John Joseph Anderson, DPM, FACFAS

• Chief of Surgery
• Gerald Champion Regional Medical Center
• Alamogordo, New Mexico

The use of sentinel node biopsy is controversial in this group of patients depression definition in spanish generic 150 mg wellbutrin sr mastercard, and many have looked for risk factors that may predict a higher incidence of nodal metastases vegetative symptoms depression definition order wellbutrin sr 150mg without a prescription. In a series of 254 patients reported by Gershenwald depression forums order wellbutrin sr 150 mg with amex, no patient with T1 lesions and a positive sentinel node had positive nodes on completion lymphadenectomy anxiety medication for children cheap 150 mg wellbutrin sr free shipping. Regression by itself was not found a risk factor for nodal disease in thin lesions mood disorder ontario discount 150mg wellbutrin sr overnight delivery. Untreated nodal metastasis can be expected to ulcerate depression symptome test kostenlos purchase wellbutrin sr 150mg on line, impinge on neural structures, and cause pain in patients whose life expectancy is more than 1 year. The median survival was significantly worse for those with deep nodes positive with survival of 53, 42, 14, and 9 months, respectively. An inguinal groin dissection can be either superficial, including all nodes below the inguinal ligament, or complete, including the deep iliac and obturator nodes accessed through retroperitoneal exposure. The superficial dissection is carried out through a longitudinal incision with the removal of subcutaneous tissues, lymphatics, and the anterior portion of the femoral sheath. A sartorius muscle flap is used in closure to protect the femoral vessels and decrease wound complications. Case series suggest that performing a deep inguinal dissection increases the morbidity of the operation and does not to offer an obvious survival advantage in a radiologically negative pelvis. They argue that those with grossly positive pelvic nodes should have a predictably worse prognosis since those patients had significantly more positive lymph nodes of generally larger size. The 5- and 10-year survival for those patients was 24% and 20%, respectively, with the number of positive iliac nodes an independent prognostic factor. The authors suggest that deep lymph node dissection may be of benefit as up to 20% of patients are long-term survivors who would otherwise would have had residual disease if treated only by a superficial dissection. Rarely, in patients without evidence of distant disease and with positive supraclavicular nodes, a lower cervical node dissection may be performed by resection of the middle third of the clavicle. With one, two, three, or more than four nodes, the 5-year survival was 62%, 51%, 28%, and 5%, respectively. Patients with recurrent lymph nodes or nodes that are fixed have a 5-year survival of 13%. Neck Dissections 276 A functional neck dissection is indicated with the preservation of the jugular vein, sternocleidomastoid, and spinal accessory nerve unless directly involved with tumor. Modification of the extent of dissection is appropriate relative to the site of the primary tumor. Superficial, nerve-sparing parotidectomy is indicated for palpable metastatic lesions for local tumor control. Although controversial, some advocate the use of adjuvant radiotherapy for high-risk lesions because of the higher rate of recurrence in head and neck lesions. Popliteal and Antecubital Nodal Dissection Infrequently, the popliteal nodes become involved with metastatic disease and cause palpable enlargement. In the absence of distant unresectable disease, popliteal nodal dissection should be performed through an S-shaped incision. There are no data demonstrating survival benefit of this operation as there are only small case series in the literature. This occurs in up to 24% of patients and may be upward of 40% with prolonged follow-up. A strict regimen of daily leg elevation and routine use of elastic stockings decreases the severity of symptoms. The lateral femoral cutaneous nerve is commonly sacrificed with resultant numbness of the lateral thigh. The Intergroup Melanoma Trial reports a 50% wound complication rate in inguinal lymphadenectomies. In 112 patients there were 23 wound breakdowns, 24 cases of lymphedema, one deep vein thrombosis, and one pulmonary embolism. Neuropraxia secondary to brachial plexopathy is also a rare event that is usually resolved within 3 to 6 months. Proper positioning, careful placement of retractors and careful dissection minimize this event. Lymphocele rates are 7%, and the incidence of arm edema is much lower than nodal dissection for breast cancer. A vigorous search for suspicious lesions is mandatory in these patients with a low threshold for biopsy. In patients with unknown primary melanomas, the distribution of metastases as localized to a region or multiple sites at