indicates the presence of a tumor outside the radiation \201eld. Several studies have sh own that survival is longer in patients with a fall in serum CEA level during chemotherapy than in those in whom there is no change or an increased level. Follow-up and detection of relapse In about 65% of patients with recurrent colorectal cance r, a rise in ser- ial serum CEA values predicts recurrence, on average 11 months before it becomes clinically apparent. OHO-06(63-80) 11/16/02 11:07 AM Page 73 OVARIAN CANCER 73 Ovarian cancer CA 125 is the most commonly used tumor marker for ovarian cancer and is found in derivative s of coelomic epithelium, including pleura, pericardium, and peritoneum, but not in normal ovarian tissue. Diagnosis CA 125 is elevated in >95% of patients with advanced (stage III or IV) ovarian ca ncer, but in <50% of patients with stage I disease. Levels >30 IU ml \200\2231 are frequent ly seen during the \201rst trimester of pregnancy in patients with endometriosis or cirrh osis, especially if ascites is pre- sent. It is elevated in >40% of patients with advanced non-ovarian intra-abdominal malignancies and in 1% of healthy controls. Screening Apart from women at high risk of familial ovarian cancer, screening for ovarian c ancer should not be offered to women outside a clinical trial. CA 125 has no proven value i n screening for ovarian cancer. Prognosis and response to treatment Very high CA 125 levels prior to surgery are associated with a worse prognosis. In women with stage I disease a pre-operative level >65 U/ml is a powerful adverse prognostic indicator, and such patients are candidates for chemotherapy ra ther than surveillance. Elevated CA 125 levels after one, two, or three courses of chemo- t herapy are important adverse prognostic factors for survival. Serial changes in CA 125 are recognized as one of the best methods for monitoring therapy. A persistently elevated CA 125 after oophorectomy for suspected stage I disease is evidence of residual tumor. A biological response based on CA 125 has been de \201ned as either a 50% or a 75% reducti on in CA 125 levels. To reduce the chance of falsely predicting a response, the 50% CA 125 response de \201nition requires four CA 125 levels \200\224two initial elevated samples, a nd the sample showing a 50% decrease requires con \201rmation by a fourth sample. The 75% CA 125 response de \201nition requires only three CA 125 levels, with a serial decrease of at least 75%. In both 50% and 75% response de \201nitions, the \201nal sample has to be at least 28 days after the previous sample. Detection of progression or relapse A serial rise of CA 125 of >25% is the most accurate me thod of predicting progression of ovarian cancer during therapy. There is OHO-06(63-80) 11/16/02 11:07 AM Page 74 STAGING OF CANCER 74 controversy however over the role of serial CA 125 measurements during follow-up. However, if relapse is suspected, a con \201rmed dou- bling from the upper limit of normal during f ollow-up predicts relapse with almost 100% speci \201city. OHO-06(63-80) 11/16/02 11:07 AM Page 75 PROSTATE CANCER 75 Prostate cancer Prostate-speci \201c antigen (PSA) has superseded prostatic acid phos- phatase as a marker , as it is elevated in a higher proportion of men with prostate cancer. Diagnosis, screening, and staging Elevated levels of PSA (>4 ng ml \200\2231) occur in abou t 53% of men with intracapsular microscopic and 77% of men with intracapsular macro- scopic prostatic cancer, but can also occur in 30 \200\22350% of men with benign prostatic hypert rophy (BPH). A combination of PSA and digi- tal rectal examination, followed by prostatic u ltrasound in patients with abnormal \201ndings, is commonly used for screening in US but is not recommended in the UK. As yet, there is no de \201nite evidence of survival bene \201t from screen detection of early prostate cancer. About 40% of patients with PSA levels of 4.0 \200\2239.9 ng ml \200\2231 at screening will already have tumor spread outside the prostate. The ratio of free to total PSA is being used to improve diagnostic speci \201city \200\224 more of the PSA is protein-bound in patients with prostate cancer compared with BPH. The ra tio of free to total PSA is low (about 10%) in prostate cancer compared to >16% in BPH and prostatitis. Bone or lymph node metastases are usually, but not always, associated with an elevated PSA. Prognosis/monitoring response/recurrence detection A high pre-treatment PSA is associated w ith a poor prognosis. PSA levels fall rapidly to undetectable levels after complete removal of a tumor by radical prostatectomy. The rate of fall is slower and the nadir higher after successful radiotherapy or endocrine therapy. A ser- ial rise in PSA frequently precedes o ther evidence of disease progres- sion in the patient with a past history of prostate cance r. Development of bone pain in the