Comparative dosimetry between iridium wires and seed ribbons.

We have undertaken a computer study that explores the conditions under which seed ribbons may replace iridium 192 wires in the Paris System. Compared with continuous iridium 192 wires, seed ribbons demonstrate greater inhomogeneity and loss of flexibility, simplicity, and other advantages. Nonetheless, we have defined the conditions where seed ribbons may be used in the Paris System to give satisfactory dose distributions and acceptable levels of heterogeneity within any given implant volume. These conditions include seed length, spacing between seeds, number of seeds per ribbon, and geometric arrangement of ribbons.

Intracavitary irradiation of carcinomas of the uterus and cervix: the Créteil method.

The Créteil method is a logical and simple system for intracavitary therapy of cervical and uterine cancer. The system is based on the use of a plastic cervico-vaginal moulage loaded with 0.5 mm diameter iridium 192 wire sources. The dimensions of both the moulage and the sources correspond to the size of the cervix being treated according to precisely defined relationships. The dose is specified on a reference isodose of a "fixed" value enclosing the pear-shaped target volume whose dimensions depend on the geometry of the sources. Source geometry in turn, depends on the size of the cervix. Thus, the dimensions of the target volume can be accurately predicted at the time of the application. Furthermore, treatment can be performed in a single application, with all sources having the same linear reference air kerma rate (or activity). Radioprotective measures are simple but effective and the patient is not subjected to the restrictions imposed by attachment to an after-loading apparatus. Our clinical results for early Stage T1 and T2a cervical tumors show excellent local control without major treatment complications or long term sequelae.

Update on low dose rate irradiation for cancers of the oropharynx--May 1986.

At the conclusion of our recently published article in this Journal on low dose rate irradiation in moderately extensive cancers of the oropharynx, we updated our results in May 1986. Here we report on an expanded group of 65 patients with a 2 year minimum follow-up; 32 patients were treated by low dose rate irradiation and 33 by conventional fractionation. Forty-four percent (14/32) low dose irradiation patients survived with NED vs 8/33 (24%) conventional fractionation patients. The highly significant differences in the level of local recurrences between patients treated by low dose rate irradiation, 5/32 (16%), compared with conventional fractionation, 20/33 (61%), highlights the enhanced efficacy of the low dose rate irradiation technique in the local cure of cancers of the oropharynx. This superior local control however is achieved at the cost of a number of necrosis, 5/32 (16%).

A comparison between low dose rate radiotherapy and conventionally fractionated irradiation in moderately extensive cancers of the oropharynx.

We report the comparative results for local tumor control between two groups of patients treated by radiotherapy fractionated in a conventional manner at normal high dose rate (29 patients with 2 years minimum follow-up and 24 patients with 3 years minimum follow-up) and by low dose rate radiotherapy (19 patients with 2 years minimum follow-up, 14 patients with 3 years minimum follow-up) with moderately extensive cancers of the oropharynx (T2b-T3a, 3-5 cm in diameter). At 2 and 3 years follow-up, the number of local recurrences in the patients treated with low dose rate radiotherapy is half (26 and 21%) that for those treated with conventionally fractionated radiation at normal high dose rates (52 and 54%). These results require more rigorous confirmation.

Management of epistaxis in Rendu-Osler disease: is brachytherapy effective?

PURPOSE: This paper reviews the results of intranasal brachytherapy for epistaxis in 43 patients with Rendu-Osler disease treated between 1971-1991 at Henri Mondor Hospital. METHODS AND MATERIALS: 2-3 intranasal catheters were afterloaded with 192Ir sources. Computer dosimetry was performed and then the dose was prescribed to an isodose thought to cover the nasal mucosa. The dose rate ranged from 0.16 Gy/h-0.63 Gy/h with a median of 0.34 Gy/h. Dose at one application ranged from 15-35 Gy with a median of 30 Gy. The severity of epistaxis was graded 1 to 5. RESULTS: The time to recurrence of significant epistaxis ranged from 6-178 months with a median of 24 months. The dose prescribed did not correlate with control rate. The only brachytherapy complication was septal perforation in 4 patients; in one this was a result of repeated nasal coagulation. CONCLUSION: We suggest that intranasal brachytherapy is a useful modality in the management of epistaxis in Rendu-Osler disease.

