300 mg/m2 5 days / wk during pelvic XRT '
Abbreviations: XRT, radiation therapy; CTX, chemotherapy; CI, continuous infusion; 5-FU, tluorouracil; NR, not reported.
Reprinted with permission from Janjan NA, Delclos ME, Ballo MT, Crane CH. Hie colon and rectum. In: Cox JD, Ang KK, eds. Radiation Oncology: Rationale, Technique, Results. 8th ed. St. Louis, MO: Mosby; 2003:497-536.
infusion 5-FU during preoperative chemoradiation. With lower total doses of preoperative radiation (45 Gy) and continuous infusion of 5-FU, down-staging rates were similar to those in series that administered higher total radiation doses. When accelerated fractionation (concomitant boost) was used to deliver a total radiation dose of 52.5 Gy with a continuous infusion of 5-FU, the pathologic downstaging rates were approximately 20% higher and the pathologic complete response rates were nearly twice those of other series using the same or higher doses of radiation and bolus or intermittent infusion of 5-FU (Table 10-6).
Besides permitting sphincter-preserving surgery, tumor downstaging may also have prognostic importance. The degree of response to preop-erative radiation therapy also has been reported to influence survival rates in patients with locally advanced rectal cancers. Five-year overall survival rates after preoperative radiation therapy were 92% for patients whose tumors were downstaged to Duke's stage 0 or A but only 67% and 26%, respectively, for patients whose tumors were downstaged to Duke's stage B or C (Berger et al, 1997).
Hematologic and gastrointestinal side effects need to be closely monitored during the course of chemoradiation. Chemotherapeutic agents used in the treatment of rectal cancer, like 5-FU and irinotecan, cause diarrhea. In addition to these side effects, other side effects of chemotherapy include hand-foot syndrome, mucositis, and mucosal superinfection, especially candidiasis. Occasionally mild nausea can occur, so nutritional status and fluid balance must be evaluated. Because radiation effects are well defined, gastrointestinal side effects that occur in the first 2 weeks of radiation therapy are generally attributable to chemotherapy. A pharmacokinetic study showed a wide variation in 5-FU metabolism and showed that these variations were directly correlated with variations in toxicity (Gamelin et al, 1996). Acute side effects correlated with plasma 5-FU levels greater than 3,000 mg/l and not with the 5-FU dose that was administered. Possible infection with Clostridium difficile should always be considered in patients with intractable diarrhea. Clinical signs, like fever and blood in the stool, may suggest underlying sepsis and should initiate prompt evaluation. Other etiologies should be considered if the symptoms are not typical or if they are refractory to usual supportive-care strategies.
A 3-step bowel management program has been instituted at M. D. Anderson (Callister et al, 2000) (Table 10-7). At the time of treatment simulation, all patients receive written instructions in bowel management and prescriptions for an antidiarrheal (loperamide) and an antiemetic to be used if symptoms develop. The 3-step program anticipates the development of treatment-related side effects; at the first sign of symptoms, patients proceed to the next step of the bowel management strategy. Under this program, patients should not have more than 3 bowel movements in
Table 10-7. The University of Texas M. D. Anderson Cancer Center 3-Step Bowel Management Program
1 Loperamide (1-2 tablets) as needed.
2 Loperamide (1-2 tablets) 4 times a day on a scheduled basis half an hour before meals and before bedtime.
3 • Continue loperamide (1-2 tablets) 4 times a day and begin opioid analgesics.
• Add a sustained-release analgesic like morphine or oxycodone and an immediate-release analgesic for breakthrough abdominal cramping or stooling.
• The analgesics are titrated to effect using the same principles that are used in pain management.
• Because of difficulties in titration and changing needs over the course of radiation therapy, the use of a fentanyl patch is avoided unless fentanyl is required for primary pain management.
• The goal is to give sufficient medications to consistently control frequent stooling and abdominal cramping.
* If one step is ineffective, the next step is used. Medications are titrated to effect. The goal is to maintain 3 or fewer stools per day.
a day; it is important to recognize that patients do not need to have watery or loose stools to follow the bowel management guidelines. The goal is to prevent, rather than treat, symptoms like frequent stooling, fluid and electrolyte imbalance, and skin irritation.