presentation was 43% and 57%, respectively. The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared, and they should be treated accordingly. This study was undertaken because of the favorable experience with adjuvant radiotherapy reported by Ang et al. In 39 patients with clinically positive nodes and 67 patients with recurrent local regional tumor who received postoperative local regional radiotherapy, 5-year local regional control rates were 92% and 88%, respectively, while survival rates were 41% and 45%, respectively. Arm or leg edema and brachial neuropathy associated with radiation fibrosis are concerns with high-dose fraction radiotherapy of lymph node regions. If observed surrounding the site of the primary tumor, the term satellitosis is sometimes used. The probability of developing locoregional cutaneous relapse is highly associated with histologic evidence of lymphatic invasion seen in the initial primary lesion. Regional nodal metastases are common and seen in up to two-thirds of patients with in-transit disease. The 5-year survival rate following locoregional recurrence of melanoma of the extremities is approximately 20%. Treatment options are not standardized, and until more effective systemic therapy is developed, aggressive local treatment is indicated for this group of patients. In-transit disease most often is found between the primary lesion and the draining lymph nodes but in advanced instances is able to track beyond these sites, presumably through lymphatic connections. Wide excisions are unnecessary and excessively morbid in patients whose lymphatics are already contaminated. Amputation should only be considered if the limb is nonfunctional or hygiene cannot be maintained. When amputations are necessary, they should be performed as either a hip disarticulation or hemipelvectomy as distal amputations usually fail locally. The 5-year disease-free survival after amputation in older series is approximately 20% to 35%. Approximately 50% of primary melanomas occur in the extremities, and approximately 10% of those patients have a recurrence as in-transit disease. Prospective randomized trials that examine regimen, toxicity, dosage, and response are in development. Melphalan can be safely delivered locally at doses ten times higher than systemically tolerated. Those with locoregionally advanced melanoma such as satellitosis and in-transit metastasis and those in need of palliation who have bulky regional disease and limited systemic metastasis. However, there has been wide skepticism regarding the results of this small study. Median disease-free survival was 17 months in the perfusion group and 10 months in the control group. There were 15 locoregional recurrences in the perfusion group and 24 in the control group. The disease-free survival was better for the perfusion group than for the control group, but no significant difference in overall survival was noted. All venous and arterial branches including the hypogastric artery are ligated to prevent systemic leak syndrome. The extracorporeal perfusion circuit is primed with 700 mL saline, 1 U of packed red blood cells, and 1500 U of heparin, and flow is maintained in the range of 50 mL/L limb volume per minute (. The amount of systemic leak is measured using 131I radiolabeled albumin or 99mTc-labeled red blood cells with the gamma counter over the precordium. If clinical trials are performed demonstrating similar efficacy using isolated limb infusion, the simplification of the treatment of regional disease may enable a more widespread treatment. Melphalan is an alkylating agent that is the mustard derived from phenylalanine, an essential precursor used in melanin synthesis by melanocytes. Weiberdink developed a regional toxicity scoring system to grade the reaction based on actual measurement of limb volume (Table 42. Based on this dosing regimen, a dose of 10 mg/L for the lower extremity and a dose of 13 mg/L for the upper extremities were developed to limit severe toxicities and optimize response. In one series of 136 patients with recurrent extremity melanoma, a minimum temperature of 41. Specific tumoral vasculature destruction with sparing of the normal vessels is also seen. Melanomatous lesions soften and flatten, and biopsies show melanin pigment within macrophages without evidence of melanoma cells. Patient age is not an absolute contraindication for perfusion as adverse effects do not appear to be significantly greater in patients greater than 70 years of age. The degree of limb toxicity, since it has no correlation with tumor response, should be avoided. Renal failure secondary to myoglobinuria can be prevented by maintaining adequate urine output (greater than 4 L/d) and alkalization (pH greater than 7. Mild neuropathies are noted in up to 20% to 40% of patients (possibly from the tourniquet) after perfusion (Table 42. The use of dacarbazine, cisplatin, or carboplatin