Prognostic factors of local outcome for T1, T2 carcinomas of oral tongue treated by iridium 192 implantation.

The results of Iridium 192 implantation for 121 node negative T1 or T2 squamous carcinomas of mobile tongue were reviewed to look for predictors of local control and necrosis. Age, sex, total dose, dose rate, linear activity, and intersource spacing were examined. Minimum follow-up was 2 years but no patient with local recurrence or necrosis was excluded. There were 57 T1N0 tumors, 45 T2aN0 (2.1-3.0 cm), and 19 T2bN0 (3.1-4.0 cm). Local failures occurred in 14% of T1, 11% of T2a, and 26% of T2b. Univariate analysis showed that local control increased with increasing dose (55-60 Gy: 73%; 65-75 Gy: 92%, p = 0.005), whereas multivariate analysis revealed both sex and total dose to be significant. Radiation necrosis occurred in 17% of T1, 29% of T2a, and 47% of T2b (p = 0.034). Half were limited to soft tissue and the majority healed with conservative management. Univariate analysis showed that necrosis increased with increasing dose (55-60 Gy: 16%; 65-75 Gy: 33%, p = 0.037), as well as increasing dose rate, linear activity, and intersource spacing. With multivariate analysis only stage, dose rate, and spacing remained predictive of necrosis. Total dose was not adjusted for dose rate or tumor volume. This analysis suggests that within the therapeutic range of low dose rate brachytherapy, correction of total dose according to dose rate is unnecessary. We recommend 65 Gy. Lower dose rate (0.4-0.5 Gy/hr) and closer intersource spacing (12-14 mm) should be aimed for to minimize necrosis.

The second ten years: long-term risks of breast conservation in early breast cancer.

A retrospective cooperative study was undertaken to analyze the fate of 300 clinical Stage I and II breast cancer patients who were alive and apparently cured with both breasts preserved, 10 years following primary limited surgery with irradiation. All patients had been treated by tumor excision, with or without axillary dissection, followed by megavoltage radiation therapy. Follow-up ranged from 10.5 to 26 years, median 14.5 years. The overall actuarial survival (Kaplan-Meier) of the 300 "cured" patients was 86% at 15 years and 78% at 20 years, with 38.5% of deaths attributable to breast cancer. The actuarial probability of remaining free of metastatic disease was 91% at both 15 and 20 years, independent of age or clinical stage. Sixteen patients (5.3%) developed recurrent cancer in the treated breast beyond the tenth year, the actuarial probability of remaining free of breast recurrence being 94% and 90% at 15 and 20 years, respectively. Contralateral breast cancers developed during the second decade in 5 patients, with a cumulative risk of 6.5% at 20 years. Significant treatment-related problems appeared during the second decade in 5 patients, including one chest wall sarcoma; all of these patients had received at least 60 Gy to breast and regional nodal areas. A comparison of these results with those in the literature allowed the following conclusions to be drawn: (a) the risk of death, as well as breast cancer mortality during the second decade, are similar for both conservatively and radically treated patients with Stage I and II breast cancer; (b) the risk of contralateral breast cancer is not greater than that observed following primary radical surgery without radiation therapy; (c) ipsilateral breast "recurrences" continue to occur at about 1% per year during the second decade. Such late recurrences are highly operable and have a favorable prognosis; (d) late progression of treatment-related sequelae is uncommon. This analysis supports the continued use of breast-conserving surgery with radiation therapy in the treatment of Stage I and II breast cancer.

External irradiation prior to conservative surgery for breast cancer treatment.

From 1981 to 1987, 138 patients with breast cancer unsuitable for primary tumorectomy received initial external radiotherapy (45 Gy/25f/35d) in order to reduce the tumor volume so that secondary limited surgery could be performed. There were 81 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. After completion of the radiotherapy, 22 patients (16%) showed no more evidence of a tumor either clinically or radiologically and received a boost of 25 Gy. In 52 cases (38%) the tumor regression allowed for secondary tumorectomy followed by a boost of 20 Gy. Sixty-four patients (46%) showed either little or no tumor regression: radical surgery was performed in 14 cases (10%) and high dose boost curietherapy (37 Gy) in the 50 (36%) remaining patients who refused mastectomy. Breast conservation in good condition was thus obtained in 74 patients (54%). Sufficient tumor regression to allow secondary tumorectomy was more often observed in T2 than in T3, in poorly differentiated tumors or mucinous type, and in tumor with well defined mammographic aspects. Actuarial 5-year local control and disease-free survival rates after limited surgery were, respectively, 90% and 73%. No particular complications were observed after secondary tumorectomy. This therapeutic approach is encouraging in patients with large T2 and T3 breast tumors, but a longer follow-up is required to assess definitive conclusions.