presence of an elevated PSA level suggests the developme nt of bone metastases. OHO-06(63-80) 11/16/02 11:07 AM Page 76 STAGING OF CANCER 76 Breast cancer The most widely investigated mucin marker in breast cancer is CA 15-3. Diagnosis and screening Although elevated levels of CA 15-3 are found in 55 \200\223100% of patients with advanced breast cancer, serum CA 15-3 is raised in only 10 \200\22346% of pa tients with primary breast cancer and in about 10% of patients with early (T1-2NoMo) operab le disease, as well as 2 \200\22320% of patients with benign breast disease. Prognosis/monitoring response to treatment Elevated pre-operative levels of CA 15-3 are ass ociated with a poorer prognosis. Although tumor marker levels can fall with reduction in tu mor burden following system therapy, the variation between patients makes this tumor marker unreliable for assessing response. Early detection of relapse The observation that over 60% of patients who develop recurrent breast cancer have raised levels of CA 15-3 suggests potential value in early detection of recurrence. OHO-06(63-80) 11/16/02 11:07 AM Page 77 OTHER CANCERS 77 Other cancers (cid:2) Serum AFP is elevated at presentation in 50 \200\22380% of UK patients with hepatoc ellular carcinoma and may be used in screening of high-risk populations. (cid:2) Neuron-speci \201c enolase (NSE) is elevated in many patients with advanced small- cell lung cancers and in children with neuroblas- toma. (cid:2) Paraprotein levels are very important in the management of patients with myeloma, w here B2-micro-globulin may be of prog- nostic value. (cid:2) Carcinoid tumors can be monitored by urine levels of 5-hydroxy- indole acetic acid (5HIAA), and polypeptides such as gastrin or glucagon are useful in the management of rare gastrointestinal tumors. (cid:2) Squamous cell carcinomas are associated with elevated levels of squamous cell carci noma antigen (SCC) as well as cytokeratin frag- ments. SCC and CA 125 give valuable prognos tic information in patients with cervical carcinoma and may indicate relapse before scans. (cid:2) Calcitonin and calcitonin-related peptide are used in diagnosis and screening for medullary thyroid carcinoma. (cid:2) Serum S-100 and reverse transcriptase polymerase chain reaction to detect mRNA of t yrosinase on circulating melanoma cells are being studied for staging and follow-up of pati ents with melanoma. OHO-06(63-80) 11/16/02 11:07 AM Page 78 STAGING OF CANCER 78 TNM staging of cancer Staging is the assessment of a patient \200\231s tumor burden. It rises from the observatio n that survival rates are higher for cases in which disease is localized rather than dissem inated. It is performed prior to therapy and can be subdivided into clinical, radiological, and pathological. Staging of cancer at presentation is essential for the patients, allow- ing accurate predic tion of prognosis and planning of treatment modalities. It is also allows comparison of car e to be made between different institutions and treatment approaches and for results betwee n different chronological groupings to be compared. A generic approach is the TNM system: T \200\224extent of the primary tumor. N \200\224abse nce or presence and extent of regional lymph node metastases. M \200\224absence or presence of distant metastases. Adding numbers to these components indicates the extent of the disease and any progressive increase in the tumor burden. Primary tumor (T) Tx \200\224primary tumor cannot be assessed. T0 \200\224no evidence of primary tumor. Tis \200\224carcinoma in situ. T1, T2, T3, T4 \200\224increasing size and/or local extent of pr imary tumor. Regional lymph nodes (N) Nx \200\224regional lymph nodes cannot be assessed. N0 \200\224no regional lymph node metas tases. N1, N2, N3 \200\224increasing involvement of regional lymph nodes. Direct extension of primary tumor into lymph nodes is classi \201ed as lymph node metastases; involvement o f nodes other than regional is classi \201ed as distant metastases. Distant metastases (M) Mx \200\224presence of distant metastases cannot be assessed. M0 \200\224no distant metasta ses. M1 \200\224distant metastases. OHO-06(63-80) 11/16/02 11:07 AM Page 79 TNM STAGING OF CANCER 79 The category M1 is often subdivided according to the following notation: Pulmonary \200\224PUL. Osseous \200\224OSS. Hepatic \200\224HEP. Brain \200\224BRA. Skin \200\224SKI. Peritoneum \200\224PER. Marrow \200\224MAR. Pleura \200\224PLE. Using this methodology it is possible to assign a TNM class to any patient. Speci \201c rules for each subset of tumor type are published by the International Union A gainst Cancer (UICC) and the American Joint Committee on Cancer (AJCC). OHO-06(63-80) 11/16/02 11:07 AM Page 80 STAGING OF CANCER 80 Performance status A patient \200\231s general condition profoundly affects treatment decisions, and his/her c ondition may be