Principles of radiation therapy in low‐resource and well‐developed settings, with particular reference to cervical cancer

Gynecological cancers are common in low-resource countries. Cervical cancer is one of the leading cancers in women in India and the fourth most common cancer in women globally. Surgery with or without radiotherapy is commonly used to treat uterine, vulvovaginal, and early cervical cancer. Radiotherapy plays an important role in the management of cervical cancer, where it is routinely used in radical/curative, adjuvant, and palliative settings [1,2]. The aim of radiation therapy is to achieve loco-regional control of cancer while preserving normal tissue functions. Solid tumors have a variable fraction of clonogenic cells that proliferate like any other normal tissues in the body. All clonogenic tumor cells must be eradicated to achieve a cure. To improve the chances of cure, radiation doses may have to be increased in proportion to the clonogens found in the tumor. An increased radiation dose may also increase toxic and/or acute reactions. The increased acute toxicity may be acceptable, provided it heals without any deleterious effects on the quality of life in surviving patients. Late radiation effects from pelvic radiotherapy may result from damage to the rectosigmoid colon, bladder, small bowel, pelvic and femoral bone, and bone marrow. The long-term effects of radiation in these tissues can be minimized by using shrinking radiation fields, appropriate shielding and, where possible, conformal radiation techniques giving differential doses to subclinical disease and gross disease while sparing surrounding non tumor-containing normal tissues. The tolerance of the cervix and uterus to radiation is usually more than 200 Gy. With these doses, the rate of necrosis is less than 1%. The upper vagina and distal vaginal mucosa can be treated up to140 Gy and 100 Gy, respectively. Threshold doses reported for vesicovaginal fistula and rectovaginal fistula are 150 Gy and 80–90 Gy, respectively. However, these fistulas can occur at much lower doses when the bladder base or rectovaginal septum has been grossly infiltrated by tumor. The radiation-induced adverse effects and their manifestations depend on the type of tissues receiving radiation. Early responding tissues such as the skin and intestinal mucosa have a high cell turnover and they express radiation injury at about 2–3 weeks following radiotherapy. Late responding tissues such as spinal cord, rectal wall, bladder, and kidneys have a slow cell turnover. Radiation injury in these tissues is expressed in months or years after radiotherapy, as the radiated cell population slowly enters the active cell cycle phase. In summary, the radiation tolerance is relatively high for the cervix and vagina and low for adjacent organs. The standard of care for cervical cancers FIGO Stage Ib2 − IIIb is radical radiation therapy with or without concomitant cisplatin chemotherapy. Radical radiation therapy for cervical cancer consists of a combination of external beam radiotherapy (EBRT) to the pelvis covering the uterus, cervix, parametria, and pelvic nodes. This is followed by brachytherapy to the primary tumor. The aim is to deliver a dose, equivalent to 80–85 Gy EQD2 (equivalent dose in 2 Gy per fraction) to point A. The planned radical radiation/concomitant chemoradiation should be completed within 8 weeks. Prolonging overall treatment time results in poorer outcomes [3]. Using conventional fractionation, a dose of 40–50.4 Gy in 1.8 or 2 Gy fractions over a period of 4–6 weeks is recommended. Anterior-posterior (AP-PA) portals or a four-field box arrangement can be used. Shielding corners of radiation fields helps in reducing the dose to the rectum, bladder, and small bowel, thereby reducing the toxicities. Either conventional fluoroscopy-guided or computerized tomography (CT)-based planning can be used for EBRT. CT-based planning is increasingly used because of the wider availability of CT simulators in many centers throughout the world. Fluoroscopy-guided conventional planning is usually performed with the patient in the supine position. Where a belly board is available, patients can be planned and treated in the prone position. This helps to push the small bowel loops out of the pelvis into the abdomen. Under fluoroscopy guidance, bony landmarks are used to mark the portals. For the AP-PA two-field technique, the upper border of the pelvic treatment portal is located at the L4–5 or L5–S1 interspace. The lower extent of the pelvic field is located at the midpubis or inferior border of the obturator foramina or to a line 2–3 cm below the lowest vaginal disease level. Radio-opaque markers may be placed in the vaginal cavity to identify the disease on the cervix or vagina. The