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Whole abdominal and pelvic irradiation in patients with minimal disease at second-look surgical reassessment for ovarian carcinoma
GYNECOLOGIC ONCOLOGY
20, 271-280 (1985)
Whole Abdominal and Pelvic Irradiation in Patients with Minimal Disease at Second-Look Surgical Reassessment for Ovarian Carcinoma’ WM.
J. HOSKINS, M.D. ,2 ALLEN S. LIGHTER, M.D., R. WHITTINGTON, M.D., L. E. ARTMAN, M.D., M. C. BIBRO, M.D., AND R. C. PARK, M.D.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Uniformed Services University of the He&h Sciences, and the Radiation Oncology Branches of the Nnvul Hospitul. Bethesda, Maryland 20814, and National Cancer Institute. Bethesda, Maryland 20205 Received December 8, 1983 Aggressive cytoreductive surgery followed by combination chemotherapy for stage III ovarian carcinoma has resulted in a significant percentage of complete clinical responses. However, 30-50% of patients with no clinical evidence of disease are found to have residual carcinoma at second-look surgical reassessment. Because recent reports have indicated a high degree of effectiveness utilizing abdominal and pelvic irradiation as primary therapy for ovarian carcinoma with small residual disease, the authors treated eight patients found to have residual disease of less than 1 cm at second-look reassessment with either open field or split field abdominal and pelvic irradiation. All eight patients had initially undergone aggressive cytoreductive surgery and seven of the eight patients had received multidrug chemotherapy. Patients were treated either at the National Cancer Institute or the Naval Hospital Bethesda both with and without intraperitoneal radiation sensitizers. Fifty percent of the patients required early termination of therapy due to myelosuppression. All eight patients have recurred and three have died. Six of the eight patients have required major surgical procedures for gastrointestinal complications. Based on this experience. we cannot advocate this form of therapy in patients with minimal residual ovarian carcinoma following second-look surgical reassessment.
Aggressive surgical debulking of Stage III epithelial ovarian adenocarcinoma followed by combination chemotherapy has resulted in a significant number of patients without clinically detectable disease. A large number of these patients, however, are found to have residual disease at second-look surgical reassessment. Curry et al. [I], reported a 37% incidence of positive second-look laparotomy and Park and Hoskins [21 reported that 39% of patients had residual disease at second-look surgical reassessment. ’ The opinions and assertions contained herein are those of the authors and are not to be construed as official or as representing those of the Uniformed Services University of the Health Sciences, Department of Defense, Department of the Army, Department of the Navy. ’ To whom reprints requests should be addressed. 271 0090~8258/85$1.50
272
HOSKINS
ET AL.
Numerous reports in the literature indicate that the response rate with “second line” chemotherapy is quite low. Bruchner et al. [3], reported a 48% response rate utilizing cyclophosphamide, hexamethlymelamine, adriamycin, and &platinum in patients who had failed non-cis-platinum-containing chemotherapeutic regimens. The complete response rate, however, was only 14% and the mean survival for all responders was only 16 months. Weiss [4] summarized several studies and reported only 27 responders out of 139 patients using hexamethylmelamine as a second line agent. Bruchner et al. [5], reported the use of high-dose c&platinum (120 mg/m’) in patients who had failed either c&platinum-containing or non-cisplatinum-containing regimens. In 12 patients who had not previously been treated with &-platinum, they reported 3 complete responses and in patients who had previously been treated with &-platinum they achieved no complete responses. None of these studies addressed long-term survival. Dembo, Bush, and their co-workers [6-81 at the Princess Margaret Hospital in Toronto, Canada have reported a high degree of effectiveness utilizing whole abdominal and pelvic irradiation in previously untreated patients with minimal residual carcinoma. They reported only 8 out of 23 recurrences in Stage III disease with minimal or no residual disease after initial surgery. Fourteen of these patients were known to have only microscopic residual disease. They stated that only 3 of 183 patients receiving pelvic or pelvic and abdominal irradiation suffered serious complications and that abdominal strip irradiation had not given rise to long-term complications. Because many patients treated with multidrug chemotherapy at the Naval Hospital in Bethesda and the National Cancer Institute have been found to have minimal residual disease after completion of chemotherapy and because results with second line chemotherapy have been disappointing, it was elected to utilize whole abdominal and pelvic irradiation as a salvage regimen in these patients. Because the excellent results obtained by the Princess Margaret group were seen primarily in patients with minimal residual disease, all patients offered this form of therapy in our series had documented intraabdominal disease of less than 1 cm. MATERIALS
AND METHODS
From 1979 through 1982 eight patients found to have minimal persistent disease at either second-look celiotomy or peritoneoscopy were offered, and accepted, irradiation therapy. Four patients had undergone initial cytoreductive surgery, chemotherapy, and second-look celiotomy at the Naval Hospital, Bethesda, Maryland. Two patients had initial surgical therapy, chemotherapy, and secondlook celiotomy at other medical facilities and were referred either to the Naval Hospital or to the National Cancer Institute for further treatment. Two patients had been treated by the Medicine Branch of the National Cancer Institute and were found to have minimal persistent disease by peritoneoscopy. Table 1 summarizes the characteristics of the patients. The median age was 57 years with a range of 45 to 63 years. All patients had Stage III epithelial carcinoma at initial exploration and seven of the eight patients had grade 3 tumors. One patient’s tumor was grade 2. Three patients had endometrioid carcinomas,
Endometrioid
Adenocarcinomaundifferentiated
61
63
55
56
51
C.C.
F.F.
C.C.
D.J.
J.L.
Serous cystadenocarcinoma
Endometrioid
III13
III/3
III/3
III/3
III/2
11113
Endometrioid
54
M.F.
Serous cystadenocarcinoma
III/3
Serous cystadenocarcinoma
45
B.K.