directly in \202uenced by the underlying cancer or may re \202ect other c oncomitant illness, age, nutritional status, mental condition, etc. Patients with poor perf ormance status tolerate therapy worse and response less often than those with good performa nce status. Performance status does not necessarily parallel the stage of cancer. It does, however, provide additional prognostic information and should be recorded for all patients at presentation and throughout therapy and follow-up. Two common systems are in frequent use: Karnofsky scale (KPS) (cid:2) Normal; no complaints; no evidence of disease. (cid:2) Able to carry on normal acti vity; minor signs or symptoms of disease. (cid:2) Able to carry on normal activity with eff ort; some signs or symp- toms of disease. (cid:2) Cares for self; unable to carry on normal activity or do active work. (cid:2) Requi res occasional assistance but is able to care for most of own needs. (cid:2) Requires considerable assistance and frequent medical care. (cid:2) Disabled; requi res special care and assistance. (cid:2) Severely disabled; hospitalization indicated altho ugh death not imminent. (cid:2) Very sick; hospitalization necessary; active supportive treatment necessary. (cid:2) Moribund; fatal processes progressing rapidly. (cid:2) Dead. Eastern Co-operative Oncology Group (ECOG) (cid:2) Fully active; able to carry on all activities without restriction. (cid:2) Restrict ed in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. (cid:2) Ambulatory and capable of all self-care but unable to carry out any work activities ; up and about more than 50% of waking hours. (cid:2) Capable of only limited self-care; co n \201ned to bed or chair 50% or more of waking hours. (cid:2) Completely disabled; cannot carry on any self-care; totally con \201ned to bed or chair. OHO-07(81-92) 11/16/02 11:19 AM Page 81 Part 2 Principles of treatment 7 Surgical oncology 83 8 Principles of radiation oncology 93 9 Principles of chemotherapy 1 35 10 Hormone therapy 181 11 Immunotherapy of cancer 189 OHO-07(81-92) 11/16/02 11:19 AM Page 82 This page intentionally left blank OHO-07(81-92) 11/16/02 11:19 AM Page 83 Chapter 7 Surgical oncology General considerations 84 Diagnosis and staging 86 Curative surgery 87 Palliative surgery 8 8 Surgery for metastatic disease 91 OHO-07(81-92) 11/16/02 11:19 AM Page 84 SURGICAL ONCOLOGY 84 General considerations Surgery is the mainstay of treatment \200\224and principal hope of cure \200\224 for most p atients with solid tumors. Surgery is most effective when cancer is localized, and substant ial numbers of long-term survivors can be achieved with some tumor types that show metastat ic disease at presentation. Surgery has an advantage over radiotherapy as long-term morbidity of treating tissues witho ut the primary tumor is signi \201cantly less; this must be balanced against disruption of normal anatomy inherent in radical resection of cancer, with potential loss of cosmesis an d function. Surgery has three main roles in the management of cancer patients: (cid:2) Diagnosis and staging (cid:2) Curative (cid:2) Palliative Surgery is the longest-es tablished treatment for cancer and remains the foremost curative treatment of choice for ma ny localized cancers. It has a role to play in the treatment of both primary and secondary cancer as well as palliation. Tumor behavior An understanding of tumor biology is essential to the planning of surgical t reatment for cancer. The behavior of solid tumors is diverse and the implications for surgery are often paradoxi cal. The three principal methods of spread are: (cid:2) Direct in \201ltration (cid:2) Lym phatic (cid:2) Blood-borne Most cancers disseminate by all three methods, although one meth od of spread may be predominant. Breast and colorectal cancer exhibit both blood and lympha tic spread whereas cancers arising in the upper gastrointestinal tract and the upper airway s metastasize via the lymphatics. Even cancers arising from the same cell type behave dif- ferently \200\224papillary and follicular tumors of the thyroid give rise to lymphatic and haematogenous metastases respectively. Different surgical approaches will be required depen ding on tumor type. Surgical techniques The en-bloc technique is most often used in cancers with a pre- dominan tly lymphatic spread and is best developed in surgery of head OHO-07(81-92) 11/16/02 11:19 AM Page 85 GENERAL CONSIDERATIONS 85 and neck cancer. It is increasingly being used for stomach and oesophageal cancers. No adva ntage has been reported for aggressive en-bloc resection of loco-regional lymphatics in sur gery of large bowel cancer. Surgery is often more successful in the treatment of cancers with haematogenous spread comp ared to those with more developed local and lymphatic metastases. Growth rates of cancers vary enormously. Patients with breast can- cer may relapse many