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Management of Primary Carcinoma of the Ovary
Management of Primary Carcinoma of the Ovary EDWARD H. COPENHAVER, M.D. SAMEER ABU-RUSTUM, M.D.
The average annual death rate for cancer of the ovary for 1960 to 1962 was 7.7 per 100,000 white women-a 7 per cent increase over the previous decade. 10 The lack of improvement reflects the fact that there is no practical proved method for early detection of ovarian cancer. Yet there is some room for guarded optimism and limited progress is being made. First, there is evidence, as demonstrated by Keettel and his associates,4 that the five-year survival rate can be increased by instilling a tumoricidal agent into the peritoneal cavity following the complete removal of an early tumor. Second, chemotherapy is of proved value in the palliation of approximately one half of the patients with advanced tumor. Case 4, in this report, suggests that chemotherapy may offer the hope of cure for advanced ovarian cancer. The qualitative roles of surgery, irradiation, and chemotherapy in the management of carcinoma of the ovary are assessed; our current, flexible approach to therapy is outlined; and case reports which emphasize the merits of chemotherapy are presented. Three basic factors influence the prognosis in cases of malignant ovarian tumor regardless of the method of therapy: (1) the histologic type, (2) the clinical extent, and (3) the microscopic grade. Morton's reviewll of 13 series of cases from the recent literature disclosed the following five-year survival rates for these common histologic types, which accounted for 81 per cent of the reported ovarian cancers: pseudomucinous cystadenocarcinoma, 47 per cent; papillary serous cystadenocarcinoma, 24 per cent; and solid adenocarcinoma, 6 per cent. The overall average survival rate for the series was 28 per cent, with a range of 18 to 37 per cent. As expected, within each histologic group the more extensive and the more anaplastic the tumor, the worse was the prognosis. Surgical Clinics of North America-Vol. 47, No.3, June, 1967 715
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ROLE OF SURGERY
The limitations of surgery in the treatment of cancer of the ovary are more striking than its assets. The minority of ovarian malignant tumors can be satisfactorily resected. Even in this favorable group the results may be frustrating. Kottmeier 6 has implied a detrimental role to overzealous surgery for fixed ovarian tumors, observing that most patients so treated died within 21 months. He advocated exploration, irradiation, and surgical resection in that order when fixation is present. The second-look program of Gilbertsen and Wangensteen3 has been limited. Three of 14 patients with persistent carcinoma of the ovary were survivors at 38, 45, and 147 months, presumably because a second look was taken. Their second look has been at six months, but they stated it may be wiser to defer the examination for 10 to 12 months. Although their philosophy has not engendered enthusiastic acceptance, perhaps all of us dealing with the problem should consider a second look when there have been pelvic adhesions, tumor spillage in the pelvis, or a questionable resection.
ROLE OF IRRADIATION
The role of irradiation is a nebulous one that has sharp critics and staunch supporters. The complexity of ovarian cancer, the individualization of therapy, the inevitable selection of patients for different modes of treatment, and the variations of x-ray therapy itself confuse the status of irradiation. Latour and Davis7 concluded that in their experience x-ray therapy has failed to prove its value. As a case in point, they presented the history of a patient who lived for 13 years without any treatment, implying that such cases would be considered dramatic results if irradiation had been employed. Raventos, Lewis, and Chidiac12 observed that only the clinical extent and histology of the disease correlated with the survival rate which showed no significant difference with postoperative irradiation. On the positive side for irradiation, Kottmeier 6 reported a 6.8 per cent survival rate without and a 23.2 per cent survival rate with irradiation. Kent and McKay 5 demonstrated an increase in survival for a 5- through 20-year follow-up period when x-ray treatment was added to surgery. Rubin, Grise, and Terry13 thought that irradiation has definite curative value, reflecting upon their 44 per cent five-year cure rate for patients with inoperable tumor limited to the pelvis. It is common to think of irradiation for carcinoma of the ovary in terms of supervoltage x-ray therapy postoperatively. However, flexibility should be recognized here, also. As pointed out, Kottmeier6 favored irradi-
\
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
717
ation before resection of a fixed ovarian malignant tumor. In addition he believed that preservation of the uterus with subsequent intra-uterine radium plays an important role in the treatment. He utilized radioactive colloidal gold for both intrapleural and intraperitoneal administration. Keettel' and his associates cite three reports including their own with survival rates of 73,83, and 83.7 per cent when prophylactic intraperitoneal implantation of radioactive gold was employed after intact removal of the ovarian cancer. Their 83 per cent survival figure compares with a 52 per cent one for a previous similar group of patients treated without the gold therapy at the same institution.
