26 Treatment of Anal Carcinoma in the Elderly Feasibility and Outcome of Radical Radiotherapy with or without Concomitant Chemotherapy Abdelkarim S. Allal M.D.1 Mirjana Obradovic M.D.2 France Laurencet M.D.1 Arnaud D. Roth M.D.3 Alexandra Spada M.D.3 Marc-Claude Marti M.D.3 John M. Kurtz M.D.1 1 Division of Radiation Oncology, University Hospital, Geneva, Switzerland. 2 Geneva Tumor Registry,2 Geneva, Switzerland. 3 Department of Surgery, University Hospital, Geneva, Switzerland. BACKGROUND. For most cancers, information on treatment tolerance and results for elderly patients is quite limited. This study was conducted to investigate the feasibility and results of curative nonsurgical treatment of patients age 75 years or older with anal carcinoma. METHODS. From January 1976 through June 1996, invasive anal squamous cell carcinoma was diagnosed in 58 patients age ⱖ75 years. Curative treatment was administered to 47 patients (81%), of whom 42 received radiotherapy (RT), either used alone (21) or associated with concomitant chemotherapy (CT). RT was administered in two sequences, the first in which a median dose of 39.6 gray (Gy) was delivered with megavoltage photon beams, followed (after a median interval of 43 days) by a boost with either brachytherapy or external beam (median dose, 20 Gy). CT started on Day 1 and generally consisted of 1 cycle of mitomycin C (MMC; median dose, 9.5 mg/m2) and a 96-hour infusion of 5-fluorouracil (5-FU; median dose, 600 mg/m2/day). The median follow-up for all patients was 48 months (range, 5–163 months). RESULTS. Of 40 patients (95%) who completed curative treatment, acute toxicity resulted in shortening of the planned first irradiation sequence in 2 patients (1 in each group) and an unplanned treatment break in 11 patients (4 in the RT group and 7 in the RT-CT group). Grade 2 and 3 acute reactions (RTOG) were observed in 43% and 54% of patients, respectively. Among all Grade 3 reactions, 32% occurred in the RT group and 68% in the RT-CT group. In patients receiving RT-CT, Grade 2–3 leukopenia was observed in 25% of patients, Grade 2–3 fatigue was observed in 58% of patients, and Grade 2 cardiac toxicity related to 5-FU occurred in 1 patient. At 5 years, the overall survival was 54% (49% and 59% for the RT and RT-CT groups, respectively, P ⫽ 0.28), and the actuarial local control rate was 78.5% (73% and 83% for the RT and RT-CT groups, respectively, P ⫽ 0.36). Five patients presented with Grade 3– 4 late complications, all of them in the RT-CT group. CONCLUSIONS. The current series confirms the feasibility of sphincter-conserving treatment for elderly patients who present with anal carcinoma. Rates of acute or late complications appeared similar to those observed in younger patients, and the oncologic results were at least as favorable as those commonly reported. Cancer 1999;85:26 –31. © 1999 American Cancer Society. KEYWORDS: elderly patients, anal carcinoma, radiotherapy, chemotherapy, sphincter conservation. Address for reprints: Abdelkarim S. Allal, M.D., Hôpital Cantonal Universitaire de Genève, Division de Radio-oncologie, 1211 Geneva 14, Switzerland. Received February 25, 1998; revision received May 14, 1998; accepted May 14, 1998. © 1999 American Cancer Society I n Western countries, the rapid increase in the elderly population will inevitably lead to a marked rise in the number of new cancer cases.1 Currently, nearly 60% of all cancers are diagnosed in patients age ⱖ65 years.2 Epidemiologic studies have demonstrated an increase in the incidence of anal carcinoma in recent decades.3 Although this increase may not be related solely to population aging, more than one-third of Treatment of Elderly Patients with Anal Carcinoma/Allal et al. patients presenting with anal carcinomas are age ⱖ70 years.4 Nonetheless, for elderly patients with anal carcinomas the feasibility of curative therapy and the outcomes of such treatments are poorly documented. To our knowledge, no study of this uncommon disease in a substantial series of geriatric patients has yet appeared in the international literature. With these considerations in mind, we retrospectively reviewed the types of treatment, treatment