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Primary Combined-Modality Therapy for Esophageal Cancer

Primary Combined-Modality Therapy for Esophageal Cancer

ABSTRACT: Based on positive results from the Radiation Therapy Oncology Group (RTOG) 85-01 trial, the conventional nonsurgical treatment of esophageal carcinoma is combined-modality therapy. Dose intensification of the RTOG 85-01 regimen, examined in the Intergroup (INT)-0123/RTOG 94-05 trial, did not improve local control or survival. Areas of clinical investigation include the development of combined-modality therapy regimens with newer systemic agents, the use of 18F-fluorodeoxyglucose positron-emission tomography to assist in the development of innovative radiation treatment planning techniques, and the identification of prognostic molecular markers. The addition of surgery following primary combined-modality therapy apparently does not improve survival, but this finding is controversial.

Combined-modality therapy has been used for preoperative, postoperative, and primary nonoperative treatment in patients diagnosed with esophageal cancer. Most contemporary trials of combined-modality therapy have included both patients with squamous cell cancers and those diagnosd with adenocarcinomas. This trend will continue as the incidence of adenocarcinoma increases relative to that of squamous cell cancers.[1]

However, the impact of histology on outcome in this patient population is unclear. Presently, the data are conflicting; some series have reported different results by histology, whereas others have reported no difference. Fortunately, the US Intergroup randomized trials are stratified by histology. Until these data are available, the impact of histology cannot be assessed adequately, and it is reasonable to treat patients with squamous cell cancer and those with adenocarcinoma similarly.

Radiation Therapy Alone

Many historical series have reported the results of external-beam radiation therapy alone. Most have included patients with unfavorable features (eg, unresectable T4 disease). In the series by De-Ren, 184 of 678 patients had stage IV disease.[2] Overall, the 5-year survival rate for patients treated with radiation therapy alone is 0% to 10%.[2-4] Even in the radiation therapy-alone arm of the Radiation Therapy Oncology Group (RTOG) 85-01 trial, in which patients received 64 Gy with modern techniques, all patients succumbed to their disease within 3 years.[5,6]

There have been limited reports of radiation therapy given to patients with clinically early-stage disease. The trial by Sykes et al was limited to 101 patients (90% with squamous cell carcinoma) with tumors smaller than 5 cm who received 45 to 52.5 Gy in 15 to 16 fractions; the 5-year survival of that cohort was 20%.[7] Sai et al reported more favorable results in 34 patients with clinical stage I squamous cell cancers who were treated with external-beam radiation alone (median dose: 64 Gy) or external beam (median dose: 52 Gy) plus brachytherapy; the 5-year survival in that series was 59%.[8]

In summary, radiation therapy alone should be reserved for palliation or for patients who are medically unable to receive chemotherapy. In contrast, combined-modality therapy—the standard of care—has produced more favorable results.

Standard Approaches to Combined-Modality Therapy

Six randomized trials have compared radiation therapy alone with combined-modality therapy, but the only trial designed to deliver adequate doses of systemic chemotherapy with concurrent radiation therapy was the RTOG 85-01 trial.[5,9,10] In this Intergroup trial, which primarily included patients with squamous cell carcinoma, patients received four cycles of fluorouracil (5-FU)/cisplatin and 50 Gy of radiation therapy concurrently, beginning on day 1 of chemotherapy. The control arm received radiation therapy alone, although at a higher dose (64 Gy) than that received by the combined-modality therapy arm.

Compared with those given radiation therapy alone, patients receiving combined-modality therapy exhibited a significant improvement in median survival (14 vs 9 months) and 5-year survival rate (27% vs 0%; P < .0001).[9] The 8-year survival rate was 22%.[10] Histology did not significantly influence the results, with 21% of 107 squamous cell carcinoma patients surviving at 5 years, compared with 13% of 23 adenocarcinoma patients. African-Americans had larger primary tumors, all of which were squamous cell cancers. However, no difference in survival was noted between African-American and white patients.[11] The incidence of local failure as the first site of failure (defined as local persistence or recurrence) was also lower in the combined-modality arm (47% vs 65%). These positive results led to an early closing of the protocol. Thereafter, an additional 69 eligible patients were treated with the same combined-modality regimen; in this nonrandomized group, the 5-year survival rate was 14%, and the local failure rate was 52%.

Combined-modality therapy is associated with a higher incidence of toxicity. According to the 1997 report of the RTOG 85-01 trial, patients given combined-modality therapy had a higher incidence of acute grade 3 (44% vs 25%) and grade 4 toxicity (20% vs 3%) than did patients given radiation therapy alone. Including one treatment-related death (2%), the incidence of total acute grade 3+ toxicity was 66% in the combined-modality therapy group.[9] Results from the 1999 report of the same trial showed the incidence of late grade 3+ toxicity to be similar in the combined-modality and radiation-alone arms (29% vs 23%).[10] However, grade 4+ toxicity remained higher among patients receiving combined-modality therapy (10% vs 2%). Interestingly, the nonrandomized combined- modality therapy group experienced a similar incidence of late grade 3+ toxicity (28%), a lower incidence of grade 4 toxicity (4%), and no treatment-related deaths.