ROLE OF CHEMOTHERAPY
The palliative benefit of chemotherapy in cancer of the ovary is an established fact. Some reported experiences are enthusiastic while others are restrained. Frick and his associates2 acknowledged the benefit of chemotherapy while employing multiple agents. However, they found that only 15 per cent of their patients treated with alkylating agents showed an objective response for six months or more. Encouraging are these random reports by Burns et a1. 1 who noted complete control of effusion in 71 per cent of their patients with ascites using L-sarcolysin (Alkeran, melphalan), Masterson and Nelson9 who observed tumor regression in 140 of 280 patients treated with chlorambucil (Leukeran), and Lebherz et a!. 8 who noted that 65 per cent of their patients had a sustained response to chlorambucil with 80 per cent of the effusions controlled with this alkylating agent. The role of the long-acting progestins in the endometrial carcinomas of the ovary remains to be defined. Although the occurrence of a typical endometrial adenocarcinoma arising within a focus of ovarian endometriosis must be rare, many adenocarcinomas are similar to those arising in the uterine fundus. Certainly, it would seem logical to subject the patient with such an adenocarcinoma to a trial of the progestins when she fails to respond to other modes of chemotherapy. Over the years improved palliation by chemotherapy has resulted from more prolonged use of the drugs, by flexibility in their use, and by their effective concentration at the tumor site. The following case reports exemplify the flexibility and the teamwork so vital in the management of advanced ovarian cancer.
REPORT OF CASES CASE 1. Extensive Metastatic Papillary Adenocarcinoma Treated with Chlorambucil. The patient, a 77-year-old para 5, had had a supracervical hysterectomy
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in 1930 because of uterine bleeding. In July 1965, the patient was seen at the clinic with complaints of pain and pressure in the lower part of the abdomen of one month's duration. Physical examination revealed nodular induration and a mass extending 6.0 em. superior, posterior, and to the right of a normal cervical stump. Proctoscopy, gastrointestinal x-ray series, chest roentgenogram, and a Papanicolaou test were within normal limits. After pelvic examination under anesthesia and a period of observation, exploratory laparotomy was recommended but the patient refused operation until October 1965 when symptoms of abdominal and rectal pain became worse. At that time a 10 by 12 cm. mass in the right lower quadrant was palpable and pleural effusion had developed. At laparotomy, the entire pelvic region was frozen with friable tumor nodules up to 2.0 cm. in diameter involving the sigmoid, the small intestine, the liver, and the peritoneum. Loops of bowel were adherent, forming masses. About 500 cc. of ascitic fluid was present. A biopsy specimen taken from the omentum revealed metastatic papillary adenocarcinoma of the ovary. On October 18, 1965, a regimen of chlorambucil, 18 mg. per day in three divided doses, was started. After one month, the dose was changed to 6 mg. per day. In November 1965 a 10 cm. pelvic mass was palpable. In January 1966 only a 3 cm. pelvic induration was present. She remained asymptomatic until late December 1966 when obstruction of the sigmoid colon necessitated a transverse colostomy. CASE 2. Extensive Metastatic Papillary Adenocarcinoma with Massive Ascites and Right Hydrothorax Treated with Chlorambucil. The patient, a 56-year-old, nulliparous, married woman, complained of anorexia, loss of weight, and discomfort in the lower part of the abdomen since June 1965. In November 1965, abdominal swelling became progressive and was associated with episodes of diarrhea. The pertinent physical findings included pronounced ascites, dullness over the right lower lung field with absence of fremitus, and an ill-defined mass in the left and midpelvic region displacing the uterus posteriorly. Vaginal smears showed atypical cells suggestive of adenocarcinoma. Roentgenologic studies confirmed the presence of a large pelvic mass on the left side, ascites, and right pleural effusion (Fig. 1, A). La.parotomy in January 1966 demonstrated a huge left ovarian mass, 17.0 cm. in diameter, surrounded by extensive adhesions. The pelvic organs were fixed by fine metastatic nodules over the serosal surface; the small intestine and omentum were also involved. About 6000 ml. of straw-colored ascitic fluid was removed. Omentectomy and bilateral salpingo-oophorectomy were performed. The pathological diagnosis was papillary adenocarcinoma with extension to the tubes, right ovary, and omentum. Postoperatively, a moderate amount of ascitic fluid reaccumulated. In March 1966, chlorambucil, 16 mg. per day, was given for one month, 8 mg. per day for another month, and then a maintenance dose of 4 to 6 mg. daily. The ascites and pleural effusion completely disappeared (Fig. 1, B), the rectovaginal fullness subsided, and a good appetite returned with a 16-pound increase in weight. This improvement had remained stable when the patient was last seen in September 1966. However, vaginal staining was associated with a twofold increase in the size of the uterine fundus. At this point it was believed that tumor extension to the uterus was not responding to the chemotherapy; therefore, pelvic irradiation was advised and carried out at a hospital near the patient's home, where she died in late November 1966, three weeks after surgery for an intestinal obstruction. The full course of irradiation had not been completed.
