Chemotherapeutic Treatment of Colorectal Cancer in Pregnancy
Chemotherapeutic Treatment of Colorectal Cancer in Pregnancy
In a review of 205 cases of CRC in pregnancy, the mean age at diagnosis was 31 years and 85% of these cancers were below the peritoneal reflection, as in our patient. CRC during pregnancy is believed to affect the chances of the pregnancy's being carried to full term with delivery of a live infant. Presenting symptoms of CRC, such as abdominal pain, constipation, vomiting and anemia, may be attributed to common gastrointestinal complaints in pregnancy. Rectal bleeding may be attributed to hemorrhoids, as occurred in our patient. A diagnosis is often delayed until after the 20th week of gestation, and patient prognosis at presentation is usually poor, with most patients presenting after metastasis has occurred in Dukes stages C and D.
The diagnosis and staging of cancer in pregnancy can prove to be a challenge for the treating physician. Carcinoembryonic antigen levels are usually normal or mildly elevated in pregnancy; therefore, they can be used in the same manner as they are in non-pregnant patients. Imaging modalities considered safe in pregnancy include diagnostic X-rays, ultrasounds, sigmoidoscopies and MRI, whereas others pose a considerable risk to the fetus, such as CT, barium enemas and radioisotope scans, owing to the higher doses of ionizing radiation delivered to the fetus.
Radiation effects are dependent largely on both the patient size and the radiation dose; however, gestational age is not significantly linked to the fetal dose of radiation. Although a single abdominal or pelvic CT scan delivers a radiation dose of approximately 24 mGy to the fetus, which is considered below the safety threshold, as a general rule, radiation imaging, as well as chemotherapeutic treatments and primary surgeries, is best delayed if possible until the second trimester, when organogenesis is complete and the size of the uterus allows proper surgical intervention.
Clinical guidelines for the management of cancer in pregnancy are available in the literature. However, these guidelines are based mostly on case reports of, and guidelines for, non-pregnant patients. Treatment is aimed at starting therapy for the mother as soon as possible, weighing the decision of early delivery of the fetus against completion of fetal growth and lung maturity. It is recommended that delivery occur after 32 to 35 weeks of gestation when lung maturity and fetal growth are deemed satisfactory. The decision to deliver by cesarean section or vaginally depends on the presence of obstruction of the delivery canal or obstetric indications; cancer per se is not an indication to perform a cesarean section.
The recommendation for resectable CRC diagnosed before 20 weeks of gestation is surgical resection to decrease the chance of dissemination occurring later in the pregnancy. Surgical resection can often be performed without the need for a hysterectomy and without disturbing the pregnancy. If diagnosis occurs after 20 weeks of gestation, surgery can be postponed, allowing for fetal lung maturity to be achieved and facilitating surgical exploration. If cesarean section is the decided method of delivery, colorectal tumor resection can be performed during delivery, or it can be delayed for several weeks post-partum to allow for involution of the uterus and resolution of vascular engorgement of pregnancy.
In our patient, a decision was made to perform a left salpingo-oophorectomy at 13 weeks of gestation because of evidence of ovarian metastases. The incidence of ovarian metastases in pregnant patients with CRC is 25% and is associated with a poor prognosis. Owing to the higher frequency of ovarian metastases, it is recommended that bilateral salpingo-oophorectomy be performed at the time of primary tumor resection; however, this approach is associated with a high incidence of spontaneous abortion, particularly in the first trimester, and risks as well as desire for future pregnancies should be discussed with the patient.
Although radiation therapy can be considered in the treatment of cancers located remote from the fetus, radiation doses required for treatment of cancers located in the pelvis carry a serious risk of severe or lethal effects for the fetus and are recommended to be postponed until after delivery or pregnancy termination.
Decisions to use chemotherapy during pregnancy are weighed against the risk of teratogenicity and the limited clinical evidence of late effects. The decision relies on the analysis of risks and benefits and clearly defined aims of using chemotherapy, which are often to prolong the gestational age of the fetus and to improve the mother's quality of life. The evidence for selection and use of chemotherapeutic agents during pregnancy is limited, owing to the relatively low incidence of this treatment. However, FOLFOX regimes are often used in the treatment of advanced CRC, as recommended by National Comprehensive Cancer Network guidelines for patients with advanced or metastatic disease. The FOLFOX regime consists of oxaliplatin, leucovorin and 5-FU. The U.S. Food and Drug Administration safety rating for the use of oxaliplatin and 5-FU during pregnancy is class D. The FOLFOX regimes are considered the gold standard for treating advanced CRC in non-pregnant patients.