Influence of dose rate on local control of breast carcinoma treated by external beam irradiation plus iridium 192 implant.

From 1971 to 1983, 20 T1, 267 T2, and 53 T3 biopsy-proven adenocarcinomas of breast were definitively managed by radiotherapy. The breast and regional nodes received 45 Gy of 60Co irradiation in 25 fractions over 5 weeks (45 Gy/25/5 wks). Electrons were used to deliver a further 15 Gy/7/1.5 weeks to the internal mammary chain and 25 Gy/11/2.5 weeks to the lower axilla. The primary tumor was boosted by Iridium 192 implant for a further 37 Gy prescribed at 85% of the basal dose rate (Paris system). Rigid needles were secured by templates in single plane (58/398) or double plane (340/398) geometry. Results of the 340 two-plane implants have been analyzed to look for a possible influence of dose rate on local control. Follow-up for patients free of local recurrence is 4-204 months (median: 92 months). The 340 tumors were divided into three groups according to dose rate: 0.32-0.49 Gy/hr (n = 95), 0.50-0.59 Gy/hr (n = 120), and 0.60-0.90 Gy/hr (n = 125). The three groups are statistically comparable according to age, tumor size, mean 60Co dose, mean Iridium dose, overall treatment time, and follow-up. The local failure rate in the three groups is 27% (26/95), 20% (24/120), and 13% (16/125) (p less than 0.03, Chi square). At 15 years the estimated local control (Kaplan Meier) is 60%, 72%, and 84% (p less than 0.02, Logrank), respectively. This analysis indicates that there is a significant effect of dose rate on local control for carcinoma of the breast treated by combined external beam (45 Gy) plus Iridium 192 implantation (37 Gy). To maximize local control the authors recommend an implant dose rate of greater than or equal to 0.6 Gy/hr.

Conservative treatment of bladder carcinoma by partial cystectomy and interstitial iridium 192.

From 1971 to 1984, 85 patients with bladder carcinoma were treated conservatively at the Henri Mondor Hospital by a combination of short course of pre-operative external pelvic irradiation, iliac node dissection, partial cystectomy, and iridium 192 implantation. There were 79 transitional cell carcinomas (G1: 12, G2: 25, G3: 36, Gx: 6) and 6 squamous cell carcinomas. By clinical stage, based on endoscopic resection, there were 43 T1, 30 T2, 5 T3, and 7 Tx. After partial cystectomy the pathologic stage distribution was: 41 pT1, 31 pT2, and 13 pT3. Crude disease-free survival at 5 years is 72% for T1 tumors and 55% for T2, but overall only 16% of patients died of bladder carcinoma. Local failures were seen in 11.5% of T1 and 0% of T2 tumors, and second bladder tumors developed at a distance from the treated site in 11.5% of T1 and 7% of T2. There is a non significant trend for intravesical recurrences (both local failures and second tumors) to occur more frequently for G1 tumors (25%) than for G2 (16%) or G3 (7%). At 5 years 95% of disease-free survivors have a functioning bladder. Regional or distant metastases occurred in 54% of patients with pT3 tumors and 10% of those with pT1 or pT2; within each stage there was no apparent influence of grade on metastatic risk. The four patients with histologically positive iliac nodes received additional post-operative external pelvic irradiation; three died of metastases and one is disease free at 10 years. No abdominal scar recurrences were seen. Late complications occurred in 6% of the population. For T1 tumors we suggest modification of the described protocol, eliminating the pre-operative irradiation and the lymph node dissection. If there is no doubt as to the pathologic stage after complete endoscopic resection, iridium 192 implantation delivering a dose of 60 Gy, without partial cystectomy, may be sufficient management. By contrast, for T2 tumors, all elements of the protocol seem important to obtain optimal results.

Interstitial iridium 192 for cutaneous carcinoma of the external nose.