At first glance the lO-month survival of this patient would not seem
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
719
impressive. However, a closer look reveals that the patient who was dyspneic, incapacitated, and semiterminal, returned to a productive and comfortable existence for eight months after palliative treatment. CASE 3. Extensive Metastatic Papillary Adenocarcinoma Treated with Methotrexate. The patient, a 61-year-old nullipara, 10 years postmenopausal, was first seen in April 1965 when she complained of a foul vaginal odor without discharge, and one episode of postcoital bleeding 6 months previously. Examination revealed a mass, measuring 7.5 cm. by 5.5 cm., in the right cul-de-sac. Chest roentgenograms, barium enema x-ray series, and Papanicolaou tests were within normal limits. Intravenous pyelogram revealed a mass in the pelvis with extrinsic pressure on the bladder. At exploratory laparotomy, about 500 to 600 cc. of ascitic fluid was present. Both ovaries were replaced by a soft tumor measuring 7 cm. by 6 cm. by 3 cm. in its greatest dimension; a large tumor mass was present in the rectovaginal septum, and tumor had extended to the omentum and the peritoneum. A bilateral salpingooophorectomy and omentectomy were performed, and 15 mg. of nitrogen mustard diluted in 150 cc. of saline solution was injected into the peritoneal cavity. Pathological diagnosis was papillary adenocarcinoma of the ovaries and metastatic papillary adenocarcinoma in the omentum. After operation, the patient was given 2 million volt x-ray therapy receiving 5100 r to the true pelvis and 2600 r to the entire abdomen. In September 1965, methotrexate, 5 mg. daily in four divided doses, was started under the supervision of Dr. Robert D. Sullivan and Dr. Richard A. Oberfield. The dose has been adjusted or discontinued briefly according to the toxic manifestations of the drug. The first definite diminution in size of the rectovaginal mass was noted in January 1966 nine months after surgery, five months after the completion of x-ray therapy, and four months after the initiation of methotrexate chemotherapy. Further diminution in the size of the mass was noted in March 1966. When she was last seen in December 1966 her weight had remained stable and she had been asymptomatic.
Figure 1 (Case 2). A, Before chlorambucil therapy with right pleural effusion (January 1966). B, After chlorambucil therapy (April 1966).
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CASE 4. Recurrent M esonephronic Adenocarcinoma of the Ovary Treated by Actinomycin-D Infusion. The patient, a 53-year-old single woman, six months postmenopausal, was explored in October 1961 for a pelvic mass. At laparotomy a 10 cm. by 12 cm. right ovarian tumor was found without evident metastasis or extension but with fine adhesions to the sigmoid colon. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The pathological diagnosis was mesonephroma of the ovary. Postoperatively, 2 mev. x-ray therapy was delivered to the abdomen (2500 r) and to the pelvis (4900 r) over a seven-week period. In August 1962, massive recurrent tumor appeared in the pelvis, ascites developed, and the patient started losing weight. An intravenous pyelogram revealed a pelvic tumor and right hydronephrosis. The patient was transferred to the chemotherapy service under the supervision of Dr. Robert D. Sullivan and Dr. Elton Watkins. Exploratory operation performed by Dr. Watkins revealed a necrotic, hemorrhagic pelvic tumor between the bladder and rectum with metastasis to the spleen. Catheters were placed in both internal iliac arteries and a splenectomy was performed. The pathological diagnosis was malignant tumor consistent with metastatic mesonephroma. Actinomycin-D (15 mcg.jkg.jday) was infused by means of catheters over a three-week period until leakage of the infusate was observed; actinomycin-D was administered intravenously for a fourth week. One month later a colostomy was performed by Dr. Ruben A. Teixido of Wilmington, Delaware, because of obstruction of the sigmoid colon. In October 1966, five years after the first operation and more than four years after chemotherapy for recurrent tumor, the patient is living and well. Only induration and thickening of the pelvic tissues exist at the site of the large recurrent malignant tumor. Stenosis of the sigmoid colon persists; no effort has been made to revise this obstruction for fear of disturbing the previous tumor site.
COMMENT
A flexible treatment program that has evolved at the Lahey Clinic Foundation is outlined in Table 1. Much of the advocated treatment schedule is based on logical rather than statistical conclusions. For example, it is a logical concept that following complete resection of the tumor recurrent cancer may result from viable cells circulating in the peritoneal cavity and that the local instillation of an alkylating agent would eliminate or diminish such cells. Keettel's4 result with colloidal gold offers statistical validation for this concept; yet his and other reported computative conclusions can be challenged since they are not controlled studies. It is logical to employ irradiation postoperatively because of its proved value in converting a variety of cancer cells to a nonviable state, although there are conflicting conclusions throughout the medical literature concerning its value. The authors believe that there is more evidence in favor of irradiation than conversely. In deference to the eminence and experience of Kottmeier 6 and to the logic of the situation, it makes good sense medically to irradiate a fixed pelvic tumor with the hope of reducing the viability of the cells before attempting a difficult and uncertain surgical dissection.
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
Table 1.
Outline
721
of Management of Ovarian Carcinoma
TUMOR STATUS
SURGICAL TREATMENT
Resectable No ascites or adhesions
Total abdominal hysterectomy, bilateral salpingo-oophorectomy, instillation of nitrogen mustard (0.4 mg./kg. in 200 cc. saline solution) Ascites or slight adhe- Total abdominal hysterectomy, bilateral salpingo-oophosions or both rectomy, instillation of nitrogen mustard
!
