Chemotherapy in the treatment of anal canal carcinoma

Squamous cell carcinomas of the anal canal are generally diagnosed at a localized or locally advanced stage and only 5% are metastatic at the time of diagnosis. Advanced forms are therefore much rarer than localized forms and usually correspond to metachronous metastases of initially localized disease. Systemic chemotherapy is indicated for the treatment of both localized disease, in combination with radiotherapy, and metastatic disease. The purpose of this article is to define the current indications and modalities of chemotherapy in the treatment of these cancers based on a review of the published data and in the light of available guidelines.     

Pseudosarcomatous carcinoma of the anal canal

A polypoid pseudosarcoma of the anal canal in a 45-year-old woman was surgically treated. Morphologic characteristics of the tumor were essentially identical with those in hitherto-described pseudosarcomas of the esophagus, larynx, fauces, or oral cavity. Histologic features of the tumor support the presumption of epithelial origin of the sarcoma-like element on the basis of the presence of a clearly epithelial element in the sarcoma-like areas, justifying the term “pseudosarcomatous carcinoma,” instead of “pseudosarcoma.” This is the first report of this tumor type detected in the anal canal.     

Epidermoid carcinoma of the anal canal

Thirty consecutive patients with epidermoid carcinomas of the anal canal larger than 2 cm were treated with the concomitant application of radiation and two cycles of chemotherapy (5FU and mitomycin-C) between January 1982 and January 1988. Twenty-eight patients were treated with curative intention and two for palliation only. All patients were reexamined after a period of one to 2 months, under light general anesthesia, and any residual tumor or scar tissue was biopsied. Control biopsy was positive in eight patients. Three of six patients who had abdominoperineal excision died from locoregional recurrence; the remaining are alive and cancer free after 1 to 4 years. Two patients had local excision; one is alive and the other died of other cancer metastasis four years later. Seventeen patients who had negative biopsies are alive and free of disease after 1 to 5 years; two died of unrelated causes, two died with distant metastasis (present prior to treatment), and one died with locoregional recurrence. Locoregional failures occurred in four patients (13.3 percent) in the entire series. Individualization of each patient, adjustment of doses, and carefully executed radiation and chemotherapy are the most important points for the success of treatment. Read at the meeting of the American Society of Colon and Rectal Surgeons, Anaheim, California, June 12 to 17, 1988.     

Combined therapy for cancer of the anal canal

Nineteen patients with squamous-cell cancer of the anal canal have been treated with combined chemotherapy and radiation therapy, followed by appropriate surgery. The authors are convinced that the combined therapy is effective enough to avoid abdominoperineal resection if disappearance of the lesion is proven by adequate examination and biopsy. Although they believe cancers 5 cm or less in maximum diameter are generally adequately managed in this manner, experience is still too limited to justify, a recommendation, to change currently accepted management. Read at the meeting of the American Society of Colon and Rectal Surgeons, Hollywood, Florida, May 11 to 16, 1980. This paper received the New York Society of Colon and Rectal Surgeons Award.     

HIV-positive patients with anal carcinoma have poorer treatment tolerance and outcome than HIV-negative patients

PURPOSE: Anal carcinoma is being found in HIV-positive patients with increasing frequency. Most patients are treated with combined chemotherapy and radiation. It was our impression that HIV-positive patients do not fare as well as HIV-negative patients in terms of both response to and tolerance of therapy. METHODS: To test this hypothesis, we reviewed our experience with anal carcinoma and compared HIV-positive to HIV-negative patients by age, gender, sexual orientation, stage at diagnosis, treatment rendered, response to treatment, tolerance, and survival. From 1985 to 1998, 98 patients with anal neoplasms were treated. Seventy-three patients had invasive squamous-cell carcinoma (including cloacogenic carcinoma), and this cohort was analyzed. Thirteen patients were HIV positive and 60 were HIV negative. RESULTS: The HIV-positive and HIV-negative groups differed significantly by age (42vs. 62 years,P<0.001), male gender (92vs. 42 percent,P<0.001), and homosexuality (46vs. 15 percent,P<0.05). There were no differences by stage at diagnosis or radiation dose received. Acute treatment major toxicity differed significantly (HIV positive 80 percentvs. HIV negative 30 percent;P<0.005). Only 62 percent of HIV-positive patients were rendered disease free after initial therapyvs. 85 percent of HIV-negative patients (P=0.11). Median time to cancer-related death was 1.4vs. 5.3 years (P<0.05). A survival model did not show age, gender, stage, or treatment to be independent predictors. CONCLUSION: We found that HIV-positive patients with anal carcinoma seem to be a different population from HIV-negative patients by age, gender, and sexual orientation. They have a poorer tolerance for combined therapy and a shorter time to cancer-related death. A strong trend to poorer initial response rate was also seen. These results suggest that the treatment of HIV-positive patients with anal carcinoma needs to be reassessed.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 25 to 29, 2000.     

Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy

PURPOSE: Before the development of highly active antiretroviral therapy for the treatment of HIV infection, HIV patients diagnosed with invasive squamous-cell carcinoma of the anal canal carried a very poor prognosis. This study was designed to determine the outcome in a similar group of patients in the era of highly active antiretroviral therapy.METHODS: HIV-positive patients treated for invasive squamous-cell carcinoma of the anal canal at the University of Texas Medical Center affiliated hospitals from 1980 to 2001 were identified from operative data and cancer registries. We reviewed these records and collected data regarding age, CD4 count, highly active antiretroviral therapy, cancer treatment, complications, and survival. The patients were divided into two groups based on the presence or absence of highly active antiretroviral therapy and compared using a Kaplan-Meier approach.RESULTS: Fourteen patients with HIV and invasive squamous-cell carcinoma of the anal canal were identified. Six were in the prehighly active antiretroviral therapy group and eight in the highly active antiretroviral therapy group. All were considered for treatment with chemotherapy and radiation. In the prehighly active antiretroviral therapy group, one patient refused therapy and three were unable to complete the squamous-cell carcinoma therapy as planned because of complications. Four of eight highly active antiretroviral therapy patients were unable to complete the squamous-cell carcinoma therapy as planned. The prehighly active antiretroviral therapy patients had a mean age of 40 years and a mean CD4 count of 190 at the time of diagnosis. The highly active antiretroviral therapy patients had a mean age of 44 years and a mean CD4 count of 255 at the time of diagnosis. The 24-month survival was 17 percent in the prehighly active antiretroviral therapy group and 67 percent in the highly active antiretroviral therapy group (P = 0.0524). All six patients in the prehighly active antiretroviral therapy group died with active squamous-cell carcinoma vs. two in the highly active antiretroviral therapy group. Four of the remaining six patients had no evidence of active squamous-cell carcinoma at the last follow-up visit.CONCLUSIONS: A review of patients with HIV and invasive squamous-cell carcinoma of the anal canal suggests a trend toward a higher CD4 count at the time of diagnosis and improved survival in patients receiving highly active antiretroviral therapy. In this new era, HIV-positive patients should be on highly active antiretroviral therapy. If not, highly active antiretroviral therapy should be initiated, and standard multimodality therapies for invasive squamous-cell carcinoma of the anal canal are recommended.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Epidermoid carcinoma of the anal canal

During the past ten years, substantial progress has been made in the knowledge of the natural history of epidermoid carcinoma of the anal canal and of the response of the disease to radiotherapy alone or combined with chemotherapy. At the present time, the main problem in the management of this tumor concerns identification of the best modalities to achieve local control and preservation of anal function. From a series of 276 cases, followed for more than three years, the necessity for a careful pretreatment evaluation was stressed. This included a systematic search for pelvic metastatic lymph nodes by palpation and CT scan. All patients were treated initially by irradiation except those who underwent groin dissection for inguinal node metastasis or colostomy for complete anal obstruction. Three groups of patients have been identified: 1) unresectable or disseminated tumors (33 cases), 2) resectable tumors but not suitable for sphincter conservation (21 cases) treated by radiochemotherapy and delayed surgery, and 3) resectable tumors suitable for sphincter conservation (222 cases) which were treated by a split-course regimen combining a short course of carefully planned external beam irradiation (19 days) followed by an iridium 192 implant after a two-month rest. In this group, which represents 80 percent of the whole series, 80 percent of patients have had their cancer controlled and 90 percent of controlled patients have retained normal anal function. The use of chemotherapy during the first days of irradiation is advisable in all cases to reinforce the efficacy of treatment and increase the chance of anal preservation. Results of the split-course regimen, combining external beam and interstitial irradiation, demonstrate a clear superiority over external beam irradiation alone, especially for large infiltrating tumors, which represent the majority of cases.     

