Case 11-2006 — A 54-Year-Old Woman with a Mass in the Pelvis
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《新英格兰医药杂志》
Presentation of Case
A 54-year-old woman was referred to the gynecologic oncology clinic of this hospital because of a pelvic mass. Several weeks earlier, urinary frequency, lower abdominal and pelvic pain, and a temperature of up to 37.7°C developed. She saw the nurse practitioner in the office of her primary care physician, who performed a pelvic examination that revealed a large central pelvic mass. Computed tomography (CT) of the abdomen several days later revealed a mixed solid and cystic pelvic mass, 14 by 12 cm, with moderate ascites. There were no omental implants or lymphadenopathy. She was referred to a surgeon in gynecologic oncology.
The patient had lost 9.1 kg of weight during the preceding two months, which she attributed to dieting. She had noticed no change in abdominal girth, change in bowel or bladder function, back or leg pain, leg swelling, urinary urgency, or dysuria. Spontaneous menopause had occurred approximately two and a half years earlier. She did not smoke and drank alcohol in moderation. She had two children, both with cystic fibrosis. Her father had died of colon cancer at 73 years of age; her mother was alive at the age of 76 years with hypertension and rheumatoid arthritis.
On examination she was a slender, healthy-appearing woman in no distress and with normal vital signs. The results of the general physical examination were normal except for a slightly protuberant abdomen with a fluid wave. On pelvic examination, the external genitalia and uterine cervix were normal. The rectovaginal examination disclosed a globular anterior pelvic mass extending to the left pelvic sidewall and uterosacral ligament. The results of a rectal examination were normal, with guaiac-negative stool. There was trace pedal edema. The results of routine laboratory testing, including a complete blood count, levels of serum electrolytes, and tests of liver and renal function, were normal. The serum CA-125 level was 1591 U per milliliter (normal, 0 to 35).
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Neil S. Horowitz: Dr. Lee, would you show us the imaging findings?
Dr. Susanna I. Lee: CT of the abdomen and pelvis (Figure 1A and 1B) shows an enhancing mixed solid and cystic mass, 14 by 12 cm, in the central portion of the pelvis. The uterus and ovaries are not evident. There is an aortocaval lymph node, 3 cm in diameter, at the origin of the inferior mesenteric artery. There is a moderate amount of ascites, but no soft-tissue intraperitoneal implants. Subsequent T2-weighted magnetic resonance imaging (MRI) of the pelvis (Figure 1C and 1D) shows that the large pelvic mass has both enhancing solid components that are isointense and nonenhancing fluid components that are hyperintense; the mass is separate from the uterus, indicating that it arises from the adnexa. The enlarged retroperitoneal node compresses the inferior vena cava, which is shown to be patent on the MRI performed after the administration of gadolinium.
Figure 1. Images of the Abdomen and Pelvis.
A CT image of the midabdomen obtained after the oral and intravenous administration of contrast material (Panel A) shows a heterogeneously enhancing mass, 3 by 3 cm, in the aortocaval location (white arrow) that is consistent with an enlarged lymph node, at the origin of the inferior mesenteric artery (black arrow). A CT image through the pelvis (Panel B) shows a mass (black arrows), 14 by 12 cm, with both enhancing solid and fluid-density components; free fluid is seen in the pelvis (white arrow) and under the diaphragm (not shown), but no soft-tissue intraperitoneal implants are seen. A T2-weighted sagittal magnetic resonance image (MRI) (Panel C) shows a large pelvic mass (black arrows) that contains both hyperintense fluid and isointense solid components; the uterus (white arrow) is separate from this mass, but neither ovary is evident. A T1-weighted, fat-saturated axial MRI obtained after the administration of gadolinium (Panel D) shows that the aortocaval node (black arrow) has a mass effect on the inferior vena cava; patency of the inferior vena cava (white arrow) is demonstrated by the hyperintense enhancement.
The imaging findings suggest that the most likely diagnosis is an epithelial ovarian cancer.1 Peritoneal or fallopian-tube cancers are far less common, but they mimic ovarian cancer on imaging.2 Metastases to the ovary from lymphoma and from other distant primary malignant tumors, such as those of the breast, colon, and stomach, are possible3 but unlikely, since this patient does not have a history of cancer.
Dr. Horowitz: I am aware of the diagnosis in this case; however, the differential diagnosis includes benign and malignant lesions of both gynecologic and nongynecologic origins. Although ovarian and fallopian-tube cancers have often been referred to as "silent" in their presentation, a recent case–control study4 evaluated the frequency, severity, and duration of symptoms associated with ovarian cancer as compared with symptoms associated with benign pelvic masses or with no pelvic masses. The authors reported that as compared with women with benign or nonpelvic masses, women with ovarian cancer noted symptoms (increased abdominal girth, bloating, urinary urgency, and pelvic pain) more often (20 to 30 times per month vs. 2 to 3 times per month) and that were more severe.
The CT findings and the elevated CA-125 level in this patient make cancer the most likely diagnosis. Its exact origin is unclear from the imaging results, but it may have metastasized from the ovaries, fallopian tubes, or peritoneal lining. CA-125 levels are neither sensitive nor specific for müllerian cancer; however, in a postmenopausal woman, an elevated CA-125 level in the presence of an adnexal mass is associated with cancer more than 60 percent of the time.5,6
I think the most appropriate next step for this patient is surgical exploration. Surgical management of an adnexal mass is essential to both diagnosis and treatment. Once a frozen section is obtained and the tumor burden within the abdominal cavity is ascertained, if the tumor appears to be grossly confined to the ovary or fallopian tube, a surgical staging procedure is performed; if a large, bulky tumor or metastases are found, tumor cytoreduction is performed.