yea rs after primary treatment while those with upper gastrointestinal tumors usually die withi n two years of diag- nosis. There are real differences in growth rate. Endocrine-related ca ncers often have very slow growth rates and metastases may appear years after initial resec tion. Repeated excision of metastatic disease may lead to long-term survival in such tumors but this approach would be futile for gastric or oesophageal cancer. OHO-07(81-92) 11/16/02 11:19 AM Page 86 SURGICAL ONCOLOGY 86 Diagnosis and staging The development of cross-sectional radiology, ultrasound, CT, and MRI \200\224together with the radiologist \200\231s ability to perform core biopsies or \201ne-needle aspiration c ytology combined with use of endoscopy and biopsies or cytological brushing, allows pre-ope rative diagnosis to be made in most cases. A signi \201cant advance in reducing unnecessary suffering for patients has been the use o f these procedures to stage accurately cancers prior to surgery. This has been most importa nt where surgical treatment carries signi \201cant morbidity and mortality, such as in maj or resection of the stomach or esophagus. The approach should be to establish a histological diagnosis by endoscopic biopsy with radi ological staging, using a combination of endoscopic ultrasound, CT, or MRI. A useful adjunc t to this is laparoscopy that will detect small peritoneal or liver metastases and is helpf ul in determining \201xation. Using these methods, the numbers of \200\230open and close \200\231 laparotomies for unresectable cancer can be reduced to <5%, avoiding unnecessary surgery for patients at a disease \200\231s terminal stage. OHO-07(81-92) 11/16/02 11:19 AM Page 87 CURATIVE SURGERY 87 Curative surgery The long-term outcome after cancer surgery depends on tumor type and the stage of presentat ion. Survival rates for some cancers have improved due to earlier presentation following pu blic awareness and screening programs e.g. breast and cervical cancer. Improving techniques mean larger resections can be carried out with low risk, often with excellent functional r esults e.g. limb-preserving surgery for osteosarcoma. In the CNS, vital structures continue to inhibit the extent of resection. For some cancers results are good \200\2245-year survival rate in breast cancer is over 75% and for large bowel cancer it approaches 70%. Unfortunately, the cure rate for pancreatic and gastric cancer remains low with 5-year survival rates signi \201cantly less than 10% f or patients treated in Europe. Long-term tumor control can only be expected if all the cancer is removed at the operation. Such operations for rectal cancer result in very low recurrence rates in patients with loc alized disease. Conservation surgery for breast cancer has to be diligently performed to en sure complete removal of tumor. This requires close collabora- tion between the surgeon and pathologist. With the development of high-quality radiological imaging and more accurate staging, more l ocalized, low-morbidity operations can be performed e.g. perianal excision of early rectal cancer. Minimal access surgery is associated with less trauma for the patient, a shorter ho spital stay, and a quicker return to normal function, but its role in cancer surgery is sti ll unproven. OHO-07(81-92) 11/16/02 11:19 AM Page 88 SURGICAL ONCOLOGY 88 Palliative surgery Surgical palliation falls into several different categories, requiring a broad range of exp ertise and knowledge. A patient \200\231s life expectancy may vary from weeks to years depe nding on their condition, and the surgeon must know when not to operate and to utilize pall iative care teams and interventional radiology, as well as to decide when and what operatio n is required. Bowel obstruction Patients with colon or ovarian cancer make up the bulk of those developin g small or large bowel obstruction. In a colon cancer patient, con \201rmation of incurabi lity will usually be made at laparotomy, fol- lowing a decision to treat a large bowel obst ruction. Where possible, these patients should have the primary cancer excised and intestin al continuity restored by primary anastomosis. Management of the obstructed ovarian cancer patient is usually more dif \201cult as the key decision is often whether or not the patie nt should have the operation. Many patients will have multiple obstruction sites, with thei r small and large bowel studded with tumors on the serosal surface. Such patients are not s uitable for surgical palliation. Others will have 1 or 2 site obstructions e.g. a segment o f terminal ileum embedded in pelvic tumor. They can bene \201t from debulking, resection, and anas- tomosis or bypass surgery. Differentiating these categories of patient can usually be done by a history of crampy abdo minal pain, clinical examination revealing a distended tympanitic abdomen (as opposed to an abdomen