrated by randomized, clinical trials.

24.1.1.4. Recommendation

It appears unlikely that single-modality preoperative therapy with radiation will be resurrected as a meaningful therapeutic option with curative intent. Given the body of work available, as a guideline for clinical practice, we recommend against the use of preoperative radiotherapy as standard of care, with a grade A for the level of recommendation.

24.1.2. Preoperative Chemotherapy

Preoperative chemotherapy initially appeared more promising than preoperative radiotherapy.

However, following multiple randomized trials and meta-analyses, no overall survival beneﬁ t has been shown for preoperative chemotherapy, with one exception. A wide variety of chemotherapeutic agents have been studied, including cisplatin, ﬂ uorouracil, leucovorin, paclitaxel, vinblastin, etoposide, epirubicin, mitomycin, and bleomycin. While most trials enrolled patients with squamous cell carcinoma,^17–19 the largest studies included both squamous cell and adenocarcinoma.^20,21 Accrual of patients occurred between 1983 and 1998 (Table 24.1).

At least six randomized trials of preoperative chemotherapy and surgery versus surgery alone have been performed.11,17–20,22 Five of the six showed no signiﬁ cant survival beneﬁ t.11,17–19,22

However, a large multicenter study including both squamous cell and adenocarcinoma showed improved results using a regimen of ﬂ uorouracil and cisplatin in the arm receiving induction therapy.²⁰ The investigators reported a median survival of 16.8 months versus 13.3 months (difference, 107 days; 95% CI, 30–196), and 2-year survival of 43% and 34% (difference, 9%; 95% CI, 3–14) in the group receiving chemotherapy. Esti- mated 5-year survival based on Kaplan–Meier curves was also signiﬁ cantly improved (hazard ratio 0.79; 95% CI, 0.67–0.93); estimated reduc- tion in risk of death was 21%.

Two additional randomized clinical trials examined preoperative chemotherapy and found no statistically signifi cant difference in overall survival. However, in these two trials patients in the induction therapy arm also received postoperative chemotherapy.^21,23 One of these trials²¹ included the same chemotherapeutics, at higher doses, that showed a survival benefi t in the trial described above.²⁰ It is diffi cult to recon- cile these results, but a more intense chemotherapy regimen could have adversely affected the outcome in the induction therapy arm in the latter trial.

There is no beneﬁ t to preoperative radiotherapy as standard of care in the management of resectable esophageal cancer (level of evidence 1; recommendation grade A).

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Four meta-analyses have been performed exam- ining preoperative chemotherapy versus surgery alone,^13,24–26 with only one showing a signiﬁ cant improvement in survival.

The meta-analysis by Urschel and colleagues²⁵ included 1976 patients from 11 randomized, controlled trials and found no statistically sig- niﬁ cant difference between preoperative chemotherapy with surgery over surgery alone for survival at 1, 2, or 3 years. A Cochrane Review meta-analysis²⁶ included 2051 patients from 11 trials and calculated the relative risk for survival at 1, 2, 3, 4, and 5 years. A statistically signiﬁ cant difference in survival for patients who received preoperative chemotherapy was detected only at 5 years (RR = 1.44; 95% CI, 1.05–1.97; p = 0.02).

However, both of these analyses included trials that used postoperative chemotherapy in addi- tion to preoperative treatment.

Bhansali and colleagues²⁴ analyzed eight randomized controlled trials and found an odds ratio for risk of death of 0.96 (95% CI, 0.75–1.22).

The systematic review and meta-analysis performed by Malthaner and coworkers¹³ included a total of 1241 patients from six trials that studied only preoperative chemotherapy versus surgery alone, and showed no survival beneﬁ t at 1 year (RR = 1.00; 95% CI, 0.83–1.19;

p = 0.98).

A number of systematic reviews address the effi cacy of preoperative chemotherapy in resectable esophageal cancer.^13–16 The majority of these reviews conclude that despite the benefi t seen in the most recent large randomized trial,²⁰ there is not yet suffi cient evidence to institute preoperative chemotherapy as standard of care.