toxicities, and oncologic results in elderly patients presenting with anal carcinoma in Geneva, Switzerland. MATERIALS AND METHODS According to the Geneva Tumor Registry, between January 1976 and June 1996 invasive anal squamous cell carcinoma was diagnosed in 58 patients age ⱖ75 years. Six patients were treated palliatively because of impaired general condition or metastatic disease, and 5 did not receive any oncologic treatment because of metastatic disease (2), poor general condition (1), patient refusal (1), or an unknown reason (1). Curative treatment was given to 47 patients, with radiotherapy (RT; 23), radiotherapy and concomitant chemotherapy (RT-CT; 21), or surgery (3). The current analysis of toxicity and oncologic results is limited to 42 patients who underwent sphincter-conserving treatment. Excluded from this analysis were 11 patients who did not receive curative therapy, 3 patients treated with radical surgery, and 2 patients treated with brachytherapy alone. The characteristics of the 42 study patients are displayed in Table 1. Radiotherapy Radiotherapy was delivered in a split course to 39 patients and in continous course to 1 patient, whereas two patients received only the first sequence (see “Results”). External megavoltage beams (EBRT) were always used for the first sequence, whereas the second consisted of a “boost” directed to areas of initial macroscopic disease, using interstitial brachytherapy for 27 patients and EBRT for 12 patients. Detailed treatment techniques have been reported previously.6 The technical parameters of RT in the current study are presented in Table 2. In the initial period, the first sequence consisted of 30 Gy in 10 fractions (dose specified at a median depth of 4 cm) delivered by a direct perineal telecobalt field, complemented in all but selected small tumors by 18 Gy through a posterior presacral field (Papillon’s technique).7 In the mid1980s, the technique of EBRT was modified to treat adequately the inguinal, external iliac, and hypogastric lymph nodes, using two large anteroposterior (AP/ PA) opposed pelvic fields with photons of 6 MV or more. In addition, the total dose and dose per fraction 27 TABLE 1 Patient Characteristics Characteristics Median age, yrs (range) Female/male Tumor location Canal ⫾ anorectal junction Margin Canal ⫹ margin Tumor status Primary Recurrence postsurgery Postexcisional biopsy Histology Keratinizing squamous Basaloid and transitional Undifferentiated Clinical stage (UICC TNM5) T2 (%) T3 T4 N0 N1–3 RT 21 patients RT-CT 21 patients Total 42 patients 82 (75–90) 17/4 79 (75–87) 18/3 81 (75–90) 35/7 18 0 3 18 1 2 36 1 5 16 1 4 21 0 0 37 1 4 12 8 1 13 8 0 25 16 1 18 (86) 2 1 20 1 (5) 6 (28) 13 2 14 6 (29) 24 15 3 34 7 RT: radiotherapy; CT: chemotherapy; UICC: International Union Against Cancer. were modified to avoid severe acute toxicities, typically delivering 40 Gy in 20 –22 fractions over 4 – 4.5 weeks. The boost type (EBRT or brachytherapy) was chosen according to the extent of disease and the patient’s general condition. Brachytherapy consisted of a low dose rate interstitial iridium-192 implant performed 6 – 8 weeks after the end of EBRT; the dose was calculated according to the rules of the “Paris system.”8 Patients who received an EBRT boost were treated most commonly with photons of 6 MV or more using various field arrangements. Chemotherapy Twenty-one patients (50%) received concomitant chemotherapy. This association was reserved initially for advanced stages, but gradually was extended to include less advanced stages except patients with very favorable tumors or in poor general condition. CT usually started on Day 1 and consisted of one cycle of MMC (median dose, 9.5 mg/m2) and a 96-hour continuous infusion of 5-fluorouracil (5-FU; median dose, 600 mg/m2/day). One patient received 5-FU alone. During the boost treatment, five patients received a second course of 5-FU (with MMC in three cases). The doses of the different agents were adjusted according to the age and general condition of each patient. Statistical Evaluation Actuarial local control rate, overall survival, and disease free survival rates were calculated by using the 28 