59_03
Treatment of Anal Canal Cancer
Four randomized trials have established that the combination of radiation therapy, 5-fluorouracil, (5-FU), and mitomycin is the standard against which other treatments should be compared (3,6,36,121). Nonrandomized comparisons of radical resection with this radiation-chemotherapy combination (53,84), or with radiation therapy alone (22,95) have shown the ability of radiation-based regimens to produce survival rates at least equal to those of surgical series, while allowing preservation of anorectal function in the majority of patients.
Combined-Modality Therapy
Primary Tumor
Interest in combined-modality therapy originated with the report in 1974 by Nigro et al. (88) of complete tumor regression in three patients treated by radiation therapy and concurrent 5-FU and mitomycin or porfiromycin before planned abdominoperineal resection. The effectiveness of this combination as a radical treatment, rather than as an adjuvant to surgery, has been demonstrated since in numerous nonrandomized studies and confirmed in randomized trials.
The randomized trials conducted by the United Kingdom Coordinating Committee for Cancer Research (UKCCCR) (121) and the European Organisation for Research on Treatment of Cancer (EORTC) (6) both showed significant improvement in control of the primary cancer and in colostomy-free survival in patients who received irradiation combined with chemotherapy. The larger UKCCCR trial also showed improved cause-specific survival. Although the overall survival rates of those who received radiation and chemotherapy were slightly better than those of the patients treated with radiation therapy alone, the advantage did not reach statistical significance in either trial (Table 59.3).
In the UKCCCR trial (121), 577 patients with all stages (UICC Staging System, 1987 edition, which is the same as the 2002 edition [112]) of squamous cell cancer of the anal canal or anal margin were randomly assigned to receive radiation alone or radiation combined with chemotherapy. Forty percent had primary cancers >5 cm in size (T3) or deeply invasive (T4), 20% were lymph node positive, and 2% had extrapelvic metastases. The radiation dose was 45 Gy in 20 to 25 fractions in 4 to 5 weeks. Those randomized to chemotherapy received 5-FU (1,000 mg/m2/day for 4 days or 750 mg/m2/day for 5 days) by continuous peripheral intravenous infusion in the first and final weeks of radiation treatment, plus mitomycin (12 mg/m2)
P.1387
by bolus intravenous injection on day 1 of the first course of chemotherapy. The patients were reassessed clinically 6 weeks after treatment. If the primary tumor had not regressed by at least 50% (as occurred in 10% in each group), surgery was recommended; otherwise, the patients received an additional 15 Gy in six fractions by a perineal field or 25 Gy over 2 to 3 days by iridium-192 implant. Locoregional failure, defined as the presence of residual or recurrent cancer in the primary site or regional nodes, treatment-related morbidity requiring surgery, or inability to close a colostomy opened prior to treatment, was observed in 81/285 (28%) patients treated by radiation therapy and chemotherapy but in 147/283 (52%) patients who received irradiation only. Surgery that included colostomy was necessary for management of toxicity in 10 patients (3.5%) in each study group. There were six (2%) deaths due to treatment in the combined-modality arm and two (0.7%) in the irradiation-alone arm. Acute toxicity, other than hematologic, was considered comparable in each group. The mortality rate from anal cancer was significantly reduced in the combined-modality treated patients, but the overall survival rate was not improved.
In the EORTC study, 103 patients with advanced cancers of the anal canal were randomized in a trial of similar design (6). Eighty-five percent of those entered had category T3 or T4 cancers (112) and 51% had abnormal nodes. The radiation dose was 45 Gy in 25 fractions over 5 weeks. Chemotherapy included 5-FU (750 mg/m2/day for 5 days) in weeks 1 and 5 of radiation, and a single dose of mitomycin (15 mg/m2) by bolus intravenous injection on day 1 of the first course of 5-FU only. After 6 weeks, boost irradiation of 15 Gy (if complete clinical response to previous treatment had occurred) or 20 Gy (after partial response) was given by external-beam or interstitial irradiation. The probability of complete tumor regression was significantly improved after combined-modality treatment; the colostomy-free survival rate of the patients who received irradiation and chemotherapy was 58% at 3 years, compared with only 35% for those treated by irradiation alone. One of 51 patients who received combined modality treatment died of toxicity. Otherwise, acute and late toxicity rates did not differ markedly. The hazards to which patients with advanced anal cancer are subject are illustrated by the finding in this trial that the probability of surviving 3 years or more without relapse, major morbidity from treatment, or a colostomy was only about 30%.
The Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) established in a randomized trial that the combination of mitomycin with 5-FU and radiation is more effective than 5-FU alone with radiation (36). In that study, 291 patients with cancers of the anal canal of any T and N category (RTOG staging system) who did not have evidence of extrapelvic metastases received 45 to 50.4 Gy in 25 to 28 fractions over 5 weeks plus two courses of 5-FU (1,000 mg/m2/day by continuous peripheral intravenous infusion) over 4 days, with or without mitomycin (10 mg/m2 by bolus intravenous injection) on the first day of each course of chemotherapy. Chemotherapy was administered in weeks 1 and 5 of radiation therapy. Approximately 40% had cancers larger than 5 cm or invading adjacent organs, and 17% had abnormal lymph nodes. Patients were required to undergo biopsy of the primary tumor site 6 weeks after irradiation and chemotherapy. Biopsies were positive in 15% of those who received 5-FU only and in 8% of those who received both mitomycin and 5-FU (p =.14). Patients with positive biopsies had the option of receiving an additional 9 Gy in five treatments concurrently with a 4-day infusion of 5-FU (1,000 mg/m2/day) and a single injection of cisplatin (100 mg/m2) if it was thought that anal function might still be salvaged. At 5 years, the rates of colostomy (11% vs. 22%; p =.02) significantly favored treatment with radiation, 5-FU, and mitomycin, although colostomy-free survival rates did not differ significantly. There was no significant difference in overall survival rates (67% vs. 65%), although the disease-free survival rate was improved by the three-agent combination (67% vs. 50%; p =.006). Acute hematologic toxicity was more common in the patients who received mitomycin, but the rates of other acute and late toxic effects were similar in each treatment group. Four of 146 (2.7%) patients who received both 5-FU and mitomycin suffered fatal toxicity as did 1/145 treated with radiation and 5-FU alone.
In a further trial by the RTOG (RTOG 9811), so far reported only in abstract (3), induction 5-FU and cisplatin followed by 5-FU and cisplatin concurrent with radiation failed to improve disease-free survival compared to 5-FU and mitomycin with radiation. This trial included a higher total radiation dose than the earlier RTOG randomized trial, based on analysis of nonrandomized studies that suggested a dose-control relationship (17,103), and on pilot studies, which had demonstrated that a proportion of patients could tolerate uninterrupted radiation schedules of up to 59.4 Gy over 6.5 weeks with either concurrent mitomycin with 5-FU (66,67) or cisplatin with 5-FU (79). In RTOG 9811 (3), one study group received 59 Gy in 6.5 weeks (45 Gy in 1.8-Gy fractions), followed without interruption by 14 Gy in 2-Gy fractions), with concurrent 5-FU (1,000 mg/m2/day) by continuous infusion on days 1 to 4 and 29 to 32 plus mitomycin 10 mg/m2 intravenous bolus on days 1 and 29; the other group received 5-FU (1,000 mg/m2/day) days 1 to 4, 29 to 32, 57 to 60, and 85 to 88 plus cisplatin (75 mg/m2 bolus injection on days 1, 29, 57, and 85) with the same 59-Gy radiation schedule (start day 57). At the time of reporting, 598 patients were analyzable. Twenty-eight percent had primary cancers >5 cm in size, and 26% had clinically positive nodes. The preliminary results showed an actuarial 5-year disease-free rate of 56% for radiation, 5-FU, and mitomycin versus 48% for radiation, 5-FU, and cisplatin (p =.28), with overall survival rates of 69% for both arms. The 5-year colostomy rate was 10% for the mitomycin-containing arm and 20% for the cisplatin arm (p =.12). Acute grade 3 or 4 nonhematologic toxicity rates were 75% in each arm, but hematologic toxicity was higher in the mitomycin-containing arm (67% vs. 47%).
Several other randomized trials are in progress. The UKCCCR Anal Cancer Trial II incorporates a double randomization: the first compares 5-FU plus mitomycin with 5-FU plus cisplatin concurrently with radiation; the second compares two courses of adjuvant 5-FU plus cisplatin with no adjuvant therapy. The radiation dose is 50.4 Gy in 1.8-Gy fractions over 5.5 weeks without interruption.