For patients with resectable esophageal cancer for whom surgery is considered appropriate, we recommend surgery alone (without preoperative chemotherapy) as standard practice, with a grade of A for level of recommendation.

24.1.3. Preoperative Chemoradiotherapy

The preoperative therapy that has shown the most promise and has generated much interest is combination chemotherapy and radiation. In fact, despite a lack of deﬁ nitive evidence, it has become the de facto standard of care at many institutions.

Six randomized trials compared preoperative chemoradiotherapy to surgery alone.^11,27–31 These trials have been small, thus limiting the power of each study to detect differences in overall survival. Furthermore, the design, therapeutic regimens, surgical approaches, and histologies varied widely across studies, making comparison of the trials difﬁ cult. Accrual of patients occurred between 1983 and 1995 (Table 24.2).

Five of the six trials failed to show a statistically signiﬁ cant beneﬁ t in overall survival for the groups receiving preoperative chemoradiotherapy.

Initial results reported high treatment-related mortality of more than three times that of surgery alone in one trial,²⁸ and exceeding 24% in another.¹¹ Lack of stratiﬁ cation by stage and unequal distribution of patients makes results difﬁ cult to interpret.¹¹ Inadequate power to detect small differences also plagued many studies.

Patient accrual based on promising large differences between phase II studies and historical controls that ultimately failed to show a statistically signiﬁ cant survival beneﬁ t may simply be due to type II error.

The one trial that has shown a signiﬁ cant survival beneﬁ t included both squamous cell and adenocarcinoma, and used various techniques for surgical resection.³¹ The authors found a 3- year survival of 32% in the group who received preoperative chemoradiotherapy versus 6% in the surgery alone arm (p = 0.01), with a median

For patients with resectable esophageal cancer for whom surgery is considered appropriate, surgery alone (without preoperative chemotherapy) is standard practice (level of evidence 1; recommendation grade A).

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TABLE 24.2. Multimodality induction therapy – randomized, controlled trials of preoperative chemoradiation versus surgery alone. Median Study Level of Patients survivalOverall survival (percentage) Statistical Author and yeartype Type of cancer Accrual evidence Treatment groups enrolled (months)1 year2 year3 year4 year5 yearsignificance Nygaard et al. RCT Squamous 1983–1988 1− Cisplatin, bleomycin, 537 392317p = 0.3 1992 35-Gy Surgery Surgery alone 50 7 34139 Apinop et al. RCT Squamous 1986–1992 1+ Cisplatin, 5-FU 40-Gy 35 9.7 4930 262424p = 0.4 1994 Surgery Surgery alone 347.4 392320 1910 LePrise et al. RCT Squamous 1988–1991 1+ Cisplatin, 5-FU 20-Gy 41 11472719p = 0.56 1994 Surgery Surgery alone 4511473314 Walsh et al. RCT Adenocarcinoma 1990–1995 1− Cisplatin, 5-FU 40-Gy 58 16523732p = 0.01 1996 Surgery Surgery alone 551144266 Bossert et al. RCT Squamous 1989–1995 1+ Cisplatin 37-Gy 143 18.669 48393533p = 0.78 1997 Surgery Surgery alone 139 18.66743373432 Urba et al. RCT Squamous 1989–1994 1++ Cisplatin, 5-FU 45-Gy 50 17.672 4230 2520 p = 0.15 2001 Adenocarcinoma Surgery Surgery alone 50 16.95838 161410 5-FU, 5 fluoro uracil; RCT, randomized, controlled trial.

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follow-up of 11 months. However, the 6% 3-year survival in the control arm was lower than other published survival rates for surgery alone, with most centers reporting between 20% and 30% 3- year survival. Only after patients had received preoperative chemoradiotherapy and were re- evaluated was stage reported. This may have resulted in an overall downstaging of patients in the NCRT group and a false impression that patients in the surgery alone arm had more advanced disease. Uncertainty regarding the true baseline characteristics of patients limits our ability to interpret the effect of preoperative stage on outcome. However, despite these problems, the cited benefi t in this trial carried a signifi cant impact and widely infl uenced clinical practice. A 5-year follow-up study was also published with the fi nding of a signifi cantly improved median survival from 12 months for surgery alone to 17 months for multimodal therapy (p = 0.002).³²

A meta-analysis by Urschel and colleagues³³ included 1116 patients from nine randomized clinical trials, though three had been published only in abstract form. There was no statistically signiﬁ cant difference in 1-year or 2-year survival.