III/3
Mixed epithelial
Stage/grade
62
Cell type
TABLE 1
TAH; BSO, omentectomy cytoreductive surgery
<3
il
<3
<3
<3
BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery
13
>3
<3
(cm)
Initial residual
TAH; BSO, omentectomy cytoreductive surgery
TAH: BSO, omentectomy cytoreductive surgery BSO, omentectomy cytoreductive surgery
Initial surgical procedure Status prior to irradiation
Peritoneoscopy: < I -cm tumor abdomen and pelvis
Second-look celiotomy
CHEMOTHERAPY
Cyclophosphamide, Adriamycin, and cisplatinum (12 courses) Cyclophosphamide, hexamethylmelamine, 5-flurouracil, and cisplatinum (7 courses) Cyclophosphamide, hexamethylmelamine. 5-flurouracil, and cisplatinum (I2 cycles/ip) 5 FU (6 courses/ip) adriamycin (6 courses)
Adriamycin and cis-platinum (10 courses) Melphalan (12 courses)
Adriamycin and cis-platinum (IO courses) Adriamycin and &-platinum (8 courses) Adriamycin and &-platinum (13 courses)
Chemotherapy
OF PATIENTS WITH MINIMAL RESIDUAL OVARIAN CARCINOMA FOLLOWING WHO WERE TREATED WITH WHOLE ABDOMINAL AND PELVIC IRRADIATION
P.T.
Patient Age
CHARACTERISTICS
274
HOSKINS ET AL.
three had serous cystadenocarcinomas, and one each had mixed epithelial and undifferentiated adenocarcinoma. All patients had initially undergone a complete cytoreductive operation. Six of eight patients had residual disease greater than 1 cm, but less than 3 cm. One patient had only microscopic residual disease and one patient had residual disease greater than 3 cm. The initial chemotherapy was a platinum-containing multidrug regimen in all but one patient. She had refused multidrug therapy and was treated with Melphalan for 12 courses. The median number of multidrug courses was 10 with a range from 7 to 13. At secondlook surgical reassessment, five patients had visible disease less than 1 cm in diameter. One patient had only positive cell washings and one patient had a 4 x 4 cm vaginal recurrence but negative abdominal peritoneoscopy. One patient had a negative second-look procedure and recurred in the pelvis after 14 months. She underwent resection of the pelvic recurrence including a portion of the sigmoid colon and was left with residual pelvic disease of less than 1 cm. The remainder of the abdominal exploration was normal. The irradiation therapy is detailed in Table 2. In three patients treated at the Naval Hospital in Bethesda, the entire pelvis was treated first at 180 rad/day for
TABLE 2 CHARACTERISTICSOF WHOLE ABDOMINAL AND PELVIC IRRADIATION
Patient Patient
B.K.
M.F.
C.C.
F.F. C.C. D.J. J.L.
Irradiation dose schedule and technique Split field technique Pelvis: 200 radiday Abdomen: radlday Split field technique Pelvis: 200 radiday Abdomen: radlday Open field-pelvis treated first Pelvis: 180 rad/day Abdomen: radiday Open field-pelvis treated first Pelvis: 180 rad/day Abdomen: radlday Open field-pelvis treated first Pelvis: 180 radiday Abdoman: radlday Split field technique Pelvis: 200 rad/day Abdomen: radlday Open field technique Abdomen: Pelvis: 200 rad/day radlday Split field technique Pelvis: 200 radiday Abdomen: radlday
Radiation sensitizers
150
150
None Desmethylmisonidazole, 2 ip with 2-hr “dwell”: 6 courses
150 None 150 None 150
150
None Desmethylmisonidazole, 2 g ip with 2-hr “dwell”: 6 courses
100
Misonidazole, 4 g ip with 2-hr “dwell”: 6 courses
150 None
ABDOMINAL
IRRADIATION
FOR OVARIAN
CARCINOMA
275
11 fractions using an 18 MeV linear accelerator. Following the pelvic treatment, the patients were treated at 150 rad/day utilizing a field which included the entire pelvis and abdomen extending to 1 cm above the diaphragm on maximal expiration. Posterior kidney blocks were used and the liver was not shielded. Five patients were treated at the National Cancer Institute. One patient was treated similar to the above technique, but the abdominal field was treated at 100 rad/day instead of 150 rad/day. The remaining four patients were treated with a split field technique [9] in which the pelvis received 200 rad and after a 2-hr rest, the abdomen (above the pelvic field) received 1.50rad. The planned total dose was 5000 rad to the pelvis and 3000 rad to the whole abdomen with the open field technique and 4000 rad to the pelvis and 3000 rad to the abdomen with the split field technique. Three patients at the National Center Institute received intraperitoneal radiation sensitizers via a Tenchoff catheter [IO]. In two patients 2 g of desmethylmisonidazole was administered for six courses with a “dwell” of 2 hr. One patient received six courses of misonidazole at a dose of 4 g with a “dwell” of 2 hr. RESULTS
Table 3 illustrates the total irradiation dose administered, describes modifications of therapy, and shows the white blood counts and platelet levels at the conclusion or termination of therapy. Four patients received the entire planned course of therapy without breaks or modification of therapy. In all but one of these patients the white blood cell counts and the platelet counts were over 3000 and 100,000 cells/mm3, respectively, at the conclusion of the treatment. The remaining four patients required modification or early termination of therapy due to hematologic toxicity. In two of these patients the modification was minimal (less than a 10% dose reduction from the planned total dose). Thus six of eight patients received at least 90% of the planned therapy although two of these patients completed treatment with white blood cell counts of less than 3000 cells/mm3 and platelet counts of less than 100,000 cells/mm3. Table 4 shows the irradiation complications and the treatment of these complications in the eight patients. Six patients developed symptoms of partial or complete intestinal obstruction 1 to 8 months following completion of irradiation therapy. One patient was managed successfully by diet restriction. The other five patients required surgical intervention because of small bowel obstruction. Of these five, one died intraoperatively, one died of postoperative complications, and three patients underwent intestinal resection or bypass and have been discharged from the hospital. Of these three patients discharged two are able to maintain their weight orally and one requires supplemental home parenteral nutrition. Table 5 summarizes the status of disease, further treatment, and survival. All five patients who underwent surgical exploration were found to have persistent intraabdominal disease. Two other patients had positive peritoneal washings and peritoneoscopy was positive for persistent disease. The eighth patient developed a pelvic mass 8 months postirradiation and fine-needle aspiration revealed recurrent carcinoma. Thus all eight patients were proven to have persistent or recurrent disease 2 to 10 months following completion of their irradiation therapy. Two patients died secondary to attempted surgical correction of intestinal
J.L.
