Neoadjuvant Chemoradiation With Cisplatin(Drug information on cisplatin)/5-FU vs Mitomycin(Drug information on mitomycin)/5-FU
Several phase II clinical trials showed promising results for 5-FU, cisplatin, and radiation combined in the treatment of anal cancer,19,20 prompting the investigation of this combination in phase III clinical trials (Table 3).
RTOG 98-11 randomized 682 patients with T2–4, M0 anal cancer to 5-FU plus mitomycin and radiation vs neoadjuvant chemotherapy followed by 5-FU plus cisplatin with radiation.21 The induction chemotherapy in the cisplatin arm consisted of two cycles of cisplatin plus 5-FU prior to definitive cisplatin plus 5-FU with radiation. The mitomycin arm did not receive any induction chemotherapy.
Chemotherapy treatment in the mitomycin group consisted of mitomycin at 10 mg/m2 on days 1 and 29 and 5-FU continuous infusion at 1,000 mg/m2/d on days 1 to 4 and 29 to 32 (with radiation starting on day 1). Chemotherapy on the cisplatin arm consisted of cisplatin at 75 mg/m2 on days 1 and 29 and repeated on days 57 and 85 (with radiation starting on day 57) and 5-FU continuous infusion at 1,000 mg/m2/d on days 1 to 4, 29 to 32, 57 to 60, and 85 to 88. It is important to recognize that the total length of treatment with neoadjuvant chemotherapy followed by 5-FU plus cisplatin with radiation was 56 days longer than in the 5-FU plus mitomycin and radiation arm. Additionally, the initiation of radiation therapy was delayed 57 days.
Radiation was given to a minimum dose of 45 Gy in 25 fractions of 1.8 Gy using anteroposterior-posteroanterior or multifield techniques. Initial radiation fields included the pelvis, anus, perineum, and inguinal lymph nodes, with the superior border at L5-S1 and the inferior border to include the anus with a minimum margin of 2.5 cm around the anus and tumor.21 Radiation fields were reduced further at 30.6 Gy and 36 Gy (for lymph node–negative patients). Patients with T3–4 disease, positive lymph nodes, or residual disease at the completion of 45 Gy, received an addition boost of 10 to 14 Gy (2 Gy fractions).21
The 3- and 5-year disease-free survival rates in the mitomycin arm were 67% and 60%, respectively. In the cisplatin arm, the 3- and 5-year disease-free survival rates were 61% and 54%, respectively. This mitomycin-favoring trend did not reach statistical significance (P = .17). The 5-year locoregional recurrence rates were 25% and 33%, and the 5-year distant relapse rates were 15% and 19% in the mitomycin and cisplatin arms, respectively. Similarly, a nonsignificant trend (P = .10) favored mitomycin therapy for 3-year survival (84% vs 76%) and 5-year survival (75% vs 70%). Treatment with 5-FU and mitomycin plus radiation resulted in a statistically significant reduction in the colostomy rate at 3 years (10% vs 16%) and 5 years (10% vs 19%).
Both treatments resulted in a 74% grade 3/4 toxicity rate in each arm. The mitomycin arm showed a significantly increased hematologic toxicity rate, even though the arm receiving neoadjuvant chemotherapy followed by cisplatin plus 5-FU with radiation got chemotherapy for almost 2 additional months.21 RTOG 98-11 failed to show any superiority for neoadjuvant chemotherapy followed by the cisplatin plus 5-FU with radiation regimen over standard care in rectal cancer—ie, mitomycin plus 5-FU with radiation.
The addition of neoadjuvant chemotherapy to the cisplatin arm complicated the study design, as it did not allow a direct comparison of radiation with either mitomycin or cisplatin. The role of neoadjuvant chemotherapy in the treatment of anal cancer is unclear, especially as it prolonged the total duration of therapy by 56 days. Additionally, it is unknown whether the 57-day delay of initiating radiation influenced study outcomes, especially among patients who failed to respond to neoadjuvant chemotherapy.
The second UK Anal Cancer Trial (ACT II), as reported at the American Society of Clinical Oncology 2009 meeting, addressed the issues in the RTOG study design and directly evaluated the role of mitomycin vs cisplatin in the neoadjuvant chemoradiation of anal cancer.22 A total of 940 patients (T1–4) were randomized to receive 5-FU plus cisplatin with radiation or 5-FU plus mitomycin with radiation. Both the mitomycin and cisplatin arms were randomized further to receive adjuvant cisplatin plus 5-FU for two cycles (maintenance) or to observation. Those patients randomized to maintenance therapy began adjuvant chemotherapy 4 weeks after completion of chemoradiation.22
The mitomycin chemoradiation arm in the ACT II trial consisted of a 5-FU continuous infusion at 1,000 mg/m2/d on days 1-4 and 29-32 and mitomycin at 12 mg/m2 on day 1 of radiation, 50.4 Gy in 28 fractions. The cisplatin chemoradiation arm consisted of 5-FU continuous infusion at 1,000 mg/m2/d on days 1 to 4 and 29 to 32 and cisplatin at 60 mg/m2 on days 1 and 29, with radiation starting on day 1.