Appropriate surgical staging of ovarian and fallopian-tube cancers is critical to the treatment. The results of a meticulous, systematic exploration for occult metastases can be used to divide patients into prognostic subgroups, ensuring that women with advanced disease will receive necessary adjuvant chemotherapy and those with early-stage disease will avoid this toxic treatment. Unfortunately, approximately 50 percent of sites that appear negative for cancer on palpation and observation are positive on histologic evaluation.7,8 Accurate surgical staging and treatment require training and experience: studies suggest that both correct staging9,10,11 and survival are markedly better when the woman is cared for by a gynecologic oncologist rather than by a surgeon who is not a specialist in that field.12,13 Although there are no randomized, prospective data delineating the benefits of tumor cytoreduction in patients with advanced ovarian or fallopian-tube cancer, there are retrospective data that show that the amount of residual disease at the conclusion of surgery is the most important determinant of survival. As in early-stage disease, surgical cytoreduction by a gynecologic oncologist, rather than by a general surgeon, is associated with significantly better survival.14,15,16,17,18
The goal of cytoreduction is to remove all visible tumor. If complete removal is not possible, the definition of cytoreduction is determined by the maximal diameter of remaining tumor implants (not the cumulative remaining volume). Although not uniformly defined, optimal cytoreduction results range from the presence of a tumor no larger than 2 cm in diameter to the absence of residual disease. Aggressive surgical procedures are often used to remove all disease and may include bowel resection (resection of ureters, the bladder, or both), extensive dissection of pelvic or paraaortic lymph nodes, stripping or resection of the diaphragm, splenectomy, nephrectomy, and partial hepatectomy.
Early work from this hospital19 suggested that patients whose largest residual mass at the end of the operation was 1.5 cm or less in diameter survived significantly longer than those whose residual tumors were more than 1.5 cm in diameter. Another study20 showed that patients whose largest residual lesion was no more than 5 mm in diameter had a median survival of 40 months, whereas those with residual lesions greater than 15 mm in diameter had a median survival of 6 months. These findings were confirmed by the results of two large cooperative studies by the Gynecologic Oncology Group.21,22 Cases can thus be grouped into three categories after initial cytoreductive surgery: those with no gross residual disease, those with residual tumors no larger than 2 cm in diameter, and those with residual tumors no larger than 2 cm in diameter, with four-year survival rates of 60, 35, and 20 percent, respectively. In more recent studies, survival rates have remained fairly constant (Table 1).22,23,24,25
Table 1. Survival among Patients with Stage III Ovarian Cancer According to the Extent of Residual Disease after Surgical Cytoreduction.
The diagnostic procedure in this case was an exploratory laparotomy. The findings included two to three liters of ascitic fluid; a bulky, central pelvic mass that was adherent to the posterior aspect of the uterus and involved the peritoneum of the anterior and left pelvic sidewall, uterosacral ligaments, and the anterior surface of the bladder; and a mass, 6 by 4 by 4 cm, that was presumed to be a lymph node and was adherent to the aorta, vena cava, and inferior mesenteric artery. The upper portion of the abdomen was normal. Cytoreduction was accomplished by gastrocolic omentectomy, modified radical hysterectomy with bilateral salpingo-oophorectomy, excision of the pelvic peritoneum, bilateral pelvic lymphadenectomy, and resection of the paraaortic and precaval mass, including a small segment of the medial wall of the inferior vena cava. There was no gross residual disease.
Dr. Neil S. Horowitz's Diagnosis
Carcinoma of the ovary, fallopian tube, or both.
Pathological Discussion
Dr. Esther Oliva: The right adnexa contained a lobulated mass, 10 by 8.5 by 7.5 cm, located in the paraovarian tissue and the fimbriated end of the right fallopian tube (Figure 2A). Sectioning revealed a solid, tan, cut surface, with scattered cysts filled with clear fluid and extensive areas of necrosis. The right ovary was grossly normal. There were nodules of tumor adjacent to the left ovary and in the left paraovarian soft tissues, the cul-de-sac, and the serosa of the uterus.
Figure 2. Resected Specimen of the Pelvic Mass.
Gross examination shows that a large, multinodular mass (Panel A) has replaced the fimbriated end of the fallopian tube and encases its midportion. The fallopian-tube lumen at its distal portion is distended and obliterated by carcinoma (Panel B, hematoxylin and eosin). Neoplastic cells with high-grade cytologic atypia line the cribriform glands and complex papillae with slit-like spaces, which is characteristic of serous carcinoma (Panel C, hematoxylin and eosin). Wide and solid anastomosing trabeculae that contain cells with abundant eosinophilic cytoplasm are also present and are indicative of transitional-cell carcinoma (Panel D, hematoxylin and eosin).
On histopathological examination (Figure 2B, 2C, and 2D), the tumor was a mixed high-grade serous and transitional-cell carcinoma of the fimbriated end of the tube that involved the uterine serosa, the contralateral ovary and the meso-ovarian soft tissues, Douglas' cul-de-sac, 1 of 11 left-sided pelvic lymph nodes, and 1 of 2 right-sided paraaortic lymph nodes. On cytologic examination, the ascitic fluid was negative for malignant cells.
Carcinoma of the fallopian tube reportedly accounts for approximately 1 percent of all gynecologic malignant tumors,26,27 but since cases are categorized as primary ovarian cancer when disease involves both the tube and the ovary,28 tumors that arise in the fallopian tube and present as ovarian cancer after the transport of neoplastic cells from the tube to the ovary may be misclassified as ovarian in origin.29,30,31,32 Serous carcinomas are the most common subtype, followed in frequency by endometrioid and transitional-cell subtypes.33,34,35 Both serous and transitional-cell types were seen in this patient.
The current staging for tubal carcinoma of the American Joint Commission on Cancer and the International Federation of Gynecology and Obstetrics (FIGO) are summarized in Table 2, with modifications suggested by Alvarado-Cabrero and colleagues34 to take into account some distinctive features of this type of cancer. This patient's tumor is FIGO stage IIIC.
Table 2. The American Joint Commission on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO) Staging Systems for Tubal Carcinoma.
Discussion of Management
Dr. Carolyn N. Krasner: This patient has an advanced-stage, high-grade fallopian-tube cancer.
