RU2360712C1 - Therapy of locally advanced nonresectable rectal cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in 1^st, 9^th, 17^th and 24^th days of therapy, 5-fluorouracil 750 mg and cisplatin 30 mg incubated with autoblood are introduced intravenously. In 7^th, 15^th and 23^rd days, cisplatin 10 mg incubated with autoplasma, Novocaine 0.5% 20 ml, hydrocortisone 1.0 ml, analginum 50% 2.0 ml, vitamin B12 1.0 ml and gentamycin 1.6 g are introduced into presacral of small pelvis. From 10^th to 14^th days, 2 hours prior to radiotherapy session, a mixture containing Doxorubicin-Ebewe 5 mg, Viferon ointment 2.5 mg, Vinilin 2 ml, Synthomycin emulsion 2 ml and Dimexide 5% 4 ml is supplied to primary-site tumour through a perforated rubber tube. From 18^th to 22^th days, a mixture containing Mitomycin C 2.5 mg, Viferon ointment 2.5 mg, Vinilin 2 ml, Synthomycin emulsion 2 ml and Dimexide 5% 4 ml is supplied to primary-site tumour through a perforated rubber tube. After an 14-day recess, the therapeutical actions are repeated once again as specified.

EFFECT: involution of tumour, reduced radiation exposure and toxic by-effects of antitumour therapy.

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Description

The invention relates to medicine, namely to Oncology, and can be used to treat patients with locally advanced unresectable processes of colorectal cancer.

A known method of treating locally advanced colorectal cancer using intravenous administration of 5-fluorouracil at a dose of 225 mg per 1 m ² body weight daily in the course of radiation treatment carried out in accelerated fractionation mode (Vorobyev G.I., Odaryuk T.S., Kostromina K.N. et al. / Preoperative radiation therapy using 5-fluorouracil as a radio modifier in the treatment of locally advanced colorectal cancer (3-year results) // Russian Oncological Journal No. 1, 2001, pp. 4-9). 1 hour after the introduction of the indicated dose of 5-fluorouracil, the patient received a dose of 1 Gy of ionizing radiation. After 4 hours, a repeated irradiation session at a dose of 1.5 Gy. By the end of the course of treatment, the total focal dose was 46-50 Gy, and the total dose of chemotherapy was 5-7 Gy.

However, general, hematological and local radiation reactions were observed in 71.4% of patients, which in 63% of patients required a break in radiation for 10-14 days and corrective therapy.

A known method of treating radiation injuries of the colon after irradiation of the pelvic organs, involving the introduction of a mixture of drugs into the rectum against the background of laser therapy (Mazurov S.T., Poddubny B.K., Karaman S.N., Gladilina I.A. / Diagnosis and possibilities of endoscopic treatment of radiation injuries of the colon. // Medical Radiology and Radiation Safety, 2002, Volume 47, No. 2. P.68-72).

Patients are recommended warm cleansing enemas with chamomile broth, microclysters in the morning and evening of 50-75 ml of a 5% solution of Dimexidum in combination with 30 mg of prednisolone, microclysters with sea buckthorn, rosehip, karatolin oil (can be mixed with 10% methyluracil ointment. Authors, noting a good (on average, at the level of 50% of cases), the effect of this approach for the treatment of radiation injuries of the intestine does not have the experience of using the proposed package of measures for chemoradiotherapy of locally advanced rectal cancer.

There is a method of treating colorectal cancer metastases in the liver by autohemochemotherapy - AHCT (Musinov D.R., Abdrakhmanov R.Z. / Use of autoerythrocytes for targeted delivery of chemotherapy drugs in the treatment of colorectal cancer metastases in the liver // Sat. "New Technologies in Oncology Practice". Mat. Ross. Scientific and practical conference with international participation., Barnaul, 7-8.06.05. S.95-96). In order to implement the ideas of creating systems for delivering chemotherapy drugs to the tumor lesion focus and improving the quality of treatment, the technique of incorporating cytostatics into red blood cells by hypoosmotic dialysis was used. Autohemochemotherapy using pharmacocins for the delivery of campto preparations 320 mg / m ² + 5-fluorouracil 500 mg / m ² with the preliminary administration of 30 mg / m ² leucovorin on autologous blood was used as a component of treatment with colorectal cancer metastases in the liver. The authors point to the effectiveness of the method with a marked reduction in the toxicity of chemotherapy compared with the generally accepted intravenous administration of these cytostatics.