fields may be extended superiorly if microscopic or gross metastatic disease is suspected in para-aortic nodes. The lateral borders of the pelvic field are placed at least 1.5–2.0 cm lateral to the pelvic brim (bony pelvic sidewall). The lateral borders can be increased and corner shielding reduced in obese patients to compensate for patient movement during treatment. Using a four-field technique results in lower radiation toxicities compared with two-field AP-PA portals. In the four-field technique (anterior-posterior and bilateral portals), the anterior border of the field should be 1 cm anterior to the pubis to adequately cover the uterine fundus and the anterior extent of the external iliac group of nodes with adequate margins. The posterior border should be at the S3 vertebra to include the pre-sacral nodes located in front of the first and second sacral vertebrae and uterosacral ligaments. Customized blocks to shield the small bowel region anterior-superiorly and the lower anorectal region on the lateral fields are helpful in reducing late radiation toxicities in these tissues. Additionally, inguinal nodes should be included if the disease is extends into or beyond the lower third of the vagina. A planning CT (slices 3–5 mm in thickness) of the abdomen and pelvis using fiducial skin markers with intravenous contrast is commonly used. Intravenous contrast assists in differentiating between vessels and nodes. Conformal planning with two fields AP-PA or a four-field box technique with blocks or multileaf collimators is planned after contouring various structures and targets individually. Various conformal radiation techniques are used. These include the three-dimensional conformal radiation technique (3D-CRT), intensity modulated radiation therapy (IMRT) with or without image guidance (IGRT). The ultimate in dose conformity and dose escalation for primary tumors of the cervix is achieved using brachytherapy. The use of brachytherapy results in organ sparing and improved therapeutic outcome in terms of local control and reduced toxicities. In the recent past, IMRT/SBRT boost have been tried in place of brachytherapy. The results of such treatments have been significantly inferior [4]. An accurately placed brachytherapy application delivers high radiation doses to the cervix, upper vagina, and medial parametria and relatively lower doses to the rectum and bladder. Historically, brachytherapy was delivered with low dose rate (LDR) and medium dose rate (MDR) systems. This is being progressively replaced with fractionated high dose rate (HDR) systems. Randomized trials and meta-analysis comparing LDR with HDR brachytherapy in cancer of the uterine cervix have shown to be equally effective in terms of local control and survival [5,6]. Either LDR or HDR brachytherapy can be used, taking into account the availability of equipment and other logistics of treatment delivery. HDR brachytherapy can be performed as a day procedure in contrast to approximately 15–20 hours of continuous LDR treatment. LDR treatment requires an overnight hospital stay as an inpatient. Radiobiological considerations arising from using HDR radiation would require 3–5 applications of brachytherapy compared with 1–2 applications of LDR. There are increasing reports of fewer complications and better local control using HDR and this is becoming the preferred option [6]. Fractionated HDR brachytherapy treatment is started in the fifth week of external radiation preferably after obtaining optimum primary tumor shrinkage. A dose of 7 Gy to point A per fraction and 3–5 fractions depending on the EBRT doses and cumulative doses to the organs at risk (bladder and rectum) is delivered. For early stage (IB − IIA) cancer, local control rates of 75% and disease-free survival of 60% − 62% at 8 years have been reported. The disease outcome is better for small tumor sizes where both EBRT and brachytherapy have been used. For advanced disease, the outcome is better for FIGO IIB (65% − 70% at 8 years) as compared with FIGO IIIB (40% at 8 years). Radical radiation therapy with conventional 2 Gy per fraction and higher total doses with intracavitary brachytherapy without concomitant chemotherapy improves disease-free survival, which has been reported in a low-resource country setting [7]. The outcome improves with refinement of treatment protocols, a multimodality treatment approach, and with improved compliance to planned treatment [7]. Five randomized Phase III trials of radical radiotherapy alone versus concurrent cisplatin-based chemotherapy and radiotherapy for the treatment of cancer of the uterine cervix have shown the superiority of concurrent chemoradiotherapy [2,8–11]. A further meta-analysis has shown an absolute benefit in overall survival and progression-free