Loss of heterozygosity and HIV infection in patients with anal squamous-cell carcinoma

PURPOSE: This study was designed to determine whether loss of heterozygosity and/or microsatellite instability correlate with HIV infection and tumor recurrence after chemoradiation therapy in patients with squamous-cell carcinoma of the anus. BACKGROUND: The molecular mechanisms leading to the progression of HIV-related squamous-cell carcinoma of the anus are poorly understood. In particular, genetic alterations responsible for resistance to chemoradiation have important clinical and functional implications. METHODS: In a case-control study, we analyzed normal and tumor DNA samples of four patients with squamous-cell carcinoma of the anus who were successfully treated with chemoradiotherapy and four patients with radio-resistant squamous-cell carcinoma of the anus who required abdominoperineal resection for local recurrence. To determine the presence of microsatellite instability, we used the reference panel of five pairs of microsatellite primers recommended for colorectal cancer specimens. These include the microsatellite markers BAT25, BAT26, D5S346 (APC), D2S123 (hMSH2), and D17S250 (P53). In addition, we used microsatellite markers for loss of heterozygosity analyses that were tightly linked to tumor suppressor genes. These included D3S1611 (hMLH1), D17S513 (P53), D18S46 and 18qTA (DCC/SMAD4), D5S107 (APC), and CA5 (hMSH2). RESULTS: There were two HIV-positive and two HIV-negative patients in each group. Three HIV-positive patients (one in the chemoradiotherapy group and two in the nonchemoradiotherapy group) demonstrated loss of heterozygosity. In the chemoradiotherapy group, one HIV-positive patient demonstrated loss of heterozygosity at the hMLH1 locus. In the nonchemoradiotherapy group, two HIV-positive patients exhibited a total of four instances of loss of heterozygosity. One tumor had loss of heterozygosity at hMSH2 and DCC/SMAD4; another tumor demonstrated loss of heterozygosity at hMSH2 and APC. Microsatellite instability-low was found in two HIV-positive patients. No instances of loss of heterozygosity and microsatellite instability were detected in HIV-negative patients. CONCLUSION: Loss of heterozygosity and microsatellite instability, which reflect inactivation of tumor-suppressor genes and genomic instability, occur with increased frequency in HIV-associated squamous-cell carcinoma. These data demonstrate for the first time evidence of loss of heterozygosity at the APC and DCC/SMAD4 gene loci in anal carcinoma. Although the findings presented here need to be expanded in a larger study, the recurrent loss of heterozygosity at D2S123, which was demonstrated in HIV-positive patients with radio-resistant squamous-cell carcinoma of the anus, is notable.Supported by a grant from the SICPA foundation and an educational grant from the Eleanor Naylor Dana Charitable Trust Fund.     

Infiltrating adenocarcinoma arising in a villous adenoma of the anal canal

Primary neoplasms arising in the anal canal are relatively unusual. In particular, adenomas and adenocarcinomas are distinctly rare entities in this region. We describe an infiltrating, well-differentiated adenocarcinoma arising in a villous adenoma from the distal anal canal, in an otherwise healthy patient at low risk for gastrointestinal malignancy. This is the case of an octogenarian man with a several year history of hemorrhoids and intermittent rectal bleeding, more recently complaining of continuous hematochezia. Examination revealed a blood-covered pedunculated mass with a long stalk protruding from the anus. The lesion was amputated at the bedside. Microscopic evaluation revealed an infiltrating well-differentiated adenocarcinoma, arising from a villous adenoma. This was further evaluated under anesthesia and complete excision of distal anal tissue was performed. Our report is the first describing the possible malignant degeneration of a villous adenoma in the anal canal.     

