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Treatment and survival of patients with cancer of the cervix and nodal metastases
ht.
1. Radiation
Oncology Bid.
Phys.. 1976. Vol.
I. pp. 1091-1097.
Pergamon Press.
Printed in the U.S.A
TREATMENT AND SURVIVAL OF PATIENTS WITH CANCER OF THE CERVIX AND NODAL METASTASESt HENRY
KEYS, M.D.S and ROBERT C. PARK, M.D.§
Radiation Therapy and Gynecologic Oncology Services, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. Since 1962, 39 patients with lymph node meta&ases from carcinoma of the cervix have been treated at Walter Read Army Medical Center. While a revkw of the literature would suggest a very poor prognosk for these patients, we obtafned a 695% 5 year absdute survival. Tbe combination of surgery and radiatkm therapy appeared to be the most e&ctive approach. Survival and disease-free interval were inRuenced by clinical stage and level of lymph node invdvement. Recommendations and our current program of management are presented. Radiation
therapy,
Carcinoma
of the cervix, Lymph
INTRODUCTION The use of a clinical staging system for carcinoma of the cervix which is based on physically examinable criteria reflects both the need for readily defined stages for comparison and communication, as well as the tendency of the disease to remain locally confined, recur locally and cause death locally. However, as regional surgical and radiation therapy become applied more effectively and more aggressively, non-local failure pathways are being identified. The recognition of significant numbers of lymph node failures has stimulated the use of investigative procedures to find the patients with this pattern of spread in the hope that improved staging will increase the accuracy of treatment applied, and that this, in turn, will improve survival. Studies are underway currently to compare the accuracy of lymphangiographic and surgical staging of lymphatic metastases. The accuracy of the information that is obtained by these procedures must be weighted against the overall effect of more aggressive treatment on survival and compli-
tpresented at the Annual Meeting, American Society of Therapeutic Radiologists, San Francisco, California, October 1975. *Formerly, Chief, Radiation Therapy Service, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. Presently, Division of Radiation
node metastases.
cation rates of those patients with positive lymph nodes. If, in fact, lymph node metastases indicate incurability because of dissemination, then agressive procedures to identify and treat such metastases clearly are not justified.
METHODS
AND MATERIALS
Patient series
The present paper reports on 39 patients who were treated at Walter Reed Army Medical Center from 1962 to 1973 for carcinoma of the cervix with lymph node disease in a program that was directed initially by Drs. Edward Zimmermann and John Maier. Table 1 shows the patient material by stage and nodal station. During that interval, a total of 532 patients with invasive cervical carcinoma were treated; they have been reported previously.2~3~‘During 3 those 12 years, the treatment policy for carcinoma of the cervix remained basically constant at Walter Reed. Patients with Stage I carcinomas who were medically fit were treated by primary surgery with radical Wertheim-Taussig hysterectomy and
Oncology, University of Rochester Cancer Center, Strong Memorial Hospital, Rochester, NY 14642, U.S.A. Khief, Gynecologic Oncology Service, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. 1091
1092
Radiation Oncology 0 Biology 0 Physics
November-December
1976, Vol. 1, No. 11 and No. 12
Table 1. Cervix cancer: highest node and clinical stage Clinical stage
Pelvic
I-B II-A II-B III
17 2 6 0
1 0 1 1
4 1 4 2
22 3
zs
3
-11
-39
Common
pelvic lymphadenectomy. Patients with Stage II disease and beyond were treated with radiation therapy only. In 1971, we began to examine patients in the more advanced stages by lymphangiography to help outline treatment portals. Since 1973, a program of lymphangiography has been underway for all Stage I and II patients, followed by exploratory laparotomy to confirm lymphangiographic findings.” These patients are not included in this report. The patients were staged by the staffs of Gynecology and Radiation Therapy Departments at a joint conference. Staging examination was done in the Clinic without anesthesia. All patients had a standard neoplastic work-up including admission chest X-ray, barium enema, intravenous pyelogram (IVP) and cystoscopy. Routine blood chemistries and complete blood counts were obtained on all patients. Some patients had isotope scans, metastatic bone surveys and sigmoidoscopy, but these were not a consistent feature. These 39 patients represent all cases with known nodal disease and are derived from several treatment series at Walter Reed: 1. There were 14 patients with Stage I-B disease who underwent radical WertheimTaussig hysterectomy and pelvic lymphadenectomy, and in whom pelvic lymph nodes disease was discovered pathologically. 2. There were 5 patients with Stage I-B disease who were to undergo WertheimTaussig hysterectomy and lymphadenectomy, but in whom this procedure was not performed because of abnormal nodes with frozen section confirmation of metastatic carcinoma. 3. There were 12 patients (Stages II and III)
iliac
Para aortic
Total
11
3
who had grossly abnormal lymphangiograms without surgical confirmation. 4. There were 8 patients with Stages I and II disease who had abnormal lymphangiograms with surgical confirmation. Undoubtedly, more Stage II and III patients had node metastases than were recognized, but these later stages were not investigated routinely until the last three years of the study period. No intentional bias in selection exists, except that the series is heavily weighted with Stage I-B patients, because of the surgical management of these patients.
