Principles and practice of radiation oncology free download

The biological action of radiation undoubtedly constitutes an issue of actual con cern, particularly after incidences like those in Harrisburg or Chernobyl. These considerations, however, were not the reason for writing this book although it is hoped that it will also be helpful in this respect. The interaction of radiation with biological systems is such an interesting research objective that to my mind no special justification is needed to pursue these problems. The combination of physics, chemistry and biology presents on one hand a fascinating challenge to the student, on the other, it may lead to insights which are not possible if the dif ferent subjects remain clearly separated.

Special problems of radiation biology have quite often led to new approaches in physics or vice versa , a recent example is 'microdosimetry' chapter 4. Biological radiation a9tion comprises all levels of biological organization.

It starts with the absorption in essential atoms and molecules and ends with the development of cancer and genetic hazards to future generations. The structure of the book reflects this. Beginning with physical and chemical fundamentals, it then turns to a description of chemical and subcellular systems. Cellular effects form a large part since they are the basis for understanding all further responses.

Combined modality Most patients with locally advanced or metastatic thymoma can be effectively treated with combined modality consisting of radiation therapy, chemotherapy, and surgery with acceptable results 47,53,, In a study by Macchiarini and colleagues , all seven patients with stage III invasive thymoma treated with neoadjuvant cisplatinum, epirubicin and etoposide were able to undergo surgical resection. Four were complete and three were incomplete resections.

It has also been shown that neoadjuvant chemotherapy, and then surgery, followed by additional chemotherapy and irradiation may improve the survival of the patients with locally advanced thymoma Shin and colleagues reported that nine out of ele ven patients with unresectable stage III and IV thymoma were able to undergo complete resection after induction chemotherapy consisting of cyclophosphamide, doxorubicin and cisplatinum All nine patients were given additional postoperative radiotherapy and chemotherapy.

Out of these patients, seven continued to be disease-free at a median follow-up of 43 months. Table 13 shows the results of combination chemotherapy with and without surgery and radiation in patients with mostly advanced thymoma. Most received cisplatinum-based regimens. Furthermore, postoperative radiation therapy was not routinely given in all series. All patients who achieved a pathologic complete response had received cisplatinum-containing regimens. These encouraging results are being evaluated in a prospective intergroup study that treats previously untreated patients with unresectable thymomas limited to the mediastinum with cisplatinum-doxorubicin- cyclophosphamide PAC chemotherapy plus irradiation The impact of multimodality therapy on survival for these patients still needs to be evaluated.

The role of chemotherapy as an adjuvant therapy after resection has not been established. However, it has been reported in conjunction with radiation therapy in unresectable surgical cases, including patients with advanced and recurrent disease ,,,, However, thymectomy is not always successful in reversing the neurologic symptoms seen in patients with thymoma compared to those with other thymic abnormalities 27,32,91, Similar results have been reported by Jaretzki and colleagues Braitman and colleagues 36 analyzed the results of surgery in 33 patients with thymic tumors, 17 of whom had associated myasthenia gravis.

Administration of an anticholinesterase such as pyridostigmine bromide and immunosuppressive medication may alleviate the associated symptoms.

For patients who have failed anticholinesterase therapy and other modalities, adrenal corticosteroids have been suggested The results of thymic irradiation for myasthenia gravis have been similar to those of surgery In a report from Massachusetts General Hospital , 45 patients diagnosed with myasthenia gravis were treated with thymic irradiation only. Again, no significant difference in results was found between patients harboring an associated tumor and those having no tumor.

The dose of irradiation to the thymic area in these studies ranged from 15 to 30 Gy with conventional fractionation. Currier and associates 76 reported on 28 patients with progressive myasthenia gravis without thymoma who received treatment of 30 Gy to the anterior mediastinum. The follow-up was from 5 to 18 years. Of 24 patients with generalized myasthenia in this series, 20 patients had an improved median survival time of 1.

In the other 4 patients, who had ocular myasthenia gravis only, the course of disease was not altered by radiation treatment. Older patients had longer remissions than younger patients. The recommended postoperative radiation dose after gross total resection for malignant thymoma is Gy in 1. For microscopically positive resection margins and grossly positive margins, higher radiation doses of 54 Gy and 60 Gy, respectively, administered in 1.

Although one retrospective study did not find any relationship between radiation dose and local control 12 , others have noted that radiation dose was a significant prognostic factor for local control , It is difficult to prove a consistent improvement in local tumor control with higher doses in part due to the rarity of this tumor and prospective clinical trials.

However, excellent local tumor control has been reported with doses higher than 40 Gy and increased local recurrences have been reported with doses lower than 40 Gy.

When resection is impossible, doses of 60 Gy or more to gross disease may be required for adequate tumor control, but not without higher associated risks of complications such as pericarditis or radiation myelitis Dose to the spinal cord should be limited to 45 Gy using oblique mediastinal fields.