may have less adverse effects but no trial has directly compared the therapeutic and toxic effects of these various regimens. The incidence of wound complications increases significantly in patients who undergo concurrent lymphadenectomy. Prevention of systemic leak and fluid loading before tourniquet release may help prevent the need for vasopressors. Fifteen patients treated with systemic vinblastine and dacarbazine and intraarterial cisplatin were observed to have a 67% response rate. Only 45% were complete responses and one was pathologically positive at subsequent biopsy. Given the significant toxicities of this regimen, it is necessary to have more experience before any recommendations can be made. Among the 14 survivors, 8 have had no limb recurrence and the remaining required further treatments to control disease. The use of electrical pulses directly applied to cutaneous metastases after administration of local or systemic bleomycin may have activity against melanoma. In one series, a 91% response rate was noted without any significant reported side effects. Photodynamic therapy can specifically ablate malignant cells at depths up to 1 cm. Patients with in-transit disease may be ideal candidates for immunobiologic intervention because of their low tumor burden. Morton from the John Wayne Cancer Institute has used the CancerVax vaccine for patients with in-transit disease, and in nonrandomized patients suggests an approximate 50% 5-year survival. Patients previously enrolled in trials of adjuvant therapy have been those at high risk, in whom relapse and mortality risk exceed 50% at 5 years. For this reason, stage I patients are unlikely to benefit from such therapy and have not been the focus of any adjuvant therapy trials. Eligibility criteria included the presence of a T4 primary lesion with or without regional lymph node involvement or primary lesions of any depth with pathologically proven regional lymph node involvement. Patients with cutaneous melanoma of any thickness, but with the regional lymph nodes as the site of initial and only relapse were also eligible. All patients underwent regional lymph node dissection and were stratified with respect to clinical and pathologic stage of disease. At a median follow-up of 7 years, a significant improvement in both median relapse-free survival (1. Patients with established lymph node involvement, de novo or recurrent, appeared to derive the greatest benefit from treatment. Only a limited number of patients (31) who were clinically and pathologically node-negative (T4 pN0) entered the study, and an imbalance in the distribution of the important prognostic variable, ulceration, made it difficult to draw firm conclusions for this subset. Dose-modification or delays were required at least once in 50% of patients during the intravenous induction phase and in 48% of patients during the subcutaneous maintenance phase. This compares favorably with the rigorous Canadian benchmark of $20,000 per quality-of-life-year gained and is comparable with other accepted adjuvant therapies of breast and colorectal cancer. This trial was designed and implemented before the availability of mature data from the E1684 trial. Eligibility criteria for E1690 were similar to those for E1684 but dropped the requirement for regional lymphadenectomy for patients with deep (T4, greater than 4 mm) primary lesions. Of note, the median overall survival for patients assigned to observation in E1690 was 6 years as compared with only 2. Other factors that could potentially account for the improved outcome for patients on this trial randomized to observation include the use of more accurate staging techniques or more modern surgical intervention at initial treatment, subsequent relapse, or both. For patients with regional lymph node involvement, the improvement in median recurrence-free survival was significant by Cox analysis (P2 =. The limited number of patients in this subset does not permit a firm conclusion regarding the benefit of this regimen on either relapse-free or overall survival or the treated population as a whole. A preliminary report at 22 months median follow-up suggested prolongation of recurrence-free survival among women younger than 50 years and men older than 50 years, while a somewhat more mature interim report at 39 months median follow-up revealed no durable benefit in terms of either relapse-free interval or overall survival; a final publication is pending. Firm conclusions will only be possible regarding the therapeutic benefit of these vaccines as these first randomized controlled trials are completed and mature. This group of patients has been the focus of several completed European and newly initiated North American cooperative group studies. The results of these trials are therefore difficult to apply to patients for whom more precise staging, by means of sentinel node mapping, is available.