Several implantation techniques useful for nasal skin carcinoma have been developed at the Henri Mondor Hospital in Créteil, France and are described in detail. Iridium 192 wires, 0.3 mm in diameter, are afterloaded into either supple plastic tubes or rigid needles implanted according to the rules of the Paris system. Dosimetry is performed by computer, based on either direct measurements of active lengths and spacing, orthogonal films or a tomogram oriented in the central plane of the implant. According to a recent review by the European Curietherapy Group of 468 implants, the optimal dose is 60 Gy. The overall failure rate was 2.6%. Indications for implantation and choice of technique, based on tumor size, site, and gross morphology are discussed.

Iridium-192 curietherapy for T1 and T2 epidermoid carcinomas of the floor of mouth.

From 1970 to 1986, 117 patients with T1 (47) or T2 (70) epidermoid carcinomas of the floor of the mouth (SCC) were treated by iridium-192 implantation (192 Ir). The dose was prescribed according to the Paris System and varied over those years. Follow-up information was available on 116 patients. There were 46 T1N0, 47 T2N0, and 23 T2N1-3. Neck management varied for the 93 N0 patients consisting of surveillance (24 T1, 17 T2) or elective neck dissection (22 T1:all pN-, 30 T2: 20 pN-, 10 pN+). Cause specific survival rates were 94% for T1N0, 61.5% for T2N0, and 28% for T2N1-3 at 5 years. Primary local control was 93.5%, 74.5%, and 65%, respectively, and 98%, 79%, and 65% after salvage. Patients with gingival extension or a tumor size over 3 cm (T2b) had a local control of 50% (9/18) and 58% (15/26), respectively. Nodal control was 93.5% for Stage I, 85% for Stage II, and 48% for T2N1-3 patients. There was no difference in nodal control with regard to treatment policy for Stage I-II patients. There were few complications including three deaths: two from surgery and one from 192 Ir. Nodal status, tumor size defined as T1, T2a (less than or equal to 3 cm), T2b (greater than 3 cm), and gingival extension were the only independent prognostic factors. The management of T1N0 and T2N0 SCC by 192 Ir to a dose of 65 or 70 Gy, using the Paris System, is recommended for lesions 3 cm or less and without gingival extension.

Radiation therapy for carcinoma of the pinna using iridium 192 wires: a series of 70 patients.

From January 1970 to November 1982, 70 patients with carcinoma of the pinna were treated by interstitial irradiation. An afterloading technique with Iridium 192 wires was used. One patient recurred and had a total pinnectomy followed by 60 Gy external radiation. This patient was alive without evidence of disease at 134 months. Three patients who had tumors greater than 4 cm in size at presentation developed late necrosis which required subsequent total pinnectomy. Cosmetic results were assessed in 55 patients and were good with few late sequelae (in 78% of cases (36/46) when the tumor measured less than 4 cm, but only in 1/9 when the tumor measured more than 4 cm). We advocate interstitial Iridium 192 irradiation for treatment of pinna tumors smaller than 4 cm. None of 39 patients with squamous cell carcinoma had biopsy proven cervical lymph node metastasis at the time of diagnosis. Four patients with squamous cell carcinoma (4/39: 10%) later developed a regional nodal metastasis after treatment of the pinna. All four relapsed in the parotid region and were managed by partial parotidectomy and neck dissection followed by external irradiation. One of these four patients died from uncontrolled cervical node disease. In our opinion, when regular follow-up is dependable, it is reasonable to save treatment of the cervical nodes for those patients who relapse with involved metastatic cervical nodes.

Interstitial radiation therapy for squamous cell carcinoma of the tonsillar region: the Creteil experience (1971-1981).

From July 1971 to December 1981, 33 selected patients with T1, T2 tumors of the tonsillar region were treated according to the following protocol: 1. Telecobalt therapy to the primary site and to neck nodes to a dose of 45 Gy. 2. Brachytherapy to the primary site to a dose of 30 Gy using iridium 192. 3. Boost dose to involved neck nodes with electrons, or radical neck dissection, whether N1, N2, or N3. The actuarial disease-free survival was 76% when all patient groups were included and 80% for the N0 patients. The local control rate was 100%. Disease control in the neck was 94% overall and 100% for the N0 group. These results favor the use of this protocol for superficial, minimally infiltrating tumors less than 4 cm in diameter, without obvious extension to the base of the tongue or retromolar trigone.

Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx.

The risk of second cancer in the head and neck region following definitive radiation therapy was evaluated among 600 patients who were treated for T1 and T2 cancers of the oral cavity and oropharynx at the Henri Mondor hospital between January 1970 and March 1987. Seventy-five patients (12.5%) were managed with external irradiation only, 243 (40.5%) with RT and Iridium 192, and 282 (47%) with Iridium 192 alone. One hundred fifteen patients (19%) developed a second cancer from 3 to 183 months after initial therapy (median: 32 months), including 69 patients (11.5%) in whom the second malignancy was diagnosed in the head and neck region. An increased and constant actuarial risk of development of second head and neck cancer was found (2.7%/year of observation). Univariate analysis showed that age, sex, stage, and modality of the initial treatment did not influence the risk of second head and neck cancer; there was a greater risk of second head and neck malignancy for those patients with soft palate carcinoma (p less than 0.05). Multivariate analysis revealed that the only group of patients who developed a second head and neck cancer more frequently were those who were irradiated with Iridium 192 only (p = 0.0076). There was a trend toward a greater risk of second head and neck malignancy for those with soft palate carcinoma (p = 0.059). Radical treatment of the second head and neck malignancy by surgery and/or re-irradiation was performed for 67% of patients. Patients initially treated by Iridium 192 only could undergo salvage treatment more often than those who previously received external beam radiotherapy (79% vs 53%, p = 0.02). The overall 2-year and 5-year survivals after the diagnosis of the second head and neck cancer were 32% and 10%, respectively.

A new combined approach in the conservative management of rectal cancer.

Between 1980 and 1987, 25 patients with rectal cancer were treated with a combination of preoperative external irradiation of 35 Gy in 15 fractions over 3 weeks which was followed, 6 to 8 weeks later, by a tumorectomy and peroperative placement of a plastic tube loop for post-operative interstitial therapy by iridium-192. This boost dose was 20 Gy (Paris System) for submucosal lesions (seven patients) and 25 Gy for intramural (eight patients) and extramural (ten patients) lesions. With a mean follow-up of 40.5 months, there have been five local recurrences, the latest occurring 16 months post-tumorectomy. Two of these five patients are alive and disease-free 1 year post salvage abdominoperineal resection. The 20 patients with local control have preserved a full functional sphincter and 19 of them are disease-free; there were few complications. This sphincter preserving combined approach seems promising for patients with tumors of the middle and lower rectum who cannot undergo major surgery and for selected patients who refuse abdominoperineal resection.

Combined external irradiation and interstitial implantation for T1 and T2 epidermoid carcinomas of base of tongue: the Creteil experience (1971-1981).

Forty-eight patients with T1 or T2 epidermoid carcinomas of the base of tongue were treated at the Henri Mondor Hospital between 1971 and 1981. Forty-one patients received moderate dose 60Co external beam irradiation (mean: 48.6 Gy) to the primary tumor and regional nodes, followed by an interstitial iridium 192 implant to the primary tumor (mean: 32 Gy). This completed the treatment for the 30 node negative patients, but those with clinically positive nodes were managed by either an additional electron beam boost to the involved nodes or a neck dissection. Seven tumors were treated exclusively by implantation to the base of tongue (mean: 63 Gy). Five-year crude disease-free survival is 50% with 35% of patients dying of recurrent disease. Definitive local control for T1 lesions is 85% (11/13) and for T2 is 71% (25/35). A dose response effect was observed with local control of 79% (26/33) obtained with a combined dose greater than or equal to 75 Gy, but only 50% (4/8) for less than or equal to 70 Gy. For N0 patients definitive regional control is 97% and for N1-3 is 89%. Minor or moderate soft tissue ulceration was observed in 12 patients, including 3 cases that progressed to osteonecrosis. None required surgical intervention. No correlation exists between necrosis and tumor size or total dose.

Interstitial radiation therapy for carcinoma of the penis using iridium 192 wires: the Henri Mondor experience (1970-1979).