survival with chemoradiotherapy in patients with Stage IB2 − IVA and high-risk patients after hysterectomy [12,13]. While these trials vary somewhat in terms of heterogeneity in data, stage of disease, suboptimal doses of radiation, nonuniform usage of chemotherapeutic drugs, different schedules and doses of cisplatin, they all demonstrated a significant survival benefit for concurrent chemoradiotherapy. The sole exception was a Canadian trial that did not find any survival benefit of concurrent weekly cisplatin over radiotherapy alone [14]. The major criticism of the Canadian study was that nearly two-thirds of the patients who received chemoradiation had low hemoglobin, which was not corrected during radiation and this may have had a negative impact on the therapeutic outcome [14]. Subsequently, an individual patient data-based Cochrane meta-analysis suggested an estimated absolute survival benefit of 10% (Stage IA to IIA), 7% (Stage IIB), and 3% (Stage III − IVa) at 5 years. This analysis also showed a trend toward better outcome in patients receiving adjuvant chemotherapy following concomitant chemoradiation, which needs further evaluation [15]. While chemoradiation is regarded as the new standard of care for women with cervical cancer, it is worth remembering that these results were obtained in a trial setting in women from affluent countries who had better nutritional or performance status and generally had normal renal function compared with the majority of women from lower socioeconomic countries. Women from low-income countries generally present with significantly more advanced disease, poorer performance status, and may not tolerate combination therapy as well as women in better general health. Therefore, radical radiotherapy alone could be considered for women with doubtful compliance or poor tolerance to combined modality treatment, taking into account comorbid conditions and social circumstances. Results of a large ongoing, randomized study of chemoradiotherapy versus radiotherapy from India (NC00193791) are awaited. Vault cancers in patients undergoing hysterectomy for presumed benign disease or subtotal hysterectomy for invasive cancers and relapse following primary surgery may be treated either by radical radiation or pelvic exenteration. Radical irradiation (with or without concurrent chemotherapy) may cure a substantial proportion of patients with isolated pelvic failure after primary surgery. Radiation doses and volumes should be tailored to the extent of disease. A dose of 45–50.4 Gy in 1.8–2.0 Gy fractionation should be delivered to microscopic disease followed by further boost to the gross tumor volume with brachytherapy or EBRT to a total dose of 64–66 Gy. The EBRT boost dose should be reduced if concurrent chemoradiotherapy is used. Use of an appropriate brachytherapy boost—especially a perineal interstitial boost—for residual disease with or without cisplatin chemotherapy results in a clinical outcome comparable with advanced cervical cancers [16]. Where synchronous pelvic and distant recurrence is noted following primary radiotherapy for cervical cancer, a trial of chemotherapy for symptomatic control is indicated. Cisplatin and sometimes carboplatin with paclitaxel is used. The expected median time to progression or death in such patients is 3–7 months. It could be longer if disease is controlled in the radiated field and recurrence is observed outside the previously treated volume. The only potentially curative treatment of local failure after primary irradiation is surgery provided the recurrence is limited to the cervix and uterus. Pelvic exenteration is often required owing to postradiation pelvic fibrosis or if clear resection margins between the bladder and rectum are not possible. Surgical salvage is contraindicated when in addition to central recurrence there is pelvic sidewall involvement or in the presence of extrapelvic disease. The triad of unilateral leg edema, sciatic pain, and ureteral obstruction is indicative of the extension of disease to the pelvic sidewall and signifies unresectable disease. Salvage surgery should only be undertaken in centers equipped with facilities and expertise to manage complex surgery and its complications. The prognosis of recurrent disease is better for patients with a disease-free interval of greater than 6 months and with a recurrence 3 cm or less in diameter located centrally. Following proper selection of patients, the five-year survival with pelvic exenteration is in the order of 30% and in those suitable for hysterectomy it is 60%. Alternately, in a select group of patients with local recurrence, salvage re-irradiation using brachytherapy can be offered. The outcome with salvage re-irradiation is better with a longer disease-free interval and if