The cornerstone of fetal viability is maternal health anxiety 5-htp discount wellbutrin sr 150 mg otc, and a delay in surgery only jeopardizes the lives of both the mother and the child mood disorder exam questions generic wellbutrin sr 150 mg with visa. Only rarely do situations arise in which a woman with melanoma should be advised to terminate pregnancy depression retreat wellbutrin sr 150 mg mastercard. Managing a pregnant patient with disseminated melanoma can be difficult mood disorder va compensation cheap wellbutrin sr 150 mg online, but because the prognosis is so poor in these patients and treatment options are lacking mood disorder example 150 mg wellbutrin sr mastercard, the patient may reasonably decide to attempt a full-term gestation without therapy anxiety or adhd buy 150 mg wellbutrin sr otc. Cases of women receiving chemotherapy and focused spinal radiation without subsequent harm to the fetus have been reported. Uncommonly, melanoma can pass through the placenta, but usually in only far-advanced disease. Melanomas account for only 8% of the cancers that affect pregnant women but for 46% of fetal tumors acquired transplacentally. Through positive and negative selection of T cells during maturation, autoreactivity should be minimized. Proteins produced from tumor cells that induce a specific T-cell response are called tumor-associated antigens. Those that are sufficiently potent at stimulating reactivity, demonstrated by a clinical rejection of tumor, are called tumor-rejection antigens. As cancer is a genetic disease, the production of mutated proteins occurs, and these proteins were thought to be prime candidates for the development of peptide vaccines. Of course, this concept is much more complicated as T cells are, in fact, quite capable of recognizing self, and, conversely, are able to develop tolerance or anergy to foreign peptides. In fact, although some mutated self-proteins have been identified in patients that can stimulate an antitumor T-cell response, most peptides thus far identified derive from normal proteins either overexpressed in melanoma or restricted to cells of melanocytic lineage. One technique that enabled the rapid detection and identification of antigens of cancer was the technique known as serologic expression cloning. These gene products are expressed in both normal and malignant melanocytes, and immune responses against these targets have been associated with the development of autoimmune reactions against normal melanocytes. Therefore, vaccination against these targets should allow a relatively tissue-specific response to be elicited. Clinical responses were noted in 27% (8 of 30) of patients, including three complete remissions and five partial remissions. The meaningful clinical responses induced in a group of patients with poor prognosis disease is encouraging but needs further evaluation. A University of Pittsburgh Cancer Institute trial initiated in 1996 has also shown encouraging evidence of activity in 23 patients. Another patient on this study attained a complete remission sustained for over 3 years, and a third has had a partial remission. It is logical to apply these treatments to patients with a much lower burden of disease such as in the adjuvant setting, where all obvious disease is removed, but there is a high chance of relapse due to microscopic residual or metastatic disease. Performing such studies using the clinical end points of time to tumor progression or survival involves studying large numbers of patients over a long period. Three patients were reported in whom tumor regressions were seen despite having progressive melanoma at the time of entry into the study: One patient showed complete regression of tumor and the others displayed partial regressions. Immunologic responses could be generated in 91% of patients using blood lymphocytes stimulated in vitro before assay. In human clinical trials, tumor cells (autologous or allogeneic) or normal cells such as fibroblasts, have been transfected with individual cytokine gene(s) and have been used to induce tumor immunity. So far, only early toxicity results from phase I trials have been reported using this approach in advanced disease patients. Two complete responses were observed and two patients had a decrease in the size and number of their subcutaneous nodules. The vaccinated population showed an increased IgG response dominated by IgG-2, suggesting the development of an effective T-helper cell response. No clinical responses were seen, but three patients had stable disease for 7 to 15 months. Only two mixed responses were recorded, without objective clinical responses by conventional criteria. However, induction of a specific immune response was demonstrated by in vitro studies. However, induction of a specific recognition of autologous melanoma cells by peripheral blood lymphocytes was obtained after vaccination in only one of six cases studied. These results, although modest, show that the induction of a specific immune response is possible in a few patients through novel vaccination strategies. In one patient, tumor regression occurred several months after completing peptide vaccination, although the tumor had progressed while on treatment, leading to the initiation of vaccination. Cytotoxic T-lymphocyte responses against melanoma differentiation antigens correlate inversely with expression of the antigen in melanoma tissues: Patients with progressing disease have been shown in several experiences to displayed antigen-loss variants, implying in vivo immunoselection under