with mul- tiple sites of palpable tumor and ascites), plain X-rays revealing many loops of distended bowel with air \202uid levels and CT evidence of pelvic or other singl e-site tumor deposit. Laparoscopy will sometimes be helpful in the obstructed patient who has not had previous abdominal surgery. Fistulas Fistulas caused by pelvic tumors or post-radiotherapy include:- (cid:2) Rectovagin al (cid:2) Enterovaginal (cid:2) Colovesical (cid:2) Vesicovaginal (cid:2) Combination of a bove Pre-operative assessment to determine the exact type is important. A proximal end sigm oid colostomy, which can usually be performed OHO-07(81-92) 11/16/02 11:19 AM Page 89 PALLIATIVE SURGERY 89 without a formal laparotomy, is the treatment of choice for most rectovaginal \201stulas. Patients with combined rectovaginal and vesico- vaginal \201stulas may need an end colos tomy and ileal conduit. A covered stent, delivered endoscopically or at X-ray, should be co n- sidered for patients with a colovesical \201stula. Patients with an entero- vesical \201stula will require laparotomy resection of small bowel segment and anastomosis. Jaundice Obstructive jaundice can be palliated surgically by choledocho- enterostomy or cho lecystenterostomy, although these procedures have been largely superseded by endoscopic and radiological placement of stents. Stents can become blocked, resulting in repeated cholang itis. A recent trial has demonstrated a shorter overall hospital stay and decreased morbidi ty for surgical palliation of jaundice compared to endoscopic stenting and should be consid ered in medically \201t patients. Selected patients with inoperable hilar tumors will be best treated by segment III biliary enteric bypass. Ascites Peritoneal-venous (Leveen) shunts can be inserted to relieve ascites in selected ca ses. Careful pre-operative assessment should be undertaken to ensure that ascites is not lo culated and that the tumor is not muci- nous, otherwise the shunt will become blocked. Thes e are usually inserted using local anesthetic and sedation, with >50% of patients achieving good, long-term palliation. Pain There are a number of options open to oncological surgeons to help patients with pain: (cid:2) Surgical debulking of large, slow-growing tumors (e.g. intra- abdominal, soft-tiss ue sarcomas in otherwise \201t patients where expected morbidity of the procedure is low) . (cid:2) Stabilization of pathological fractures and bone metastases involv- ing >50% of cortex. (cid:2) Neurosurgical approaches for pain control including cordotomy. (cid:2) Thoracoscopi c splanchnectomy for intractable pain secondary to pancreatic cancer. (Results comparing th is technique with percuta- neous chemical ablation of coeliac splanchnic nerves are awaited .) Gastrointestinal bleeding A wide array of endoscopic and radiological techniques are availa ble to stop bleeding from benign and malignant causes in incurable can- cer patients, inclu ding injection sclerotherapy (benign ulceration), laser coagulation (neoplastic ulcers), an d radiological embolization OHO-07(81-92) 11/16/02 11:19 AM Page 90 SURGICAL ONCOLOGY 90 (should the other methods fail). Surgery should be reserved for those with a life expectanc y of 3 months or more for whom these methods fail. Palliative resection of the primary tumor Up to 10% of patients with breast cancer will pre sent with metastatic disease; patients with visceral metastases have a poor prognosis but p atients with the more frequent bone metastases have a median sur- vival of 2 years. Resecti on of the primary tumor to achieve loco- regional control may improve patients \200\231 qua lity of life, preventing fungation or uncontrolled axillary metastases. Patients with colorectal cancer are increasingly staged prior to surgery to determine the m ost appropriate therapy. In those in whom unresectable liver metastases are identi \201ed, primary tumor resection should still be considered to minimize the risk of bleeding, perfo ration, or obstruction, which may subsequently occur. OHO-07(81-92) 11/16/02 11:19 AM Page 91 SURGERY FOR METASTATIC DISEASE 91 Surgery for metastatic disease Lymphatic clearance (cid:2) May be curative (cid:2) May avoid need for adjuvant chemotherapy or radiotherapy (c id:2) Useful in \200\224breast cancer \200\224colorectal cancer \200\224gastric cancer (controversial) (cid:2) No role for prophylactic block nodal surgery in melanoma (cid:2) May be role for se ntinel node dissection in breast (trials awaited) and melanoma Liver metastases (cid:2) Most secondaries are unsuitable for resection (cid:2) Bene \201t to selected patie nts with colorectal secondaries \200\22433%, 5-year survival \200\2242%, operative mortality \200\22420%, post-operative morbidity (cid:2) Better survival if one lobe (compared to two) \200\224if size of secondary <5 cm \200\224if margin >1 cm \200\224if metachronous resec tion