Irradiation
Questionably Resectable Pelvic fixation
Biopsy, instillation of nitrogen mustard if ascites is present
!
Irradiation
!
Resection 10 to 15 days later, instillation of nitrogen mustard
!
? Chemotherapy
Not Resectable or Beyond Pelvis Biopsy, instillation of nitrogen mustard if ascites is presenG
!
Chemotherapy
!
? Irradiation
The use of chemotherapy as the "first line" of attack against advanced ovarian cancer is logical. Irradiation does not have a generalized effect and its effect would be to reduce the blood supply, which is the main avenue to action by the chemical agents. Therefore, we tend to favor chemotherapy supplemented (at a later time) by irradiation to the larger foci of tumor in the pelvis or abdomen. The authors favor the use of the alkylating agent, chlorambucil, following the program of Lebherz et al. 8 because of the ease of administration, the minimal toxicity, and the good results, especially in regard to the reduction of effusions. However, we have also been convinced by our medical and surgical colleagues of the value of the antimetabolite drugs as alternatives in a treatment program. The result achieved by Dr. Sullivan and Dr. Watkins in the treatment of an extensive, recurrent, metastatic mesonephroma (Case 4) provides more hope for the future than does any other report or observation witnessed by the authors. Lastly, it would seem appropriate at this time to utilize the long-acting progestins for intractable advanced adenocarcinomas of the ovary in the hope that they may represent variations of the so-called endometrial tumor; their merit must await the test of time.
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SUMMARY A current qualitative assessment of the roles of surgery, irradiation, and chemotherapy in the management of ovarian cancer is presented. Discouraging is the inability to improve the mortality rate through early detection of the disease. Encouraging, however, are the potential possibility of improving survival among the patients with resectable tumors by instilling radioactive materials or chemotherapeutic agents, and the continuing progress being made in the effective palliation of advanced ovarian malignant disease as exemplified by the four case reports presented reflecting the use of chlorambucil, methotrexate, and actinomycin-D. The one patient who had a mesonephroma infused with actinomycin-D at this time is considered to have obtained a five-year cure. Flexibility and teamwork among the various medical disciplines are vital in the management of ovarian cancer.
REFERENCES 1. Burns, B. C., Jr., Rutledge, F., and Gallager, H. S.: Phenylalanine mustard in the palliative management of carcinoma of the ovary. Obst. & Gynec. 22: 30-37 (July) 1963. 2. Frick, H. C., II, Atchoo, N., Adamsons, K., Jr., et al.: Efficacy of chemotherapeutic agents in the management of disseminated gynecologic cancer. Am. J. Obst. & Gynec. 93: 1112-1121 (Dec. 15) 1965. 3. Gilbertsen, V. A., and Wangensteen, O. H.: A summary of thirteen years experience with the second look program. Surg. Gynec. & Obst. 114: 438-442 (April) 1962. 4. Keettel, W. C., Fox, M. R., Longnecker, D. S., et al.: Prophylactic use of radioactive gold in the treatment of primary ovarian cancer. Am. J. Obst. & Gynec. 94: 766-779 (March 15) 1966. 5. Kent, S. W., and McKay, D. G.: Primary cancer of the ovary. An analysis of 349 cases. Am. J. Obst. & Gynec. 80: 430-438 (Sept.) 1960. 6. Kottmeier, H. L.: Radiotherapy in the treatment of ovarian carcinoma. Clin. Obst. & Gynec. 4: 865-874 (Sept.) 1961. 7. Latour, J. P., and Davis, B. A.: A critical assessment of the value of x-ray therapy in primary ovarian carcinoma. Am. J. Obst. & Gynec. 74: 968--976 (Nov.) 1957. 8. Lebherz, T. B., Huston, J. W., Austin, J. A., et al.: Sustained palliation in ovarian carcinoma. Obst. & Gynec. 25: 475-478 (April) 1965. 9. Masterson, J. G., and Nelson, J. H., Jr.: Role of chemotherapy in the treatment of gynecologic malignancy. Am. J. Obst. & Gynec. 93: 1102-1111 (Dec. 15) 1965. 10. Metropolitan Life Insurance Company: Progress in Cancer Control Among Women. Statistical Bull. 45: 1-4 (Nov.) 1964. 11. Morton, D. G.: Ovarian carcinoma. Am. J. Obst. & Gynec. 95: 359-361 (June 1) 1966. 12. Raventos, A., Lewis, G. C., Jr., and Chidiac, J.: Primary ovarian cancer. A twentyfive year report. Am. J. Roentgenol. 89: 524-532 (March) 1963. 13. Rubin, P., Grise, J. W., and Terry, R.: Has postoperative irradiation proved itself? Am. J. Roentgenol. 88: 849-866 (Nov.) 1962.