the pressure of peptide vaccination. This has enhanced the generation of cytotoxic T lymphocytes with specificity not only for the modified peptide-pulsed target cells, but also for unmodified peptide and for naturally processed peptide. One vaccine based on this approach, CancerVax, has been developed at John Wayne Cancer Institute. CancerVax is a whole cell irradiated vaccine developed from three allogeneic melanoma cell lines that were subsequently demonstrated to express several known immunogenic tumor-associated antigens. The 5-year overall survival and median survival for patients who received the vaccine appears to be improved, but it is well recognized that historic controls have great liabilities. Forty-two percent of patients who received the vaccine were alive at 5 years and the median survival was 42 months. After multivariate analysis, CancerVax therapy was suggested to be a significant predictor of survival. Vaccine preparations have been evaluated in which nonpathogenic viruses such as vaccinia virus and Newcastle disease virus, are used to lyse cells to enhance their immunogenicity (viral melanoma oncolysate). They contain multiple tumor-associated antigens and are capable of stimulating a polyvalent immune response. Most specifically, this would include the adoptive transfer of cells or antibodies. Tumor biopsies during and after treatment showed lymphocyte and mast cell infiltration, mast cell degranulation, and complement deposition. Subsequent studies with this antibody have failed to confirm this level of response. Combining R24 with cytotoxic drugs or cytokines did not increase the response rate. An alternative approach was to develop strategies to immunize with the antiidiotype (so-called Ab2) to induce a host immune response to the original antigen (Ab3). Prolonged disease-free intervals were noted in a majority of treated patients in these adjuvant studies. One patient achieved a complete remission with disappearance of multiple abdominal lymph nodes for a duration of 95 weeks. These collective results suggest that such antiidiotype antibodies may be useful in patients with melanoma. Use of cross-linked antibodies or humanized antibodies has yet to be clinically explored in this disease but may represent promising approaches. A reversal in the long-term increase in deaths attributable to malignant melanoma. 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A pilot study of the tolerability and pharmacokinetics of vinorelbine in patients with varying degrees of liver dysfunction. Improved disease-free survival and overall survival from the addition of sequential paclitaxel, but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results from an Eastern Cooperative Oncology Group trial. Characterization of the Taxol binding site on the microtubule: 2-(m-azidobenzoyl)taxol photolabels a peptide (amino acids 217-231) of beta tubulin. Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistant protein. 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Taxol-requiring mutants of Chinese hamster ovary cells with impaired mitotic spindle activity. Taxol-resistant ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. Resistance to microtubule-targeted cytotoxins in a K562 leukemia cell variant associated with altered tubulin expression and polymerization. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. Paclitaxel resistance in nonsmall cell lung cancer associated with beta tubulin gene mutations. Taxol and estramustine-induced modulation of human prostate cancer cell apoptosis via alteration in bcl-x L and bax expression. Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Taxol-induced mitotic block triggers rapid onset of a p53-independent apoptotic pathway. Microtubule-active drugs Taxol, vinblastine, and nocodazole increase the level of transcriptionally active p53. 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Effect of estramustine phosphate on the assembly of isolated bovine brain microtubules and fast axonal transport in the frog sciatic nerve. Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action. Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue. Selective antimitotic effects of estramustine correlate with its antimicrotubule properties on glioblastoma and astrocytes.

Brachytherapy is usually delivered using afterloading applicators that are placed in the uterine cavity and vagina mood disorder in children symptoms purchase wellbutrin sr 150 mg mastercard. A number of different intracavitary systems have been used; in the United States depression test for social security buy cheap wellbutrin sr 150mg on line, variations of the Fletcher-Suit-Delclos low dose-rate system are still used most commonly depression explained in a picture 150mg wellbutrin sr free shipping. Vaginal packing is used to hold the tandem and colpostats in place and to maximize the distance between the sources and the bladder and rectum depression vs manic depression cheap wellbutrin sr 150mg amex. Radiographs should be obtained at the time of insertion to verify accurate placement mood disorder background order wellbutrin sr 150 mg with mastercard, and the system should be repositioned if positioning can be improved depression definition money 150mg wellbutrin sr for sale. Encapsulated radioactive sources are inserted in the applicators after the patient has returned to her hospital bed, reducing exposure to personnel during applicator placement. Remote afterloading devices that further reduce personnel exposure are often used in departments that treat many patients