Treatment fields and dose fractionation should be carefully planned and arranged to minimize complications such as pulmonary fibrosis, pericarditis, and myelitis. The typical volume treated should include the entire thymus or tumor bed, mediastinum and part of the involved adjacent lung if there is parenchymal involvement or as delineated by CT scan or surgical clips, plus a margin of at least 2 cm to account for daily variability during treatment and allow coverage of areas of possible microscopic disease Fig.

In general, inclusion of the non-involved supraclavicular fossa is unnecessary and has not shown consistent therapeutic benefits Treatment portals may include single anterior field, opposed anterior-posterior fields with differential weighting , , or , wedge pair, and multi-field arrangements. Modern CT simulation with customized treatment planning can yield optimized isodose distribution and avoid geographic misses Fig.

Conformal therapy with three-dimensional treatment 3D -CRT planning, as described in detail in chapter 44 lung , may further minimize dose heterogeneity and radiation toxicity to adjacent non-involved structures while allowing higher doses to be delivered to the tumor. Results of Radiation Therapy There are no large prospective randomized phase 3 clinical trials to evaluate the primary endpoint of efficacy of primary or adjuvant radiation therapy in patients with thymoma.

Until recently, radiation therapy was used primarily for patients with advanced disease, especia lly in patients with stage III and IVA disease. Often, inadequate equipment or dose resulted in less than optimal results Of 23 patients treated with irradiation as the main therapy, 8 had complete regression, 10 had partial regression, and 5 had no regression With megavoltage radiation therapy, control of malignant thymomas is satisfactory.

In a report by Marks and colleagues , tumor was controlled in all nine cases treated with megavoltage irradiation with doses of 35 to 48 Gy. The average follow-up was 5. Ariaratnam and associates 11 observed tumor control in 8 of 11 patients with malignant thymoma with minimum follow-up of 2 years. Three patients died, two of whom had received only 30 Gy in 3 weeks to the mediastinum.

Postoperative radiation therapy has resulted in improved survival of patients with invasive thymomas, after both complete and incomplete resections 47, In a study of patients with thymoma, Nakahara and associates reported a 5-year survival rate of There was no significant difference in relapse rate or survival between those patients undergoing biopsy and radiation therapy versus subtotal resection and radiation therapy.

But no relapses were noted in patients who received postoperative irradiation after total resection. The benefit of postoperative radiation therapy after subtotal resection or biopsy alone of thymoma is clear. Patients undergoing radical surgery with complete resection prior to adjuvant radiation therapy often have substantially better local control and five year survival compared to those undergoing biopsy alone or limited surgery with minimal tumor resection 72,,, A summary of the results of select radiation therapy series is given in Table 14, and the overall prognoses according to stage are given in Table 15a and 15b.

Other Thymic Tumors Both thymic carcinoma and thymolipomas are much less common than thymomas. They commonly occur in the anterosuperior mediastinum. The majority of thymic carcinomas are undifferentiated, lacking the histologic features of a normal thymus; the remaining may be adenocarcinomatous, sarcomatous, squamous, basoloid, mucoepidermoid, or lymphoepithelial-like histologically. Most variants of thymic carcinoma are highly lethal with frequent metastases to regional lymph nodes, bone, liver, and lung , Proper management requires an aggressive multi-modality approach, including the use of cisplatinum-based chemotherapy often coupled with radiotherapy or surgery.

The prognosis corresponds with tumor grade and stage. Primary thymic carcinoid tumors are exceedingly rare. They arise from the neuroendocrine cells within the thymus and not the thymic epithelium. Few cases no more than cases have been reported in the literature Like other carcinoids commonly in the gastrointestinal and respiratory tracts, they are malignant neuroendocrine neoplasms with the potential for aggressive local, regional, and distant spread.

They affect males more frequently than females with a male to female ratio of Clinical symptoms at presentation resemble those with mediastinal masses In addition, Cushing syndrome, multiple endocrine neoplasia I and II, and inappropriate secretion of antidiuretic hormone SIADH are sometimes seen in patients with thymic carcinoids However, carcinoid syndrome has not been reported in patients with primary thymic carcinoid tumor in the literature The prognosis is generally poor despite aggressive surgical resection with frequent local recurrence and metastases The role of adjuvant therapy is unclear but may improve the outcome in select patients 83, The disease is more common in Caucasian males.

Pure seminomas are most common in the third decade of life, followed by the fourth and second decades. In the pediatric population, the incidence of benign and malignant mediastinal germ cell tumors is similar in both males and females. Mediastinal germ cell tumors have also been associated with other systemic diseases, including systemic mast cell disease, acute myeloid leukemia, and malignant histiocytosis 55, Natural History Extragonadal germ cell tumors occur along the body's midline from the pineal gland in the cranium, through the mediastinum, to the retroperitoneum and presacral areas.