The average annual death rate for cancer of the ovary for 1960 to 1962 was 7.7 per 100,000 white women-a 7 per cent increase over the previous decade. 10 The lack of improvement reflects the fact that there is no practical proved method for early detection of ovarian cancer. Yet there is some room for guarded optimism and limited progress is being made. First, there is evidence, as demonstrated by Keettel and his associates,4 that the five-year survival rate can be increased by instilling a tumoricidal agent into the peritoneal cavity following the complete removal of an early tumor. Second, chemotherapy is of proved value in the palliation of approximately one half of the patients with advanced tumor. Case 4, in this report, suggests that chemotherapy may offer the hope of cure for advanced ovarian cancer. The qualitative roles of surgery, irradiation, and chemotherapy in the management of carcinoma of the ovary are assessed; our current, flexible approach to therapy is outlined; and case reports which emphasize the merits of chemotherapy are presented. Three basic factors influence the prognosis in cases of malignant ovarian tumor regardless of the method of therapy: (1) the histologic type, (2) the clinical extent, and (3) the microscopic grade. Morton's reviewll of 13 series of cases from the recent literature disclosed the following five-year survival rates for these common histologic types, which accounted for 81 per cent of the reported ovarian cancers: pseudomucinous cystadenocarcinoma, 47 per cent; papillary serous cystadenocarcinoma, 24 per cent; and solid adenocarcinoma, 6 per cent. The overall average survival rate for the series was 28 per cent, with a range of 18 to 37 per cent. As expected, within each histologic group the more extensive and the more anaplastic the tumor, the worse was the prognosis. Surgical Clinics of North America-Vol. 47, No.3, June, 1967 715
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COPENHAVER, SAMEER ABU-RuSTUM
ROLE OF SURGERY
The limitations of surgery in the treatment of cancer of the ovary are more striking than its assets. The minority of ovarian malignant tumors can be satisfactorily resected. Even in this favorable group the results may be frustrating. Kottmeier 6 has implied a detrimental role to overzealous surgery for fixed ovarian tumors, observing that most patients so treated died within 21 months. He advocated exploration, irradiation, and surgical resection in that order when fixation is present. The second-look program of Gilbertsen and Wangensteen3 has been limited. Three of 14 patients with persistent carcinoma of the ovary were survivors at 38, 45, and 147 months, presumably because a second look was taken. Their second look has been at six months, but they stated it may be wiser to defer the examination for 10 to 12 months. Although their philosophy has not engendered enthusiastic acceptance, perhaps all of us dealing with the problem should consider a second look when there have been pelvic adhesions, tumor spillage in the pelvis, or a questionable resection.
ROLE OF IRRADIATION
The role of irradiation is a nebulous one that has sharp critics and staunch supporters. The complexity of ovarian cancer, the individualization of therapy, the inevitable selection of patients for different modes of treatment, and the variations of x-ray therapy itself confuse the status of irradiation. Latour and Davis7 concluded that in their experience x-ray therapy has failed to prove its value. As a case in point, they presented the history of a patient who lived for 13 years without any treatment, implying that such cases would be considered dramatic results if irradiation had been employed. Raventos, Lewis, and Chidiac12 observed that only the clinical extent and histology of the disease correlated with the survival rate which showed no significant difference with postoperative irradiation. On the positive side for irradiation, Kottmeier 6 reported a 6.8 per cent survival rate without and a 23.2 per cent survival rate with irradiation. Kent and McKay 5 demonstrated an increase in survival for a 5- through 20-year follow-up period when x-ray treatment was added to surgery. Rubin, Grise, and Terry13 thought that irradiation has definite curative value, reflecting upon their 44 per cent five-year cure rate for patients with inoperable tumor limited to the pelvis. It is common to think of irradiation for carcinoma of the ovary in terms of supervoltage x-ray therapy postoperatively. However, flexibility should be recognized here, also. As pointed out, Kottmeier6 favored irradi-
\
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
717
ation before resection of a fixed ovarian malignant tumor. In addition he believed that preservation of the uterus with subsequent intra-uterine radium plays an important role in the treatment. He utilized radioactive colloidal gold for both intrapleural and intraperitoneal administration. Keettel' and his associates cite three reports including their own with survival rates of 73,83, and 83.7 per cent when prophylactic intraperitoneal implantation of radioactive gold was employed after intact removal of the ovarian cancer. Their 83 per cent survival figure compares with a 52 per cent one for a previous similar group of patients treated without the gold therapy at the same institution.