Method of treatment
Radiation therapy was used as primary management in 25 of the 39 patients, all of whom received a combination of external plus intracavitary radiation. The remaining 14 patients had radical hysterectomies as previously mentioned. External pelvic radiation therapy was delivered using parallel opposed, three field cross-fire, or four field cross-fire techniques. Occasionally, rotational boosts were used. Whole pelvis field sizes were 15 x 15 cm to 15 x 19 cm., depending on the site of the positive lymph nodes. The whole pelvic dose maximums ranged from 4600 to 6200 rad, usually given at 200 rad per day. In order to raise the dose for the cervix and Point A to a minimum of 75OO-M)O rad in each case, one or two intracavitary applications were done with Ernst or Fletcher-Suit applicators. Para aortic fields were treated when there were positive nodes in the common iliac or para aortic region, usually the para aortic area was treated through parallel opposed fields and ocasionally with a rotational boost to
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. PARK
doses ranging imum.
from
1093
Patients with Stage I-B disease had 77% survival, Stage II, 57%, and Stage III, 33%. Table 3 shows the relation of survival to level of lymph node involvement. Of those patients with pelvic nodal disease 76% survived, but of those with common iliac or para aortic disease, only 50% survived. Those patients in whom all gross nodal disease was resected, had improved survival when compared to those who had gross residual disease (75% vs 53%) (Table 4). The 12 patients who had lymphangiogram diagnosis of lymph node metastasis survived equally well as those with surgical diagnosis (67% for each) (Table 5).
4600 to 6OOOrad max-
RESULTS Survival data presented here represent absolute survival 2-13 years after treatment. Those patients who were eligible for 5 year or longer follow-up had a 69% survival (9/13). Survival and disease-free survival were identical since all of the patients with recurrence had died. The time to recurrence (or persistence) ranged from 0 to 60 months; most often recurrence was noted in the first 2 years. Clinical stage (or “T” stage) is strongly correlated with survival as shown in Table 2.
Table 2. Cervix cancer with involved lymph nodes
*Clinical stage
Patients with positive nodes (No.)
Primary radiotherapy (No.)
Alive (No.)
Alive (%) 77 100 45 33 67
I-B II-A II-B III
22 3 11 3
8 3 11 3
17 3 5 1
Total
39
25
26139
*F.I.G.O. News Report presented by the Cancer Committee to the General Assembly of F.I.G.O., New York, April 1970. Classification of Malignant Tumors in the Female Pelvis. Am. College of Obstet. Gynecol. Tech. Bull., No. 23, August 1973.’ Table 3. Cervix cancer: highest lymph node station involved
Pelvic No. of patients No. alive Survival (%)
25 19 76
Cammon iliac
Para aortic
Common plus para aortic
Total
3 1 33
11 7 64
14 8 50
39 27 69
Table 4. Cervix cancer: influence of unresected disease on survival Patients (No.)