with gynecologic disease. Although 226Ra was used to treat most patients before the 1980s, it has gradually been replaced by 137Cs, which produces a similar dose distribution and avoids the radiation protection problems caused by the radon gas by-product of radium decay. Brachytherapy Dose Ideal placement of the uterine tandem and vaginal ovoids produces a pear-shaped distribution, delivering a high dose to the cervix and paracervical tissues and a reduced dose to the rectum and bladder (. Posteroanterior and lateral views of a Fletcher-Suit-Delclos applicator system in a patient with invasive carcinoma of the cervix. Treatment dose has been specified in a number of ways, making it difficult to compare experiences. Paracentral doses are most frequently expressed at a single point, usually designated point A. This reference point has been calculated in a number of different ways, but it is usually placed 2 cm lateral and 2 cm superior to the external cervical os, in the central plane of the intracavitary system (see. Point A lies approximately at the crossing of the ureter and the uterine artery, but it bears no consistent relationship to the tumor or target volume. Point A was originally developed as part of the Manchester treatment system (a modification of the earlier Paris system). It was meant to be used in the context of a detailed set of rules governing the placement and loading of the intracavitary system. Other measures have been used to describe the intensity of intracavitary treatment. Mg-hrs or mgRaEq-hrs are proportional to the dose of radiation at relatively distant points from the system and therefore give a sense of the dose to the whole pelvis. In 1985 the International Commission on Radiation Units and Measurements recommended use of total reference air Kerma, expressed in mGy at 1 m, as an alternative to mg-hrs that allows for the use of various radionuclides. Although normal tissue reference points provide useful information about the dose to a portion of normal tissue, several studies have demonstrated that they consistently underestimate the maximum dose to those tissues. Source strengths and positions should be carefully chosen to provide optimal tumor coverage without exceeding normal tissue tolerance. However, optimized source placement can rarely correct for a poorly positioned applicator. A detailed description of the characteristics of an ideal intracavitary system and of the considerations that influence source strength and position are beyond the scope of this chapter but can be found elsewhere. If the intracavitary placement has been optimized, this can usually be accomplished without exceeding a dose of 75 Gy to the bladder reference point or 70 Gy to the rectal reference point, doses that are usually associated with an acceptably low risk of major complications. To choose a treatment that optimizes the therapeutic ratio in these circumstances requires experience and a detailed understanding of factors that influence tumor control and normal tissue complications. A total dose (external-beam and intracavitary) of 50 to 55 Gy appears to be sufficient to sterilize microscopic disease in the pelvic nodes in most patients. It is customary to boost the dose to a total of 60 to 65 Gy in lymph nodes known to contain gross disease and in heavily involved parametria. Brachytherapy Dose Rate Traditionally, cervical brachytherapy has been performed with sources that yield a dose rate at point A of approximately 40 to 50 cGy/h. These low dose rates permit repair of sublethal cellular injury, preferentially spare normal tissues, and optimize the therapeutic ratio. In an effort to reduce the 3 to 4 days of hospitalization needed to deliver an appropriate dose of low dose-rate irradiation, some investigators have explored the use of intermediate dose-rate brachytherapy (80 to 100 cGy/h). On the basis of laboratory studies, Amdur and Bedford have suggested that differences in the magnitude of the dose-rate effect between tumor and normal tissues may in part reflect differences in the half-times for repair of sublethal radiation damage. High dose-rate intracavitary therapy is now being used for radical treatment of cervical cancer by a number of groups, including several in Japan, Canada, and Europe, and more recently by some groups in the United States. However, unless it is heavily fractionated, high dose-rate brachytherapy loses the radiobiologic advantage of low dose-rate treatment, potentially narrowing the therapeutic window for complication-free cure. Published experiences suggest that survival rates are roughly similar to those achieved with traditional low dose-rate treatment, but these experiences are difficult to compare because of the same potential problems of selection bias that confound other nonrandomized comparisons. The use of high dose-rate brachytherapy for cervical cancer continues to be a source of controversy. Several groups have advocated the use of interstitial brachytherapy to treat patients whose anatomy or tumor distribution make it difficult to obtain an ideal intracavitary placement. Interstitial implants are usually placed transperineally, guided by a Lucite template that encourages parallel placement of hollow needles that penetrate the cervix and paracervical spaces; needles are usually loaded with 192Ir. Advocates of the procedure describe the relatively homogeneous dose distribution achieved with this method, the ease of inserting implants in patients whose uteri are difficult to probe, and the ability to place sources directly into the