CANCER January 1, 1999 / Volume 85 / Number 1 TABLE 2 Characteristics of Radiotherapy Fields and doses (1st course) AP/PA pelvic fields ⫹ other Perineal ⫾ sacral fields Boost technique (2nd course) A) EBRT Perineal field AP/PA ⫾ lateral fields Other techniques B) Interstitial brachytherapy Median dose–median dose rate Median interval between courses Median total treatment duration RT 21 patients RT-CT 21 patients Total 42 patients Median dose/ fraction/days 9⫹2 10 20 ⫹ 1 0 29 ⫹ 3 10 39.6 Gy/22/31 30 Gy/10/20 6 3 1 2 14 25 Gy–76 cGy/hr 37 73 6 1 3 2 13 20 Gy–75 cGy/hr 48 76 12 4 4 4 27 23 Gy–75 cGy/hr 43 days 75 days 20 Gy/10/12 RT: radiotherapy; CT: chemotherapy; EBRT: external beam RT; AP/PA: anteroposterior opposed fields; Gy: gray; cGy: centigray. Kaplan–Meier method.9 Fisher’s exact test and the log rank test were used to assess for significant differences between simple proportions and survival curves. RESULTS Compliance and Toxicity Because of acute toxicity, two patients refused to receive the brachytherapy boost (one in the RT group and one in the RT-CT group). Moreover, the planned first irradiation sequence was shortened in 2 patients (1 in each group), and 11 required an unplanned treatment interruption (4 in the RT and 7 in the RT-CT group), with a median split duration of 7 days (range, 2–34 days). According to the Radiation Therapy Oncology Group (RTOG) grading system,10 43% of patients presented with Grade 2 and 54% (53% in the RT group and 55% in the RT-CT group) with Grade 3 acute reactions. Among all Grade 3 reactions, 32% occurred in the RT group and 68% in the RT-CT group. Grade 3 reactions concerned mostly pelvic/perineal skin (50%) and diarrhea (32%). Grade 3 skin reactions were observed in 19% and 47% of the RT and RT-CT groups, respectively (P ⫽ 0.08). In the RT-CT group, according to the World Health Organization (WHO) grading system,11 Grade 2–3 leukopenia was observed in 25% of patients, Grade 2–3 fatigue in 58%, and 1 Grade 2 cardiac toxicity related to 5-FU was recorded. No Grade 4 acute toxicity or treatmentrelated death occurred in either group. Thirty-five patients were evaluable for long term complications (patients with available data), with 29 and 27 patients at risk at 2 and 3 years, respectively. Sixty-six percent of late complications were RTOG Grade 1–2. All Grade 3– 4 complications (5 patients) were observed in female patients in the RT-CT group (Table 3). Grade 3 complications consisted of one severe anal stenosis and one chronic diarrhea, both managed conservatively. Grade 4 complications consisted of one case of anal necrosis treated with abdominoperineal resection (APR) and two cases of pelvic osteonecrosis and bone fracture managed conservatively. Clinical Outcome At last follow-up, 13 patients were still alive and 1 was lost to follow-up at 58 months without evidence of disease. Of the patients who died, anal carcinoma was considered the cause of death among 7, including both patients who did not complete the planned treatment, and 3 patients died of a second malignancy. The median follow-up for all patients was 48 months (range, 5–163 months). The 5- and 8-year actuarial overall survival rates were 54% and 36% (Fig. 1). No significant difference was observed between the RT and RT-CT groups (5-year survival, 49% vs. 59%, P ⫽ 0.28). The 5-year disease free survival for all study patients (Fig. 2) was 70% (65% and 74% for the RT and RT-CT groups, respectively, P⫽ 0.42) and 74% for the 40 patients who completed the planned schedule. During follow-up, 8 patients were documented to have local (7) or locoregional (1) failures, and 3 had distant metastases (Table 4). The 5-year actuarial local control rate (Fig. 2) was 78.5% (73% and 83% for the RT and RT-CT groups, respectively, P ⫽ 0.36). Salvage surgery was attempted in 5 of 8 patients with locoregional failures (3 APR and 2 conservative surgery), leading to definitive locoregional control in 3 patients. DISCUSSION In current oncologic practice, the management of elderly patients poses particular problems. Before arriv- Treatment of Elderly Patients with Anal Carcinoma/Allal et al. FIGURE 1. Actuarial overall survival for the 42 patients. FIGURE 2. 