However, a statistically signiﬁ cant improvement in 3-year survival was found for the group receiving preoperative chemoradiation [odds ratio (OR)

= 0.66; 95% CI, 0.47–0.92; p = 0.016].

A meta-analysis by Malthaner and coworkers¹³ included 753 patients in six trials. No signiﬁ cant difference in the 1-year survival for preoperative chemoradiation and surgery compared to surgery alone was detected. However, at 3 years a statistically signiﬁ cant difference in the risk of mortality was found favoring neoadjuvant chemoradiation (RR = 0.87; 95% CI, 0.80–0.96, p = 0.004).

In the meta-analysis by Fiorica and coworkers,³⁴ 3-year survival was improved in the group receiving preoperative chemoradiotherapy (OR 0.53; 95% CI, 0.31–0.93, p = 0.03), but the magni- tude of the benefi t was small. Two other meta- analyses showed a trend towards improved survival with preoperative chemoradiotherapy, but which failed to reach statistically signifi cant benefi t.^35,36

Based on the body of evidence available and lack of consistently demonstrated survival beneﬁ t, systematic reviews have recommended against using preoperative chemoradiotherapy as standard of care.^13–15

For patients with resectable esophageal cancer for whom surgery is considered appropriate, surgery alone (without preoperative chemoradiotherapy) is recommended as standard practice, with a grade of A for level of recommendation.

For patients with resectable esophageal cancer for whom surgery is considered appropriate, surgery alone (without preoperative chemoradiotherapy) is standard practice (level of evidence 1; recommendation grade A).

24.1.4. Other Treatments

24.1.4.1. Combinations of Neoadjuvant and Adjuvant Therapy

Because the design of clinical trials has varied substantially with respect to comparisons of neoadjuvant or adjuvant therapy versus surgery alone or one regimen versus another, Malthaner and colleagues performed a systematic review and meta-analysis of 12 such combinations.¹³ None were found to be superior, and the authors concluded that surgery alone should remain the standard of care for treatment of resectable esophageal cancer.

24.1.4.2. Hyperthermia

A novel modality in esophageal carcinoma that has been shown to have a role in the treatment of other cancers, such as peritoneal malignancies and melanoma, is hyperthermia.^37–39 When studied in combination with preoperative chemoradiotherapy versus preoperative chemoradiotherapy alone, the 3-year survival was doubled in one trial.⁴⁰ While these results bear further inves- tigation, this modality may provide renewed enthusiasm for induction therapy.

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24.2. Impact on Clinical Practice

Every patient deserves an optimistic surgeon.

However, this optimism must be tempered by ﬁ rst principles, namely, to do no harm.

While it is diffi cult to dismiss the theoretical advantages of induction therapy, there is cur- rently not suffi cient evidence to recommend its use as standard practice. Furthermore, the increased cost as well as quality of life associated with chemotherapy and radiation must be considered in judging the clinical signifi cance of the small survival benefi ts that have been shown in a few cases.

However, as new chemotherapeutic agents become available, and as improvements in molec- ular diagnostics allow for more careful patient selection, there may be a role for further study of induction therapy. Thus it is crucial to maintain clinical equipoise.

The question that lies at the heart of proper utilization of evidenced-based medicine, is “how much evidence is enough?” In the face of multiple negative studies, is one well-designed positive trial suffi cient to be paradigm shifting? Although improved methodologies have been developed for categorizing data, evaluating trials, and creat- ing guidelines, there is no clear answer to these questions. In the context of continuing to strive for advances in scientifi c knowledge, we must remember that medicine is a profoundly human profession – at the end of the day, it is the com- petent and compassionate clinician who must understand the intersection between scientifi c evidence and individual values in order to lead a patient to an informed decision.

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