as opposed to synchronous (cid:2) A further later liver resection is possible Treatment options (cid:2) Cryotherapy (cid:2) Laser (may have a role but unproven currently ) (cid:2) Radio-frequency ablation Injection of alcohol (cid:2) Lung metastases (cid:2) 10 \200\22360% 5-year survival after resection of solitary lung secondary (cid:2) L ong-term survival in patients with primary tumors of \200\224oropharynx \200\224kidney \200\224testis \200\224colon \200\224sarcoma (cid:2) Occasionally repeated resection is bene \201cial OHO-07(81-92) 11/16/02 11:19 AM Page 92 SURGICAL ONCOLOGY 92 Bone metastases Internal \201xation is useful if \200\224weight-bearing bone, especially if lesion is >2 .5 cms or involves (cid:2) circumference \200\224painful secondary after radiotherapy \200\224will improve mobilization and nursin g care \200\224patient is \201t \200\224Bone quality will support \201xation (cid:2) Considerations in spinal secondary \200\224stability of spine \200\224spinal cord compression Treatment options (cid:2) Radiotherapy (cid:2) Hormone manipulation (cid:2) Surgery \200 \224stabilization Brain metastases (cid:2) Good palliation (cid:2) Underused (cid:2) Occasionally curative (cid:2) Post-operat ive radiotherapy helps (cid:2) Anatomical site important Further reading Gilbert, J.M., Jaffrey, I., Evens, M. et al. (1984) Sites of recurrent tumo r after curative colorectal surgery: implications for adjuvant therapy. British Journal of Surgery 71, 203 \200\2235. Rao, A.R., Kagan, A.R., Chan, P.M. et al, (1981) Pattern of recurrence following curative r esection alone for adenocarcinoma of the rectum and sigmoid colon. Cancer 48, 1492 \200\223 5. Veronesi, U. (1987) Rationale and indications for limited surgery in breast cancer: current data. World Journal of Surgery 11, 493 \200\2238. Kaibara, N., Sumi, K., Yonakawa, M. et al. (1990) Does extensive dissection of lymph nodes improve the result of surgical treatment of gastric cancer? American Journal of Surgery 159 , 218 \200\22321. OHO-08(93-134) 11/16/02 11:19 AM Page 93 Chapter 8 Principles of radiation oncology Radiobiology of normal tissues 94 Radiotherapy fractionation 98 External beam radiotherapy 101 Electron beam therapy 106 Treatment planning 111 Total body irradiation (TBI) 116 Brach ytherapy 120 Intra-operative radiotherapy 125 The role of unsealed radionuclides 128 OHO-08(93-134) 11/16/02 11:19 AM Page 94 PRINCIPLES OF RADIATION ONCOLOGY 94 Radiobiology of normal tissues Effects of radiation on tissues are generally mediated by one of two mechanisms: (cid:2) Lo ss of mature functional cells by apoptosis (active form of cell death, usually within 24 hours of irradiation). (cid:2) Loss of reproductive capacity. Different cell types show large differences in radio sensitivity to either of these processes and only a limited number of cell types predomi- n antly respond by apoptosis. These include some cells of haemo- poietic lineage and salivary glands. As most tissues or organs have redundant functional cells, they may lose a signi \201cant fraction of this cell population by apoptosis without clinical impairment of tissu e function. Usually lost cells are replaced by proliferation of surviving stem cells or pro genitor cells. These may be cells surviving in irradiated tissue or cells migrating from un irradiated margins. When cell loss occurs predominantly through loss of proliferative capacity, the rate of cel l renewal (proliferation) of a particular organ determines the time of appearance of tissue damage, varying from days to even years after irradiation. This has led to the arbitrary d is- tinction of acute and late effects of radiation, with acute effects being restricted to changes developing during a fractionated course of radiotherapy of 6 \200\2238 weeks. Acute and late effects of radiation Acute effects of radiation comprise the dose-limiting n ormal tissue reactions during a course of radiotherapy and involve mainly the mucosa and th e haemopoietic system. Although initial cell loss may be partly through apoptosis, the pred ominant effect is loss of repro- ductive capacity, interfering with the replacement of lost cells. Thus, tissues with fast normal cellular turnover (epithelia of skin and gut, bone m arrow) display effects of irradiation earliest. Timing of radiation effects also depends on rate of dose administra- tion. After a single d ose of 10 Gy, the mucosal lining of the intestinal tract is depleted in a few days, while i t may take several weeks during a fractionated course of radiotherapy with daily doses of 2 Gy. The speed of recovery of acute reaction depends on the level of stem cell depletion, and va ries from a few days to several months. If the number of surviving stem cells is too low, s evere epithelial damage may persist as a chronic ulcer. Late effects occur predominantly in slowly proliferating tissues (such as the