Alive (No.)
nodal
% survival
Gross residual nodal disease No gross residual nodal disease
I5
8
53
24
Total
39
18 26
75 67
Radiation Oncology 0 Biology ??Physics
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November-December
1976. Vol. 1, No. 11 and No. 12
Table 5. Cervix cancer:
comparison of survival of lymphangiogram surgically diagnosed patients
Patients Lymphangiogram positive + radiation Surgically positive nodes + radiation Total
Recurrences within the treated area were relatively uncommon, 9 of 13 patients had part or all of their recurrent disease beyond the irradiated volume (Table 6). There were four significant complications: two cases of small bowel injury occurred in patients who were treated with combined surgery and radiation therapy (one, with pelvic portals only, and one with pelvic and para aortic portals). Two cases of proctitis occurred in patients whose primary cervical cancer was treated with radiation therapy after lymph node biopsy (one case) or abnormal lymphangiogram (one case). Table
6. Cervix cancer: site of recurrence patients with positive nodes
Recurrence volume
in
within treated 4
Recurrence outside treated volume Recurrence both in and out of treated volume Total
6 3 13
DISCUSSION
The ability of clinical stage alone, determined in the absence of any knowledge of lymph node status, to predict survival in a group of patients, all of whom had lymph node metastasis, lends support to the prognostic value of the stage system. It suggests either that more advanced “T” stage disease is associated with more advanced lymph node disease, or that the larger primary tumors are more difficult to control with or without nodal metastases. The numbers in this study are too small for statistical analysis but probably both
(No.)
Alive (No.)
and
% survival
12
8
67
27 39
18 26
67 67
factors contribute to the “T” stage dependence of survival here. As would be expected. the more proximal the lymph nodes disease, the less favorable the prognosis. Patients with positive lymph nodes within the pelvis (and hence within the usual radiation portal arrangements) survived almost as well as patients without lymph node disease. However, these patients were treated more aggressively in terms of dose and size of radiation fields than would have been done routinely in the absence of known nodal disease. The salvage of the patients with high common iliac and para aortic node metastases was poorer (50%), but still better than anticipated.3.7.19 Fletcher,6 among others, has reported on the radiation curability of carcinomas in terms of the dose required for various tumor sizes. The limitations of normal tissue tolerance determined the dose to be delivered to areas of lymph node disease (4600-6200rad). In our series, 24 patients had no evidence of gross disease after surgery, although some (if not most) undoubtedly had significant microscopic tumor remaining. Their survival as a group (75%) corroborates the favorable results of treatment of small amounts of disease with moderate radiation doses. It is unlikely that any of these patients had as large as 2 cm aggregates of tumor, whereas in patients with gross residual disease, almost certainly the diameter of the disease in nodes was 2 cm or greater. The 53% survival of the latter group reflects the higher dose tolerance of pelvic structures, since they were treated to larger total doses in areas of known disease. The three patients with surgically unresectable nodal disease all have died. The survival in the lymphangiogram and
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. Pm
radiation therapy group (67%) is surprisingly good as it equals that of the group having surgery followed by post-operative irradiation. Although the numbers are small, they are even more interesting because these patients had more advanced disease and by definition had gross residual disease present at the time of irradiation. Most (24/27) of the surgical series had no gross residual disease. One fault with this analysis is that some incidence of false positivity of the lymphangiogram cannot be excluded without surgical confirmation. Data in the literature are sparse concerning the accuracy of lymphangiograms in detecting nodal disease in cervical cancer. Piver and Bar10w’~ have published impressive results which have not yet been reproduced by others. They suggest that false positive diagnoses can all but be eliminated if adherence to strict criteria is maintained. This is satisfactory if all patients are to have surgery, but false negative interpretations would prevent adequate radiation therapy from being given to some patients. Clearly, more lymphangiogram-exploratory surgical correlation is needed before the adequacy of lymphangiographic staging alone can be determined. This may have particular importance if, as suggested here, many patients, especially those with less bulky nodal disease, can be treated effectively by irradiation alone with improved survival. In our series, scalene node biopsies were
not done consistently for patients with positive nodes, However, data- from Ketcham et al.” suggests that this procedure is worthwhile even in the absence of palpable abnormality. In patients with lymphangiographic evidence of lymph node metastases a positive scalene node biopsy could greatly alter the proposed treatment. The opposing view is expressed by Delgado eC al.“ who found only one patient with a positive scalene biopsy in a series of 18 patients with positive pelvic and/or para aortic node biopsies. About 50% of the time, recurrences appeared only outside the area treated, suggesting that more distant dissemination had occurred at the time of treatment. However, 4 patients remained uncontrolled clearly within the treated volume and 3 others had both forms of recurrence. These last three may be local failures with further spread after treatment or simultaneous occurrence of local recurrence/persistence with the appearance of pre-existing distant disease. In either case, the control of tumor at the primary site and in involved nodes was quite good. Scattered throughout many papers7-9.1k’9are data on the management of patients with lymph node disease in cancer of the cervix. Several approaches have been used and selected results are pooled and summarized in Table 7. Surgery alone appears less effective in these patients than some combination of surgery and irradiation. The series reporting
Table 7. Cervix cancer: results of treatment of patients positive lymph nodes by stage and treatment modality
with
Treatment/stage
No.