ROLE OF CHEMOTHERAPY
The palliative benefit of chemotherapy in cancer of the ovary is an established fact. Some reported experiences are enthusiastic while others are restrained. Frick and his associates2 acknowledged the benefit of chemotherapy while employing multiple agents. However, they found that only 15 per cent of their patients treated with alkylating agents showed an objective response for six months or more. Encouraging are these random reports by Burns et a1. 1 who noted complete control of effusion in 71 per cent of their patients with ascites using L-sarcolysin (Alkeran, melphalan), Masterson and Nelson9 who observed tumor regression in 140 of 280 patients treated with chlorambucil (Leukeran), and Lebherz et a!. 8 who noted that 65 per cent of their patients had a sustained response to chlorambucil with 80 per cent of the effusions controlled with this alkylating agent. The role of the long-acting progestins in the endometrial carcinomas of the ovary remains to be defined. Although the occurrence of a typical endometrial adenocarcinoma arising within a focus of ovarian endometriosis must be rare, many adenocarcinomas are similar to those arising in the uterine fundus. Certainly, it would seem logical to subject the patient with such an adenocarcinoma to a trial of the progestins when she fails to respond to other modes of chemotherapy. Over the years improved palliation by chemotherapy has resulted from more prolonged use of the drugs, by flexibility in their use, and by their effective concentration at the tumor site. The following case reports exemplify the flexibility and the teamwork so vital in the management of advanced ovarian cancer.
REPORT OF CASES CASE 1. Extensive Metastatic Papillary Adenocarcinoma Treated with Chlorambucil. The patient, a 77-year-old para 5, had had a supracervical hysterectomy
718
EDWARD
H.
COPENHAVER, SAMEER ABu-RuSTUM
in 1930 because of uterine bleeding. In July 1965, the patient was seen at the clinic with complaints of pain and pressure in the lower part of the abdomen of one month's duration. Physical examination revealed nodular induration and a mass extending 6.0 em. superior, posterior, and to the right of a normal cervical stump. Proctoscopy, gastrointestinal x-ray series, chest roentgenogram, and a Papanicolaou test were within normal limits. After pelvic examination under anesthesia and a period of observation, exploratory laparotomy was recommended but the patient refused operation until October 1965 when symptoms of abdominal and rectal pain became worse. At that time a 10 by 12 cm. mass in the right lower quadrant was palpable and pleural effusion had developed. At laparotomy, the entire pelvic region was frozen with friable tumor nodules up to 2.0 cm. in diameter involving the sigmoid, the small intestine, the liver, and the peritoneum. Loops of bowel were adherent, forming masses. About 500 cc. of ascitic fluid was present. A biopsy specimen taken from the omentum revealed metastatic papillary adenocarcinoma of the ovary. On October 18, 1965, a regimen of chlorambucil, 18 mg. per day in three divided doses, was started. After one month, the dose was changed to 6 mg. per day. In November 1965 a 10 cm. pelvic mass was palpable. In January 1966 only a 3 cm. pelvic induration was present. She remained asymptomatic until late December 1966 when obstruction of the sigmoid colon necessitated a transverse colostomy. CASE 2. Extensive Metastatic Papillary Adenocarcinoma with Massive Ascites and Right Hydrothorax Treated with Chlorambucil. The patient, a 56-year-old, nulliparous, married woman, complained of anorexia, loss of weight, and discomfort in the lower part of the abdomen since June 1965. In November 1965, abdominal swelling became progressive and was associated with episodes of diarrhea. The pertinent physical findings included pronounced ascites, dullness over the right lower lung field with absence of fremitus, and an ill-defined mass in the left and midpelvic region displacing the uterus posteriorly. Vaginal smears showed atypical cells suggestive of adenocarcinoma. Roentgenologic studies confirmed the presence of a large pelvic mass on the left side, ascites, and right pleural effusion (Fig. 1, A). La.parotomy in January 1966 demonstrated a huge left ovarian mass, 17.0 cm. in diameter, surrounded by extensive adhesions. The pelvic organs were fixed by fine metastatic nodules over the serosal surface; the small intestine and omentum were also involved. About 6000 ml. of straw-colored ascitic fluid was removed. Omentectomy and bilateral salpingo-oophorectomy were performed. The pathological diagnosis was papillary adenocarcinoma with extension to the tubes, right ovary, and omentum. Postoperatively, a moderate amount of ascitic fluid reaccumulated. In March 1966, chlorambucil, 16 mg. per day, was given for one month, 8 mg. per day for another month, and then a maintenance dose of 4 to 6 mg. daily. The ascites and pleural effusion completely disappeared (Fig. 1, B), the rectovaginal fullness subsided, and a good appetite returned with a 16-pound increase in weight. This improvement had remained stable when the patient was last seen in September 1966. However, vaginal staining was associated with a twofold increase in the size of the uterine fundus. At this point it was believed that tumor extension to the uterus was not responding to the chemotherapy; therefore, pelvic irradiation was advised and carried out at a hospital near the patient's home, where she died in late November 1966, three weeks after surgery for an intestinal obstruction. The full course of irradiation had not been completed.