However, the authors do not have experience using AHCT in the chemoradiotherapy of primary locally advanced colorectal cancer.

There is a method of treating locally advanced colorectal cancer, we have chosen as a prototype, including 2 options for chemoradiotherapy of locally advanced colorectal cancer (Chissov V.I., Daryalova S.L., Boyko A.V. et al / Non-traditional approaches to the treatment of patients with locally advanced rectal cancer. "Russian Journal of Oncology, No. 2, 2000, pp. 10-12).

The first - with intravenous administration of 5-fluorouracil in a single dose of 350 mg / m ² for 5 days and the implementation of remote radiation therapy according to the dynamic fractionation scheme after a 2-day break. In the first 3 days, radiation therapy in a single dose of 4 Gy was carried out after intravenous administration of 30 mg of platinum. Further, the continuation of radiation therapy by the method of superfractionation at 1 Gy × 2 times a day with an interval of 5 hours to a total focal dose of 30 Gy, equivalent to 36 Gy with classical fractionation. Partial tumor regression (from 50 to 75%) in 80% of patients against the background of general toxic reactions. The overall survival of patients from 6 months to 3 years is 75%, progression of 1 year in 25% of patients.

The second option is carried out against the background of radiation treatment in a similar regime of dynamic fractionation, with paratumoral administration of 5-fluorouracil as a synchronizer, methotrexate as a cytostatic agent and metrogil as a radiosensitizer of the hypoxic fraction of the tumor. Partial tumor regression - (50-75%) in all patients. Surgical treatment was performed in 50% of patients. Overall survival from 6 months to 3 years was 53.8%.

The effectiveness of the treatment is manifested after the surgical benefit following paratumoral chemotherapy in the form of early relapse, and progression of 1 year after treatment was recorded in 30.7% of people, i.e. in every third patient.

The aim of the present invention is to improve the immediate and long-term results of treatment of patients with locally advanced rectal cancer, inoperable due to concomitant general somatic pathology and / or refused surgical treatment.

This goal was achieved by the fact that, against the background of traditional remote gamma-therapy, on 1, 9, 17 and 24 days they conduct AHCT with 5-fluorouracil and cisplatin. On days 7, 15 and 23, paratumoral administration of small doses of methotrexate and cisplatin incubated with autoplasma into the presacral spaces of the pelvis (left and right) is performed. From 10 to 14 days of treatment, 2 hours before the radiation therapy session, the patient receives microclysters containing viferon, vinylin, synthomycin emulsion, doxorubicin-ebewe and 5% dimexide solution on a perforated rubber tube brought to the tumor site. From 18 to 22 days in the specified composition of microclysters, doxorubicin is replaced by mitomycin C. A break in treatment for 14 days, after which the whole complex of drug measures is repeated 1 more time in the indicated sequence.

The invention, “A method for the treatment of locally advanced inoperable rectal cancer,” is new, as it is unknown from the level of medicine in the field of oncology in the combined treatment of locally advanced rectal cancer with chemotherapy in combination with radiation treatment.

Analysis of known methods of locally advanced colorectal cancer and the developed one allows us to state that the proposed method has novelty. The novelty of the method lies in the combination of radiation treatment, enhanced by systemic and local effects of cytostatics with a different mechanism of radiosensitizing action and points of application of the antitumor effect depending on the phase of the tumor cell cycle.

Theoretical and experimental prerequisites allow us to attribute 5-fluorouracil to the synchronizing agents. Under the influence of this preparation, cells located in different phases of the cycle are inhibited before entering S phase and presumably enter into it together and together reach the mitosis phase, which is the most sensitive to radiation. In addition, it is known that tumor cells in the DNA synthesis phase that are resistant to radiation exhibit sensitivity to 5-fluorouracil. Therefore, with the combined use of it and irradiation, one can expect to increase the damage to the tumor.

Cisplatin preparations have a diverse effect. They not only have a direct cytotoxic effect, but also inhibit the repair of sublethal and potentially fatal post-radiation injuries, increasing the degree of tumor resorption, and this requires doses significantly lower than therapeutic ones.