there are no late toxicities from prior radiotherapy. This is achieved with higher brachytherapy doses [17]. Chemotherapy has a palliative role in patients with metastatic or recurrent cervical cancer. There are a number of chemotherapeutic agents with activity in metastatic or recurrent cervical cancer. Cisplatin is the most active cytotoxic agent, with a response rate of 20%–30% and a median survival of 7 months. A combination of paclitaxel and carboplatin was superior to cisplatin alone in terms of response, progression-free survival, and sustained quality of life but not overall survival [18]. In another Gynecologic Oncology Group (GOG) study, the combination of topotecan and cisplatin was superior to cisplatin alone for response, progression-free survival, and overall survival [19]. Therefore, selected patients with recurrent or metastatic disease in good general condition could be offered one of the combination regimens. For others, single agent cisplatin or carboplatin and best supportive care continue to be appropriate choices. Many biological agents have been tried in the treatment of recurrent, persistent, or metastatic cervical cancer. In a recent randomized study, the use of bevacizumab in addition to chemotherapy (paclitaxel plus carboplatin or topotecan plus paclitaxel) has shown an improvement in median overall survival of 3.7 months [20]. Distant metastases should be treated with palliative intent using chemotherapy or radiotherapy or symptomatic and supportive care only. Local treatment with radiation therapy is indicated to sites of symptomatic metastatic disease. The symptoms may arise from skeletal metastases, enlarged para-aortic or supra-clavicular nodes, or because of other distant metastases. Occasionally, fully fractionated chemoradiotherapy to isolated para-aortic nodal metastases can result in long-term survival and should be attempted. In view of the shortened life expectancy of patients with metastatic cervical cancer, palliative radiotherapy should be given using larger fractions over shorter periods than the duration of conventional radical courses of treatment. Prospective evaluation of hypofractionated radiotherapy of advanced pelvic cancers was carried out by the Radiation Therapy Oncology Group. A total dose of 44.40 Gy was given in 12 fractions over three courses. Each course consisted of 4 fractions (QUAD SHOT) given twice a day over 2 days and repeated after an interval of 4 weeks. The regimen was modified to 14 Gy in 4 fractions repeated two or three times, based on the patient's general condition, giving a total dose of 42 Gy over 2 months. The moderate acute effects are usually seen at around 10 days following the fourth fraction and these usually heal by the time the patient returns for the subsequent course. This regimen is better tolerated than 42 Gy given in 12 fractions and given over 5 days a week, which produces higher and longer-lasting acute effects on normal tissues for a similar tumor response [21]. Acute complications manifest during treatment, subacute complications occur at 3–6 months, and late effects manifest after 6 months of treatment. During pelvic radiotherapy, most patients experience mild to moderate fatigue and diarrhea, which respond to rest and antidiarrheal medications. Some women experience bladder irritation. These acute symptoms are increased when combined with concurrent chemotherapy or extended field radiation. Patients receiving concurrent chemotherapy may additionally have hematological and nephrotoxicity (cisplatin). The late sequelae following radiation therapy commonly affect rectal, bladder, and small bowel function. These effects are radiation dose-dependent and usually become evident on prolonged follow-up. The reported grade III/IV late toxicities (requiring hospital admission or intervention) range from 5% to 15%. In patients treated with image-guided brachytherapy, the incidence of such radiation effects has been reduced to less than 3% [22]. Late rectal sequelae in the form of chronic tenesmus, telangiectasia and profuse bleeding, rectal ulceration, and strictures have been reported (5%–8%). These are usually seen during the 18–36-month follow-up period. The treatment options include steroid enemas, argon plasma coagulation, laser, or formalin application to the affected mucosa. Occasionally a diversion colostomy may be required. Late bladder complications may manifest as hematuria, necrosis, and rarely vesicovaginal or urethrovaginal fistula. The incidence of symptomatic grade III/IV late toxicities of the bladder after radical radiation is 4%–8%. When other measures fail, hyperbaric oxygen therapy (HBOT) may be tried for the treatment of hematuria. The use of HBOT remains controversial however [23]. Late small bowel sequelae may manifest as