At first glance the lO-month survival of this patient would not seem
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
719
impressive. However, a closer look reveals that the patient who was dyspneic, incapacitated, and semiterminal, returned to a productive and comfortable existence for eight months after palliative treatment. CASE 3. Extensive Metastatic Papillary Adenocarcinoma Treated with Methotrexate. The patient, a 61-year-old nullipara, 10 years postmenopausal, was first seen in April 1965 when she complained of a foul vaginal odor without discharge, and one episode of postcoital bleeding 6 months previously. Examination revealed a mass, measuring 7.5 cm. by 5.5 cm., in the right cul-de-sac. Chest roentgenograms, barium enema x-ray series, and Papanicolaou tests were within normal limits. Intravenous pyelogram revealed a mass in the pelvis with extrinsic pressure on the bladder. At exploratory laparotomy, about 500 to 600 cc. of ascitic fluid was present. Both ovaries were replaced by a soft tumor measuring 7 cm. by 6 cm. by 3 cm. in its greatest dimension; a large tumor mass was present in the rectovaginal septum, and tumor had extended to the omentum and the peritoneum. A bilateral salpingooophorectomy and omentectomy were performed, and 15 mg. of nitrogen mustard diluted in 150 cc. of saline solution was injected into the peritoneal cavity. Pathological diagnosis was papillary adenocarcinoma of the ovaries and metastatic papillary adenocarcinoma in the omentum. After operation, the patient was given 2 million volt x-ray therapy receiving 5100 r to the true pelvis and 2600 r to the entire abdomen. In September 1965, methotrexate, 5 mg. daily in four divided doses, was started under the supervision of Dr. Robert D. Sullivan and Dr. Richard A. Oberfield. The dose has been adjusted or discontinued briefly according to the toxic manifestations of the drug. The first definite diminution in size of the rectovaginal mass was noted in January 1966 nine months after surgery, five months after the completion of x-ray therapy, and four months after the initiation of methotrexate chemotherapy. Further diminution in the size of the mass was noted in March 1966. When she was last seen in December 1966 her weight had remained stable and she had been asymptomatic.
Figure 1 (Case 2). A, Before chlorambucil therapy with right pleural effusion (January 1966). B, After chlorambucil therapy (April 1966).
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H.
COPENHAVER, SAMEER ABu-RuSTUM
CASE 4. Recurrent M esonephronic Adenocarcinoma of the Ovary Treated by Actinomycin-D Infusion. The patient, a 53-year-old single woman, six months postmenopausal, was explored in October 1961 for a pelvic mass. At laparotomy a 10 cm. by 12 cm. right ovarian tumor was found without evident metastasis or extension but with fine adhesions to the sigmoid colon. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The pathological diagnosis was mesonephroma of the ovary. Postoperatively, 2 mev. x-ray therapy was delivered to the abdomen (2500 r) and to the pelvis (4900 r) over a seven-week period. In August 1962, massive recurrent tumor appeared in the pelvis, ascites developed, and the patient started losing weight. An intravenous pyelogram revealed a pelvic tumor and right hydronephrosis. The patient was transferred to the chemotherapy service under the supervision of Dr. Robert D. Sullivan and Dr. Elton Watkins. Exploratory operation performed by Dr. Watkins revealed a necrotic, hemorrhagic pelvic tumor between the bladder and rectum with metastasis to the spleen. Catheters were placed in both internal iliac arteries and a splenectomy was performed. The pathological diagnosis was malignant tumor consistent with metastatic mesonephroma. Actinomycin-D (15 mcg.jkg.jday) was infused by means of catheters over a three-week period until leakage of the infusate was observed; actinomycin-D was administered intravenously for a fourth week. One month later a colostomy was performed by Dr. Ruben A. Teixido of Wilmington, Delaware, because of obstruction of the sigmoid colon. In October 1966, five years after the first operation and more than four years after chemotherapy for recurrent tumor, the patient is living and well. Only induration and thickening of the pelvic tissues exist at the site of the large recurrent malignant tumor. Stenosis of the sigmoid colon persists; no effort has been made to revise this obstruction for fear of disturbing the previous tumor site.
COMMENT
A flexible treatment program that has evolved at the Lahey Clinic Foundation is outlined in Table 1. Much of the advocated treatment schedule is based on logical rather than statistical conclusions. For example, it is a logical concept that following complete resection of the tumor recurrent cancer may result from viable cells circulating in the peritoneal cavity and that the local instillation of an alkylating agent would eliminate or diminish such cells. Keettel's4 result with colloidal gold offers statistical validation for this concept; yet his and other reported computative conclusions can be challenged since they are not controlled studies. It is logical to employ irradiation postoperatively because of its proved value in converting a variety of cancer cells to a nonviable state, although there are conflicting conclusions throughout the medical literature concerning its value. The authors believe that there is more evidence in favor of irradiation than conversely. In deference to the eminence and experience of Kottmeier 6 and to the logic of the situation, it makes good sense medically to irradiate a fixed pelvic tumor with the hope of reducing the viability of the cells before attempting a difficult and uncertain surgical dissection.
MANAGEMENT OF PRIMARY CARCINOMA OF THE OVARY
Table 1.
Outline
721
of Management of Ovarian Carcinoma
TUMOR STATUS
SURGICAL TREATMENT
Resectable No ascites or adhesions
Total abdominal hysterectomy, bilateral salpingo-oophorectomy, instillation of nitrogen mustard (0.4 mg./kg. in 200 cc. saline solution) Ascites or slight adhe- Total abdominal hysterectomy, bilateral salpingo-oophosions or both rectomy, instillation of nitrogen mustard
!