The current standard of adjuvant care consists of the intravenous administration of platinum-based and taxane-based chemotherapy. Platinum analogues remain the most active agents for the treatment of this disease, with the first trials having used cisplatin.36,37 The toxic effects associated with cisplatin led to the substitution of carboplatin for cisplatin.38,39,40 The most commonly used standard regimen at this hospital consists of a combination of carboplatin at a dose calculated to produce an area under the concentration–time curve of 5.0 with paclitaxel at a dose of 175 mg per square meter of body-surface area over a three-hour period. This regimen produces response rates of about 90 percent, with about 75 to 80 percent of patients having a complete clinical remission. Unfortunately, most women have a relapse of the disease, with only 10 to 30 percent having long-term survival. The addition of maintenance chemotherapy has not improved this discouraging figure.41
Intraperitoneal chemotherapy has emerged as an alternative or an addition to intravenous therapy for uterine adnexal cancer. Three randomized trials conducted by the Gynecologic Oncology Group have shown a survival advantage for the use of intraperitoneal chemotherapy, as compared with a standard intravenous regimen. In the most recent of these trials, previously reported in the Journal,42 the patients who received intraperitoneal therapy had more severe effects, including abdominal pain and infectious complications. Only 42 percent of those receiving the experimental regimen completed the planned six cycles. However, there was a significant improvement in progression-free and overall survival (Table 3).38,42,43,44
Table 3. Results of Randomized Gynecologic Oncology Group Trials Comparing Intraperitoneal (IP) with Intravenous (IV) Chemotherapy.
The toxic effects of intraperitoneal therapy may be altered by changing the agents, doses, and schedules used. Carboplatin has been shown to have efficacy equivalent to that of cisplatin when used intravenously and, like cisplatin, has a pharmacokinetic advantage when given intraperitoneally but has a lower rate of metabolic complications, emesis, and neurotoxic effects. Phase 2 trials have documented responses to intraperitoneal carboplatin in patients with relapsed disease.45,46 Although some phase 1 and phase 2 trials suggest that cisplatin is more effective than carboplatin when administered intraperitoneally, there are no directly comparative studies and the dose of carboplatin in these trials may have been too low to be effective.47,48
This patient was given the option of either receiving standard intravenous carboplatin and paclitaxel or participating in an in-house phase 2 trial of intraperitoneal chemotherapy (Figure 3). She chose the trial. In this trial, we are attempting to maximize the benefit of the intraperitoneal route, by giving all chemotherapy after the initial cycle intraperitoneally. The first cycle is administered intravenously to allow the patient to recover from bowel resection before catheter insertion, as well as to allow us to compare the pharmacology of intravenous and intraperitoneal dosing in the same patient. Carboplatin is used instead of cisplatin. Paclitaxel is given in divided doses, since the dose-limiting toxic effect of this drug administered by the intraperitoneal route is abdominal pain. In addition to evaluating feasibility and response rates, assessed by a second-look operation, this trial will attempt to answer some pharmacologic questions.
Figure 3. Treatment Regimen for Phase 2 Trial of Intraperitoneal (IP) Carboplatin and Intravenous (IV) Paclitaxel after Optimal Cytoreduction of Ovarian Cancer.
Ports for administration of chemotherapy are inserted at the time of the initial cytoreduction or after the first cycle of chemotherapy if cytoreduction includes colon resection. AUC denotes area under the concentration–time curve, and PK pharmacokinetics.
Dr. Jeffrey G. Supko: In this case, pharmacokinetic sampling was performed to compare the plasma concentration–time profiles of paclitaxel and carboplatin after intravenous and intraperitoneal administration. Anticancer agents rarely achieve effective concentrations in peritoneal fluid after intravenous administration, because of the inefficient distribution of drugs from systemic circulation into third-space fluids.49 Cytotoxic concentrations can readily be achieved and sustained within the peritoneum when a drug is given intraperitoneally. In addition, the drug is absorbed into the systemic circulation, which is therapeutically important because access to regions of a tumor that are not in close contact with peritoneal fluid depends on vascular transport of the drug.50 In this patient, intraperitoneal administration of paclitaxel resulted in a peak concentration of the drug in plasma after six hours that was approximately 10 times lower than the peak concentration for intravenous administration (Figure 4). The duration of exposure to paclitaxel at concentrations greater than 0.05 μmol per liter, a threshold that has been associated with pharmacologic effects of the drug,52,53 was actually greater for intraperitoneal than for intravenous administration. However, the peak concentration of paclitaxel in plasma was more than 50 percent lower in cycle 6 than cycle 2 and the absolute bioavailability of the drug was also reduced. The possible decrease in systemic exposure to paclitaxel on repeated intraperitoneal dosing could compromise its therapeutic effectiveness. In contrast, plasma profiles for free platinum were similar for the intravenous dose and the initial intraperitoneal dose of carboplatin, and there was no evidence of reduced systemic availability on repeated intraperitoneal dosing (data not shown).
Figure 4. Pharmacokinetics of Intraperitoneally (IP) Administered Paclitaxel.
Plasma concentration–time profiles are shown for paclitaxel, administered as a one-hour intravenous (IV) infusion in the first cycle of therapy and administered intraperitoneally during the second and sixth cycles of therapy. The horizontal dashed line designates the 0.05 micromolar threshold. The peak concentration of paclitaxel in plasma achieved at the end of the intravenous infusion was 1.67 μM. Values for total body clearance (20.0 liters per hour per square meter of body-surface area) and apparent terminal-phase half-life (13.1 hours) are consistent with data from a previous study.51 In comparison, when the same dose was given intraperitoneally in the second cycle of therapy, the concentration of the drug in plasma slowly increased to a maximum that was approximately 10 times lower than the peak level after intravenous administration, four to eight hours after dosing. The bioavailability of the initial intraperitoneal dose of paclitaxel was 86 percent. Equilibrium is eventually achieved between the drug remaining in the peritoneal cavity and that in the plasma, as indicated by the parallel terminal region of the two curves.