D.J.
C.C.
F.F.
C.C.
M.F.
B.K.
P.T.
Patient
TOTAL
4000 3000 4000 3000 5000 3000 5000 3000 5000 3000 4000 3000 5000 3000 4000 3000
4000 3000 4000 3000 5000 3000 4000 2000 4800 3000 3600 2700 6000 1600 3800 2800
STATUS AT CONCLUSION
Terminated early due to myelosuppression Abdomen stopped early due to myelosuppression Terminated early due to myelosuppression
Terminated early due to myelosuppression None
None
None
None
Breaks or modification of therapy
AND HEMATOLOGIC
TABLE 3 OF THERAPY
Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen
MODIFICATION
Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen
AND GIVEN:
Total dose given bad)
PLANNED
Total dose planned b-ad)
DOSE OF IRRADIATION
THERAPY
WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets
3,600 124,000 2,300 150,000 3,000 102,000 1,800 15,100 1,700 60,000 3,100 54,000 2,000 70,000 3,300 35,000
Hematologic parameters at completion of therapy
OF THE IRRADIATION
ABDOMINAL
IRRADIATION
FOR OVARIAN
277
CARCINOMA
TABLE 4 COMPLICATIONS
Patient P.T. B.K. M.F. cc. F.F. C.C. D.J. J.L.
OF THERAPY
AND TREATMENT
Complication and time of onset Intestinal obstruction-onset of symptoms 5 months postirradiation Intestinal obstruction--onset of symptoms 3 months post irradiation Intestinal obstruction--onset of symptoms 5 months postirradiation Intestinal obstruction--onset of symptoms 4 months postirradiation None None Partial intestinal obstructiononset of symptoms 1 month postirradiation Intestinal obstruction-onset of symptoms 8 months postirradiation
Treatment of complication Ileotransverse colostomy with mucous fistula-postooerative death Resection of distal ileum and ascending colon with ileo ascending colostomy Resection of ielum and ascending colon with ileo ascending colostomy Ileotransverse colostomy with mucus fistula-requires home TPN None None Conservative therapy-no surgery required Exploratory celiotomy-intraoperative death secondary to hemorrhage
obstructions. Two patients previously treated with platinum-containing regimens were found to have persistent disease and are receiving melphalan. One patient who had initially received melphalan is receiving Adriamycin and cis-platinum. Two other patients who had received platinum-containing multidrug regimens were treated with high-dose (120 mg/mJ &-platinum. One patient has received no further therapy because of persistent hematologic depression. TABLE 5 DISEASE STATUS,
Patient P.T. B.K. M.F. C.C. F.F. C.C. D.J. J.L.
Diagnosis of persistent disease (months) 5 (at time of surgery for intestinal obstruction) 12 (at time of surgery for intestinal obstruction) 10 (at time of surgery for intestinal obstruction) 6 (at time of surgery for intestinal obstruction) 8 (Fine needle aspiration of pelvic mass) 7 (postive washings and peritoneoscopy) 2 (Peritoneoscopy) 8 (at time of intestinal obstruction)
FURTHER THERAPY,
Further therapy None Melphalan
AND SURVIVAL
Survival Postoperative death Alive with tumor
Survival from completion of irradiation (months) 9
20
Melphalan None Adriamycin and cis-platinum High dose cis-platinum High dose cis-platinum None
Alive with tumor Alive with tumor
12
Alive with tumor
11 IO
Alive with tumor
19
Alive with tumor Intraoperative death
8 8
278
HOSKINS ET AL.
In addition to the two patients who died of surgical complications, one patient has died of disease 8 months postirradiation therapy. The other five patients are alive with disease from 10 to 20 months following completion of their irradiation therapy. DISCUSSION
The chances of obtaining a complete remission with second line chemotherapy after patients fail aggressive multidrug therapy is small. Hope for long-term survival in such patients is apparently unjustified. Although the Princess Margaret data and recent reports from other authors [11,12] indicate whole abdomen and pelvic irradiation may be quite effective in previously untreated patients with minimal residual disease, our experience with these eight patients has not shown this to be effective for persistent or recurrent disease following chemotherapy. Previous experience with whole abdominal and pelvic irradiation for persistent disease is quite limited. Smith and Rutledge [ 131in 1970reported utilizing abdominal strip irradiation, 2500 to 2800 rad in 55 Stage III or IV patients following chemotherapy. They reported a 10% 5-year survival, but did not discuss complications. Piver et al. [14], in 1974, prospectively treated eight patients with chemotherapy, second-look surgical reassessment (including debulking) followed by whole abdominal irradiation. They delivered 3000 rad of whole abdominal irradiation and in seven of eight patients treated the pelvis with an additional 1000 to 2000 rad. Four of these patients had no residual at the onset of irradiation therapy and the other four had disease from 1.5 to 3 cm in diameter. Seven of the eight patients so treated developed recurrent cancer within the irradiated field from 3 to 20 months following completion of therapy. These authors did not mention dose-limiting bone marrow toxicity or post-treatment gastrointestinal complications. Recently Hainsworth et al. [15], reported the utilization of whole abdominal and pelvic irradiation in 17 patients who had residual disease of less than 2 cm at second-look surgical reassessment. All 17 patients had undergone 6 months of multidrug chemotherapy prior to second-look surgery. These authors planned 3000 rad to the whole abdomen by an open field technique followed by additional irradiation to the pelvis in selected patients. They were able to achieve this dose in only 7 patients (41%) because of dose-limiting myelosuppression. Eight patients (47%) had platelet counts of less than 50,000/mm3and 