lung, kidney, heart, liver, and the central nervous system) but are not OHO-08(93-134) 11/16/02 11:19 AM Page 95 RADIOBIOLOGY OF NORMAL TISSUES 95 necessarily restricted to these slowly renewing cell systems (e.g. in the skin, in addition to the acute epidermal reactions, late changes such as \201brosis, atrophy, or telangiec tasia can develop up to several years later). The distinction between acute and late effect s has important clinical implications. Since acute reactions are usually observed during th e course of a conventionally fractionated radiotherapy schedule (1.8 \200\2232 Gy per fract ion, \201ve times a week), it is possible to adjust the dose in the event of unexpectedly severe reactions, allowing a suf \201cient number of stem cells to survive. Surviving ste m cells will repopulate and restore the integrity of the rapidly proliferating tissue. When overall treatment time is reduced, the acute reactions may not reach maximal intensity unt il after completion of treatment. This precludes adjustment of the dose regimen to the seve rity of reactions. If intensive fractionation schedules reduce the number of surviving stem cells to below the level needed for effective tissue restoration, acute reactions may pers ist as chronic injury, called consequential late complications. By de \201nition, late radiation reactions are not apparent until a con- siderable time af ter irradiation and these are by no means always predicted by the severity of the acute rea ction. Although the total dose of radiation is most important, another major determinant of late radiation effect is the dose of radiation per fraction of treatment. The time elapsing between radiation and the clinical appearance of a radiation-induced lesi on has basically no relationship with the radiosensitivity or tolerance of the relevant nor mal tissue. Some acutely responding tissues such as the skin and mucosa are relatively resi stant, in contrast to the highly radiosensitive haemopoietic tissues and germ cells. Conver sely, typically late responding tissues like the lung and kidney are among the most sensiti ve, while the brain is in the more resistant part of the spectrum. Radiation effects in speci \201c tissues Skin (cid:2) Erythema \200\224week 2 \200\2233 (cid:2) Desquamation \200\224later (cid:2) Ulcera tion \200\224later (cid:2) Shorter course increases severity of acute skin reaction (cid:2) Dose per fraction is less important in acute reaction (cid:2) Tolerance for late effects d ecreases with increasing dose per fraction Late effects include: (cid:2) Atrophy (cid:2) Contraction (cid:2) Radiation \201brosis (c id:2) Telangiectasia OHO-08(93-134) 11/16/02 11:19 AM Page 96 PRINCIPLES OF RADIATION ONCOLOGY 96 Oral mucosa (cid:2) Severe mucositis after a dose of 70 Gy in 6 weeks (cid:2) Severity relates to treat ment time and volume irradiated Gastrointestinal tract (cid:2) Acute mucositis causes diarrhea and gastritis; if occurs, cease treatment for a few days (cid:2) Late effects \200\224mucosal ulceration, atrophy, \201brosis, necrosis Nervous system (cid:2) Dose of 50 Gy \200\224low risk of injury (cid:2) Dose of 60 Gy \200\2245% risk of m ajor complications (cid:2) Early reaction (6 months) \200\224demyelination; brain (somnolen ce); spinal cord (Lhermitte \200\231s syndrome) (cid:2) Later reaction (1 \200\2232 years) \200\224radiation necrosis, initially in white matter; then telangiectasia, focal hemorrhage (cid:2) Peripheral nerves may be more radiore sistant Lung (cid:2) Responds late (cid:2) Radiation pneumonitis \200\2242 \200\2236 months after treatm ent (cid:2) Dose tolerance \200\22410 Gy in single treatment; 25 Gy in 2 Gy fractions (cid: 2) Lung \201brosis \200\2246 months to years Kidney (cid:2) Responds later (cid:2) Large reserve capacity, therefore effects occur up to 10 yea rs later (cid:2) Radiation nephropathy \200\224proteinuria, hypertension Heart (cid:2) Pericarditis (6 months \200\2232 years); settles spontaneously (cid:2) Cardiomyopat hy \200\224decreased ventricular ejection; conduction blocks (10 \200\22320 years) New developments High-precision or conformal radiotherapy A combination of new imaging technologies (MR, CT, portal imag- ing), new treatment planning approaches, and high-precision acceler- ators pe rmit higher radiation doses to more precisely delineated target volumes. By these high-prec ision techniques, smaller volumes of nor- mal tissue are irradiated, but to a higher dose. OHO-08(93-134) 11/16/02 11:19 AM Page 97 RADIOBIOLOGY OF NORMAL TISSUES 97 Normal tissue tolerance to re-treatment Recent studies have shown some tissues and organs h ave a substantial ability to recover from subclinical radiation injury, allowing the re- tr eatment of previously irradiated sites. The large capacity of long- term regeneration of th e CNS allows the possibility to re-treat parts of the brain or the spinal cord and offers n ew