Ms. Maria Roche: There are highly specific complications associated with the intraperitoneal delivery of chemotherapy. Abdominal pain is common, especially with paclitaxel, and may require the use of nonsteroidal antiinflammatory agents or narcotics. Catheter malfunctions such as leakage and blockage also occur. There is potential for both localized and disseminated intraabdominal and systemic infections. It is possible to keep the catheter in place while treating a local infection, but removal is indicated in the event of abscess or systemic infection. Extravasation of the drug from the catheter has been reported and may increase the chance of infection.54,55 Bowel perforation may occur, and reports of abdominal pain should be investigated carefully.56
The safe delivery of intraperitoneal chemotherapy calls for approximately 2 liters of normal saline to be administered into the peritoneal cavity to facilitate the distribution of the chemotherapeutic agent; this may cause abdominal bloating, distention, and discomfort. The patient must also change position frequently to enhance distribution to all intraperitoneal surfaces.57 Accessing the peritoneal catheter, generally located in the right or left upper quadrant, may be difficult depending on the body habitus, and the procedure requires careful sterile technique. For these reasons, this therapy requires an experienced multidisciplinary team.
This patient received a total of 14 intraperitoneal doses of chemotherapy. One dose of weekly paclitaxel was withheld because of the presence of mild thrombocytopenia; she had no hair loss or neuropathy, minimal myelosuppression, mild fatigue, and only mild abdominal pain.
Dr. Horowitz: Despite three randomized trials that have showed improved survival among women with advanced-stage ovarian cancer when the disease was treated with intraperitoneal rather than intravenous chemotherapy, this mode of delivery has not become the standard of care. Several areas of concern from a surgical standpoint are that the precise catheter-insertion technique, ideal type of catheter, and the timing of catheter placement have not been standardized. Options for placement include the right or left upper quadrant in the midaxillary line along the costal margin or lower down along the anterior middle or lateral abdominal wall. Although there are specific ports designed for intraperitoneal therapy, many surgeons use the same vascular ports used for intravenous chemotherapy.
Ideally, catheters would be placed at the time of initial cytoreductive surgery, thus avoiding another procedure. In the recent trial by the Gynecologic Oncology Group, of the 60 percent of patients who did not receive all planned cycles of intraperitoneal chemotherapy, approximately 35 percent discontinued therapy because of complications related to the catheter (such as infection, leakage, and blockage). Approximately 45 percent of patients who did not complete intraperitoneal therapy had undergone a resection of either the small or large bowel as part of their debulking procedure.54 Whether these two events are related is unclear, but this issue needs to be addressed.
If catheters are not placed at the time of cytoreduction, other options include fluoroscopically guided placement with interventional radiology or laparoscopically assisted placement. At this institution, the ports are placed at the time of initial surgical resection except when cytoreduction has included colon resection. In that circumstance, the ports are placed as a laparoscopically assisted second procedure. We place the ports in the upper quadrants along the costal margins, since we believe that this provides the easiest access for the nursing staff, is the most secure site, and allows easy removal. We use a vascular-access port, advancing the catheter from the costal margin approximately 7 to 10 cm before it enters the peritoneal cavity.
Because this patient had elected to enroll in our intraperitoneal-chemotherapy trial, the intraperitoneal port was placed by Dr. Fuller in the right upper quadrant of the patient's abdomen at the conclusion of surgery.
Dr. Nancy Lee Harris (Pathology): Was BRCA2 testing done in this patient?
Dr. Krasner: We consider BRCA2 testing for all patients with malignant müllerian tumors and particularly women with fallopian-tube cancers. This patient declined testing.
Dr. Arlan F. Fuller (Gynecologic Oncology, Gillette Center for Women's Cancers): In many centers, this patient would never have undergone surgery, because she met several criteria that predict unresectability of tumors, including a level of CA-125 greater than 500 U per milliliter and a mass involving the inferior vena cava and aorta. In this case, superb imaging results were essential; we performed MRI to rule out gross invasion of the aorta and vena cava, which would have rendered this tumor unresectable. Another problem was the extent of small-bowel mesenteric disease. After we evaluated the MRI, we believed it reasonable to make a limited initial incision and assess the resectability of the aortocaval lesion before extending the incision and doing an extensive procedure. We found that 2.5 cm of the vena cava was involved; we were able to remove the involved segment and we oversewed it, narrowing the lumen of the vena cava by about 3 mm.
I performed a second-look laparoscopy after the patient had completed the chemotherapy; there was no gross or microscopical evidence of carcinoma, and I removed the port and catheter. When I last saw her, 14 months after the initial operation, she was feeling well with no evidence of recurrent tumor and a normal CA-125 level.
Anatomical Diagnosis
Mixed high-grade serous papillary and transitional-cell carcinoma of the fallopian tube, FIGO stage IIIC.
Ms. Roche reports having received consulting fees from Orthobiotech; and Dr. Horowitz, lecture fees from GlaxoSmithKline and grant support from Sanofi-Synthelabo, Eli Lilly, and Genentech.
Source Information
From the Gillette Center for Women's Cancers (C.N.K., M.R., N.S.H.), Gynecologic Oncology (N.S.H.), the Clinical Pharmacology Laboratory at the Massachusetts General Hospital Cancer Center (J.G.S.), and the Departments of Radiology (S.I.L.) and Pathology (E.O.), Massachusetts General Hospital; and the Departments of Medicine (C.N.K., J.G.S.), Obstetrics, Gynecology, and Reproductive Biology (N.S.H.), Radiology (S.I.L.), and Pathology (E.O.), Harvard Medical School.
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Dedrick RL, Myers CE, Bungay PM, DeVita VT Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 1978;62:1-11.
Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol 2003;4:277-283.
Fennelly D, Aghajanian C, Shapiro F, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187-192.
Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995;13:180-190.
Georgiadis MS, Russell EK, Gazdar AF, Johnson BE. Paclitaxel cytotoxicity against human lung cancer cell lines increases with prolonged exposure durations. Clin Cancer Res 1997;3:449-454.