Definitive combined modality therapy of carcinoma of the anus

Thirty patients with epidermoid carcinoma of the anus, ranging in age from 40 to 89 years, were treated with combined chemotherapy (CT) and radiation therapy (RT) in lieu of abdominoperineal resection. Two courses of 5-FU (1000 mg/m²/day×four days) by continuous infusion and mitomycin-C (10–15 mg/m² IV bolus on day 1 of each course) were given 3 to 4 weeks apart simultaneously, with whole pelvis RT to 4140 to 4500 cGy. Twenty-one of 28 patients had T₃-T₄ primaries and ten had positive nodes (N1). Two of the 30 patients were treated for local recurrence following surgical excision and one was treated immediately after local excision. Twenty-six of the 30 patients attained biopsy-confirmed complete remission. Four of the 30 patients demonstrated residual disease at completion of therapy but all subsequently achieved complete remission with additional nonsurgical treatment. One patient, initially treated for local recurrence following excision failed locally at four years and was salvaged with chemotherapy followed by abdominoperineal resection. No patient has experienced distant failure. Twenty-seven of 30 patients were alive and disease free after 9 to 76 months of follow-up and three died, disease-free, of unrelated causes. Acute toxicities were mild and did not necessitate interruption of treatment. A brisk perineal reaction and diarrhea were noted in all patients. Late complications were unusual. All patients were treated in a community-based, private practice setting. The authors conclude that combined CT-RT, as employed herein, represents a first-line curative treatment for the majority of patients with epidermoid anal carcinoma. For patients who demonstrate residual disease following this therapy, salvage regimens such as 5-FU infusion and cisplatin, or sequential MTX-5-FU-Leucovorin with additional synchronous RT should be employed before resorting to radical surgery.     

Results of age-dependent anal canal cancer treatment: A single centre retrospective study

BackgroundInformation concerning management of anal canal cancer among the elderly is scarce and much less abundant than for younger subjects.Population and methodsWe retrospectively analysed 115 patients treated for anal epidermoid cancer between 2000 and 2010. The population was divided according to age (<70 years and ≥70 years).ResultsOf the 115 patients, 81 (70.4%) were <70 years old and 34 were ≥70 years (29.6%). Tumour characteristics were identical between the two groups and median follow-up was 62 months. Elderly patients had a less favourable performance status (p = 0.001) and fewer had received radiochemotherapy (61.8% vs 82.5%, p = 0.004). Treatment-related grade 3 and 4 hematologic toxicity was observed more often among elderly subjects. The results at 5 years were less favourable for overall, disease-specific, and disease-free survival (respectively p = 0.002, p = 0.001, and p = 0.001). For patients treated with a curative intent, at 5 years there was no difference between the two groups in terms of overall survival (p = 0.2). However, there was a statistically significant difference in favour of the younger group for disease-free survival and metastasis-free survival.ConclusionIf radiochemotherapy can be delivered to elderly subjects with a good general status, the effects appear less favourable than in younger patients.     

Prognostic factors of squamous cell carcinoma of the anal margin treated by radiotherapy: the Lyon experience

Background To report our patient experience with squamous cell carcinoma of the anal margin and to evaluate the prognostic factors influencing outcome. Materials and methods Between 1980 and 2001, 26 patients with anal margin squamous cell carcinoma were treated in Lyon-Sud: 7 T1, 14 T2, 4 T3, and 1 T4 with 20 N0, 3 N1, and 3 N2. The anal canal was invaded in five patients. Treatment consisted of definitive external irradiation in 14 patients and adjuvant irradiation (after a local excision) in 12 patients. External irradiation was combined with chemotherapy in seven patients, brachytherapy in four patients, and both brachytherapy and chemotherapy in one patient. Results The local control rate was initially 61.4%, and it was 80.8% after salvage treatment. The 5-year overall and specific survival rates were 71 and 88.3%, respectively. Three factors correlated with specific survival: cell differentiation (P=0.038) and T (P=0.001) and N category (P=0.0005). A salvage abdominoperineal resection was successfully employed in five of seven local recurrences. Four grade 3 and two grade 4 toxicities were observed. Sphincter preservation was possible in 66% of alive patients. Conclusion Our results confirm the dominating place of definitive irradiation and radiochemotherapy in the treatment of anal margin squamous cell carcinoma. The indications for abdominoperineal resection must be limited to local relapse. The prognosis of squamous cell carcinoma is correlated to T and N staging and cell differentiation.     