This corresponds to the embryologic urogenital ridge, which extends from C-6 to L The origin of these extragonadal germ cell tumors remains controversial.

Several theories have been proposed as to their development 52,,, It is presumed that extragonadal germ cell tumors arise from germ cells that have abnormally migrated along the urogenital ridge during embryonic development , These tumors are the result of malignant transformation of these germinal elements, displaced to extragonadal sites without there ever having been a gonadal primary tumor These tumors are generally not metastasis from occult gonadal primaries; primary testicular tumors that metastasize to the anterior mediastinum are uncommon , Retroperitoneal germ cell tumors, however, have been more frequently associated with a gonadal primary than their mediastinal or pineal counterparts.

The mediastinum is the most common site for the development of extragonadal germ cell tumors. In a review by Martini and colleagues , the tumor was located in the anterior mediastinum in all 30 of the reported patients. Despite the fact that mediastinal germ cell tumors have the same morphologic and histologic appearance as germinal tumors of the testes, germ cell tumors of extragonadal origin have a poorer prognosis with much more aggressive biological behavior than their gonadal counterparts 8,93, Primary germ cell tumors of the mediastinum are commonly divided histologically into seminomas and nonseminomas.

They can be seen in any age group but most commonly occur in adults from 20 to 40 years of age. There is no gender predilection. Surgical resection is often curative. On the other hand, malignant nonseminomatous germ cell tumors are generally more aggressive with a tendency to metastasize.

Nonseminomatous germ cell tumors are most commonly found in the anterior mediastinum and appear grossly as lobulated masses with a thin capsule. They appear on CT scan as large inhomogeneous masses containing areas of hemorrhage and necrosis.

One study reported the ratio of metastatic germ cell tumors in the chest to primary mediastinal germ cell tumors as However, the metastases occurred through out the chest. If anterior mediastinal metastases are present, middle and posterior mediastinal lymph nodes, as well as retroperitoneal nodes, are frequently involved Rather and associates described fibrotic scars in the testes after detailed histologic examination of patients with disseminated germ cell tumors.

However, Luna and Tamariz found evidence of a scar or occult tumor in the testes in only 2 of 20 cases of mediastinal germ cell tumors. A number of unusual malignant processes are associated with nonseminomatous germ cell tumors; associated hematologic malignancies include acute myeloid leukemia, acute nonlymphocytic leukemia, acute megakaryocytic leukemia, erythroleukemia, myelodysplastic syndrome, and malignant histiocytosis ,,, Less frequently, solid tumors such as embryonal rhabdomyosarcoma, small cell undifferentiated carcinoma, neuroblastoma, and adenocarcinoma have also been described Similarly, Klinefelter's syndrome has been recognized in patients with mediastinal germ cell tumors, but not in patients with testicular ge rm cell tumors 77,, Clinical Presentation As with most patients having mediastinal tumors, local symptoms are usually caused by tumor compression or invasion of adjacent structures Table Patients with mediastinal germ cell tumors may be entirely asymptomatic, particularly when the tumor is a teratoma or seminoma , Embryonal cell carcinoma, teratocarcinoma, and choriocarcinoma are more aggressively infiltrating neoplasms.

They produce constitutional symptoms including weakness, weight loss, and fever, and substernal pleuritic pain. They are occasionally associated with dyspnea, cough, and hemoptysis more commonly than seminoma. Diagnostic Workup Mediastinal germ cell tumors are most often detected on chest x-rays with almost all masses noted in the anterosuperior mediastinum. As with evaluation of other mediastinal tumors, CT is the radiologic method of choice 31, The chest CT scan frequently shows a large anterior mediastinal mass, often with a homogeneous appearance in case of seminoma, and with multiple areas of hemorrhage and necrosis in nonseminomatous germ cell tumors ; cystic areas and calcification within the tumor may be seen.

Abdominal imaging should also be performed to assess other common sites of metastasis including liver and retroperitoneal lymph nodes. Careful examination of the testes should be performed. If testes abnormalities are present, appropriate radiologic examinations should be obtained for a testicular or retroperitoneal neoplasm ultrasonography, CT, and possibly lymphangiography. Similarly, retroperitoneal adenopathy suggests a testicular primary and also warrants testicular ultrasound.

There is no need to perform blind orchiectomy or testicular biopsy in patients with normal physical examinations and unremarkable ultrasound findings , Germ cell tumors may elaborate two proteins that are useful in the diagnosis and follow-up of mediastinal germ cell tumors.