In step 1, loperamide is used as needed. In step 2, scheduled administration of loperamide is begun to prevent, rather than treat, symptoms of frequent stooling. In step 3, opioid analgesics are added to the loperamide, to relieve the symptoms of abdominal cramping and to exploit the constipating effects of opioid analgesics. Established principles for pain management are used to titrate the dose to effect. Unlike the case with loperamide, there is no dose limit with opioid analgesics, and usually the doses of opioids required in step 3 are modest. Because the treatment-related changes in the bowel do not resolve during therapy, a sustained-release analgesic is preferred in step 3 to avoid the need for multiple doses of medications during the day. Medications that have a 3-hour duration of effect, like tincture of opium or short-acting analgesics, can result in cycles of symptoms and disrupted sleep if a strict schedule of administration is not followed. Fentanyl patches are usually avoided because of the difficulty in titration and because analgesic needs are not always stable as patients undergo radiation therapy. However, fentanyl in lozenge form is highly effective in relieving incident-related pain, like pain during defecation, in patients with distal rectal cancers.
Results of this bowel management program were prospectively evaluated using a validated bowel assessment survey. With a 95% compliance rate for completion of the survey each week during the course of chemora-diation, no significant differences were documented between the presenting symptoms and the symptoms that were reported at the completion of chemoradiation (Callister et al, 2000).
Cases of secretory diarrhea can be controlled with octreotide. Octreotide prolongs intestinal transit time, promotes absorption of electrolytes in the intestine, and decreases the secretion of fluids and electrolytes. Complete response rates of more than 90% were observed after 3 days of treatment in 2 pilot trials in patients being treated with 5-FU-based chemotherapy regimens (Wadler et al, 1998; Kornblau et al, 2000). In these 2 studies, octreotide was injected subcutaneously at a dose of 100 mg twice a day to 500 mg 3 times a day. In other studies, octreotide has been given as a continuous intravenous infusion. The optimal dose and route of administration of octreotide are currently unknown and have been indexed to the clinical presentation.
Generally, the intergluteal and perianal regions are the only areas that have any skin reaction during chemoradiation. With the first signs of dry desquamation, an emollient that also acts as a barrier for the skin, like Lantiseptic's Skin Protectant (Marietta, GA), is maintained on the skin. When the skin is compromised, routine use of toilet paper can result in irritation, and small regions of moist desquamation in the perianal area can place the patient at risk for a secondary infection due to bacteria in the stool. Soft hydrated wipes are recommended to reduce trauma to the skin and improve hygiene. Sitz baths or warm compresses and Domeboro, an aluminum acetate solution (Bayer Corporation, Pittsburgh, PA), are also used to maintain good hygiene and provide symptomatic relief among patients with moist desquamation in the perineal region. Sulfadi-azine (Silvadene) cream is used in areas of moist desquamation to soothe symptoms and as an antibacterial agent. Among patients who develop candidiasis in the perianal region, a compound with nystatin, Desitin ointment (zinc oxide ointment), and lidocaine is beneficial. However, this ointment must be removed at the time of treatment to reduce the effects of scatter radiation.
Recurrent rectal cancer can vary significantly in its clinical presentation. Because the morbidity of recurrent disease is so profound, aggressive therapeutic attempts are frequently undertaken to secure local-regional control. Routine follow-up testing and early evaluation of symptoms improves the chance of early detection of recurrent disease and long-term disease-free survival. Complete macroscopic resection of disease can be achieved in 57% of cases of recurrent rectal cancer, and partial resection with gross residual disease is possible in 29%; 14% of recurrent tumors are inoperable. The survival rate is improved with complete or partial resection, and the 5-year disease-free survival rate after complete or partial resection is 23%.
Palliative radiation therapy relieves bleeding in 100% of cases and pain in 65% of cases. A variety of palliative radiation schedules have been used at M. D. Anderson. These have been tailored according to prognosis and to accommodate patients. These radiation schedules include 35 Gy in 14 fractions of 2.5 Gy; 39 Gy in 26 fractions of 1.5 Gy given twice daily; and 30 Gy in 6 fractions of 5Gy given twice weekly. Disease that recurs in a previously irradiated area necessitates the use of specialized techniques to minimize potential bowel damage. Approaches have included reirradiation with intensity-modulated radiation therapy, intraoperative radiation therapy, and CT-guided brachytherapy implants. These techniques minimize the dose to the surrounding tissues while concentrating the dose in the tumor. With intraoperative radiation therapy in addition to surgery, overall survival rates were 72% at 1 year, 45% at 2 years, and
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