In three case studies, authors have reported the use of FOLFOX regimes to treat CRC during pregnancy. Gestational age at initiation of chemotherapy ranged from 13 weeks to 24 weeks, and all reported positive fetal outcomes. The follow-up periods ranged from 11¾ months to 3½ years, and all children were reported to be within the normal limits for height, weight and neurological development. The mothers were started on FOLFIRI regimes once delivery had occurred, and two underwent surgical resection. Maternal outcomes varied from being disease-free at 1 year, dying 1 year after diagnosis (6 months post-delivery) and dying 5 months after diagnosis (16 weeks post-delivery). Only one recent case report included in our present literature review described use of the FOLFIRI regime, consisting of irinotecan, leucovorin and 5-FU, during pregnancy, followed by FOLFOX post-delivery. Oxaliplatin was excluded from first-line therapy in that patient because of its neurotoxicity side effects. However, irinotecan was administered for only three cycles, which limits the results.
The low incidence of cancer during pregnancy and a patient's decision to abort her pregnancy limit the establishment of high-level evidence for chemotherapeutic guidelines during pregnancy. Congenital fetal abnormalities have been reported in a number of pregnancies in which 5-FU was administered in the first trimester because of organogenesis taking place at this point of fetal development. This incidence can range from 14% to 19%, depending on the drug used. This rate is reduced significantly to 1.3% when administration occurs in the second and third trimesters. This is evident in past case reports, as well as in our patient, when chemotherapy was administered from the second trimester onward and no fetal malformations were reported. This is concurrent with previous literature reports of healthy neonates born after being exposed to 5-FU during the second and third trimesters only. However, follow-up during school years in such cases would assist in evaluation of any side effects that may present later in development.
Less positive maternal outcomes were reported in two cases. Only one study reported the mother to be disease-free at 1 year. In that patient, CRC was detected during the first trimester (12 weeks of gestation), giving some evidence of a better maternal outcome with early detection and before extensive dissemination. However, suspicion of malignancy during pregnancy remains low among physicians. A recent case report involved a 37-year-old woman admitted with suspicion of a ruptured membrane who underwent an emergency cesarean section. She was discharged and returned post-operatively with persistent abdominal pain and anemia and underwent a colonoscopy that revealed a large tumor of the transverse colon.
Discussion
In a review of 205 cases of CRC in pregnancy, the mean age at diagnosis was 31 years and 85% of these cancers were below the peritoneal reflection, as in our patient. CRC during pregnancy is believed to affect the chances of the pregnancy's being carried to full term with delivery of a live infant. Presenting symptoms of CRC, such as abdominal pain, constipation, vomiting and anemia, may be attributed to common gastrointestinal complaints in pregnancy. Rectal bleeding may be attributed to hemorrhoids, as occurred in our patient. A diagnosis is often delayed until after the 20th week of gestation, and patient prognosis at presentation is usually poor, with most patients presenting after metastasis has occurred in Dukes stages C and D.
The diagnosis and staging of cancer in pregnancy can prove to be a challenge for the treating physician. Carcinoembryonic antigen levels are usually normal or mildly elevated in pregnancy; therefore, they can be used in the same manner as they are in non-pregnant patients. Imaging modalities considered safe in pregnancy include diagnostic X-rays, ultrasounds, sigmoidoscopies and MRI, whereas others pose a considerable risk to the fetus, such as CT, barium enemas and radioisotope scans, owing to the higher doses of ionizing radiation delivered to the fetus.
Radiation effects are dependent largely on both the patient size and the radiation dose; however, gestational age is not significantly linked to the fetal dose of radiation. Although a single abdominal or pelvic CT scan delivers a radiation dose of approximately 24 mGy to the fetus, which is considered below the safety threshold, as a general rule, radiation imaging, as well as chemotherapeutic treatments and primary surgeries, is best delayed if possible until the second trimester, when organogenesis is complete and the size of the uterus allows proper surgical intervention.
Clinical guidelines for the management of cancer in pregnancy are available in the literature. However, these guidelines are based mostly on case reports of, and guidelines for, non-pregnant patients. Treatment is aimed at starting therapy for the mother as soon as possible, weighing the decision of early delivery of the fetus against completion of fetal growth and lung maturity. It is recommended that delivery occur after 32 to 35 weeks of gestation when lung maturity and fetal growth are deemed satisfactory. The decision to deliver by cesarean section or vaginally depends on the presence of obstruction of the delivery canal or obstetric indications; cancer per se is not an indication to perform a cesarean section.