5 patients (29%) had white blood cell counts of less than 1500/mm3at the conclusion of therapy. Of the 17 patients in this series, 14 (82%) developed recurrence from 2 to 19 months following completion of irradiation therapy. Of these 14 patients who recurred 8 had only microscopic residual disease when treated with irradiation. Of the 7 patients who completed a full course of irradiation therapy, 6 (86%) recurred. The poor results experienced in the present series of eight patients treated with whole abdomen and pelvic irradiation following second-look surgical reassessment has forced us to abandon this technique. Of the eight patients, all have recurred. One has died of disease and two have died from therapy-related complications. The remaining five patients are alive but have persistent cancer. Five of the eight patients have required surgical intervention for gastrointestinal complications of their therapy. Other authors, in the reports summarized above, have
ABDOMINAL
IRRADIATION
FOR OVARIAN
CARCINOMA
279
had similar experiences with failure to achieve cures although none have reported an incidence of gastrointestinal complications as high as we have experienced. The reasons for this high degree of gastrointestinal toxicity are not entirely clear. A recent report by Dembo and his associates [16] indicates that in previously untreated patients, the success of whole abdomen and pelvic irradiation is equal to moving strip irradiation and they did not experience increased complications with the open field technique. It is possible that prior aggressive chemotherapy or persistent tumor make these patients more susceptible to intestinal injury. The addition of a second extensive surgical procedure (second-look surgical reassessment) may also contribute to the increased number of gastrointestinal complications. SUMMARY
Our results in this small group of patients combined with the few similar reports in the literature appears to indicate that whole abdominal and pelvic irradiation is a poor “salvage regimen” for patients with minimal residual disease. A large percentage of patients may not be able to complete the therapy because of myelosuppression and, in our series, the gastrointestinal complication rate is very high. Even the most optimal patients (with microscopic residual disease) exhibited a high rate of recurrence. These patients remain candidates for new investigational drugs or other new therapeutic approaches. REFERENCES I. Curry, S. L., Zembo. M. M., Nahhas, W. A., Jahshan, A. E., Whitney, C. W., and Mortel, R. Second-look laparotomy for ovarian cancer, Cancer (Philndelphia) 11, 114-I 18 (1981). 2. Park, R. C., and Hoskins. W. J. Re-operating to assess ovarian cancer treatment, Confemp. Oh-Gyn
17, 159-162 (1981).
3. Bruchner, H. W., Cohen, C. J., Deppe, G., Kabakow. B., Wallach, R., Ratner, L., and Holland, J. F. Treatment of chemotherapy-resistant advanced ovarian cancer with a combination of cyclophosphamide, hexamethylmelamine, adriamycin and cis-diamminedichloroplatinum (CHAD). Gyned. Oncol. 12, 150-153 (1981). 4. Weiss, R. B. The role of hexamethylmelamine in advanced ovarian carcinoma, Gynecol. Oncol. 12, 141-149 (1981).
5. Bruchner, H. W., Wallach, R., Cohen, C. J.. Deppe, G., Kabahon, B., Ratner, L., and Holland, J. F. High dose platinum for the treatment of refractory ovarian cancer, G~necol. Oncol. 12, 64-67 (1981). 6. Bush, R. S., Allt, W. E. C., Beale, F. A., Bean, H., Pringle, J. F.. and Sturgeon, J. Treatment of epithelial carcinoma of the ovary: Operation, irradiation, and chemotherapy, Amer. J. Obstet. Gynecol. 127, 692-704 (1977). 7. Dembo, A. J., Bush, R. S., Beale, F. A.. Bean, H. A., Pringle, J. F., and Sturegon, J. F. G.
The Princess Margaret Hospital study of ovarian cancer: Stages I, II, and asymptomatic Ill presentations, Cancer Treat. Rep. 63, 249-254 (1979). 8. Dembo, M. B., Bush, R. S., Beale, F. A., Bean, H. A., Pringle, J. F., Sturgeon, J., and Reid. J. G. Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with a completed pelvic operation, Amer. J. Obstrt. Gynecol. 134, 793-800 (1979). 9. Flink. H., Lichter, A., Rosenshein, N.. and Order, S. Maximal irradiation by a new technique in the treatment of stage III ovarian cancer, Int. J. Rudiut. On&. Biol. Phys. 4, 441-443 (1978). IO. Gianni, L., Jenkins, J.. Green, R. et crl. Pharmacokinetics of the hypoxic radiosensitizers mi-
280
11. 12. 13. 14.
15.
16.
HOSKINS ET AL.
sonidazole and desmethylmisonidazole after intraperitoneal administration in humans. Cancer Res. 43, 913-916 (1983). Potish, R., Brookes, D. et al. Sequential surgery, radiation therapy and alkeran in the management of epithelial carcinoma of the ovary, Cancer 45, 2754-2758 (1980). Haas, J. S., Mansfield, C. M., Hartman, G. V. et al. Results of radiation therapy in the treatment of epithelial carcinoma of the ovary, Cancer 46, 1950-1956 (1980). Smith, J. P., and Rutledge, F. Chemotherapy in the treatment of cancer of the ovary, Amer. J. Obstet. Gynecol. 107, 691-703 (1970). Piver, M. S., Barlow, J. J., Less, F. T., and Vongtana, V. Sequential therapy for advanced ovarian adenocarcinoma: Operation, chemotherapy, second-look laparotomy, and radiation therapy, Amer. J. Obstet. Gynecol. 122, 355-357 (1974). Hainsworth, J. D., Malcolm, A., Johnson, D. H., Barnett, L. S., Jones, H. W., and Greco, F. A. Advanced minima1 residual ovarian carcinoma: Abdominopelvic in-adiation following combination chemotherapy, Obstet. Gynecol. 61, 619-623 (1983). Dembo, A., Bush, R., Beale, F. et al. A randomized clinical trial of moving verus open held whole abdomen irradiation in patients with invasive epithelal cancer of the ovary, Proc. Amer. Sot. Clin. Oncol. 2, 146 (1983) (Abstract).