The a - fetoprotein AFP , an a1-globulin, is produced in the liver, yolk sac, and gastrointestinal tract of the fetus. Patients with benign teratomas are serum tumor marker-negative, and elevations of HCG and AFP suggest a malignant component to the tumor. Although less specific, serum lactate dehydrogenase LDH is elevated in the majority of patients with mediastinal seminomatous and nonseminomatous germ cell tumors 20,, These biomarkers have been studied extensively with testicular tumors; several reports indicate that they are of similar value in extragonadal germ cell tumors 44,81, The diagnosis of nonseminomatous germ cell tumors may be made without tissue biopsy In many centers, the presence of an anterior mediastinal mass in a young male with elevated serum tumor markers is adequate to initiate treatment Table If a tissue diagnosis is deemed necessary, fine-needle-guided aspiration with cytologic staining for tumor markers is the least invasive and may be used for confirmation.

Some of these tumors e. Pathologic Classification Conventionally, mediastinal germ cell tumors can be broadly classified as benign or malignant. The malignant germ cell tumors are divided into seminoma or dysgerminoma and non-seminomatous tumors The latter include embryonal carcinomas, teratocarcinomas, choriocarcinomas, yolk sac tumors, and immature teratomas.

Staging Although there is no single widely accepted staging system for mediastinal germ cell tumors, Moran and associates have recently proposed a simple clinical staging scheme that may be helpful in categorizing patients and defining their treatment and prognosis Table 18 , Prognostic Factors The most important prognostic factor in anterior mediastinal extragonadal germinal tumors is histologic type. Mature teratomas and seminomas are highly curable and carry a substantially better prognosis than immature teratomas and nonseminomatous germ cell tumors.

Poorer prognosis is associated with extrathoracic involvement, age greater than 35 years, superior vena cava syndrome, lymphadenopathy, fever, hilar disease on chest x-ray, and incomplete resection 45,93, Common metastatic sites include lung, pleura, lymph nodes, liver, and, less commonly, bone , Normalizing serum tumor markers in response to chemotherapy are a significant favorable prognostic factor.

Seminomas are very sensitive to both radiation therapy and chemotherapy and all patients with mediastinal seminoma should be treated with curative intent. Radical resection has a limited role in the definitive treatment of seminoma , In general, complete radical resection may be considered in selected patients if technically feasible.

Postoperative radiation therapy is often required by most patients even after complete surgical resection. Some advocate surgical resection followed by radiation therapy in patients with small, asymptomatic seminomas; however, surgical debulking of large tumors has not been shown to be of consistent benefit in improving local tumor control , In comparison to chemotherapy, radiation therapy is generally more tolerable, far less toxic, and has a high salvage rate with systemic chemotherapy following a failure A review of recommendations for radiation therapy treatment in extragonadal seminoma was recently reported by Hainsworth and Greco , Doses of Gy are commonly used.

Although doses as low as 20 Gy have been curative, some investigators report higher rates of local recurrence with doses less than 45 Gy Radiation treatment portals should include a shaped mediastinal field and both supraclavicular areas and not necessarily the retroperitoneum 45,, In cases of bulky, extensive, locally invasive disease, larger irradiation portals may be required. Such large fields may result in excessive irradiation of surrounding normal lung and mediastinal organs unless careful treatment planning and modern radiotherapy equipments are used.

Although systemic multiagent chemotherapy is highly effective, in most reported series, chemotherapy was reserved for locally advanced seminomas, failures of surgery and irradiation, or metastatic disease at presentation. Most series have been using cisplatinum-based combination chemotherapy with good results. Minimum follow-up was 1 year, and four patients were in complete remission for longer than 2 years. Roth and co-workers treated 26 patients with disseminated seminoma; 14 survived for a median of Lemarie and coworkers reported that 12 of 13 patients treated experienced complete remission, with two recurrences after treatment.

Cisplatinum-based combination therapy achieved a complete response in 3 of 5 patients treated by Giaccione A recent collective review of 73 patients was undertaken by Hainsworth and Greco All underwent chemotherapy with cisplatinum and various combinations of cyclophosphamide, vinblastine, bleomycin, or etoposide.

Some patients also received radiation therapy. With encouraging results, chemotherapy has been used as initial therapy in many series. In a non-randomized study from Memorial comparing initial therapies, 5 of 9 patients treated with initial radiation therapy remained disease free compared with 10 of 11 patients receiving initial chemotherapy Residual radiographic abnormalities after completing chemotherapy are not uncommon for patients with bulky mediastinal seminoma.

The management of patients with residual radiographic abnormalities is still controversial. Residual teratomas are also rare. The authors recommended biopsy or resection of the residual masses if they were 3 cm or greater ,49, Others recommend close follow up of these patients with early intervention if the mass enlarges on chest x-ray or CT scan, reserving radiotherapy or further chemotherapy for those patients who subsequently develop progressive disease ,,, Nonseminomatous Germ Cell Neoplasms Local treatment with surgery or radiation therapy alone is inadequate for germ cell tumors with nonseminomatous histologies, which include choriocarcinoma, embryonal carcinoma, teratocarcinoma, endodermal sinus yolk sac tumors, and malignant teratoma.