29 Actuarial local control and disease free survival for the 42 patients. ing at a decision, questions are frequently asked by the patient, his family, and his physicians concerning treatment tolerance, sequelae, and oncologic results. However, because almost all prospective trials exclude patients older than 75 years, reliable information on tolerance and results of curative treatment for elderly patients is often unavailable. Moreover, older patients tend to be less regularly screened and subsequently may more often present with advanced disease, and they also tend to be treated inadequately or not at all.12,13 These age-related variations may be related to the patient’s real or perceived health status, the patient’s preferences, and his or her physician’s attitudes.14 In addition, discouraging findings regarding the efficacy of treatment for elderly patients reported for some malignancies15–17 might tend to encourage less adequate management. However, due particularly to progress in the management of comorbidities in elderly patients, curative treatment has become more frequently used.18 Indeed, recent reports have stressed that advanced chronologic age is not sufficient justification for excluding patients from optimal treatment with surgery, radiotherapy, or chemotherapy.19 –21 Moreover, age by itself often does not represent a negative prognostic factor.22–24 In a study of 1619 patients from trials of the European Organisation for the Research and Treatment of Cancer, Pignon at al.25 found no differences in acute or late complications, nor in survival, among different age groups of patients treated with pelvic irradiation for various malignancies. Similar observations were reported regarding elderly patients treated with radiotherapy for cervix carcinoma26 and for oropharyngeal cancers.21 However, to our knowledge, no reports dealing exclusively with the treatment of anal carcinomas in a geriatric population have previously appeared in the literature. The current study suggests that in Geneva elderly patients with anal carcinoma do not appear to be less adequately treated, as 47 of 58 (81%) of them underwent treatment given with curative intent. Moreover, decisions to offer palliative treatment or to abstain from specific oncologic therapy did not seem to be primarily related to the age factor. The second finding of this study was that a full course of curative radiotherapy, with or without concomitant chemotherapy, was feasible for a significant proportion of those patients: 40 of 42 (95%). Radiotherapy technique and dosage were quite similar to those usually employed at our institution.27 However, for elderly patients, doses of MMC and 5-FU were usually 20% lower than those routinely given to younger patients. Although retrospective assessment of toxicity is problematic, some useful information could be drawn from this study. As expected, acute toxicity was the limiting factor, particularly in patients treated with combined modalities, whereas more unplanned interruptions were required and the planned treatment gap was longer than for patients treated with RT alone. Moreover, whereas the proportion of patients presenting with Grade 3 acute toxicity was quite similar, the number of Grade 3 complications was higher in the RT-CT group. In particular, Grade 3 skin reactions were more frequent in the RT-CT group (19% vs. 47%, P ⫽ 0.08). Otherwise, systemic toxicity in the RT-CT group was dominated by fatigue (Grade 2–3 in 58% of patients), whereas hematologic toxicity (Grade 2–3 leukopenia in 25% of patients) and cardiac toxicity (in 1 patient) remained acceptable. The increase in acute toxicities when chemotherapy is added to RT is well documented in a prospective trial.28 Except for fatigue, which seemed to be more marked in elderly subjects, acute toxicities appeared to be similar to those reported in a prospective trial that included patients younger than 76 years.29 30 CANCER January 1, 1999 / Volume 85 / Number 1 TABLE 3 Characteristics of Patients with Grade 3–4 Complications Radiotherapy Age TN dose (EBRT ⴙ IB), Grade and type of (yrs) stage Gy complication 83 79 78 75 79 T2N0 T3N2 T3N0 