The complete response rate at 6 months in the ACT II trial was similar in the mitomycin (94.5%) and cisplatin (95.4%) arms. The colostomy rate at 3 years was 13.7% on the mitomycin arm vs 11.3% on the cisplatin arm (P = .26). No difference was noted in locoregional recurrence between the mitomycin arm (11%) vs the cisplatin arm (13%). Nonhematologic toxicities were seen to the same extent in both arms, while hematologic toxicities were significantly higher in the mitomycin arm.22 The ACT II study showed that the outcomes and nonhematologic toxicities with cisplatin were equivalent to mitomycin while resulting in significantly lower hematologic toxicity (grade 3/4 hematologic toxicity during chemoradiation was 13.4% in the cisplatin-arm vs 24.7% in the MMC-arm).
Addition of Induction or Maintenance Chemotherapy to Chemoradiation
The relevance of induction chemotherapy prior to definitive chemoradiation was addressed by RTOG 98-11. This study, detailed above, did not show any advantage to neoadjuvant cisplatin plus 5-FU followed by cisplatin-based chemoradiation over mitomycin-based chemoradiation without induction.21 The effect of an extended overall treatment time with neoadjuvant chemotherapy is unknown. The effect of a nearly 2-month delay in initiating radiation, especially among patients who do not respond to neoadjuvant chemotherapy, is also unknown.
Given that cisplatin- and mitomycin-based radiation were shown to be equivalent in the ACT II study, it would be highly unlikely that a beneficial effect of neoadjuvant 5-FU/cisplatin was negated by the effect of cisplatin-based radiation in RTOG 08-11.21,22 This is supported further by a recent analysis of the efficacy data from the ACCORD 03 trial.23 This was a 2×2 factorial design phase III study that randomized patients to two cycles of cisplatin plus 5-FU followed by chemoradiation (5-FU plus cisplatin with radiation) or to chemoradiation (5-FU plus cisplatin with radiation) alone. The induction arm consisted of cisplatin at 80 mg/m2 on day 1 and 5-FU at 800 mg/m2/d on days 1 to 4 of weeks 1, 5, 9, and 12, with radiation starting on week 9 of treatment. The upfront chemoradiation arm consisted of the same chemotherapy regimen but given only on weeks 1 and 5 of radiation. Radiation consisted of 45 Gy in 25 fractions. These arms were randomized further to a standard 15-Gy boost or to a higher-dose boost of 20 to 25 Gy.23 Neither induction chemotherapy nor the additional boost of radiation resulted in any improvement in outcome measures (colostomy-free survival, event-free survival, local control, or overall survival).23
The relevance of maintenance (adjuvant) chemotherapy was addressed in the ACT II study (described above).22 Patients were randomized to an arm receiving two cycles of cisplatin plus 5-FU (maintenance) or to a "no maintenance arm" following completion of chemoradiation. The 3-year disease-free and overall survival rates were 75% and 85% on the maintenance arm vs 75% and 84% on the "no maintenance" arm.22 The lack of a clinical benefit for induction or maintenance chemotherapy does not support the implementation of these strategies in clinical practice outside the setting of a clinical trial.
Effect of Overall Treatment Time on Tumor Control
Multiple studies have shown the importance of time-related factors in the treatment of anal cancer, suggesting that accelerated repopulation of tumor clonogens during radiation therapy may be detrimental to tumor control.24-26 It is likely that the lack of prolonged radiation treatment interruptions in anal cancer will have a similar beneficial effect on tumor control, as that has been well-documented for carcinomas of the head and neck, lung, and uterine cervix.24,27
Weber et al found that a treatment gap of more than 35 days correlated with lower locoregional control rates in patients with anal cancer.24 Similarly, in a French study of 305 patients, Deniaud-Alexandre et al reported that a treatment interval greater than 38 days independently decreased the probability of disease-free survival in patients with anal cancer.26
A comparison of results from the RTOG 92-08 trial with those of the RTOG 87-04 trial showed that survival in the RTOG 92-08 cohort with no mandatory radiation treatment interruption was higher than that in the mandatory 2-week treatment break cohort of RTOG 92-08, but similar to survival results in RTOG 87-04 and other published series with uninterrupted treatment.17,28 The colostomy rate was fourfold higher in the mandatory treatment break cohort, despite the increase in overall radiation dose. These data demonstrated that prolonged treatment breaks resulted in poorer therapy outcome than continuous-course therapy, despite the higher total radiation dose delivered in the study that mandated a treatment break.
Combined-modality treatment of patients with anal cancer can cause considerable morbidity from acute skin and mucosal toxicity, potentially resulting in treatment interruptions. One way to decrease skin toxicity is to use intensity-modulated radiotherapy (IMRT), which delivers highly conformal doses of radiation that could potentially minimize toxicity and treatment breaks.29 The RTOG is currently evaluating the feasibility of IMRT concurrent with chemotherapy in a phase II study.30