Other malignant components including adenocarcinomas, squamous cell carcinomas, and sarcomas may be present. Patients with mediastinal nonseminomatous germ cell tumors NSGCT do not respond as well to chemotherapy as those with other extragonadal or testicular presentations to chemotherapy. After 4 courses of chemotherapy, patients should then be restaged with serum tumor markers and CT scan of the chest and abdomen.

Patients with negative tumor markers and negative CT scans following initial chemotherapy require no further treatment. Persistent elevation of serum tumor markers requires salvage chemotherapy Patients who are serum tumor marker-negative but have radiographic evidence of residual disease are commonly seen.

These patients should undergo surgical resection of residual disease 4 to 6 weeks after completion of chemotherapy ,, Complete resection should be attempted, as it can be associated with prolonged survival Patients found to have residual viable germ cell tumor undergo two additional cycles of chemotherapy. Equivalent results are obtained in all histologic subtypes. In a series of 32 patients with primary NSGCT treated with surgery and combination chemotherapy, 4 survived with relapse, although follow-up was short Dulmet and co-workers 93 reported median survival times of 4.

However, Toner and associates compared 50 patients with poor prognosis extragonadal nonseminomatous germ cell tumors with 99 patients with poor risk testicular primary site. Patients with residual radiographic masses following treatment with normalization of tumor markers are frequently found to have either benign teratomas or necrotic non-viable tumors. Surgical resection of residual masses may prevent subsequent local regrowth or malignant degeneration of these tumors.

These patients have a very poor prognosis. The treatment of recurrent disease is difficult; standard salvage chemotherapy has not proven consistently beneficial, and few patients achieve remission. Nonseminomatous germ cell tumors are sensitive to radiation. But the role of radiation therapy in NSGCT has not been defined and the optimal dose and fields of radiation therapy have not been established.

In addition to palliation, because of the poor resectability rate and high incidence of residual masses after chemotherapy, radiation therapy has been used for this group of patients to improve local tumor control.

However, depending on the amount of bone marrow treated, irradiation given before chemotherapy may adversely affects the patient's ability to tolerate full cytotoxic doses. Kersh and associates reported on 14 patients with NSGCT and noted that none achieved local control with radiation doses of They believed that objections to the use of radiation therapy are no longer warranted because of the more limited fields and smaller amounts of marrow irradiation with modern techniques, and they suggested use of doses closer to those required for epithelial tumors.

If radiation therapy is contemplated, however, its administration should probably be after maximal response to chemotherapy. If there is no evidence of metastatic disease, high doses of 60 Gy or more appear to be necessary to achieve better local control. The treatment of benign mediastinal teratoma is complete surgical resection, which results in excellent long-term cure rates In general, irradiation and chemotherapy play no role in the management of this tumor and limited published data shows no tumor response to either radiation therapy or chemotherapy However, some investigators have suggested that the preservation of vital structures may be more important than the completeness of resection because incomplete resection of benign teratomas has not resulted in subsequent evidence of tumor recurrence In general, resection of mature teratomas results in prolonged survival with no significant chance of recurrence 93, However, malignant transformation of the teratoma can occur and is often refractory to cisplatinum-based chemotherapy with a very poor prognosis 8, Immature teratomas are potentially malignant tumors.

Their prognosis is influenced by the anatomic site of the tumor, patient age, and the immature fraction of the tumor In patients 15 years of age and older, they may behave as highly malignant tumors. One recent study suggests that a combination cisplatinum, vinblastine sulfate, and bleomycin sulfate regimen may result in improved long-term survival in these patients Radiation Therapy Techniques There are variations in the radiation doses and treatment techniques to treat mediastinal seminomas 19,45,64,,, A review of the literature indicates that doses ranging from 20 to 60 Gy have been used.

Based on experience with testicular seminoma, some have suggested similar lower radiation doses may be adequate.

However, Bush and colleagues 45 recommended higher doses because of the frequently bulky nature and, despite similar histology, also the difference in radiosensitivity of mediastinal seminomas. They noted no local failures with doses greater than 47 Gy. The one patient in their series with a local failure received 45 Gy and was declared not to be a geographic miss. Cox 73 analyzed the dose-time relationship in irradiation of germ cell tumors.

Based on his data from Walter Reed and Massachusetts General Hospitals, he suggested that 30 Gy given in 15 fractions over 3 weeks is adequate. However, Kersh and colleagues suggested doses of 30 to 45 Gy for control of local and regional disease and Bagshaw and colleagues 19 recommended 40 to 50 Gy in 4 to 4.