%
No.
%
III No. %
Surgeryt Pre-Op irradiation + surgery+ Pre-Op Irradiation + surgery and Post-Op§
39
384
49
26.5
N/A
25
56
44
20
54
42
26
32
55
55
63
40
II
I-B
2
50
N/A
Surgery + Post-Op Irradiation
1095
4
50
tFrom Brunschwig (1968)’ SFrom Brunschwig (1%8),’ Parker et al. ( 1%7)14and Rousseau et al. (1972).” §From Brunschwig (1%8),’ Nieminen et al:(l974),” Pilleron et al. (1972).” (From Brunschwig (1968)’ Guttman (1970): Kelso (1959)9 and Rousseau et al. (1972).”
1096
Radiation Oncology 0 Biology 0 Physics
the results of pre-operative irradiation followed by surgery, with or without postoperative irradiation may give artefactually poor results, because those patients with the most minimal nodal disease may be cured prior to surgery and not appear in the positive node category at all. A randomized study at M.D. Anderson Hospital” compared curative radiation therapy with the same treatment followed by pelvic lymphadenectomy at 3 months post irradiation; there was no improvement in survival even though 8 of 142 patients (5.7%) were found to have resectable nodal disease within the previously irradiated field. Parenthetically, the complication rate was quite high when these radical treatments were combined in this sequence. While our survival rates are better than the pooled data for surgery and post-operative irradiation, Guttman’ and Kelso9 show almost as good survival with all patients followed for 5 years. No reports of irradiation only for nodal metastases were found, but our small numbers suggest that it may be a viable alternative, especially for patients who are poor surgical candidates. Reliable lymphangiographic diagnosis is a pre-requisitive to this form of management.
RECOMMENDATIONS As aggressive treatment is effective in controlling significant numbers of patients who have lymph node metastases from cancer of the cervix; such treatment requires radia-
November-December
1976. Vol. 1, No. 11 and No. 12
tion therapy to higher doses and larger fields than is given customarily in the absence of known nodal disease. These results appear to more than offset the small increase in morbidity resulting from more aggressive diagnosis and treatment techniques. Therefore it appears warranted to propose the following program for patients with cervical carcinoma, Stages I-B and above: 1. Bipedal lymphangiogram be performed on all patients. 2. At least until further data become available, staging laparotomy should be used in each institution to establish reliability of lymphangiography, as used in their own hands. 3. Limited “debulking” lymphadenectomy should be done for diagnosis and to reduce the volume of tumor to be treated by irradiation. 4. Should lymphangiograms prove adequate, then this debulking procedure should be reserved for those patients with a greater than 2 cm bulk of disease. 5. Curative dose (cu. 6000 rad) radiation therapy should be delivered to all known areas of nodal disease and next higher nodal station should be treated to elective dose levels (4500-5000 i-ad). 6. Scalene node biopsies should be considered for patients with positive lymphangiograms prior to exploratory laparotomy or curative radiotherapy. 7. Further exploration of combined chemotherapy, radiotherapy and/or surgery is needed, since no effective systemic treatment exists now for patients with disseminated or locally unmanageable disease.
REFERENCES Brunschwig, A.: Treatment of cancer of the cervix, all stages, by surgical excision. In Proc. 6th Nat1 Cancer Conf. 1970, Lippincott, Philadelphia, sponsored by American Cancer Society and National Cancer Institute, pp. 353-360.
4. Delgado, G., Smith, J.P., Ballantyne, A.J.: Scalene node biopsy in carcinoma of the cervix. Cancer 35: 784-786, Mar. 1975.