Walker JL, Armstrong DK, Huang HQ, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in stage III optimal ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 2006;100:27-32.
Makhija S, Leitao M, Sabbatini P, et al. Complications associated with intraperitoneal chemotherapy catheters. Gynecol Oncol 2001;81:77-81.
Sakuragi N, Nakajima A, Nomura E, et al. Complications relating to intraperitoneal administration of cisplatin or carboplatin for ovarian carcinoma. Gynecol Oncol 2000;79:420-423.
Stiver W. Fundamentals of administration. In: Polovich M, White JM, Kelliher LOIP. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh: Oncology Nursing Press, 2005:53-77.(Carolyn N. Krasner, M.D.,)
A 54-year-old woman was referred to the gynecologic oncology clinic of this hospital because of a pelvic mass. Several weeks earlier, urinary frequency, lower abdominal and pelvic pain, and a temperature of up to 37.7°C developed. She saw the nurse practitioner in the office of her primary care physician, who performed a pelvic examination that revealed a large central pelvic mass. Computed tomography (CT) of the abdomen several days later revealed a mixed solid and cystic pelvic mass, 14 by 12 cm, with moderate ascites. There were no omental implants or lymphadenopathy. She was referred to a surgeon in gynecologic oncology.
The patient had lost 9.1 kg of weight during the preceding two months, which she attributed to dieting. She had noticed no change in abdominal girth, change in bowel or bladder function, back or leg pain, leg swelling, urinary urgency, or dysuria. Spontaneous menopause had occurred approximately two and a half years earlier. She did not smoke and drank alcohol in moderation. She had two children, both with cystic fibrosis. Her father had died of colon cancer at 73 years of age; her mother was alive at the age of 76 years with hypertension and rheumatoid arthritis.
On examination she was a slender, healthy-appearing woman in no distress and with normal vital signs. The results of the general physical examination were normal except for a slightly protuberant abdomen with a fluid wave. On pelvic examination, the external genitalia and uterine cervix were normal. The rectovaginal examination disclosed a globular anterior pelvic mass extending to the left pelvic sidewall and uterosacral ligament. The results of a rectal examination were normal, with guaiac-negative stool. There was trace pedal edema. The results of routine laboratory testing, including a complete blood count, levels of serum electrolytes, and tests of liver and renal function, were normal. The serum CA-125 level was 1591 U per milliliter (normal, 0 to 35).
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Neil S. Horowitz: Dr. Lee, would you show us the imaging findings?
Dr. Susanna I. Lee: CT of the abdomen and pelvis (Figure 1A and 1B) shows an enhancing mixed solid and cystic mass, 14 by 12 cm, in the central portion of the pelvis. The uterus and ovaries are not evident. There is an aortocaval lymph node, 3 cm in diameter, at the origin of the inferior mesenteric artery. There is a moderate amount of ascites, but no soft-tissue intraperitoneal implants. Subsequent T2-weighted magnetic resonance imaging (MRI) of the pelvis (Figure 1C and 1D) shows that the large pelvic mass has both enhancing solid components that are isointense and nonenhancing fluid components that are hyperintense; the mass is separate from the uterus, indicating that it arises from the adnexa. The enlarged retroperitoneal node compresses the inferior vena cava, which is shown to be patent on the MRI performed after the administration of gadolinium.
Figure 1. Images of the Abdomen and Pelvis.
A CT image of the midabdomen obtained after the oral and intravenous administration of contrast material (Panel A) shows a heterogeneously enhancing mass, 3 by 3 cm, in the aortocaval location (white arrow) that is consistent with an enlarged lymph node, at the origin of the inferior mesenteric artery (black arrow). A CT image through the pelvis (Panel B) shows a mass (black arrows), 14 by 12 cm, with both enhancing solid and fluid-density components; free fluid is seen in the pelvis (white arrow) and under the diaphragm (not shown), but no soft-tissue intraperitoneal implants are seen. A T2-weighted sagittal magnetic resonance image (MRI) (Panel C) shows a large pelvic mass (black arrows) that contains both hyperintense fluid and isointense solid components; the uterus (white arrow) is separate from this mass, but neither ovary is evident. A T1-weighted, fat-saturated axial MRI obtained after the administration of gadolinium (Panel D) shows that the aortocaval node (black arrow) has a mass effect on the inferior vena cava; patency of the inferior vena cava (white arrow) is demonstrated by the hyperintense enhancement.
The imaging findings suggest that the most likely diagnosis is an epithelial ovarian cancer.1 Peritoneal or fallopian-tube cancers are far less common, but they mimic ovarian cancer on imaging.2 Metastases to the ovary from lymphoma and from other distant primary malignant tumors, such as those of the breast, colon, and stomach, are possible3 but unlikely, since this patient does not have a history of cancer.
Dr. Horowitz: I am aware of the diagnosis in this case; however, the differential diagnosis includes benign and malignant lesions of both gynecologic and nongynecologic origins. Although ovarian and fallopian-tube cancers have often been referred to as "silent" in their presentation, a recent case–control study4 evaluated the frequency, severity, and duration of symptoms associated with ovarian cancer as compared with symptoms associated with benign pelvic masses or with no pelvic masses. The authors reported that as compared with women with benign or nonpelvic masses, women with ovarian cancer noted symptoms (increased abdominal girth, bloating, urinary urgency, and pelvic pain) more often (20 to 30 times per month vs. 2 to 3 times per month) and that were more severe.
The CT findings and the elevated CA-125 level in this patient make cancer the most likely diagnosis. Its exact origin is unclear from the imaging results, but it may have metastasized from the ovaries, fallopian tubes, or peritoneal lining. CA-125 levels are neither sensitive nor specific for müllerian cancer; however, in a postmenopausal woman, an elevated CA-125 level in the presence of an adnexal mass is associated with cancer more than 60 percent of the time.5,6
I think the most appropriate next step for this patient is surgical exploration. Surgical management of an adnexal mass is essential to both diagnosis and treatment. Once a frozen section is obtained and the tumor burden within the abdominal cavity is ascertained, if the tumor appears to be grossly confined to the ovary or fallopian tube, a surgical staging procedure is performed; if a large, bulky tumor or metastases are found, tumor cytoreduction is performed.