20, 271-280 (1985)
Whole Abdominal and Pelvic Irradiation in Patients with Minimal Disease at Second-Look Surgical Reassessment for Ovarian Carcinoma’ WM.
J. HOSKINS, M.D. ,2 ALLEN S. LIGHTER, M.D., R. WHITTINGTON, M.D., L. E. ARTMAN, M.D., M. C. BIBRO, M.D., AND R. C. PARK, M.D.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Uniformed Services University of the He&h Sciences, and the Radiation Oncology Branches of the Nnvul Hospitul. Bethesda, Maryland 20814, and National Cancer Institute. Bethesda, Maryland 20205 Received December 8, 1983 Aggressive cytoreductive surgery followed by combination chemotherapy for stage III ovarian carcinoma has resulted in a significant percentage of complete clinical responses. However, 30-50% of patients with no clinical evidence of disease are found to have residual carcinoma at second-look surgical reassessment. Because recent reports have indicated a high degree of effectiveness utilizing abdominal and pelvic irradiation as primary therapy for ovarian carcinoma with small residual disease, the authors treated eight patients found to have residual disease of less than 1 cm at second-look reassessment with either open field or split field abdominal and pelvic irradiation. All eight patients had initially undergone aggressive cytoreductive surgery and seven of the eight patients had received multidrug chemotherapy. Patients were treated either at the National Cancer Institute or the Naval Hospital Bethesda both with and without intraperitoneal radiation sensitizers. Fifty percent of the patients required early termination of therapy due to myelosuppression. All eight patients have recurred and three have died. Six of the eight patients have required major surgical procedures for gastrointestinal complications. Based on this experience. we cannot advocate this form of therapy in patients with minimal residual ovarian carcinoma following second-look surgical reassessment.
Aggressive surgical debulking of Stage III epithelial ovarian adenocarcinoma followed by combination chemotherapy has resulted in a significant number of patients without clinically detectable disease. A large number of these patients, however, are found to have residual disease at second-look surgical reassessment. Curry et al. [I], reported a 37% incidence of positive second-look laparotomy and Park and Hoskins [21 reported that 39% of patients had residual disease at second-look surgical reassessment. ’ The opinions and assertions contained herein are those of the authors and are not to be construed as official or as representing those of the Uniformed Services University of the Health Sciences, Department of Defense, Department of the Army, Department of the Navy. ’ To whom reprints requests should be addressed. 271 0090~8258/85$1.50
272
HOSKINS
ET AL.
Numerous reports in the literature indicate that the response rate with “second line” chemotherapy is quite low. Bruchner et al. [3], reported a 48% response rate utilizing cyclophosphamide, hexamethlymelamine, adriamycin, and &platinum in patients who had failed non-cis-platinum-containing chemotherapeutic regimens. The complete response rate, however, was only 14% and the mean survival for all responders was only 16 months. Weiss [4] summarized several studies and reported only 27 responders out of 139 patients using hexamethylmelamine as a second line agent. Bruchner et al. [5], reported the use of high-dose c&platinum (120 mg/m’) in patients who had failed either c&platinum-containing or non-cisplatinum-containing regimens. In 12 patients who had not previously been treated with &-platinum, they reported 3 complete responses and in patients who had previously been treated with &-platinum they achieved no complete responses. None of these studies addressed long-term survival. Dembo, Bush, and their co-workers [6-81 at the Princess Margaret Hospital in Toronto, Canada have reported a high degree of effectiveness utilizing whole abdominal and pelvic irradiation in previously untreated patients with minimal residual carcinoma. They reported only 8 out of 23 recurrences in Stage III disease with minimal or no residual disease after initial surgery. Fourteen of these patients were known to have only microscopic residual disease. They stated that only 3 of 183 patients receiving pelvic or pelvic and abdominal irradiation suffered serious complications and that abdominal strip irradiation had not given rise to long-term complications. Because many patients treated with multidrug chemotherapy at the Naval Hospital in Bethesda and the National Cancer Institute have been found to have minimal residual disease after completion of chemotherapy and because results with second line chemotherapy have been disappointing, it was elected to utilize whole abdominal and pelvic irradiation as a salvage regimen in these patients. Because the excellent results obtained by the Princess Margaret group were seen primarily in patients with minimal residual disease, all patients offered this form of therapy in our series had documented intraabdominal disease of less than 1 cm. MATERIALS
AND METHODS
From 1979 through 1982 eight patients found to have minimal persistent disease at either second-look celiotomy or peritoneoscopy were offered, and accepted, irradiation therapy. Four patients had undergone initial cytoreductive surgery, chemotherapy, and second-look celiotomy at the Naval Hospital, Bethesda, Maryland. Two patients had initial surgical therapy, chemotherapy, and secondlook celiotomy at other medical facilities and were referred either to the Naval Hospital or to the National Cancer Institute for further treatment. Two patients had been treated by the Medicine Branch of the National Cancer Institute and were found to have minimal persistent disease by peritoneoscopy. Table 1 summarizes the characteristics of the patients. The median age was 57 years with a range of 45 to 63 years. All patients had Stage III epithelial carcinoma at initial exploration and seven of the eight patients had grade 3 tumors. One patient’s tumor was grade 2. Three patients had endometrioid carcinomas,
Endometrioid
Adenocarcinomaundifferentiated
61
63
55
56
51
C.C.
F.F.
C.C.
D.J.
J.L.
Serous cystadenocarcinoma
Endometrioid
III13
III/3
III/3
III/3
III/2
11113
Endometrioid
54
M.F.
Serous cystadenocarcinoma
III/3
Serous cystadenocarcinoma
45
B.K.