With paratumoral (presacral) administration, small doses of cisplatin and methotrexate, incubated on autoplasma, are deposited in the pelvic tissue for a long time, provide an antitumor and radiosensitizing effect on tumor cells that have settled in the lymph nodes, and activate T and B cellular units of the immune system local immunity (Fatkina NB, 2007 “Paratumoral autoplasmochemotherapy in combination with radiation treatment of locally advanced cervical cancer” // Abstract of thesis ... Candidate of Medical Science. op. Rostov-on-Don, 2007, 24 p.)

Doxorubicin-ebewe is an antitumor antibiotic of the anthracycline series. It interacts with DNA, forms free radicals, and also acts directly on the cell membrane with suppression of nucleic acid synthesis. Cells are sensitive to the drug in phase S and G ₂ . (Translatorova N.I., 2005. “A Guide to the Chemotherapy of Tumor Diseases” / 2nd edition., Supplemented by N.I. Translatorova // M .: Practical Medicine, 2005. 704 p.)

Mitomycin C is an antitumor antibiotic. It inhibits DNA synthesis, is most active in phases G and S of mitosis. After enzymatic activation in tissues, it acts as a bi- or trifunctional alkylating agent.

The composition of medicinal agents, locally brought to the tumor of the rectum, includes drugs that have anti-inflammatory, antimicrobial, antifungal and generating properties.

No available information sources in Russia, the CIS countries and abroad indicate a similar method for improving the results of treatment of locally advanced rectal cancer, inoperable due to concomitant general somatic pathology and / or who refused surgical treatment.

The invention is industrially applicable, as it can be repeatedly reproduced and repeated in healthcare in medical institutions with a specialized profile.

The method is as follows. On the first day of treatment, 100 ml of blood is taken from the patient's ulnar vein in 2 sterile vials containing the anticoagulant glugitsir. 750 mg of 5-fluorouracil is added to one bottle, and 30 mg of cisplatin to the second. Vials with 5-fluorouracil and cisplatin are incubated for 30 minutes at 37 ° C and the contents of each vial are reinfused intravenously, drip. This stage is designated as autohemochemotherapy (AHCT). From the 2nd to 5th day, remote gamotherapy (DHT) is performed on the primary lesion (rectum) and regional metastasis zones with a single focal dose (ROD) of 2 Gy daily to a total focal dose (SOD) 10 Gr. On day 7, free of DHT, paratumoral autoplasmopolychemotherapy (PAPCT) is performed. 10 mg of cisplatin and 10 mg of methotrexate are introduced into the right and left presacral spaces of the small pelvis, previously incubated separately for 30 minutes at 37 ° C in 5 ml of patient’s autoplasm. At the same time, 20 ml of a 0.5% solution of novocaine, 1 ml of a suspension of hydrocortisone, 2 ml of a 50% analginum, 1 ml of a 0.01% solution of vitamin B ₁₂ , 1.6 g of gentamicin are administered in half doses. The eighth day - free from therapeutic effects. On day 9, AGHT No. 2 is carried out by a similar AGHT No. 1 composition of cytostatics.

From the 10th to the 14th day, DHT ROD = 2 Gy continues to SOD = 20 Gy.

At the same time, 2 hours before each irradiation session, therapeutic microclysters (LMCs) are introduced into the rectum. Directly to the tumor on a rubber, perforated on one side or circularly (depending on the nature of the tumor lesion), a drug mixture is fed with holes with a diameter of 1 mm: 2.5 mg of viferon, 2 ml of vinylin, 2 ml of synthomycin emulsion, 4-5 ml of 5% solution dimexide and 5 mg doxorubicin-ebewe. Before the introduction of the drug mixture, the rectal mucosa is cleaned with a warm cleansing microclyster containing 50 ml of chamomile broth with 10 mg of chemotrypsin dissolved in it.

On day 15, PAPCT No. 2 is carried out with a similar composition of cytostatics.

16 days free from treatment.

On day 17, a similar AGHT No. 3 is carried out.

From the 18th to the 22nd days, DHT is carried out to SOD = 30 Gy. At the same time, 2 hours before each irradiation session, LMC is carried out with a similar composition of concomitant drugs, but containing 25 mg of mitomycin C.

On day 23, PAPCT No. 3 is carried out with a similar composition.

On day 24, AGHT No. 4 is performed and a general break in treatment is made for 2 weeks. From the 39th day, the entire complex of medical benefits is repeated in the indicated sequence.