parametrium. Early reports were enthusiastic, describing these theoretical advantages and high initial local control rates, but these early reports rarely included sufficient numbers of patients or had long enough follow-up to provide long-term survival rates. Local control rates were 22% and 44%, respectively, and for patients with local control, the rate of complications requiring surgical intervention was high. However, outside of an investigational setting, interstitial treatment of primary cervical cancers should probably be limited to patients who cannot accommodate intrauterine brachytherapy and patients with distal vaginal disease that requires a boost with interstitial brachytherapy. During radiotherapy of the pelvis, most patients have mild fatigue and mild to moderate diarrhea that usually is controllable with antidiarrheal medications; some patients have mild bladder irritation. When extended fields are treated, patients may have nausea, gastric irritation, and mild depression of peripheral blood counts. Unless the ovaries have been transposed, all premenopausal patients who receive pelvic radiotherapy experience ovarian failure by the completion of treatment. Perioperative complications of intracavitary therapy include uterine perforation, fever, and the usual risks of anesthesia. All four fatal pulmonary embolisms were in patients with advanced pelvic wall disease. Estimates of the risk of late complications of radical radiotherapy vary according to the grading system, duration of follow-up, method of calculation, treatment method, and prevalence of risk factors in the study population. However, most reports quote an overall risk of major complications (requiring transfusion, hospitalization, or surgical intervention) of 5% to 15%. Although the actuarial risk was greatest during the first 3 years of follow-up, there was a continuing risk to surviving patients of approximately 0. During the first 3 years after treatment, rectal complications are most common and include bleeding, stricture, ulceration, and fistula. In the study by Eifel and colleagues,356 the risk of major rectosigmoid complications was 2. Major gastrointestinal complications were rare 3 years or more after treatment, but a constant low risk of urinary tract complications persisted for many years (. Complication rates were calculated actuarially, and patients who died without experiencing a major complication were censored at the time of death. The risk is increased dramatically in patients who have undergone transperitoneal lymph node dissection. More significant vaginal shortening can occur, particularly in elderly, postmenopausal women and those with extensive tumors treated with a high dose of irradiation. Although these studies differed in their inclusion criteria, treatment specifics, and control treatments, each demonstrated reduction in the relative risk of recurrence of 30% to 50% with cisplatin-containing chemoradiation (Table 36. Prospective Randomized Trials That Investigate the Role of Concurrent Radiotherapy and Cisplatin-Containing Chemotherapy for Patients with Loco-Regionally Advanced Cervical Cancer Individual investigators and multiinstitutional groups have been exploring combinations of chemotherapy and radiation in patients with cervical cancer for more than 25 years. However, until relatively recently, studies had failed to demonstrate a clear benefit. The first of these 361 compared hydroxyurea (80 mg/kg given twice per week during external-beam irradiation) with misonidazole, a nitroimidazole hypoxic cell sensitizer that has since been demonstrated to be of no benefit in several trials that compared misonidazole with a placebo. All three of the cisplatin-containing arms had local control and survival rates superior to those for the control (hydroxyurea and radiation) arms. Patients who received cisplatin were more likely to have a complete histologic response and were more likely to be disease free at the time of preliminary analysis. In a preliminary analysis, patients who received chemotherapy in this study also had a better disease-free survival rate. This is the only study in which chemotherapy was administered during both the brachytherapy and external-beam components of treatment. The results of this trial were released early when highly significant differences were detected in the rates of local control, distant metastasis, overall survival, and disease-free survival favoring the treatment arm that included chemotherapy. Although acute toxic effects of treatment were greater with chemotherapy, the dose and duration of radiation were similar in the two arms, and in an early analysis, there was no significant difference in the incidence of late treatment-related complications. This work clearly demonstrates that the addition of concurrent cisplatin-containing chemotherapy benefited patients with locally advanced cervical cancer who were treated with radiation in these studies. However, all of the studies explicitly excluded patients with evidence of paraaortic lymph node metastases, poor performance status, or impaired renal function. In the future, clinicians will be challenged to determine how these favorable results can be generalized to patients with cervical cancer who may not have been included in the prospective trials because of severe medical or social problems and to the developing nations where invasive cervical cancer is epidemic. These studies raise other interesting questions that will undoubtedly be the subjects of future studies. Other drugs that are being studied for