With regard to volume, the entire mediastinum should be treated. Uematsu and colleagues found four of six patients treated with involved-field irradiation had marginal relapses, while none of the three patients treated with whole mediastinal irradiation relapsed, suggesting the efficacy of the whole mediastinal irradiation. Others recommended inclusion of lower cervical, infraclavicular, high abdominal, and para-aortic lymph nodes to cover sites of metastatic spread with minimal additional morbidity 45,97,, In summary, 30 Gy in 15 fractions over 3 weeks may be adequate for small volume disease.

For gross tumors, 40 Gy 1. As functional imaging becomes better to delineate the true biological target volume BTV , the treatment portal may exclude more uninvolved normal tissue in selected cases. Results of Radiation Therapy Data on mediastinal seminoma treated with primary radiation therapy are generally good. Treatment results of mediastinal seminoma are shown in Table Some of these results were in the prechemotherapy era when salvage therapy was less effective, although even metastatic disease has been reported to be cured with multiple courses of radiation therapy In a multi-institutional retrospective review by Kersh and associates , no patient with me diastinal NSGCT had local control despite radiation doses of 30 to In the 30 to 50 Gy range used for seminoma, late effects such as secondary malignancies, may be expected to be similar to those of patients with Hodgkin's disease treated with mediastinal irradiation , Nonhematologic toxicities include gastrointestinal sequelae nausea, vomiting and esophagitis , severe hearing loss, disabling tinnitus, peripheral neuropathy, salt-losing nephropathy, deep venous thrombosis, and pulmonary embolus.

The esophagus, thyroid, parathyroids, and trachea are derived from the same outpouching of the embryonic foregut; the lungs arise from terminal tracheal buds. This embryology dictates the blood supply of the trachea: inferior thyroidal arteries supply the superior trachea while branches of the bronchial arteries with contributions from the supreme intercostal, internal thoracic, innominate, and subclavian arteries supply the inferior portion.

These arteries course into the trachea from side-to-side. The average adult trachea is cm in length and 2. The upper border lies around the 6th or 7th cervical vertebra; the lower border around the 4th full expiration or 6th full inspiration thoracic vertebra. There are approximately 2 cartilaginous rings per cm Epidemiology Primary tracheal tumors are rare; the incidence of primary laryngeal and lung cancer is likely 75 and times greater, respectively The estimated U.

Males are more commonly affected than females if the histology is squamous Male to female ratio seems equal regarding adenoid cystic carcinoma With squamous cell variants, the usual presenting age is the sixth decade of life; adenoid cystic carcinomas appear to present at a younger age. Other various histologies found in primary tracheal neoplasms include carcinoid, carcinosarcoma, granular cell tumor, hemangioma, chondroma, and chondrosarcoma Neurogenic tumors of the trachea have been described Data as to the contributing factors for the development of these neoplasms is non- existent.

Many assume, however, that tobacco use leads to squamous cell carcinoma of the trachea just as it does to other squamous cell carcinomas of the upper aerodigestive tract. Other primary sites can metastasize to the trachea or invade it directly lung and esophageal cancers being the most likely culprits here , but the majority of tracheal neoplasms are primary in nature This section will focus on the presentation and management of primary tracheal neoplasms alone.

Natural History and Presenting Symptoms The clinical presentation of these tumors is varied. Hempotysis is far more common in squamous cell carcinoma, thus bringing these patients to diagnosis sooner.

Dysphagia is sometimes seen and has been noted to be ominous; interestingly, however, tracheoesophageal fistula is seldom mentioned as a presenting comorbidity for primary tracheal neoplasms. The survival course is relatively prolonged, however, even in the face of distant metastases; in one series median survival for these patients was 37 months The median survival for all from time of diagnosis is probably 5 years These lesions have an indolent course yet are not easily locally controlled.

When tumor spread occurs, it is almost always distant rather than to locoregional lymph nodes. Failure after treatment is usually local, and recurrences 10 or more years after treatment are not uncommon. In contrast to adenoid cystic carcinoma, squamous cell carcinoma the most common tumor of the trachea has a more aggressive course.

Median survival times range from months and are quite dependent on whether or not the primary lesion is resected ,, For other pathologic variants, the clinical course and natural history are variable. Adenocarcinoma and sarcomas behave poorly.

Staging and Prognostic Factors No universally accepted system for staging tracheal neoplasms has been adopted. A staging system proposed by Licht et al seemed not to have any predictable prognostic value patients with positive nodes fared better than those without.

Studies examining the lymph node question have found no statistically significant adverse prognostic association ,,, Size and location of tumor seem to be important prognostically: this featur e probably represents the extent of surgical resection necessary to remove the tumor and those carinal resection patients have heightened postoperative mortality Acute respiratory compromise or distant metastases at presentation—regardless of histology—are predictors of poor outcome As mentioned earlier, adenoid cystic carcinoma and probably lymphoma has a better prognosis than any other histologic variants.