From 1970 to 1979, a group of 50 patients was treated for squamous cell carcinoma of the penis by interstitial irradiation using an afterloading technique and iridium 192 wires. The group included 9 patients with T1 tumors, 27 with T2 tumors, and 14 with T3 tumors. Forty-five patients presented with no metastatic inguinal nodes (N0), 3 patients with N1 nodes, and 2 patients had N3 nodes. After treatment, 11 patients (1 T1, 6 T2 and 4T3) developed local recurrences; 10 of these 11 patients underwent penile amputation which controlled the tumor in 7 of the patients. One patient refused amputation. Three patients developed post-therapeutic necrosis which necessitated partial amputation in 2 cases. Eight patients developed post-therapeutic urethral stenosis, which required surgical treatment in three of the cases. Overall, at their last follow-up examinations, 74% of the patients were free of disease with conservation of penile morphology and function. Most patients without metastatic nodes (37/45) at diagnosis did not receive prophylatic treatment of the groin. Two of these patients developed delayed metastatic nodes; one was successfully salvaged. All 5 patients presenting with metastatic nodes at diagnosis died, four with uncontrolled regional disease. Twenty-one percent of the patients died of their disease. We advocate interstitial irradiation using iridium 192 wires for the treatment of non-infiltrating or moderately infiltrating squamous cell carcinoma of the penis in which the largest dimension does not exceed 4 cm. Pre-implant circumcision and regular long-term follow-up are necessary. More extensive tumors are better managed surgically. When regular follow-up can be assured, it is reasonable to forgo prophylactic treatment of the inguinal nodes in patients presenting without groin metastasis.

Curie medal lecture 2000. The optimization of delivered dose in radiotherapy: is it related to low dose rate?

From the beginning of the 20th century with Pierre and Marie Curie, it was found that the preparation of radium into needles and tubes results in a continuous low dose rate radiation in which the total time to give an optimal dose of 60 Gy is reduced to 5 or 6 days. Clinical results quickly followed, showing that tumour sterilization was better ensured by low dose rate radiation over several days than by fractionated high dose rate radiation over several weeks. In the light of my experience of very good results with modern 192 Ir endocurietherapy at an optimal dose rate of 0.6 Gy per h for very bulky tumours, I finally became convinced of the need to study low dose rate in teletherapy using telecobalt with low activity sources (1 Gy per h to achieve long duration sessions of 7-8 h per day over a short total duration of 5 or 7 days).I started in January 1970, at the Institut Gustave Roussy and, after my appointment, at the Henri Mondor Hospital in Creteil, a variety of cancer sites were treated but mostly advanced head and neck cancers. Finally I decided to do a trial of classical fractionated high dose rate radiation vs. subcontinuous low dose rate radiation of advanced breast cancers (T3). The results at 3 months were conclusive: 20% of the cancers treated by 45 Gy fractionated irradiation at high dose rate were sterilized while the proportion sterilized at low dose rate was 70% whether the patients received 45 or 35 Gy. This work opened the way to further study but my retirement loomed and I was not able to pursue it.

The hazy dawn of brachytherapy.

The discovery of radium by Pierre and Marie Curie in December 1898 opened a new era in science and within a few years provided medicine with a new means of tumor treatment. Their personal contribution to the start and early development of clinical applications should not be overlooked. The Curies did not limit their support to providing radium sources to medical pioneers but took a deep interest in the horizons of radium therapy. Pierre was one of the first to search for and demonstrate a biological effect of radium radiation. He investigated the radioactivity of the waters of hydrotherapeutic resorts. Marie took care of the measurement of the medical sources personally, convinced that the result of the treatment depends on the precise knowledge of the amount of radium applied. Her perseverance resulted in the establishment of the Institut du Radium (1909) in which, besides the physico-chemical laboratory, a biological department was set up. The latter became the Fondation Curie (1920), a leading medical center of treatment and training, with an integrated team of physicists, radiobiologists and clinicians led by Regaud. One hundred years after the discovery of radium, patients benefit today from the extensive clinical experience that has been collected over the years and from sophisticated developments in application techniques, dosimetry and quality assurance; the professional risk has been precisely assessed and the improvements in material and procedure have enabled the medical personnel to work in hazard-free conditions. This outcome results from the continuous progress that the pioneers gave impulse to. This paper intends to recall their efforts and achievements, as well as the difficulties and the problems they encountered during the first 2 decades when the sturdy foundations of brachytherapy were built.