肛管癌治疗进展

肛管癌的发病在过去几十年明显升高,并且未来也将呈持续升高态势。随着对于肛管癌生物学行为的认识深入,治疗模式发生了根本性的改变。主要的治疗手段已经不再是有创的手术切除,放射治疗同步化疗不仅可以达到根治目的,而且避免了腹会阴联合切除术给患者带来人工肛门的困扰。同步放化疗作为一线治疗,其应用越来越广泛。5氟尿嘧啶＋丝裂霉素在肛管癌的治疗中有明确的作用,可以提高完全缓解率、提高保肛率和无病生存率。当患者在同步放化疗结束后仍有肿瘤残存时,可以尝试挽救性同步放化疗或密切随诊,如果随诊肿瘤进展再行手术挽救。IMRT技术的应用,利于提高肛门区癌的剂量,同时保护小肠、膀胱、皮肤和股骨头等周围器官从而降低治疗副反应,减少治疗中断时间。靶向药物的应用给肛门癌的治疗带来了新的选择,但是有效性和安全性,需要更多研究数据支持。     

An evaluation of combined therapy for squamous cell cancer of the anal canal

Carcinoma of the anal canal develops in the area of the dentate line and is referred to as cloacogenic, transitional, basaloid, epidermoid, and squamous cell cancer. For years, the accepted treatment for these lesions has been abdominoperineal resection. The use of preoperative radiation and chemotherapy was begun by our group in 1972. By 1975, it became apparent that radiation and chemotherapy alone appeared effective enough so that radical operation was not done routinely. An evaluation of the results in 104 patients, 44 of whom were treated by us (the rest of the data was collected by questionnaire), suggests that radiation and chemotherapy alone are at least as effective as radical surgery in most patients with this disease. Read at the joint meeting of the American Society of Colon and Rectal Surgeons with the Section of Colo-Proctology, Royal Society of Medicine, and the Section of Colonic and Rectal Surgery, Royal Australasian College of Surgeons, New Orleans, Louisiana, May 6 to 11, 1984.     

Early closure of fistula using neo-adjuvant intra-arterial chemotherapy in locally advanced anal cancer

BackgroundLocally advanced anal cancer patients, especially with T4 disease and fistula, have a dismal prognosis. Neo-adjuvant intra-arterial chemotherapy before standard chemoradiation has been shown to be promising in this setting.AimsWe are reporting results from a larger patient population.MethodsFrom 2005 to 2015, 25 consecutive patients with locally advanced anal cancer, 18 of them fistulised, received intra-arterial chemotherapy.ResultsTwenty-two of 25 patients (88%) had T4N0-3 disease and 3 (12%) T3N3. An objective tumour response was observed in 24 of 25 patients (96%): 24 partial responses and 1 with stable disease. Fistulas’ complete closure was observed in 15 of 18 patients (83.3%). Following intra-arterial chemotherapy, 23 patients underwent chemoradiation. Twenty-one of 25 patients (84%) had a complete remission 6 months after treatment completion. Amongst 22 patients followed for 3 or more years, 18 of them (81%) are colostomy free at 3 years. Five-year overall survival is 75%. Most frequent grade 3–4 toxicity of IAC was neutropenia (25%).ConclusionsNeo-adjuvant intra-arterial chemotherapy combined to chemoradiation resulted in a high rate of fistulas closure and long-term control of locally advanced anal cancer. This interesting approach in the treatment of fistulised anal cancer, needs a prospective study before being considered a new standard strategy.     

Relationship between anal canal diameter and pressure evaluated simultaneously by endosonography and manometry in normal human subjects

The study investigated the relationship be-tween anal canal size and anal canal pressure measured simultaneously by anal endosonography and an electronic pressure probe. Twelve normal subjects were studied. Anal endosonography was performed using a 7.5-Mhz rotating transducer of 2 – 5 cm focal length covered with a sylastic balloon filled with degassed water (25 ml). During anal endosonography an electronic manometric probe was passed along the side of the probe and positioned in the anal canal. The ultrasonic image was frozen when maximal anal pressure was seen at basal, squeeze, and minimal pressure during straining. An image was also obtained at maximal anal relaxation after rectal distension with a balloon filled with 150 ml air. The results showed that anal canal pressure was significantly and linearly correlated with anal canal diameter (P<0.001). Accepted: 27 June 1997     