At SOD = 60 Gy, treatment is completed. The total total dose of cytostatics per treatment course is: 5-fluorouracil - 6000 mg, cisplatin - 240 mg, doxorubicin - 50 mg, mitomycin 20 mg.

The proposed method was used for the treatment of 49 patients with morphologically verified colorectal cancer T ₃ N _1-2 M ₀ , of which 37 patients were inoperable for somatic pathology, the rest rejected crippling surgery. At the stages of treatment, objectification of the regression effect was controlled similarly using finger examination, sonographic (general and local) and computed tomography examinations with an assessment of the condition of the primary lesion, lymphatic system and pelvic organs, as well as morphological analyzes.

The effectiveness of the proposed method of treatment was 87.7%, of which in 67.3% of cases there was a complete controlled regression of the primary tumor and metastases in the lymph nodes, partial regression (50-75%) was registered in 14.3%, tumor regression was less than 50% , but more than 25% - in 6.1%. Stabilization - at 12.3%. No disease progression was detected in any case. Three-year survival of patients was 67.6%.

To prove the effectiveness of the proposed method, we give an example of clinical application.

1. Patient P., born in 1930, medical history No. 12810 / t.

Complaints of constipation, pain during bowel movements, impurities of blood and mucus in the feces. Considers himself ill for 6-7 months.

07/05/04, Local status with digital examination: the lumen of the intestine is narrowed, the study is extremely painful. On the back wall of the rectum 5 cm from the anus, a dense tuberous mass is determined with dimensions of 6 × 8 × 4 cm. The mucous membrane of the intestine is swollen, infiltrated, dense, not dislocated. Blood on the test finger and a blood clot from the anus after examination.

07/06/04. Local status during sigmoidoscopy: a rectoscope was hardly inserted into the intestinal lumen. In the lower ampullar section, the exophytic component of the tumor formation, which performs 1/2 department, is determined along the back wall of the intestine. The surface is purplish-cyanotic color, tuberous, patches of necrosis, bleeds easily. Infiltration of underlying tissues extends to the mid-ampullar region. Conclusion: cancer of the lower ampulla of the rectum.

Histological examination No. 752900 of July 8, 2004 — moderately differentiated adenocarcinoma.

07/05/04, Ultrasound - Hyperplasia of the iliac lymph nodes. Moderate hepatosplenomegaly. Diffuse changes in the liver. Chronic cholecystopancreatitis.

07/06/04, FLO OGK No. 46 - Lungs and heart - age-related changes. Therapist consultation: IHD. Atherosclerosis. Coronarocardiosclerosis.

Clinical diagnosis: cancer of the lower ampulla of the rectum T ₃ N _X M ₀ . Cl. column 2.

The proposed surgical treatment is rejected.

General blood test from 07/06/04

HB - 126 g / l; Erie - 4.3 × 10 ¹² / L; CPU - 0.88;

Lx 11.8 × 10 ⁹ / L; P-10; S-59; E-2; B-0; Lf-17; Mon-11; ESR-20 mm / hour.

On July 12, 2004, AGHT No. 1 was held. 750 mg of 5-fluorouracil and 30 mg of cisplatin were administered intravenously after separate incubation of the preparations at 37 ° C for 30 minutes with 100 ml of autologous blood.

From July 13, 2004 to July 17, 04, DHT was performed on AGAT-R, in a static mode on the area of the primary lesion and the path of lymph outflow, from 2 diametrical, diamond-shaped fields 16 × 16 cm, RIP = 75 cm, ROD = 2 gr. SOD = 10 Gy.

04/18/04, held PAPHT number 1. 10 mg of cisplatin and 10 mg of methotrexate were introduced into the right and left sacral spaces of the pelvis, separately incubated in 5 ml of autoplasma at 37 ° C for 30 minutes. Additionally, 20 ml of a 0.5% solution of novocaine, 1 ml of a suspension of hydrocortisone, 2 ml of a 50% analgin, 1 ml of a 0.01% solution of vitamin B ₁₂ , 1.6 g of gentamicin were added to each side.

General blood test from 07/19/04

HB - 126 g / l; Erie - 4.3 × 10 ¹² / L; CPU - 0.88;

Lux 9.6 × 10 ⁹ / l; P-8; S-69; E-1; B-0; Lf-19; Mon-3; ESR-10 mm / hour.