Appropriate surgical staging of ovarian and fallopian-tube cancers is critical to the treatment. The results of a meticulous, systematic exploration for occult metastases can be used to divide patients into prognostic subgroups, ensuring that women with advanced disease will receive necessary adjuvant chemotherapy and those with early-stage disease will avoid this toxic treatment. Unfortunately, approximately 50 percent of sites that appear negative for cancer on palpation and observation are positive on histologic evaluation.7,8 Accurate surgical staging and treatment require training and experience: studies suggest that both correct staging9,10,11 and survival are markedly better when the woman is cared for by a gynecologic oncologist rather than by a surgeon who is not a specialist in that field.12,13 Although there are no randomized, prospective data delineating the benefits of tumor cytoreduction in patients with advanced ovarian or fallopian-tube cancer, there are retrospective data that show that the amount of residual disease at the conclusion of surgery is the most important determinant of survival. As in early-stage disease, surgical cytoreduction by a gynecologic oncologist, rather than by a general surgeon, is associated with significantly better survival.14,15,16,17,18
The goal of cytoreduction is to remove all visible tumor. If complete removal is not possible, the definition of cytoreduction is determined by the maximal diameter of remaining tumor implants (not the cumulative remaining volume). Although not uniformly defined, optimal cytoreduction results range from the presence of a tumor no larger than 2 cm in diameter to the absence of residual disease. Aggressive surgical procedures are often used to remove all disease and may include bowel resection (resection of ureters, the bladder, or both), extensive dissection of pelvic or paraaortic lymph nodes, stripping or resection of the diaphragm, splenectomy, nephrectomy, and partial hepatectomy.
Early work from this hospital19 suggested that patients whose largest residual mass at the end of the operation was 1.5 cm or less in diameter survived significantly longer than those whose residual tumors were more than 1.5 cm in diameter. Another study20 showed that patients whose largest residual lesion was no more than 5 mm in diameter had a median survival of 40 months, whereas those with residual lesions greater than 15 mm in diameter had a median survival of 6 months. These findings were confirmed by the results of two large cooperative studies by the Gynecologic Oncology Group.21,22 Cases can thus be grouped into three categories after initial cytoreductive surgery: those with no gross residual disease, those with residual tumors no larger than 2 cm in diameter, and those with residual tumors no larger than 2 cm in diameter, with four-year survival rates of 60, 35, and 20 percent, respectively. In more recent studies, survival rates have remained fairly constant (Table 1).22,23,24,25
Table 1. Survival among Patients with Stage III Ovarian Cancer According to the Extent of Residual Disease after Surgical Cytoreduction.
The diagnostic procedure in this case was an exploratory laparotomy. The findings included two to three liters of ascitic fluid; a bulky, central pelvic mass that was adherent to the posterior aspect of the uterus and involved the peritoneum of the anterior and left pelvic sidewall, uterosacral ligaments, and the anterior surface of the bladder; and a mass, 6 by 4 by 4 cm, that was presumed to be a lymph node and was adherent to the aorta, vena cava, and inferior mesenteric artery. The upper portion of the abdomen was normal. Cytoreduction was accomplished by gastrocolic omentectomy, modified radical hysterectomy with bilateral salpingo-oophorectomy, excision of the pelvic peritoneum, bilateral pelvic lymphadenectomy, and resection of the paraaortic and precaval mass, including a small segment of the medial wall of the inferior vena cava. There was no gross residual disease.
Dr. Neil S. Horowitz's Diagnosis
Carcinoma of the ovary, fallopian tube, or both.
Pathological Discussion
Dr. Esther Oliva: The right adnexa contained a lobulated mass, 10 by 8.5 by 7.5 cm, located in the paraovarian tissue and the fimbriated end of the right fallopian tube (Figure 2A). Sectioning revealed a solid, tan, cut surface, with scattered cysts filled with clear fluid and extensive areas of necrosis. The right ovary was grossly normal. There were nodules of tumor adjacent to the left ovary and in the left paraovarian soft tissues, the cul-de-sac, and the serosa of the uterus.
Figure 2. Resected Specimen of the Pelvic Mass.
Gross examination shows that a large, multinodular mass (Panel A) has replaced the fimbriated end of the fallopian tube and encases its midportion. The fallopian-tube lumen at its distal portion is distended and obliterated by carcinoma (Panel B, hematoxylin and eosin). Neoplastic cells with high-grade cytologic atypia line the cribriform glands and complex papillae with slit-like spaces, which is characteristic of serous carcinoma (Panel C, hematoxylin and eosin). Wide and solid anastomosing trabeculae that contain cells with abundant eosinophilic cytoplasm are also present and are indicative of transitional-cell carcinoma (Panel D, hematoxylin and eosin).
On histopathological examination (Figure 2B, 2C, and 2D), the tumor was a mixed high-grade serous and transitional-cell carcinoma of the fimbriated end of the tube that involved the uterine serosa, the contralateral ovary and the meso-ovarian soft tissues, Douglas' cul-de-sac, 1 of 11 left-sided pelvic lymph nodes, and 1 of 2 right-sided paraaortic lymph nodes. On cytologic examination, the ascitic fluid was negative for malignant cells.
Carcinoma of the fallopian tube reportedly accounts for approximately 1 percent of all gynecologic malignant tumors,26,27 but since cases are categorized as primary ovarian cancer when disease involves both the tube and the ovary,28 tumors that arise in the fallopian tube and present as ovarian cancer after the transport of neoplastic cells from the tube to the ovary may be misclassified as ovarian in origin.29,30,31,32 Serous carcinomas are the most common subtype, followed in frequency by endometrioid and transitional-cell subtypes.33,34,35 Both serous and transitional-cell types were seen in this patient.