Higher radiation dose with a shorter treatment duration improves outcome for locally advanced carcinoma of anal canal

AIM： To assess whether radiation dose and duration of treatment influence local control and survival of patients with locally advanced anal cancer treated with definitive chemoradiation. METHODS： Twenty-eight consecutive patients who were treated with definitive radiation therapy for bulky anal cancers （〉 5 cm in size） were reviewed. Nineteen patients had T3 lesions, 8 patients had T4 lesions, and 15 patients had lymph node involvement. The median tumor size was 7.5 cm. All but one patient received concurrent chemoradiation. The median radiation dose was 54 Gy. The median duration of treatment was 58 d.
RESULTS： With a median follow-up of 2.5 years in all patients and 7.8 years in living patients, the 2-year local recurrence-free probability was 570 and overall survival rate was 67%. Neither radiation dose nor duration of treatment alone was predictive of either time to local failure or overall survival. However, longer treatment breaks can potentially mask an advantage over higher radiation doses. Therefore, we examined those patients who received ≥ 54 Gy within 60 d, comparing them to the rest of the patients. Of patients who received ≥54 Gy within 60 d, local progression-free probability was 890 versus 420 for the rest of the group （P = 0.01）.
CONCLUSION： Local failure is a significant problem in locally advanced carcinomas of-the anal canal. Higher radiation doses with limited treatment breaks may offer an increase in local control and survival.     

Intensified intensity-modulated radiotherapy in anal cancer with prevalent HPV p16 positivity

AIM: To investigate the toxicity and response of intensity-modulated radiotherapy schedule intensified with a simultaneous integrated boost in anal canal cancer.METHODS: From March 2009 to March 2014, we retrospectively analyzed 41 consecutive patients treated with intensity-modulated radiotherapy(IMRT) and concurrent chemotherapy for anal canal squamous cell carcinoma at our center. Radiotherapy was delivered via simultaneous integrated boost(SIB) technique by helical tomotherapy, and doses were adapted to two clinical target volumes according to the tumor-nodemetastasis(TNM) stage: 50.6 Gy and 41.4 Gy in 23 fractions in T1N0, 52.8 Gy and 43.2 Gy in 24 fractionsin T2N0, and 55 Gy and 45 Gy in 25 fractions in all patients with N positive and/or ≥ T3, respectively, to planning target volumes 1 and 2. The most common chemotherapy regimen was 5-fluorouracil and mitomycin-based. Human papilloma virus(HPV) p16 expression was performed by immunohistochemistry and evaluated in the majority of patients. Acute and late toxicity was scored according to CTCAe v 3.0 and RTOG scales.RESULTS: The median follow-up was 30 mo(range:12-71). Median age was 63 years(range 32-84). The stage of disease was: stage Ⅰ in 2 patients, stage Ⅱin 13 patients, stage ⅢA in 12 patients, and stage ⅢB in 14 patients, respectively. Two patients were known to be HIV positive(4.9%). HPV p16 expression status was positive in 29/34(85.3%) patients. The 4-year progression-free survival and overall survival in HPVpositive patients were 78% and 92%, respectively.Acute grade 3 skin and gastrointestinal toxicities were reported in 5% and 7.3% of patients, respectively;patients' compliance to the treatment was good due to a low occurrence of severe acute toxicity, although treatment interruptions due to toxicity were required in 7.3% of patients. At 6 mo from end of treatment,36/40(90%) patients obtained complete response;during follow-up, 5(13.8%) patients presented with disease progression(local or systemic).CONCLUSION: In our experience, intensified SIBIMRT with chemotherapy is very feasible in clinical practice, with excellent results in terms of overall survival and local control.     

Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma

AIM: To investigate the role of perioperative chemoradiotherapy (CRT) in the treatment of locally advanced thoracic esophageal squamous cell carcinoma (ESCC). METHODS: Using preoperative computed tomography (CT)-based staging criteria, 238 patients with ESCC (stage ⅡⅢ ) were enrolled in this prospective study between January 1997 and June 2004. With informed consent, patients were randomized into 3 groups: preoperative CRT (80 cases), postoperative CRT (78 cases) and surgery alone (S) (80 cases). The 1-, 3-...