their radiosensitizing effects in patients with advanced disease are paclitaxel, 364 carboplatin, 365 and mitomycin C. Combinations of extended-field irradiation and chemotherapy appear to be feasible, but the acute toxicity is considerable, and late toxicity may be greater than with extended-field radiation alone. A number of investigators have explored the use of neoadjuvant chemotherapy for locally advanced cervical carcinoma, trying to exploit the encouraging response rates that have been reported for multiple-agent, cisplatin-containing regimens in previously untreated patients (see Table 36. In one small trial from South America,376 patients treated with bleomycin, vincristine, methotrexate, and cisplatin followed by radiation had a significantly poorer survival rate than did those treated with radiation alone. In addition, patients who failed to complete radiotherapy (and were excluded from the analysis) were more frequent in the neoadjuvant chemotherapy arm. Bleomycin toxicity (responsible for four of the deaths) contributed to the poor survival rate of patients treated with neoadjuvant chemotherapy in this study. Tattersall and colleagues 379 compared neoadjuvant chemotherapy (cisplatin and epirubicin) followed by radiotherapy with radiotherapy alone. This study was discontinued when an interim analysis revealed a significantly poorer outcome for patients who received neoadjuvant chemotherapy (P =. Results of Prospective Randomized Trials That Compared Neoadjuvant Chemotherapy Followed by Radiation Therapy with Radiation Therapy Alone in Patients with Locally Advanced Cervical Cancer In another interesting study, published by Chauvergne and colleagues, 373 patients who had a complete or partial response to chemotherapy followed by radiotherapy had a significantly better outcome than did those who had a poorer response to neoadjuvant chemotherapy. However, there were no significant differences in the overall response rates, disease-free survival rates, or median survival between patients treated with neoadjuvant chemotherapy and those treated with radiation alone. In summary, despite the high rate of response of locally advanced cervical cancers to initial chemotherapy, none of the randomized studies reported to date has demonstrated an improvement in outcome when neoadjuvant chemotherapy was added to radical radiotherapy. In many ways this recapitulates the experience with treatment of locally advanced head and neck cancers, in which it has been hypothesized that the failure of neoadjuvant chemotherapy to influence outcome may reflect cross-resistance of tumor cells to drugs and radiation or accelerated repopulation of tumor clones induced by neoadjuvant chemotherapy. In their study, Sardi and colleagues 299 randomly assigned 205 patients to receive radical hysterectomy with or without neoadjuvant chemotherapy. There have not yet been any comparisons between this approach and radiotherapy alone or combined with chemotherapy. Intraarterial infusion of chemotherapeutic agents delivered in the neoadjuvant setting, concurrent with radiotherapy, or as salvage treatment for recurrent disease has generated interest for some years because of the distinct arterial supply to the central pelvis. Unfortunately, this technique is difficult and invasive, the toxicity reported in some series has been substantial, and the results have been variable in several small series of patients. However, occasional optimistic reports have maintained some interest in this approach, particularly for concurrent intraarterial chemotherapy and irradiation. The care of these patients must emphasize palliation of symptoms with appropriate pain medications and localized radiotherapy. Many drugs have been studied for their activity in patients with recurrent or metastatic carcinoma of the cervix. Approximately 20 have yielded response rates (partial and complete) of at least 15% and may be of therapeutic value (Table 36. Although there appears to be a small but statistically significant increase in the response rate with a doubling of the dose to 100 mg/m 2, this has not resulted in a detectable improvement in the rates of progression-free or overall survival. More prolonged infusion of the same dose over 24 hours yields a similar response rate with less nausea and vomiting, although the development of more effective antiemetic agents reduces the clinical importance of this observation. Three studies that included patients who had not had prior radiotherapy reported response rates of 65% to 100%. Again, response rates decrease significantly if patients have had previous irradiation. The addition of mitolactol did not improve the response rate or survival duration. Localized radiotherapy can provide effective pain relief for symptomatic metastases in bone, brain, lymph nodes, or other sites. A rapid course of pelvic radiotherapy can also provide excellent relief of pain and bleeding for patients who present with incurable disseminated disease. Patients should be evaluated for possible recurrent disease if a new mass develops; if, in irradiated patients, the cervix remains bulky or nodular or cervical cytologic findings are abnormal 3 months or more after irradiation; or if symptoms of leg edema, pain, or bleeding develop after initial treatment. The diagnosis must be confirmed with a tissue biopsy, and the extent of disease should be evaluated with appropriate radiographic studies, cystoscopy, proctoscopy, and serum chemistry studies before treatment is administered.

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