III/3
Mixed epithelial
Stage/grade
62
Cell type
TABLE 1
TAH; BSO, omentectomy cytoreductive surgery
<3
il
<3
<3
<3
BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery TAH; BSO, omentectomy cytoreductive surgery
13
>3
<3
(cm)
Initial residual
TAH; BSO, omentectomy cytoreductive surgery
TAH: BSO, omentectomy cytoreductive surgery BSO, omentectomy cytoreductive surgery
Initial surgical procedure Status prior to irradiation
Peritoneoscopy: < I -cm tumor abdomen and pelvis
Second-look celiotomy
CHEMOTHERAPY
Cyclophosphamide, Adriamycin, and cisplatinum (12 courses) Cyclophosphamide, hexamethylmelamine, 5-flurouracil, and cisplatinum (7 courses) Cyclophosphamide, hexamethylmelamine. 5-flurouracil, and cisplatinum (I2 cycles/ip) 5 FU (6 courses/ip) adriamycin (6 courses)
Adriamycin and cis-platinum (10 courses) Melphalan (12 courses)
Adriamycin and cis-platinum (IO courses) Adriamycin and &-platinum (8 courses) Adriamycin and &-platinum (13 courses)
Chemotherapy
OF PATIENTS WITH MINIMAL RESIDUAL OVARIAN CARCINOMA FOLLOWING WHO WERE TREATED WITH WHOLE ABDOMINAL AND PELVIC IRRADIATION
P.T.
Patient Age
CHARACTERISTICS
274
HOSKINS ET AL.
three had serous cystadenocarcinomas, and one each had mixed epithelial and undifferentiated adenocarcinoma. All patients had initially undergone a complete cytoreductive operation. Six of eight patients had residual disease greater than 1 cm, but less than 3 cm. One patient had only microscopic residual disease and one patient had residual disease greater than 3 cm. The initial chemotherapy was a platinum-containing multidrug regimen in all but one patient. She had refused multidrug therapy and was treated with Melphalan for 12 courses. The median number of multidrug courses was 10 with a range from 7 to 13. At secondlook surgical reassessment, five patients had visible disease less than 1 cm in diameter. One patient had only positive cell washings and one patient had a 4 x 4 cm vaginal recurrence but negative abdominal peritoneoscopy. One patient had a negative second-look procedure and recurred in the pelvis after 14 months. She underwent resection of the pelvic recurrence including a portion of the sigmoid colon and was left with residual pelvic disease of less than 1 cm. The remainder of the abdominal exploration was normal. The irradiation therapy is detailed in Table 2. In three patients treated at the Naval Hospital in Bethesda, the entire pelvis was treated first at 180 rad/day for
TABLE 2 CHARACTERISTICSOF WHOLE ABDOMINAL AND PELVIC IRRADIATION
Patient Patient
B.K.
M.F.
C.C.
F.F. C.C. D.J. J.L.
Irradiation dose schedule and technique Split field technique Pelvis: 200 radiday Abdomen: radlday Split field technique Pelvis: 200 radiday Abdomen: radlday Open field-pelvis treated first Pelvis: 180 rad/day Abdomen: radiday Open field-pelvis treated first Pelvis: 180 rad/day Abdomen: radlday Open field-pelvis treated first Pelvis: 180 radiday Abdoman: radlday Split field technique Pelvis: 200 rad/day Abdomen: radlday Open field technique Abdomen: Pelvis: 200 rad/day radlday Split field technique Pelvis: 200 radiday Abdomen: radlday
Radiation sensitizers
150
150
None Desmethylmisonidazole, 2 ip with 2-hr “dwell”: 6 courses
150 None 150 None 150
150
None Desmethylmisonidazole, 2 g ip with 2-hr “dwell”: 6 courses
100
Misonidazole, 4 g ip with 2-hr “dwell”: 6 courses
150 None
ABDOMINAL
IRRADIATION
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CARCINOMA
275
11 fractions using an 18 MeV linear accelerator. Following the pelvic treatment, the patients were treated at 150 rad/day utilizing a field which included the entire pelvis and abdomen extending to 1 cm above the diaphragm on maximal expiration. Posterior kidney blocks were used and the liver was not shielded. Five patients were treated at the National Cancer Institute. One patient was treated similar to the above technique, but the abdominal field was treated at 100 rad/day instead of 150 rad/day. The remaining four patients were treated with a split field technique [9] in which the pelvis received 200 rad and after a 2-hr rest, the abdomen (above the pelvic field) received 1.50rad. The planned total dose was 5000 rad to the pelvis and 3000 rad to the whole abdomen with the open field technique and 4000 rad to the pelvis and 3000 rad to the abdomen with the split field technique. Three patients at the National Center Institute received intraperitoneal radiation sensitizers via a Tenchoff catheter [IO]. In two patients 2 g of desmethylmisonidazole was administered for six courses with a “dwell” of 2 hr. One patient received six courses of misonidazole at a dose of 4 g with a “dwell” of 2 hr. RESULTS
Table 3 illustrates the total irradiation dose administered, describes modifications of therapy, and shows the white blood counts and platelet levels at the conclusion or termination of therapy. Four patients received the entire planned course of therapy without breaks or modification of therapy. In all but one of these patients the white blood cell counts and the platelet counts were over 3000 and 100,000 cells/mm3, respectively, at the conclusion of the treatment. The remaining four patients required modification or early termination of therapy due to hematologic toxicity. In two of these patients the modification was minimal (less than a 10% dose reduction from the planned total dose). Thus six of eight patients received at least 90% of the planned therapy although two of these patients completed treatment with white blood cell counts of less than 3000 cells/mm3 and platelet counts of less than 100,000 cells/mm3. Table 4 shows the irradiation complications and the treatment of these complications in the eight patients. Six patients developed symptoms of partial or complete intestinal obstruction 1 to 8 months following completion of irradiation therapy. One patient was managed successfully by diet restriction. The other five patients required surgical intervention because of small bowel obstruction. Of these five, one died intraoperatively, one died of postoperative complications, and three patients underwent intestinal resection or bypass and have been discharged from the hospital. Of these three patients discharged two are able to maintain their weight orally and one requires supplemental home parenteral nutrition. Table 5 summarizes the status of disease, further treatment, and survival. All five patients who underwent surgical exploration were found to have persistent intraabdominal disease. Two other patients had positive peritoneal washings and peritoneoscopy was positive for persistent disease. The eighth patient developed a pelvic mass 8 months postirradiation and fine-needle aspiration revealed recurrent carcinoma. Thus all eight patients were proven to have persistent or recurrent disease 2 to 10 months following completion of their irradiation therapy. Two patients died secondary to attempted surgical correction of intestinal
J.L.