Based on the positive results from the RTOG 85-01 trial, the conventional nonsurgical treatment of choice for esophageal carcinoma is combined-modality therapy. This change is reflected in the US Patterns of Care survey (1996-1999), in which only 11% of patients diagnosed with the disease and treated with radiation as a component of their initial therapy received radiation without chemotherapy.[12] In contrast, the Japanese Patterns of Care survey (1995-1997) reported that 60% of esophageal cancer patients received radiation without chemotherapy.[13]

Intensification of Combined-Modality Therapy

After the local failure rate in the RTOG 85-01 combined-modality therapy arm was noted to be 45%, new approaches (eg, intensification of combined-modality therapy and escalation of the radiation dose) were developed in an attempt to improve these results.

Neoadjuvant Chemotherapy

A limited number of phase I/II trials have tested the use of neoadjuvant chemotherapy given before combined-modality therapy using non-5-FU-containing regimens, such as paclitaxel/cisplatin or irinotecan (CPT-11, Camptosar)/cisplatin.[14-16] The majority of patients in these trials had adenocarcinomas, and most underwent surgery, although resection was optional. Bains and associates reported that 92% of 38 patients presenting with dysphagia had relief after completing two cycles (weeks 1 and 4) of neoadjuvant paclitaxel and cisplatin.[14] Ilson et al reported similar results in 19 patients given two cycles of neoadjuvant irinotecan plus cisplatin on weeks 1, 2, 4, and 5 before starting combined-modality therapy.[16] Treatment was well tolerated, with no grade 3+ nonhematologic toxicity reported. Only 5% of patients required a feeding tube. Of 16 patients who presented with dysphagia, 81% experienced relief of this symptom after completing neoadjuvant chemotherapy.

Another potential advantage of neoadjuvant chemotherapy is the early identification of patients who may or may not respond to the regimen being delivered. Ott et al examined 35 patients with adenocarcinoma of the gastroesophageal junction or stomach who first underwent an 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) scan 2 weeks after cisplatin/5-FU/leucovorin was started and then had surgery. The scan was able to predict patients who would respond to the full course of chemotherapy, as shown by analysis of the surgical specimens.[17] Weider and associates reported similar findings in 38 patients with squamous cell cancers.[18] Although this method is investigational, it may identify nonresponders early, and changing the chemotherapeutic regimen may then be helpful.

In summary, although the results of early trials primarily using 5-FU/cisplatin-based neoadjuvant regimens did not suggest a benefit,[19] more recent trials of paclitaxel- and irinotecan-based regimens revealed more favorable response rates and rapid improvement of dysphagia.

Intensification of Intraluminal Brachytherapy

Another approach to the dose intensification of combined-modality therapy is increasing the radiation dose by using brachytherapy and/or external-beam radiation therapy. Intraluminal brachytherapy allows dose escalation to the primary tumor and protection of surrounding structures, such as the lung, heart, and spinal cord.[20] This technique has been used for primary therapy (usually as a palliative modality)[21]; it also has been used as a boost following external-beam radiation therapy or combined-modality therapy.[22] There are technical and radiobiologic differences between high-dose and low-dose rates but no clear therapeutic advantages to either.

Reports of investigational series in which doses were escalated by combining brachytherapy with either external-beam or combined-modality therapy reported results similar to those of series that did not use brachytherapy. Calais et al reported a local failure rate of 43% and a 5-year actuarial survival of 18% using combined therapy with external radiation, three cycles of concomitant chemotherapy, and then administration of high-dose-rate brachytherapy.[23] Even with the more favorable subset of patients with clinical T1-2 disease, Yorozu et al reported a local failure rate of 44% and a 5-year survival of 26% among 124 patients treated with external irradiation followed by high-dose-rate brachytherapy.[24]

In the RTOG 92-07 trial, 75 patients (92% with squamous cell cancers of the thoracic esophagus) received the combined-modality regimen (5-FU/cisplatin plus 50 Gy of external-beam irradiation) used in RTOG 85-01 followed by a boost during cycle 3 of chemotherapy with either low- or high-dose-rate intraluminal brachytherapy.[25] At a median follow-up of only 11 months, the complete response rate was 73%, and 27% of patients developed local failure as the first sign of failure. Grade 3 acute toxicity occurred in 58% of patients, grade 4 acute toxicity in 26%, and treatment-related deaths in 8%. The cumulative incidence of fistula was 18% per year, and the crude incidence was 14%. Of the six treatment-related fistulas noted, three were fatal. Given the significant toxicity reported, this treatment approach should be used with caution.

Based on this experience, the American Brachytherapy Society has developed guidelines for esophageal brachytherapy.[26] For patients treated in the curative setting, brachytherapy should be limited to tumors 10 cm or less in size with no evidence of distant metastasis. Contraindications include tracheal or bronchial involvement, cervical esophagus location, or stenosis that cannot be bypassed. The applicator should have an external diameter of 6 to 10 cm. If combined-modality therapy (defined as 5-FU-based chemotherapy plus 45-50 Gy) is used, the recommended doses of brachytherapy are 10 Gy given in two weekly fractions of 5 Gy each for the high-dose-rate regimen and 20 Gy in a single fraction at 4 to 10 Gy/h for the low dose rate. The doses should be prescribed to 1 cm from the source. Finally, brachytherapy should be delivered after the completion of external-beam irradiation and not concurrently with chemotherapy.

In patients treated in the curative setting, the addition of brachytherapy does not appear to improve results, compared with radiation therapy or combined-modality therapy alone. Therefore, the further benefit of adding intraluminal brachytherapy to radiation or combined-modality therapy, although reasonable, remains unclear.

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