T2N0 T3N1 39.6 ⫹ 24 39.6 ⫹ 24 43.6 ⫹ 20 39.6 ⫹ 25 39.6 ⫹ 24a 3: anal stenosis 3: diarrhea 4: anal necrosis 4: pubic osteonecrosis 4: femoral necks necrosis Time to occurrence (mos) 18 8 3 16 22 EBRT: external beam radiation therapy; IB: interstitial brachytherapy; Gy: gray. a EBRT boost. Concerning late morbidities, Grade 3– 4 complications were observed only in the RT-CT group (Table 3). However, the introduction of chemotherapy in Geneva coincided with the use of larger RT fields, and patients treated with combined modalities tended to have more advanced disease. As we have previously reported, skeletal complications occur preferentially in older women treated with combined modality therapy.30 Otherwise, the 14% rate of Grade 3– 4 late complications can be compared favorably with rates reported for younger patients.29 The most noteworthy finding was the 78.5% 5-year local control rate, which appeared to be at least equivalent to that reported for younger patients.28,29 In our previous report, in which different factors influencing local control were analyzed, patients older than 66 years were found to have a significantly higher rate of local control than younger patients.27 This result should remove any doubt regarding the efficacy of curative sphincter-conserving treatment in elderly patients with anal carcinoma. Similar conclusions were reported by Valentini et al.31 from a study of a small series of anorectal carcinomas in elderly patients. Moreover, in the current series 5 of the 8 patients who experienced failure after conservative treatment were able to undergo salvage surgery, leading to definitive locoregional control in 3 of them (Table 4). Despite the advanced age of the patients, the actuarial overall survival rate was 54% at 5 years, similar to that observed for younger patients.29 This rate tends to fall rapidly after 5 years, essentially reflecting deaths due to intercurrent diseases. Only 7 of the 28 deaths that occurred among the 42 patients in this study (including the two patients who did not complete the planned treatment) were caused by anal carcinoma. In conclusion, the current series establishes the feasibility of curative sphincter-conserving treatment for elderly patients with anal carcinoma. Taking into account the superiority of combined chemoradiotherapy in terms of local control,28,29 concomitant chemotherapy should be attempted whenever possible and doses modulated according to the patient’s general condition. Moreover, it may be appropriate to adapt radiotherapy technique for elderly patients with early stage disease, e.g., to irradiate only a small volume, including the primary tumor area and the perirectal lymph node drainage. A boost to the initial sites of involvement could be undertaken after a dose of 36 gray (Gy); and for patients with good response to initial chemoradiotherapy, the total dose could be limited to 55 Gy. For patients who tolerate chemotherapy, two cycles should be administered if possible. Regarding patients for whom chemotherapy is considered inappropriate, it should be borne in mind that a substantial proportion of patients can be cured with appropriately planned radiotherapy alone. Acute toxicity represents the limiting factor of such treatment. Indeed, although the objective grade TABLE 4 Characteristics of Patients with Local/Locoregional Failure TN stage Radiotherapy dose (EBRT ⴙ IB), Gy Overall treatment time (days) Chemotherapy (no. of cycles) Site of recurrence Time to occurrence (mos) T2N0 T3N0 T4N0 T2N2 T3N2 T2N0 T4N3 T2N0 24 ⫹ 25 28 ⫹ 30 50.4 ⫹ 20a 39.6 ⫹ 20a 39.6 ⫹ 24 30 ⫹ 30 39.6 ⫹ 19.8a 40b 68 52 77 102 81 143 105 30 No No No No Yes (1) No Yes (1) Yes (1) AC ⫹ inguinal & mesenteric nodes AC AC AC AC AC AC AC 16 6 0 0 26 9 7 10 EBRT: external beam radiation therapy; IB: interstitial brachytherapy; AC: anal canal; Gy: gray. a EBRT boost. b The planned treatment was not completed. Treatment of Elderly Patients with Anal Carcinoma/Allal et al. of acute toxicities appeared to be similar to those observed in younger patients, in our experience toxicity often seemed subjectively higher in elderly patients. 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