chronic enteritis, subacute intestinal obstruction, perforation, and/or strictures. The incidence of symptomatic grade III/IV late toxicities of small bowel following radical irradiation is 3%–12%. These sequelae are higher in patients receiving adjuvant radiotherapy after radical surgery especially with transperitoneal lymphadenectomies. This is due to the cumulative and additive effects resulting from the combination of two major radical treatment modalities [1]. Most patients treated with radical radiotherapy have telangiectasia and fibrosis of the vagina, and significant vaginal shortening resulting in decreased sexual satisfaction and painful intercourse. These complications can be minimized by appropriate counseling and training in the use of estrogen cream with vaginal cylinders at the time of radiotherapy. The weekly application of estrogen with a vaginal cylinder should be continued in all women irrespective of their sexual status. This is necessary to avoid thinning of vaginal mucosa thereby avoiding vaginal spotting, which may be perceived by patients as a sign of recurrent cancer. Regular sexual activity is likely to enable some stretching of the vagina. During sexual intercourse, oil-based lubricants are advised rather than water-based lubricants. Limiting doses to normal tissues: This factor is of paramount importance and is going to be increasingly relevant in the future with the practice of increasing doses to target volume [22,26–28]. Dose escalation to the gross disease volume (primary and nodes) is theoretically an important application of IMRT to any site. For cervical cancer, brachytherapy excludes most of such need at the primary tumor site. However, in locally advanced stages with inappropriate geometry and size of residual disease not suited for brachytherapy, IMRT could be used [29,30]. Concomitant boost application to special target regions can be achieved using IMRT. These regions may include pelvic or para-aortic lymph nodes or the lateral one-third of the parametrium [22]. Radical treatments for para-aortic lymph nodes: Although FIGO staging does not change with identification of para-aortic lymph nodes identified in imaging alone, the treatment should. Recently, several authors have prescribed doses of 60–66 Gy with concurrent chemotherapy and have demonstrated good local control and acceptable toxicities [28,31,32]. However, the effect of such dose escalation on long-term survival remains to be seen. Historically, the brachytherapy systems formulated by the Manchester, Paris, and Stockholm groups were based on clinical experience. These groups managed to deliver curative doses to the cervical tumor in the absence of treatment planning systems. 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The Group and the for and Oncology for and practice of the of dose volume imaging and quality These have been to these the target the gross tumor volume seen in the the high-risk clinical target volume of the cervix and presumed disease extension at the time of brachytherapy on clinical and treatment planning and the volume up to a 5 − around to the disease at also with the standard of dose either point A or the Gy and the and to target while the dose to the organ at Various dose volume to target and and organs at risk have been There are no dose volume recommended. The for various targets and for organs at risk are at present and A large from the group has reported the clinical outcome of patients treated with image-guided brachytherapy combined with conformal EBRT with or without chemotherapy The results are with local control rates of at 3 years in (Stage groups and in response (Stage groups with acceptable with their there is a in pelvic recurrence by and a in major form other centers have been reported is being further in an study several in the and and However, the use of imaging for fractionated brachytherapy planning is not routinely owing to the availability of in radiotherapy The use of imaging modalities such as CT and for is being with For low-income and countries where cervical cancer is a major use of a imaging modality like would result in to cervical brachytherapy. intracavitary brachytherapy for cervical cancer has also been The of the availability of its in and and the small would the application of this modality especially in low-resource countries. Recently, one of the single of and of conformal brachytherapy of cervical cancer reported their of late and survival The conformal brachytherapy has reduced long-term usually with brachytherapy for cervical cancer. However, the effects of such conformal radiotherapy on long-term survival to be The authors have no of to The is not for the or of any by the than should be to the for the

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