D.J.
C.C.
F.F.
C.C.
M.F.
B.K.
P.T.
Patient
TOTAL
4000 3000 4000 3000 5000 3000 5000 3000 5000 3000 4000 3000 5000 3000 4000 3000
4000 3000 4000 3000 5000 3000 4000 2000 4800 3000 3600 2700 6000 1600 3800 2800
STATUS AT CONCLUSION
Terminated early due to myelosuppression Abdomen stopped early due to myelosuppression Terminated early due to myelosuppression
Terminated early due to myelosuppression None
None
None
None
Breaks or modification of therapy
AND HEMATOLOGIC
TABLE 3 OF THERAPY
Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen
MODIFICATION
Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen Pelvis Abdomen
AND GIVEN:
Total dose given bad)
PLANNED
Total dose planned b-ad)
DOSE OF IRRADIATION
THERAPY
WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets WBC Platelets
3,600 124,000 2,300 150,000 3,000 102,000 1,800 15,100 1,700 60,000 3,100 54,000 2,000 70,000 3,300 35,000
Hematologic parameters at completion of therapy
OF THE IRRADIATION
ABDOMINAL
IRRADIATION
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277
CARCINOMA
TABLE 4 COMPLICATIONS
Patient P.T. B.K. M.F. cc. F.F. C.C. D.J. J.L.
OF THERAPY
AND TREATMENT
Complication and time of onset Intestinal obstruction-onset of symptoms 5 months postirradiation Intestinal obstruction--onset of symptoms 3 months post irradiation Intestinal obstruction--onset of symptoms 5 months postirradiation Intestinal obstruction--onset of symptoms 4 months postirradiation None None Partial intestinal obstructiononset of symptoms 1 month postirradiation Intestinal obstruction-onset of symptoms 8 months postirradiation
Treatment of complication Ileotransverse colostomy with mucous fistula-postooerative death Resection of distal ileum and ascending colon with ileo ascending colostomy Resection of ielum and ascending colon with ileo ascending colostomy Ileotransverse colostomy with mucus fistula-requires home TPN None None Conservative therapy-no surgery required Exploratory celiotomy-intraoperative death secondary to hemorrhage
obstructions. Two patients previously treated with platinum-containing regimens were found to have persistent disease and are receiving melphalan. One patient who had initially received melphalan is receiving Adriamycin and cis-platinum. Two other patients who had received platinum-containing multidrug regimens were treated with high-dose (120 mg/mJ &-platinum. One patient has received no further therapy because of persistent hematologic depression. TABLE 5 DISEASE STATUS,
Patient P.T. B.K. M.F. C.C. F.F. C.C. D.J. J.L.
Diagnosis of persistent disease (months) 5 (at time of surgery for intestinal obstruction) 12 (at time of surgery for intestinal obstruction) 10 (at time of surgery for intestinal obstruction) 6 (at time of surgery for intestinal obstruction) 8 (Fine needle aspiration of pelvic mass) 7 (postive washings and peritoneoscopy) 2 (Peritoneoscopy) 8 (at time of intestinal obstruction)
FURTHER THERAPY,
Further therapy None Melphalan
AND SURVIVAL
Survival Postoperative death Alive with tumor
Survival from completion of irradiation (months) 9
20
Melphalan None Adriamycin and cis-platinum High dose cis-platinum High dose cis-platinum None
Alive with tumor Alive with tumor
12
Alive with tumor
11 IO
Alive with tumor
19
Alive with tumor Intraoperative death
8 8
278
HOSKINS ET AL.
In addition to the two patients who died of surgical complications, one patient has died of disease 8 months postirradiation therapy. The other five patients are alive with disease from 10 to 20 months following completion of their irradiation therapy. DISCUSSION
The chances of obtaining a complete remission with second line chemotherapy after patients fail aggressive multidrug therapy is small. Hope for long-term survival in such patients is apparently unjustified. Although the Princess Margaret data and recent reports from other authors [11,12] indicate whole abdomen and pelvic irradiation may be quite effective in previously untreated patients with minimal residual disease, our experience with these eight patients has not shown this to be effective for persistent or recurrent disease following chemotherapy. Previous experience with whole abdominal and pelvic irradiation for persistent disease is quite limited. Smith and Rutledge [ 131in 1970reported utilizing abdominal strip irradiation, 2500 to 2800 rad in 55 Stage III or IV patients following chemotherapy. They reported a 10% 5-year survival, but did not discuss complications. Piver et al. [14], in 1974, prospectively treated eight patients with chemotherapy, second-look surgical reassessment (including debulking) followed by whole abdominal irradiation. They delivered 3000 rad of whole abdominal irradiation and in seven of eight patients treated the pelvis with an additional 1000 to 2000 rad. Four of these patients had no residual at the onset of irradiation therapy and the other four had disease from 1.5 to 3 cm in diameter. Seven of the eight patients so treated developed recurrent cancer within the irradiated field from 3 to 20 months following completion of therapy. These authors did not mention dose-limiting bone marrow toxicity or post-treatment gastrointestinal complications. Recently Hainsworth et al. [15], reported the utilization of whole abdominal and pelvic irradiation in 17 patients who had residual disease of less than 2 cm at second-look surgical reassessment. All 17 patients had undergone 6 months of multidrug chemotherapy prior to second-look surgery. These authors planned 3000 rad to the whole abdomen by an open field technique followed by additional irradiation to the pelvis in selected patients. They were able to achieve this dose in only 7 patients (41%) because of dose-limiting myelosuppression. Eight patients (47%) had platelet counts of less than 50,000/mm3and 5 