Irradiation
Questionably Resectable Pelvic fixation
Biopsy, instillation of nitrogen mustard if ascites is present
!
Irradiation
!
Resection 10 to 15 days later, instillation of nitrogen mustard
!
? Chemotherapy
Not Resectable or Beyond Pelvis Biopsy, instillation of nitrogen mustard if ascites is presenG
!
Chemotherapy
!
? Irradiation
The use of chemotherapy as the "first line" of attack against advanced ovarian cancer is logical. Irradiation does not have a generalized effect and its effect would be to reduce the blood supply, which is the main avenue to action by the chemical agents. Therefore, we tend to favor chemotherapy supplemented (at a later time) by irradiation to the larger foci of tumor in the pelvis or abdomen. The authors favor the use of the alkylating agent, chlorambucil, following the program of Lebherz et al. 8 because of the ease of administration, the minimal toxicity, and the good results, especially in regard to the reduction of effusions. However, we have also been convinced by our medical and surgical colleagues of the value of the antimetabolite drugs as alternatives in a treatment program. The result achieved by Dr. Sullivan and Dr. Watkins in the treatment of an extensive, recurrent, metastatic mesonephroma (Case 4) provides more hope for the future than does any other report or observation witnessed by the authors. Lastly, it would seem appropriate at this time to utilize the long-acting progestins for intractable advanced adenocarcinomas of the ovary in the hope that they may represent variations of the so-called endometrial tumor; their merit must await the test of time.
722
EDWARD
H.
COPENHAVER, SAMEER ABU-RuSTUM
SUMMARY A current qualitative assessment of the roles of surgery, irradiation, and chemotherapy in the management of ovarian cancer is presented. Discouraging is the inability to improve the mortality rate through early detection of the disease. Encouraging, however, are the potential possibility of improving survival among the patients with resectable tumors by instilling radioactive materials or chemotherapeutic agents, and the continuing progress being made in the effective palliation of advanced ovarian malignant disease as exemplified by the four case reports presented reflecting the use of chlorambucil, methotrexate, and actinomycin-D. The one patient who had a mesonephroma infused with actinomycin-D at this time is considered to have obtained a five-year cure. Flexibility and teamwork among the various medical disciplines are vital in the management of ovarian cancer.
REFERENCES 1. Burns, B. C., Jr., Rutledge, F., and Gallager, H. S.: Phenylalanine mustard in the palliative management of carcinoma of the ovary. Obst. & Gynec. 22: 30-37 (July) 1963. 2. Frick, H. C., II, Atchoo, N., Adamsons, K., Jr., et al.: Efficacy of chemotherapeutic agents in the management of disseminated gynecologic cancer. Am. J. Obst. & Gynec. 93: 1112-1121 (Dec. 15) 1965. 3. Gilbertsen, V. A., and Wangensteen, O. H.: A summary of thirteen years experience with the second look program. Surg. Gynec. & Obst. 114: 438-442 (April) 1962. 4. Keettel, W. C., Fox, M. R., Longnecker, D. S., et al.: Prophylactic use of radioactive gold in the treatment of primary ovarian cancer. Am. J. Obst. & Gynec. 94: 766-779 (March 15) 1966. 5. Kent, S. W., and McKay, D. G.: Primary cancer of the ovary. An analysis of 349 cases. Am. J. Obst. & Gynec. 80: 430-438 (Sept.) 1960. 6. Kottmeier, H. L.: Radiotherapy in the treatment of ovarian carcinoma. Clin. Obst. & Gynec. 4: 865-874 (Sept.) 1961. 7. Latour, J. P., and Davis, B. A.: A critical assessment of the value of x-ray therapy in primary ovarian carcinoma. Am. J. Obst. & Gynec. 74: 968--976 (Nov.) 1957. 8. Lebherz, T. B., Huston, J. W., Austin, J. A., et al.: Sustained palliation in ovarian carcinoma. Obst. & Gynec. 25: 475-478 (April) 1965. 9. Masterson, J. G., and Nelson, J. H., Jr.: Role of chemotherapy in the treatment of gynecologic malignancy. Am. J. Obst. & Gynec. 93: 1102-1111 (Dec. 15) 1965. 10. Metropolitan Life Insurance Company: Progress in Cancer Control Among Women. Statistical Bull. 45: 1-4 (Nov.) 1964. 11. Morton, D. G.: Ovarian carcinoma. Am. J. Obst. & Gynec. 95: 359-361 (June 1) 1966. 12. Raventos, A., Lewis, G. C., Jr., and Chidiac, J.: Primary ovarian cancer. A twentyfive year report. Am. J. Roentgenol. 89: 524-532 (March) 1963. 13. Rubin, P., Grise, J. W., and Terry, R.: Has postoperative irradiation proved itself? Am. J. Roentgenol. 88: 849-866 (Nov.) 1962.