The current staging for tubal carcinoma of the American Joint Commission on Cancer and the International Federation of Gynecology and Obstetrics (FIGO) are summarized in Table 2, with modifications suggested by Alvarado-Cabrero and colleagues34 to take into account some distinctive features of this type of cancer. This patient's tumor is FIGO stage IIIC.
Table 2. The American Joint Commission on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO) Staging Systems for Tubal Carcinoma.
Discussion of Management
Dr. Carolyn N. Krasner: This patient has an advanced-stage, high-grade fallopian-tube cancer.
The current standard of adjuvant care consists of the intravenous administration of platinum-based and taxane-based chemotherapy. Platinum analogues remain the most active agents for the treatment of this disease, with the first trials having used cisplatin.36,37 The toxic effects associated with cisplatin led to the substitution of carboplatin for cisplatin.38,39,40 The most commonly used standard regimen at this hospital consists of a combination of carboplatin at a dose calculated to produce an area under the concentration–time curve of 5.0 with paclitaxel at a dose of 175 mg per square meter of body-surface area over a three-hour period. This regimen produces response rates of about 90 percent, with about 75 to 80 percent of patients having a complete clinical remission. Unfortunately, most women have a relapse of the disease, with only 10 to 30 percent having long-term survival. The addition of maintenance chemotherapy has not improved this discouraging figure.41
Intraperitoneal chemotherapy has emerged as an alternative or an addition to intravenous therapy for uterine adnexal cancer. Three randomized trials conducted by the Gynecologic Oncology Group have shown a survival advantage for the use of intraperitoneal chemotherapy, as compared with a standard intravenous regimen. In the most recent of these trials, previously reported in the Journal,42 the patients who received intraperitoneal therapy had more severe effects, including abdominal pain and infectious complications. Only 42 percent of those receiving the experimental regimen completed the planned six cycles. However, there was a significant improvement in progression-free and overall survival (Table 3).38,42,43,44
Table 3. Results of Randomized Gynecologic Oncology Group Trials Comparing Intraperitoneal (IP) with Intravenous (IV) Chemotherapy.
The toxic effects of intraperitoneal therapy may be altered by changing the agents, doses, and schedules used. Carboplatin has been shown to have efficacy equivalent to that of cisplatin when used intravenously and, like cisplatin, has a pharmacokinetic advantage when given intraperitoneally but has a lower rate of metabolic complications, emesis, and neurotoxic effects. Phase 2 trials have documented responses to intraperitoneal carboplatin in patients with relapsed disease.45,46 Although some phase 1 and phase 2 trials suggest that cisplatin is more effective than carboplatin when administered intraperitoneally, there are no directly comparative studies and the dose of carboplatin in these trials may have been too low to be effective.47,48
This patient was given the option of either receiving standard intravenous carboplatin and paclitaxel or participating in an in-house phase 2 trial of intraperitoneal chemotherapy (Figure 3). She chose the trial. In this trial, we are attempting to maximize the benefit of the intraperitoneal route, by giving all chemotherapy after the initial cycle intraperitoneally. The first cycle is administered intravenously to allow the patient to recover from bowel resection before catheter insertion, as well as to allow us to compare the pharmacology of intravenous and intraperitoneal dosing in the same patient. Carboplatin is used instead of cisplatin. Paclitaxel is given in divided doses, since the dose-limiting toxic effect of this drug administered by the intraperitoneal route is abdominal pain. In addition to evaluating feasibility and response rates, assessed by a second-look operation, this trial will attempt to answer some pharmacologic questions.
Figure 3. Treatment Regimen for Phase 2 Trial of Intraperitoneal (IP) Carboplatin and Intravenous (IV) Paclitaxel after Optimal Cytoreduction of Ovarian Cancer.
Ports for administration of chemotherapy are inserted at the time of the initial cytoreduction or after the first cycle of chemotherapy if cytoreduction includes colon resection. AUC denotes area under the concentration–time curve, and PK pharmacokinetics.
Dr. Jeffrey G. Supko: In this case, pharmacokinetic sampling was performed to compare the plasma concentration–time profiles of paclitaxel and carboplatin after intravenous and intraperitoneal administration. Anticancer agents rarely achieve effective concentrations in peritoneal fluid after intravenous administration, because of the inefficient distribution of drugs from systemic circulation into third-space fluids.49 Cytotoxic concentrations can readily be achieved and sustained within the peritoneum when a drug is given intraperitoneally. In addition, the drug is absorbed into the systemic circulation, which is therapeutically important because access to regions of a tumor that are not in close contact with peritoneal fluid depends on vascular transport of the drug.50 In this patient, intraperitoneal administration of paclitaxel resulted in a peak concentration of the drug in plasma after six hours that was approximately 10 times lower than the peak concentration for intravenous administration (Figure 4). The duration of exposure to paclitaxel at concentrations greater than 0.05 μmol per liter, a threshold that has been associated with pharmacologic effects of the drug,52,53 was actually greater for intraperitoneal than for intravenous administration. However, the peak concentration of paclitaxel in plasma was more than 50 percent lower in cycle 6 than cycle 2 and the absolute bioavailability of the drug was also reduced. The possible decrease in systemic exposure to paclitaxel on repeated intraperitoneal dosing could compromise its therapeutic effectiveness. In contrast, plasma profiles for free platinum were similar for the intravenous dose and the initial intraperitoneal dose of carboplatin, and there was no evidence of reduced systemic availability on repeated intraperitoneal dosing (data not shown).
Figure 4. Pharmacokinetics of Intraperitoneally (IP) Administered Paclitaxel.
Plasma concentration–time profiles are shown for paclitaxel, administered as a one-hour intravenous (IV) infusion in the first cycle of therapy and administered intraperitoneally during the second and sixth cycles of therapy. The horizontal dashed line designates the 0.05 micromolar threshold. The peak concentration of paclitaxel in plasma achieved at the end of the intravenous infusion was 1.67 μM. Values for total body clearance (20.0 liters per hour per square meter of body-surface area) and apparent terminal-phase half-life (13.1 hours) are consistent with data from a previous study.51 In comparison, when the same dose was given intraperitoneally in the second cycle of therapy, the concentration of the drug in plasma slowly increased to a maximum that was approximately 10 times lower than the peak level after intravenous administration, four to eight hours after dosing. The bioavailability of the initial intraperitoneal dose of paclitaxel was 86 percent. Equilibrium is eventually achieved between the drug remaining in the peritoneal cavity and that in the plasma, as indicated by the parallel terminal region of the two curves.