07/20/04, AGHT No. 2 was carried out: the composition of cytostatics is similar to AGHT No. 1.

From July 21, 2004 to July 25, 2004, DHT was performed. 2 hours before each irradiation session, a mixture containing 2.5 mg of viferon, 2 ml of vinylin, 2 ml of synthomycin emulsion, 4 ml of 5% solution of dimexide and 5 mg of doxorubicin - was brought to the tumor located on the posterior wall of the rectum; ebee.

07/26/04, held PAPHT No. 2, similar in composition to PAHT No. 1.

General blood test dated July 27, 04

HB - 124 g / l; Erie - 4.2 × 10 ¹² / l; CPU - 0.8;

Lx 7.6 × 10 ⁹ / l; P-7; S-70; E-1; B-0; Lf-19; Mon-3; ESR-15 mm / hour.

07/28/04, held AGHT number 3, similar in composition AGHT number 1.

From 29.07.04 to 02.08.04, DHT was continued, before each session, a drug mixture containing 2.5 mg of viferon, 2 ml of vinylin, 2 ml of synthomycin emulsion, 4 ml was supplied to the tumor on the posterior wall of the rectum on a perforated tube 5% solution of dimexide and 2.5 mg of mitomycin-C.

General blood test 02.08.04,

HB - 127 g / l; Erie - 4.3 × 10 ¹² / L; CPU - 0.89;

Lx 9.1 × 10 ⁹ / l; P-10; S-74; E-2; B-0; Lf-11; Mon-3; ESR-8 mm / hour.

08/03/04, held PAPHT number 3, similar in composition PAPHT number 1.

08/04/04 was held AGHT number 4, similar in composition AGHT number 1.

08/05/07, Local status with digital examination: the intestinal lumen is freely passable. On the posterior wall of the rectum at a distance of 7 cm from the anus, a compaction site of 2 × 2 × 1 cm in size is determined with a relatively movable mucosa that is quite easy to fold.

From 08/05/04 to 08/18/04, a complete break in treatment with recommendations for the use of rectally methyluracil suppositories and general strengthening treatment.

In total, for the first stage of treatment, SOD = 30 Gy was summed up to the zone of the primary focus and the path of regional metastasis. Parenteral (intravenous) administration of 3000 mg of 5-fluorouracil and 90 mg of cisplatin. Locally, 30 mg of cisplatin, 30 mg of methotrexate, 25 mg of doxorubicin-ebewe and 10 mg of mitomycin-C are summed up to the tumor site

08/19/04 Local status during sigmoidoscopy: a rectoscope was freely inserted and the intestinal lumen was examined up to 20 cm. In the lower ampullar section 6 cm from the anus there is a section of a hyperemic velvety mucosa of the intestine with an eroded surface of up to 1 cm. In the remaining sections, the rectal mucosa is features.

Conclusion: erosion of the posterior wall of the lower ampullar part of the rectum.

Cytological study No. 55472 of 08/19/04 - blood, cells of chronic inflammation. Atypical cells were not detected.

08/20/04, Ultrasound - Moderate hepatosplenomegaly. Diffuse changes in the liver. Chronic cholecystopancreatitis. Lymph nodes are not visualized.

Clinical regression is regarded as complete.

The proposed surgical treatment is rejected.

Chemotherapy continued according to the planned program.

AHT was performed on 08/22/04, 08/30/04, 09/07/04, and 09/14/04: 750 mg of 5-fluorouracil and 30 mg of cisplatin were administered intravenously after separate incubation of the preparations at 37 ° C for 30 minutes with 100 ml of autologous blood.

08/28/04, 09/09/04, 09/13/04 PAPHT was performed 10 mg of cisplatin, incubated in 5 ml of autoplasma at 37 ° C for 30 minutes, and 10 mg of methotrexate separately were introduced into the right and left sacral spaces of the pelvis. Additionally, 20 ml of a 0.5% solution of novocaine, 1 ml of a suspension of hydrocortisone, 2 ml of a 50% analgin, 1 ml of a 0.01% solution of vitamin B ₁₂ , 1.6 g of gentamicin were added to each side.