The recommendation for resectable CRC diagnosed before 20 weeks of gestation is surgical resection to decrease the chance of dissemination occurring later in the pregnancy. Surgical resection can often be performed without the need for a hysterectomy and without disturbing the pregnancy. If diagnosis occurs after 20 weeks of gestation, surgery can be postponed, allowing for fetal lung maturity to be achieved and facilitating surgical exploration. If cesarean section is the decided method of delivery, colorectal tumor resection can be performed during delivery, or it can be delayed for several weeks post-partum to allow for involution of the uterus and resolution of vascular engorgement of pregnancy.
In our patient, a decision was made to perform a left salpingo-oophorectomy at 13 weeks of gestation because of evidence of ovarian metastases. The incidence of ovarian metastases in pregnant patients with CRC is 25% and is associated with a poor prognosis. Owing to the higher frequency of ovarian metastases, it is recommended that bilateral salpingo-oophorectomy be performed at the time of primary tumor resection; however, this approach is associated with a high incidence of spontaneous abortion, particularly in the first trimester, and risks as well as desire for future pregnancies should be discussed with the patient.
Although radiation therapy can be considered in the treatment of cancers located remote from the fetus, radiation doses required for treatment of cancers located in the pelvis carry a serious risk of severe or lethal effects for the fetus and are recommended to be postponed until after delivery or pregnancy termination.
Decisions to use chemotherapy during pregnancy are weighed against the risk of teratogenicity and the limited clinical evidence of late effects. The decision relies on the analysis of risks and benefits and clearly defined aims of using chemotherapy, which are often to prolong the gestational age of the fetus and to improve the mother's quality of life. The evidence for selection and use of chemotherapeutic agents during pregnancy is limited, owing to the relatively low incidence of this treatment. However, FOLFOX regimes are often used in the treatment of advanced CRC, as recommended by National Comprehensive Cancer Network guidelines for patients with advanced or metastatic disease. The FOLFOX regime consists of oxaliplatin, leucovorin and 5-FU. The U.S. Food and Drug Administration safety rating for the use of oxaliplatin and 5-FU during pregnancy is class D. The FOLFOX regimes are considered the gold standard for treating advanced CRC in non-pregnant patients.
In three case studies, authors have reported the use of FOLFOX regimes to treat CRC during pregnancy. Gestational age at initiation of chemotherapy ranged from 13 weeks to 24 weeks, and all reported positive fetal outcomes. The follow-up periods ranged from 11¾ months to 3½ years, and all children were reported to be within the normal limits for height, weight and neurological development. The mothers were started on FOLFIRI regimes once delivery had occurred, and two underwent surgical resection. Maternal outcomes varied from being disease-free at 1 year, dying 1 year after diagnosis (6 months post-delivery) and dying 5 months after diagnosis (16 weeks post-delivery). Only one recent case report included in our present literature review described use of the FOLFIRI regime, consisting of irinotecan, leucovorin and 5-FU, during pregnancy, followed by FOLFOX post-delivery. Oxaliplatin was excluded from first-line therapy in that patient because of its neurotoxicity side effects. However, irinotecan was administered for only three cycles, which limits the results.
The low incidence of cancer during pregnancy and a patient's decision to abort her pregnancy limit the establishment of high-level evidence for chemotherapeutic guidelines during pregnancy. Congenital fetal abnormalities have been reported in a number of pregnancies in which 5-FU was administered in the first trimester because of organogenesis taking place at this point of fetal development. This incidence can range from 14% to 19%, depending on the drug used. This rate is reduced significantly to 1.3% when administration occurs in the second and third trimesters. This is evident in past case reports, as well as in our patient, when chemotherapy was administered from the second trimester onward and no fetal malformations were reported. This is concurrent with previous literature reports of healthy neonates born after being exposed to 5-FU during the second and third trimesters only. However, follow-up during school years in such cases would assist in evaluation of any side effects that may present later in development.
Less positive maternal outcomes were reported in two cases. Only one study reported the mother to be disease-free at 1 year. In that patient, CRC was detected during the first trimester (12 weeks of gestation), giving some evidence of a better maternal outcome with early detection and before extensive dissemination. However, suspicion of malignancy during pregnancy remains low among physicians. A recent case report involved a 37-year-old woman admitted with suspicion of a ruptured membrane who underwent an emergency cesarean section. She was discharged and returned post-operatively with persistent abdominal pain and anemia and underwent a colonoscopy that revealed a large tumor of the transverse colon.