clinical possibilities for tumors recurring in or near these critical structures. Endovascular irradiation Although not strictly belonging to the \201eld of oncology, prev ention of restenosis by endovascular irradiation with small beta- or gamma- emitting radioa ctive sources is a rapidly expanding application of radiation in the cardiology clinic. Rad iation has been shown to prevent or delay the formation of new plaques by inhibition of pro - liferation of the vascular endothelium or smooth muscle cells. This immediate bene \201t needs to be counterbalanced by the risk of late complications. OHO-08(93-134) 11/16/02 11:19 AM Page 98 PRINCIPLES OF RADIATION ONCOLOGY 98 Radiotherapy fractionation Objective To choose the most appropriate combination of the number of treat- ments (fractio ns), overall time, and total dose to achieve the required level of effect on the tumor with the minimal effect to surrounding normal tissues. Basis of practice Mathematical models based on clinical and laboratory studies have been de veloped and the linear quadratic has now replaced Ellis as the preferred formula for relati ng dose and fractionation. At clinically relevant doses, tumors and early reacting tissues respond to ionizing radiati on with a linear relationship between dose and effect \200\224the linear or (cid:2)componen t. In the late reacting tissues, in the clinically relevant dose range, a large part of the effect is related to the square of the individual dose given \200\224the (cid:3)or quadrat ic element. The important implication of the linear quadratic model is that by giving radiotherapy in m any small doses, changes in the late reacting tissues should be spared, with little or no a lteration in the response of the early reacting normal tissues and of the tumor. Number of treatments Advantages of few fractions: (cid:2) Fewer attendances (cid:2) Sparing of resources (cid:2) Quicker response. Advantages of many fractions: (cid:2) Less severe acute and a lower incidence of late react ions (cid:2) Higher tumor doses can be achieved, so giving the greatest chance of cure. Expression of radiation dose The important elements of a course of radiotherapy \200\224fra ctionation, overall time, and total dose \200\224must always be considered together in orde r to assess the likely effect of a regime. The dose in the tumor target volume is normally prescribed at the center of the tumor where the beams employed usually intersect (the inter section dose), but the maximum and minimum levels also need consideration. OHO-08(93-134) 11/16/02 11:19 AM Page 99 RADIOTHERAPY FRACTIONATION 99 Radiosensitivity of tumors Some tumors, such as lymphoma and seminoma, may be controlled by doses approximately half that required for many carcinomas and sarcomas; others including gliomas and sarcomas, tend to be resistant. Radiosensitivity of normal tissues Some tissues are particularly radiosensitive and doses t o them must be limited in order to minimize the risk of late damage. If 2 Gy doses are give n, then total doses should not exceed 10 Gy to the lens of the eye; the whole kidney, 20 Gy ; whole lung, 20 Gy; the spinal cord, 50 Gy; the brain, 60 Gy; and the brachial plexus, 60 Gy. The risk of severe damage rises above 1% at these levels. The regime chosen must balance risk against likely bene \201t. The interfraction interval After a radiation treatment, some of the damage induced is compl ete but some can be repaired. With a single daily exposure, all or nearly all of the repair able damage is complete before the next treatment is given. If more than one treatment is g iven during a day, the duration of time between the fractions must be chosen with care to a llow for as much repair as possible in the normal tissues. If this is not followed, then th ere will be an increase in effect, most importantly, in the late reaction of normal tissues . Hyperfractionation By giving many small treatments, usually in a twice-a-day schedule, a hi gher total radiation dose may be achieved without an increase in the incidence of late morb idity. Such a regime was shown to be superior to conventional radiotherapy in a randomized controlled trial in oropharyngeal carcinoma. This is now being \200 tested more widely in head and neck tumors in a further EORTC trial in which cytotoxic chemotherapy is being inco rporated. Overall time and accelerated radiotherapy There is now evidence that squamous cell carcinom a in the head and neck and in the lung has the capacity to rapidly proliferate and, in some cases, the tumor cell numbers may double in a few days. This can occur during a course of treatment and be the cause of radiation failure. By shortening the overall duration, the op portunity for this to occur is reduced. \200 EORTC European Organization for Research and Treatment of Cancer OHO-08(93-134) 11/16/02 11:19 AM Page 100 PRINCIPLES OF RADIATION ONCOLOGY 100