The French Federation Francaise de Cancerolgie Digestive (FFCD 9804) trial also includes a double randomization: the first
P.1388
to two courses of neoadjuvant 5-FU and cisplatin and the second to different doses of boost irradiation. The base radiation dose is 45 Gy in 1.8-Gy fractions over 5 weeks with concurrent 5-FU and cisplatin in weeks 1 and 5. After a 2-week break, the patients receive either 15 Gy or 20 to 25 Gy, according to randomization and tumor response. Chemotherapy is not given during the boost radiation.
The EORTC 22011 trial compares single-dose mitomycin and weekly cisplatin given concurrently with radiation to mitomycin and prolonged continuous infusion 5-FU concurrently with radiation. The total radiation dose is 59.4 Gy, consisting of an initial 36 Gy in 1.8-Gy fractions over 4 weeks, followed after an interval of 2 weeks by a further 23.4 Gy in 2.5 weeks. Chemotherapy is given during both phases of radiation.
Results were not presented by T, N, or stage category in either of the randomized trials that compared radiation combined with chemotherapy to radiation alone (6,121). Five-year survival rates from nonrandomized series managed by 5-FU, mitomycin, and radiation are about 80% for cancers ≤2 cm in size (T1), 70% for tumors 2 to 5 cm (T2), 45% to 55% for larger or deeply invasive cancers (T3 or T4), and 65% to 75% overall. The corresponding local control rates (excluding salvage treatment) are about 90% to 100% (T1), 65% to 75% (T2), 40% to 55% (T3 or T4), and 60% overall (Table 59.4). Because of case mix and the preponderance of advanced cancers in many series, generally only about two-thirds of all patients treated retain anorectal function. No more than about 5% of patients overall have lost anorectal function because of treatment-related complications.
Efforts to improve results have included increases in total radiation dose and shortening of overall treatment time (both discussed below), and exploration of combinations of radiation and chemotherapy other than 5-FU plus mitomycin. Bleomycin showed no apparent benefit in nonrandomized studies (38,49,90). Of greater, and continuing, interest has been the combination of radiation, 5-FU, and cisplatin, which has produced levels of tumor control comparable to those produced by radiation, 5-FU, and mitomycin (Table 59.5). This combination has proven effective against squamous cell cancers in other sites, and cisplatin may act as a radiation sensitizer, a property lacking in mitomycin as currently used in clinical practice. However, the first report from a randomized trial did not show any superiority for cisplatin and 5-FU over mitomycin and 5-FU (3).
Much remains to be learned about the mechanisms of interaction between radiation and chemotherapy in the treatment of cancer. The synergistic interactions of various combinations of radiation, 5-FU, mitomycin and cisplatin observed in some laboratory studies are difficult to evaluate clinically, and no trials designed to study such interactions have been performed. Also, there have not been formal comparisons of more prolonged, but less daily dose-intense infusions of 5-FU with the 96- to 120-hour infusions generally favored, nor of bolus injections with continuous infusions of 5-FU or cisplatin. In most series, the timing of delivery of chemotherapy each day relative to irradiation has not been tightly controlled, and the importance of scheduling is not known.
In order to try to confirm eradication of the cancer, random biopsies from the site of the primary tumor, and/or abnormal nodes, shortly after chemoradiation have been advocated by some but are not necessary. Elective biopsies at predetermined times do not appear to lead to better results than can be achieved by biopsies directed only to areas suspected clinically of harboring residual or recurrent cancer. A negative biopsy does not exclude the possibility of cancer regrowth (87,118). Residual masses at the site of the original anal cancer may take several months to resolve fully after chemoradiation or radiation therapy alone (22,107,118). Most authors now recommend biopsy only when persistent cancer is suspected clinically.
Treatment of local residual cancer or recurrence is planned according to the extent of disease, both locoregional and extrapelvic, and the potential for preserving anorectal function. It may be possible to deliver further radiation and chemotherapy. If conservative treatment is not possible, surgery, usually abdominoperineal resection, should be considered. Although the similar overall survival rates in the trials of irradiation versus irradiation and chemotherapy are thought to reflect, in part, the ability of surgery to salvage some patients, the results of attempted salvage in many series are disappointing, with reports of high rates of unresectable cancer, further pelvic recurrence, and extrapelvic recurrences (4,59,89,102). This probably reflects the more adverse biologic characteristics of cancers not eradicated by radiation and chemotherapy. Results of attempted surgical salvage are worse in patients who present initially with locally advanced primary tumors or nodal metastases. Survival rates at 3 years after salvage surgery range from as low as 10% to better than 50%.