Management and Work-up Eventually all of these patients need a bronchoscopy. An esophagoscopy should be done in all patients to rule out esophageal invasion. CT scan of the chest is indicated to help evaluate the full extent of tumor and aid in determining the presence of pathologically involved lymph nodes.

Given the significant rate of synchronous metastases with primary tracheal neoplasms and that most of these are to the lungs , a chest CT scan is important for staging purposes as well. Treatment and Results It is clear that patients who can be resected have better prognosis than those who can not, prompting the recommendation of surgical resection for most tracheal primary tumors. For example, some recommend tracheal resection for select patients with adenoid cystic carcinoma with low-burden pulmonary metastases the pulmonary metastases can behave indolently yet many would consider a patient such as this unresectable Surely a selection bias is present at centers with low and high resectability rates, but unduly low resection rates can not be explained by selection biases alone: surgical therapy nihilism might be thwarting more appropriate treatment for some patients Furthermore especially with adenoid cystic carcinoma , submucosal or perineural spread of tumor make negative resection margins less likely.

Resection techniques have been described in the literature. Most of these patients will receive a median sternotomy and cervical collar excision. Primary anastomosis is the reconstruction of choice, yet a minority will require some form of artificial tracheal prosthesis Those with extensive subglottic or high tracheal disease may require cervical exenteration and a mediastinal tracheostomy If resection is attempted, absolute indications for adjuvant radiation therapy RT are unclear.

A reasonable argument can be made that all resected patients regardless of tumor burden, margin status, histology, or nodal status need irradiation. It is the policy at the Massachusetts General Hospital that almost all patients with tracheal primary tumors receive postoperative irradiation due to the low number of resected patients who did not receive post-op RT no retrospective comparison has been done.

The M. Anderson group noted that resection plus RT patients had a median survival of 61 months versus 16 months for those who received surgery alone resection status unknown Representative data for patients undergoing resection are presented in Table Preoperative RT has been attempted for some patients, yet the most compelling evidence for adjuvant RT comes from postoperative cases.

For patients who have a tracheal prosthesis reconstruction which is rare , postoperative RT seems risky; there are no clear indications in the literature as to the outcome of these patients post-irradiation or if doses have been tempered in this setting. Retrospective data exists supporting the use of external beam radiation therapy EBRT alone. The best results with the most patient numbers have come from studies where doses greater than 60 Gy have been given. There seems to be a dose-response relationship for tracheal neoplasms.

Increased dose also led to more complications in the another study Data summarizing select radiotherapy-alone experiences in primary tracheal neoplasms are given in Table Combined chemoradiotherapy without resection has been tried at some institutions mostly for lymphomas, small cell carcinomas, or squamous cell carcinomas , but the utility of combined modality treatment is uncertain at best. The few patients presented in the literature with squamous cell carcinoma have fared poorly; those with small cell carcinoma or lymphoma have had relatively prolonged survival months , Radiotherapy Techniques For resected patients, weeks of healing time should be allowed before beginning postoperative radiation therapy.

Modern CT-based, 3-D conformal radiotherapy or intensity-modulated radiotherapy should theoretically allow higher, safer doses to be given to the trachea.

All patients with this tumor—in either the postoperative or definitive setting—should be treated with 3-D conformal techniques.

Because local tumor control has such a profound effect on quality of life and probably prolongation of survival in this patient population, we also recommend 3-D conformal techniques along with doses in the 60 Gy range if possible be used on intermediate to good performance status patients referred for palliation. Doses to less than 40 Gy have yielded abysmal partial tumor control rates; higher doses necessitate precise planning.

For postoperative cases, experiences seem to indicate that doses of Gy should be employed. An intraluminal boost technique after EBRT may decrease late side effects ,, For the emergent airway case, thoracic surgery intervention with rigid bronchoscopy should be sought instead of urgent radiotherapy.

Respect for nearby dose limiting structures spinal cord, lung, heart, and esophagus will dictate the radiation therapy plan. Even so, adenoid cystic carcinomas notoriously recur at the anastomosis. The role of elective nodal irradiation for tracheal carcinoma is uncertain. As mentioned earlier, nodal status has not been found to be of clear prognostic significance; even cervical adenopathy was not associated with poorer outcome in a Japanese series ,, No series clearly outline what nodal regions were or were not treated.

Given the low proclivity for adenoid cystic carcinomas to spread to lymph nodes, elimination of elective nodal irradiation is certainly reasonable for this variant. With most studies showing death occurring in the setting of a local recurrence regardless of the histology , it would seem engaging in elective nodal irradiation would do little to change survival rates.

Yet if mediastinal or cervical nodes are discovered at surgery or by CT, radiation therapy to these regions is likely warranted and must be considered. Almost three-fourths will be of lipomatous, lymphangitic, or vascular origin. The remainder is somewhat equally divided among the other histologic variants. For a complete list of tumor pathologies making up the mediastinal mesenchymal spectrum, refer to Table There has not been shown to be any clear gender predilection for MMLs.