DHT was carried out independently from 08/23/04 to 08/27/04. On August 31, 04 to 04/09/04, using 2 hours before each irradiation session to the tumor bed located on the posterior rectal wall, a perforated tube of a mixture containing 2.5 mg of viferon, 2 ml of vinylin, 2 ml of synthomycin emulsion, 4 ml of a 5% solution of dimexide and 5 mg of doxorubicin-ebewe. And in the period from 09/08/04 to 09/12/04. using summing up 2 hours before each irradiation session to the tumor bed located on the posterior wall of the rectum, on a perforated tube of a mixture containing 2.5 mg of viferon, 2 ml of vinylin, 2 ml of synthomycin emulsion, 4 ml of 5% solution of dimexide and 2 mg mitomycin-C.

General blood test 09/13/04

HB - 120 g / l; Erie - 4.0 × 10 ¹² / L; CPU - 0.8;

Lx 4.8 × 10 ⁹ / l; P-18; S-51; E-0; B-0; Lf-23; Mon-6; ESR-35 mm / hour.

September 13, 2004, chemoradiation treatment was discontinued. In just 2 stages of treatment, 60 Gy were delivered to the tumor site and the zone of regional metastasis.

6000 mg of 5-fluorouracil and 180 mg of cisplatin were systemically (intravenously) administered. Locally, 60 mg of cisplatin, 60 mg of methotrexate, 50 mg of doxorubicin, 20 mg of mitomycin-C.

1 month after discharge, 10/18/04 no complaints. The bowel movement is not violated. When sigmoidoscopy from 10/18/04, atrophic mucosa on the posterior wall of the rectum. The rest of the rectal mucosa without pathology. Wedge. The diagnosis of cancer of the lower ampulla of the rectum T ₃ N _X M ₀ . Cl. column 3. Condition after chemoradiation treatment.

The patient is observed in RNII. An examination of 08/28/07 showed no signs of relapse and metastases.

The improvement in the treatment of locally advanced colorectal cancer seems to us to be a combination of various positive factors. Chemotherapy drugs administered intravenously on autologous blood (AHCT), which prevent, including distant metastasis, have a joint damaging effect on a rectal tumor; medicinal agents introduced regionally into the zone of the nearest regional metastasis (PAPCT), and cytostatics locally summed up (LMC) directly to the zone of the primary focus.

In combined polychemotherapy, cytostatics were used, which coincided in antitumor activity, but differ in the mechanism of action at the cellular level. An additional positive effect against the background of objectively reduced indicators of their general toxic effect, anti-inflammatory and analgesic effects is provided by the sensitizing effect of small doses of cisplatin in relation to ionizing radiation, as well as by the activation of small doses of methotrexate cells of the immune system.

The technical and economic efficiency of the "Method for the treatment of locally advanced inoperable rectal cancer" is that:

- A large percentage of tumor regression is achieved;

- reduced radiation exposure and toxic side effects of antitumor therapy;

- the duration increases and the quality of life of patients improves.

Claims (1)

A method of treating locally advanced inoperable colorectal cancer, comprising administering chemotherapy and external radiation, characterized in that 750 mg of 5-fluorouracil and 30 mg of cisplatin incubated with autoblood are intravenously administered on days 1, 9, 17 and 24 of the treatment; at 7, 15 and 23 days, 10 mg of cisplatin incubated with autoplasma, 10 mg of methotrexate incubated with autoplasma, 20 ml of 0.5% novocaine, 1.0 ml of hydrocortisone are introduced into presacral spaces of the pelvis, 2, 0 ml of 50% analgin, 1.0 ml of vitamin B ₁₂ , 1.6 g of gentamicin; from 10 to 14 days 2 hours before the radiation treatment session on a perforated rubber tube, a mixture containing 5 mg of doxorubicin-ebewe, 2.5 mg of viferon ointment, 2 ml of vinilin, 2 ml of synthomycin emulsion and 4 ml of 5 is applied locally to the tumor of the primary lesion % solution of dimexide; from 18 to 22 days on a perforated rubber tube, a mixture containing 2.5 mg of mitomycin C, 2.5 mg of viferon ointment, 2 ml of vinylin, 2 ml of syntomycin emulsion and 4 ml of 5% dimexide solution is applied locally to the tumor of the primary lesion; after a 14-day break, the therapeutic effects are repeated in the indicated sequence one more time.