Ms. Maria Roche: There are highly specific complications associated with the intraperitoneal delivery of chemotherapy. Abdominal pain is common, especially with paclitaxel, and may require the use of nonsteroidal antiinflammatory agents or narcotics. Catheter malfunctions such as leakage and blockage also occur. There is potential for both localized and disseminated intraabdominal and systemic infections. It is possible to keep the catheter in place while treating a local infection, but removal is indicated in the event of abscess or systemic infection. Extravasation of the drug from the catheter has been reported and may increase the chance of infection.54,55 Bowel perforation may occur, and reports of abdominal pain should be investigated carefully.56
The safe delivery of intraperitoneal chemotherapy calls for approximately 2 liters of normal saline to be administered into the peritoneal cavity to facilitate the distribution of the chemotherapeutic agent; this may cause abdominal bloating, distention, and discomfort. The patient must also change position frequently to enhance distribution to all intraperitoneal surfaces.57 Accessing the peritoneal catheter, generally located in the right or left upper quadrant, may be difficult depending on the body habitus, and the procedure requires careful sterile technique. For these reasons, this therapy requires an experienced multidisciplinary team.
This patient received a total of 14 intraperitoneal doses of chemotherapy. One dose of weekly paclitaxel was withheld because of the presence of mild thrombocytopenia; she had no hair loss or neuropathy, minimal myelosuppression, mild fatigue, and only mild abdominal pain.
Dr. Horowitz: Despite three randomized trials that have showed improved survival among women with advanced-stage ovarian cancer when the disease was treated with intraperitoneal rather than intravenous chemotherapy, this mode of delivery has not become the standard of care. Several areas of concern from a surgical standpoint are that the precise catheter-insertion technique, ideal type of catheter, and the timing of catheter placement have not been standardized. Options for placement include the right or left upper quadrant in the midaxillary line along the costal margin or lower down along the anterior middle or lateral abdominal wall. Although there are specific ports designed for intraperitoneal therapy, many surgeons use the same vascular ports used for intravenous chemotherapy.
Ideally, catheters would be placed at the time of initial cytoreductive surgery, thus avoiding another procedure. In the recent trial by the Gynecologic Oncology Group, of the 60 percent of patients who did not receive all planned cycles of intraperitoneal chemotherapy, approximately 35 percent discontinued therapy because of complications related to the catheter (such as infection, leakage, and blockage). Approximately 45 percent of patients who did not complete intraperitoneal therapy had undergone a resection of either the small or large bowel as part of their debulking procedure.54 Whether these two events are related is unclear, but this issue needs to be addressed.
If catheters are not placed at the time of cytoreduction, other options include fluoroscopically guided placement with interventional radiology or laparoscopically assisted placement. At this institution, the ports are placed at the time of initial surgical resection except when cytoreduction has included colon resection. In that circumstance, the ports are placed as a laparoscopically assisted second procedure. We place the ports in the upper quadrants along the costal margins, since we believe that this provides the easiest access for the nursing staff, is the most secure site, and allows easy removal. We use a vascular-access port, advancing the catheter from the costal margin approximately 7 to 10 cm before it enters the peritoneal cavity.
Because this patient had elected to enroll in our intraperitoneal-chemotherapy trial, the intraperitoneal port was placed by Dr. Fuller in the right upper quadrant of the patient's abdomen at the conclusion of surgery.
Dr. Nancy Lee Harris (Pathology): Was BRCA2 testing done in this patient?
Dr. Krasner: We consider BRCA2 testing for all patients with malignant müllerian tumors and particularly women with fallopian-tube cancers. This patient declined testing.
Dr. Arlan F. Fuller (Gynecologic Oncology, Gillette Center for Women's Cancers): In many centers, this patient would never have undergone surgery, because she met several criteria that predict unresectability of tumors, including a level of CA-125 greater than 500 U per milliliter and a mass involving the inferior vena cava and aorta. In this case, superb imaging results were essential; we performed MRI to rule out gross invasion of the aorta and vena cava, which would have rendered this tumor unresectable. Another problem was the extent of small-bowel mesenteric disease. After we evaluated the MRI, we believed it reasonable to make a limited initial incision and assess the resectability of the aortocaval lesion before extending the incision and doing an extensive procedure. We found that 2.5 cm of the vena cava was involved; we were able to remove the involved segment and we oversewed it, narrowing the lumen of the vena cava by about 3 mm.
I performed a second-look laparoscopy after the patient had completed the chemotherapy; there was no gross or microscopical evidence of carcinoma, and I removed the port and catheter. When I last saw her, 14 months after the initial operation, she was feeling well with no evidence of recurrent tumor and a normal CA-125 level.
Anatomical Diagnosis
Mixed high-grade serous papillary and transitional-cell carcinoma of the fallopian tube, FIGO stage IIIC.
Ms. Roche reports having received consulting fees from Orthobiotech; and Dr. Horowitz, lecture fees from GlaxoSmithKline and grant support from Sanofi-Synthelabo, Eli Lilly, and Genentech.
Source Information
From the Gillette Center for Women's Cancers (C.N.K., M.R., N.S.H.), Gynecologic Oncology (N.S.H.), the Clinical Pharmacology Laboratory at the Massachusetts General Hospital Cancer Center (J.G.S.), and the Departments of Radiology (S.I.L.) and Pathology (E.O.), Massachusetts General Hospital; and the Departments of Medicine (C.N.K., J.G.S.), Obstetrics, Gynecology, and Reproductive Biology (N.S.H.), Radiology (S.I.L.), and Pathology (E.O.), Harvard Medical School.
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