Four randomized trials have established that the combination of radiation therapy, 5-fluorouracil, (5-FU), and mitomycin is the standard against which other treatments should be compared (3,6,36,121). Nonrandomized comparisons of radical resection with this radiation-chemotherapy combination (53,84), or with radiation therapy alone (22,95) have shown the ability of radiation-based regimens to produce survival rates at least equal to those of surgical series, while allowing preservation of anorectal function in the majority of patients.
Combined-Modality Therapy
Primary Tumor
Interest in combined-modality therapy originated with the report in 1974 by Nigro et al. (88) of complete tumor regression in three patients treated by radiation therapy and concurrent 5-FU and mitomycin or porfiromycin before planned abdominoperineal resection. The effectiveness of this combination as a radical treatment, rather than as an adjuvant to surgery, has been demonstrated since in numerous nonrandomized studies and confirmed in randomized trials.
The randomized trials conducted by the United Kingdom Coordinating Committee for Cancer Research (UKCCCR) (121) and the European Organisation for Research on Treatment of Cancer (EORTC) (6) both showed significant improvement in control of the primary cancer and in colostomy-free survival in patients who received irradiation combined with chemotherapy. The larger UKCCCR trial also showed improved cause-specific survival. Although the overall survival rates of those who received radiation and chemotherapy were slightly better than those of the patients treated with radiation therapy alone, the advantage did not reach statistical significance in either trial (Table 59.3).
In the UKCCCR trial (121), 577 patients with all stages (UICC Staging System, 1987 edition, which is the same as the 2002 edition [112]) of squamous cell cancer of the anal canal or anal margin were randomly assigned to receive radiation alone or radiation combined with chemotherapy. Forty percent had primary cancers >5 cm in size (T3) or deeply invasive (T4), 20% were lymph node positive, and 2% had extrapelvic metastases. The radiation dose was 45 Gy in 20 to 25 fractions in 4 to 5 weeks. Those randomized to chemotherapy received 5-FU (1,000 mg/m2/day for 4 days or 750 mg/m2/day for 5 days) by continuous peripheral intravenous infusion in the first and final weeks of radiation treatment, plus mitomycin (12 mg/m2)
P.1387
by bolus intravenous injection on day 1 of the first course of chemotherapy. The patients were reassessed clinically 6 weeks after treatment. If the primary tumor had not regressed by at least 50% (as occurred in 10% in each group), surgery was recommended; otherwise, the patients received an additional 15 Gy in six fractions by a perineal field or 25 Gy over 2 to 3 days by iridium-192 implant. Locoregional failure, defined as the presence of residual or recurrent cancer in the primary site or regional nodes, treatment-related morbidity requiring surgery, or inability to close a colostomy opened prior to treatment, was observed in 81/285 (28%) patients treated by radiation therapy and chemotherapy but in 147/283 (52%) patients who received irradiation only. Surgery that included colostomy was necessary for management of toxicity in 10 patients (3.5%) in each study group. There were six (2%) deaths due to treatment in the combined-modality arm and two (0.7%) in the irradiation-alone arm. Acute toxicity, other than hematologic, was considered comparable in each group. The mortality rate from anal cancer was significantly reduced in the combined-modality treated patients, but the overall survival rate was not improved.
In the EORTC study, 103 patients with advanced cancers of the anal canal were randomized in a trial of similar design (6). Eighty-five percent of those entered had category T3 or T4 cancers (112) and 51% had abnormal nodes. The radiation dose was 45 Gy in 25 fractions over 5 weeks. Chemotherapy included 5-FU (750 mg/m2/day for 5 days) in weeks 1 and 5 of radiation, and a single dose of mitomycin (15 mg/m2) by bolus intravenous injection on day 1 of the first course of 5-FU only. After 6 weeks, boost irradiation of 15 Gy (if complete clinical response to previous treatment had occurred) or 20 Gy (after partial response) was given by external-beam or interstitial irradiation. The probability of complete tumor regression was significantly improved after combined-modality treatment; the colostomy-free survival rate of the patients who received irradiation and chemotherapy was 58% at 3 years, compared with only 35% for those treated by irradiation alone. One of 51 patients who received combined modality treatment died of toxicity. Otherwise, acute and late toxicity rates did not differ markedly. The hazards to which patients with advanced anal cancer are subject are illustrated by the finding in this trial that the probability of surviving 3 years or more without relapse, major morbidity from treatment, or a colostomy was only about 30%.
The Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) established in a randomized trial that the combination of mitomycin with 5-FU and radiation is more effective than 5-FU alone with radiation (36). In that study, 291 patients with cancers of the anal canal of any T and N category (RTOG staging system) who did not have evidence of extrapelvic metastases received 45 to 50.4 Gy in 25 to 28 fractions over 5 weeks plus two courses of 5-FU (1,000 mg/m2/day by continuous peripheral intravenous infusion) over 4 days, with or without mitomycin (10 mg/m2 by bolus intravenous injection) on the first day of each course of chemotherapy. Chemotherapy was administered in weeks 1 and 5 of radiation therapy. Approximately 40% had cancers larger than 5 cm or invading adjacent organs, and 17% had abnormal lymph nodes. Patients were required to undergo biopsy of the primary tumor site 6 weeks after irradiation and chemotherapy. Biopsies were positive in 15% of those who received 5-FU only and in 8% of those who received both mitomycin and 5-FU (p =.14). Patients with positive biopsies had the option of receiving an additional 9 Gy in five treatments concurrently with a 4-day infusion of 5-FU (1,000 mg/m2/day) and a single injection of cisplatin (100 mg/m2) if it was thought that anal function might still be salvaged. At 5 years, the rates of colostomy (11% vs. 22%; p =.02) significantly favored treatment with radiation, 5-FU, and mitomycin, although colostomy-free survival rates did not differ significantly. There was no significant difference in overall survival rates (67% vs. 65%), although the disease-free survival rate was improved by the three-agent combination (67% vs. 50%; p =.006). Acute hematologic toxicity was more common in the patients who received mitomycin, but the rates of other acute and late toxic effects were similar in each treatment group. Four of 146 (2.7%) patients who received both 5-FU and mitomycin suffered fatal toxicity as did 1/145 treated with radiation and 5-FU alone.
In a further trial by the RTOG (RTOG 9811), so far reported only in abstract (3), induction 5-FU and cisplatin followed by 5-FU and cisplatin concurrent with radiation failed to improve disease-free survival compared to 5-FU and mitomycin with radiation. This trial included a higher total radiation dose than the earlier RTOG randomized trial, based on analysis of nonrandomized studies that suggested a dose-control relationship (17,103), and on pilot studies, which had demonstrated that a proportion of patients could tolerate uninterrupted radiation schedules of up to 59.4 Gy over 6.5 weeks with either concurrent mitomycin with 5-FU (66,67) or cisplatin with 5-FU (79). In RTOG 9811 (3), one study group received 59 Gy in 6.5 weeks (45 Gy in 1.8-Gy fractions), followed without interruption by 14 Gy in 2-Gy fractions), with concurrent 5-FU (1,000 mg/m2/day) by continuous infusion on days 1 to 4 and 29 to 32 plus mitomycin 10 mg/m2 intravenous bolus on days 1 and 29; the other group received 5-FU (1,000 mg/m2/day) days 1 to 4, 29 to 32, 57 to 60, and 85 to 88 plus cisplatin (75 mg/m2 bolus injection on days 1, 29, 57, and 85) with the same 59-Gy radiation schedule (start day 57). At the time of reporting, 598 patients were analyzable. Twenty-eight percent had primary cancers >5 cm in size, and 26% had clinically positive nodes. The preliminary results showed an actuarial 5-year disease-free rate of 56% for radiation, 5-FU, and mitomycin versus 48% for radiation, 5-FU, and cisplatin (p =.28), with overall survival rates of 69% for both arms. The 5-year colostomy rate was 10% for the mitomycin-containing arm and 20% for the cisplatin arm (p =.12). Acute grade 3 or 4 nonhematologic toxicity rates were 75% in each arm, but hematologic toxicity was higher in the mitomycin-containing arm (67% vs. 47%).
Several other randomized trials are in progress. The UKCCCR Anal Cancer Trial II incorporates a double randomization: the first compares 5-FU plus mitomycin with 5-FU plus cisplatin concurrently with radiation; the second compares two courses of adjuvant 5-FU plus cisplatin with no adjuvant therapy. The radiation dose is 50.4 Gy in 1.8-Gy fractions over 5.5 weeks without interruption.