patients (29%) had white blood cell counts of less than 1500/mm3at the conclusion of therapy. Of the 17 patients in this series, 14 (82%) developed recurrence from 2 to 19 months following completion of irradiation therapy. Of these 14 patients who recurred 8 had only microscopic residual disease when treated with irradiation. Of the 7 patients who completed a full course of irradiation therapy, 6 (86%) recurred. The poor results experienced in the present series of eight patients treated with whole abdomen and pelvic irradiation following second-look surgical reassessment has forced us to abandon this technique. Of the eight patients, all have recurred. One has died of disease and two have died from therapy-related complications. The remaining five patients are alive but have persistent cancer. Five of the eight patients have required surgical intervention for gastrointestinal complications of their therapy. Other authors, in the reports summarized above, have
ABDOMINAL
IRRADIATION
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CARCINOMA
279
had similar experiences with failure to achieve cures although none have reported an incidence of gastrointestinal complications as high as we have experienced. The reasons for this high degree of gastrointestinal toxicity are not entirely clear. A recent report by Dembo and his associates [16] indicates that in previously untreated patients, the success of whole abdomen and pelvic irradiation is equal to moving strip irradiation and they did not experience increased complications with the open field technique. It is possible that prior aggressive chemotherapy or persistent tumor make these patients more susceptible to intestinal injury. The addition of a second extensive surgical procedure (second-look surgical reassessment) may also contribute to the increased number of gastrointestinal complications. SUMMARY
Our results in this small group of patients combined with the few similar reports in the literature appears to indicate that whole abdominal and pelvic irradiation is a poor “salvage regimen” for patients with minimal residual disease. A large percentage of patients may not be able to complete the therapy because of myelosuppression and, in our series, the gastrointestinal complication rate is very high. Even the most optimal patients (with microscopic residual disease) exhibited a high rate of recurrence. These patients remain candidates for new investigational drugs or other new therapeutic approaches. REFERENCES I. Curry, S. L., Zembo. M. M., Nahhas, W. A., Jahshan, A. E., Whitney, C. W., and Mortel, R. Second-look laparotomy for ovarian cancer, Cancer (Philndelphia) 11, 114-I 18 (1981). 2. Park, R. C., and Hoskins. W. J. Re-operating to assess ovarian cancer treatment, Confemp. Oh-Gyn
17, 159-162 (1981).
3. Bruchner, H. W., Cohen, C. J., Deppe, G., Kabakow. B., Wallach, R., Ratner, L., and Holland, J. F. Treatment of chemotherapy-resistant advanced ovarian cancer with a combination of cyclophosphamide, hexamethylmelamine, adriamycin and cis-diamminedichloroplatinum (CHAD). Gyned. Oncol. 12, 150-153 (1981). 4. Weiss, R. B. The role of hexamethylmelamine in advanced ovarian carcinoma, Gynecol. Oncol. 12, 141-149 (1981).
5. Bruchner, H. W., Wallach, R., Cohen, C. J.. Deppe, G., Kabahon, B., Ratner, L., and Holland, J. F. High dose platinum for the treatment of refractory ovarian cancer, G~necol. Oncol. 12, 64-67 (1981). 6. Bush, R. S., Allt, W. E. C., Beale, F. A., Bean, H., Pringle, J. F.. and Sturgeon, J. Treatment of epithelial carcinoma of the ovary: Operation, irradiation, and chemotherapy, Amer. J. Obstet. Gynecol. 127, 692-704 (1977). 7. Dembo, A. J., Bush, R. S., Beale, F. A.. Bean, H. A., Pringle, J. F., and Sturegon, J. F. G.
The Princess Margaret Hospital study of ovarian cancer: Stages I, II, and asymptomatic Ill presentations, Cancer Treat. Rep. 63, 249-254 (1979). 8. Dembo, M. B., Bush, R. S., Beale, F. A., Bean, H. A., Pringle, J. F., Sturgeon, J., and Reid. J. G. Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with a completed pelvic operation, Amer. J. Obstrt. Gynecol. 134, 793-800 (1979). 9. Flink. H., Lichter, A., Rosenshein, N.. and Order, S. Maximal irradiation by a new technique in the treatment of stage III ovarian cancer, Int. J. Rudiut. On&. Biol. Phys. 4, 441-443 (1978). IO. Gianni, L., Jenkins, J.. Green, R. et crl. Pharmacokinetics of the hypoxic radiosensitizers mi-
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11. 12. 13. 14.
15.
16.
HOSKINS ET AL.
sonidazole and desmethylmisonidazole after intraperitoneal administration in humans. Cancer Res. 43, 913-916 (1983). Potish, R., Brookes, D. et al. Sequential surgery, radiation therapy and alkeran in the management of epithelial carcinoma of the ovary, Cancer 45, 2754-2758 (1980). Haas, J. S., Mansfield, C. M., Hartman, G. V. et al. Results of radiation therapy in the treatment of epithelial carcinoma of the ovary, Cancer 46, 1950-1956 (1980). Smith, J. P., and Rutledge, F. Chemotherapy in the treatment of cancer of the ovary, Amer. J. Obstet. Gynecol. 107, 691-703 (1970). Piver, M. S., Barlow, J. J., Less, F. T., and Vongtana, V. Sequential therapy for advanced ovarian adenocarcinoma: Operation, chemotherapy, second-look laparotomy, and radiation therapy, Amer. J. Obstet. Gynecol. 122, 355-357 (1974). Hainsworth, J. D., Malcolm, A., Johnson, D. H., Barnett, L. S., Jones, H. W., and Greco, F. A. Advanced minima1 residual ovarian carcinoma: Abdominopelvic in-adiation following combination chemotherapy, Obstet. Gynecol. 61, 619-623 (1983). Dembo, A., Bush, R., Beale, F. et al. A randomized clinical trial of moving verus open held whole abdomen irradiation in patients with invasive epithelal cancer of the ovary, Proc. Amer. Sot. Clin. Oncol. 2, 146 (1983) (Abstract).