Age at presentation is dependent upon the pathologic variant , Clinical Presentation and Work-up MMLs can occur in any of the three main compartments of the mediastinum, but the anterosuperior mediastinum seems least commonly involved The outcome for these tumors is variable: patients with malignant-behaving lesions have been shown to have shorter survival times than those with benign-behaving lesions approximately half of all MMLs are malignant at presentation , For mediastinally-located tumors in general, malignancy is more frequently encountered in the pediatric population MMLs are often silent until reaching quite a large size.

Presenting symptoms can vary widely, yet chest pain and dyspnea are the most commonly mentioned complaints in symptomatic patients. The size and location of the tumor must be adequately illustrated first via either CT scan or MRI of the chest. The histopathology of the lesion must be identified. This can be accomplished via mediastinoscopic biopsy, FNA usually CT-guided , or bronchoscopic or esophagoscopic sampling The resectability of the lesion can then be properly ascertained.

After the diagnostic workup is complete, staging via AJCC recommendations for soft tissue tumors can be applied, but in actual practice this is seldom done owing to the rarity of these lesions. They can occur singly or multiply in the mediastinum and can simulate cardiomegaly or pleural effusion on chest X-ray. Surgery is almost always curative for these patients, and they are rarely seen intrathoracically , In contrast, liposarcoma consists of immature fat cells as well yet is malignant.

Prognosis may be related to the presence or absence of psuedoencapsulation: the few patients with well-circumscribed lesions in a review by Standerfer et al had survivals of 3 to 17 years, whereas patients with non-encapsulated tumors all died within 2 years.

Liposarcoma outcome also hinges greatly on the grade of the lesion Optimal treatment probably consists of surgery and postoperative radiation therapy even completely resected, negative-margin cases. Tumors of Lymph Tissue Tumors arising from the vascular or lymphatic components of the mediastinum make up the bulk of the remaining MMLs Pathologically, lymphangiomas and hemangiomas will look identical under the microscope hence there being some debate about the true cell of origin and can only be differentiated by the presence of red blood cells or chyle within tumor lumen Lymphangiomatosis is usually seen in children and is characterized by widespread lymphangiomas; mediastinal or pulmonary involvement carries a poor prognosis Lymphangiomyomatosis formerly known as lymphangiopericytoma is a very rare condition seen only in females of reproductive age characterized by the proliferation of smooth muscle and lymphatic tissue in mediastinal lymph nodes, lung, or retroperitoneum; the disease may in fact be a form of tuberous sclerosis 74,, Lymphangiosarcoma is a malignant variant of lymphangioma.

Whether or not there occurs malignant transformation of lymphangioma into lymphangiosarcoma for MMLs is unknown Treatment for all MMLs of lymph tissue involves surgery when possible.

The role for postoperative irradiation is unclear given previous unimpressive results in fact, malignant transformation of benign lymphangioma into malignant lymphangiosarcoma after RT has been described.

Chemotherapy may play a role in unresectable lymphangiosarcoma Johnson et al describe a young patient with surgically refractory chylothorax and lymphangioma who had prompt resolution after 20 Gy in 10 fractions of mediastinal irradiation. The addition of radiation therapy for symptomatic lymphangiomyomatosis has be en effective, as well, yet progesterone therapy should be attempted first , Hemangiomas may be capillary or cavernous.

The cavernous hemangiomas also known as angiomyomas or hamartomatous hemangiomas are distinguished from capillary hemangiomas by the presence of smooth muscle. The biological behavior is similar for the two, however Hemangiomas and hemangioendotheliomas are well circumscribed, but the hemangioendotheliomas contain cytoplasmic Weibel-Palade bodies characteristic of endothelial cells and are not encapsulated Author : Luther W. The book's comprehensive scope and abundantly illustrated format provide you with better understanding of the natural history of cancer, the physical methods of radiation application, the effects of radiation on normal tissues, and the most judicious ways in which you can employ radiation therapy in patient care.

Including epidemiology, pathology, diagnostic work-up, prognostic factors, treatment techniques, applications of surgery and chemotherapy, end results, and more. Increased emphasis on new approaches and technologies improve your understanding of three-dimensional treatment planning, intensity-modulated radiotherapy, combined modality therapy, and particle therapy. Digital version includes the complete text, index-based search, note sharing, regular content updates integrated into the text, and much more.

Authors: Luther W. Brady, Carlos A. Perez, David E. Get Books. Inside the Sixth Edition of this now-reference, you will discover encyclopedic coverage of topics ranging from basic science to sophisticated computer-based radiation therapy treatment planning and supportive care. The book's comprehensive scope and abundantly illustrated format provide you with better understanding of the natural history of cancer, the physical methods.