The French Federation Francaise de Cancerolgie Digestive (FFCD 9804) trial also includes a double randomization: the first
P.1388
to two courses of neoadjuvant 5-FU and cisplatin and the second to different doses of boost irradiation. The base radiation dose is 45 Gy in 1.8-Gy fractions over 5 weeks with concurrent 5-FU and cisplatin in weeks 1 and 5. After a 2-week break, the patients receive either 15 Gy or 20 to 25 Gy, according to randomization and tumor response. Chemotherapy is not given during the boost radiation.
The EORTC 22011 trial compares single-dose mitomycin and weekly cisplatin given concurrently with radiation to mitomycin and prolonged continuous infusion 5-FU concurrently with radiation. The total radiation dose is 59.4 Gy, consisting of an initial 36 Gy in 1.8-Gy fractions over 4 weeks, followed after an interval of 2 weeks by a further 23.4 Gy in 2.5 weeks. Chemotherapy is given during both phases of radiation.
Results were not presented by T, N, or stage category in either of the randomized trials that compared radiation combined with chemotherapy to radiation alone (6,121). Five-year survival rates from nonrandomized series managed by 5-FU, mitomycin, and radiation are about 80% for cancers ≤2 cm in size (T1), 70% for tumors 2 to 5 cm (T2), 45% to 55% for larger or deeply invasive cancers (T3 or T4), and 65% to 75% overall. The corresponding local control rates (excluding salvage treatment) are about 90% to 100% (T1), 65% to 75% (T2), 40% to 55% (T3 or T4), and 60% overall (Table 59.4). Because of case mix and the preponderance of advanced cancers in many series, generally only about two-thirds of all patients treated retain anorectal function. No more than about 5% of patients overall have lost anorectal function because of treatment-related complications.
Efforts to improve results have included increases in total radiation dose and shortening of overall treatment time (both discussed below), and exploration of combinations of radiation and chemotherapy other than 5-FU plus mitomycin. Bleomycin showed no apparent benefit in nonrandomized studies (38,49,90). Of greater, and continuing, interest has been the combination of radiation, 5-FU, and cisplatin, which has produced levels of tumor control comparable to those produced by radiation, 5-FU, and mitomycin (Table 59.5). This combination has proven effective against squamous cell cancers in other sites, and cisplatin may act as a radiation sensitizer, a property lacking in mitomycin as currently used in clinical practice. However, the first report from a randomized trial did not show any superiority for cisplatin and 5-FU over mitomycin and 5-FU (3).
Much remains to be learned about the mechanisms of interaction between radiation and chemotherapy in the treatment of cancer. The synergistic interactions of various combinations of radiation, 5-FU, mitomycin and cisplatin observed in some laboratory studies are difficult to evaluate clinically, and no trials designed to study such interactions have been performed. Also, there have not been formal comparisons of more prolonged, but less daily dose-intense infusions of 5-FU with the 96- to 120-hour infusions generally favored, nor of bolus injections with continuous infusions of 5-FU or cisplatin. In most series, the timing of delivery of chemotherapy each day relative to irradiation has not been tightly controlled, and the importance of scheduling is not known.
In order to try to confirm eradication of the cancer, random biopsies from the site of the primary tumor, and/or abnormal nodes, shortly after chemoradiation have been advocated by some but are not necessary. Elective biopsies at predetermined times do not appear to lead to better results than can be achieved by biopsies directed only to areas suspected clinically of harboring residual or recurrent cancer. A negative biopsy does not exclude the possibility of cancer regrowth (87,118). Residual masses at the site of the original anal cancer may take several months to resolve fully after chemoradiation or radiation therapy alone (22,107,118). Most authors now recommend biopsy only when persistent cancer is suspected clinically.
Treatment of local residual cancer or recurrence is planned according to the extent of disease, both locoregional and extrapelvic, and the potential for preserving anorectal function. It may be possible to deliver further radiation and chemotherapy. If conservative treatment is not possible, surgery, usually abdominoperineal resection, should be considered. Although the similar overall survival rates in the trials of irradiation versus irradiation and chemotherapy are thought to reflect, in part, the ability of surgery to salvage some patients, the results of attempted salvage in many series are disappointing, with reports of high rates of unresectable cancer, further pelvic recurrence, and extrapelvic recurrences (4,59,89,102). This probably reflects the more adverse biologic characteristics of cancers not eradicated by radiation and chemotherapy. Results of attempted surgical salvage are worse in patients who present initially with locally advanced primary tumors or nodal metastases. Survival rates at 3 years after salvage surgery range from as low as 10% to better than 50%.
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