2. Chism, S.E., Keys, H.M., Gillin, M.T.: Carcinema of the cervix: a time dose analysis of control and complications. Am. J. Roentgenol. 123: &t-90, 1975. 3. Chism, S.E.. Park, R-C., Keys, H.M.: Prospects for para-aortic irradiation in treatment of cancer of the cervix. Cancer 35: 1505-1509, 1975.
malignant tumors in the female pelvis. Am. Coll. Obstet. & Gynecol. Tech. Bull. No. 23, Aug. 1973. 6. Fletcher, G.H.: Clinical dose response curves of human malignant epithelial tumors. Br. I. Radiol. 46: 1-12, 1973. 7. Guthrie, R.T., Buchsbaum, H.J., White, A.J., Latourette, H.B.: Para-aortic lymph node ir-
1.
5. F.I.G.O. News Report presented by the Cancer Committee to the %eneral Assembly of F.I.G.O., New York, Apr. 1970. Classification of
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. PARK
radiation in carcinoma of the uterine cervix. Cancer 34: 160-168, 1974. 8. Guttman, R.: Significance of postoperative irradiation in carcinoma of the cervix: a ten year survey. Am. J. Roentgenol. 108: 102-108, Jan. 1970. 9. Kelso, J.W.: Surgical management of carcinoma of the cervix. Southern Med. J. 52: 681-687, June 1959. 10. Ketcham, A.S., Chretien, P.B., Hoye, R.C., Harrah, J.D., Dickers, P.J., Sugarbaker, E.V., Taylor, P.T., Robson, A.S.: Occult metastases to the scalene lymph nodes in patients with clinically operable carcinoma of the cervix. Cancer 31: 180-183, Jan. 1973. 11. Leman, M.H., Park, R.C.. Bacham, E,D., Chism, S.E., Petty, W.M., Patow, W.E.: Pretreatment lymphangiography in patients with Stage I and II carcinoma of the uterine cervix. Gynecol. Oncol. 3: 354-360, 1975. 12. Nieminen, U., Mattsson, T., Widholm, 0.: Radical surgery combined with radiotherapy in the treatment of cervical carcinoma. Ann. Chir. Gynecol. Feminae 63: 134-140, 1974. 13. Park, R.C., Patow, W.E., Rogers, R-E., Zimmermann, E.A.: Treatment of Stage I carcinoma of the cervix. Obstet. & Gynecol. 41: 117-122, 1973.
1097
14. Parker, R.T., Wilbanks, G.E., Yowell, R.K., Carter, F.B.: Radical hysterectomy and pelvic lymphadenectomy with and without preoperative radiotherapy for cervical cancer. Am. J. Obstet. & Gynecol. 99: 933-943, Dec. 1%7. 15. Pilleron, J.P., Durand, J.C., Lenoble, J.C.: Carcinoma of the uterine cervix, Stages I and II, treated by radiation therapy and extensive surgery (1000 cases). Cancer 29: 593-5%, Mar. 1972. 16. Piver, M.S., Barlow, J.J.: Para-aortic lymphadenectomy, aortic node biopsy, and aortic lymphangiography in staging patients with advanced cervical cancer. Cancer 32: 367-370, 1973. 17. Rousseau, J., Fenton, J., Debertrand, P.H., Mathieu, G.: Carcinoma of the cervix: a 7-year study of 1,212 cases treated at Foundation Curie, Paris. Radiology 103: 412-418, May 1972. 18. Rutledge, F.N., Fletcher, G., McDonald, E.A.: Pelvic lymphadenectomy as adjuvant to radiotherapy in cancer of the cervix. Am. J. Roentgen. 93: 607-614, 1%5. 19. Vongrama, V., Piver, S.M., Tsukada, Y., Barlow, J.J., Webster, J.H.: Para-aortic node irradiation in carcinomas. Cancer 34: 169-174, 1974.
1. Radiation
Oncology Bid.
Phys.. 1976. Vol.
I. pp. 1091-1097.
Pergamon Press.
Printed in the U.S.A
TREATMENT AND SURVIVAL OF PATIENTS WITH CANCER OF THE CERVIX AND NODAL METASTASESt HENRY
KEYS, M.D.S and ROBERT C. PARK, M.D.§
Radiation Therapy and Gynecologic Oncology Services, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. Since 1962, 39 patients with lymph node meta&ases from carcinoma of the cervix have been treated at Walter Read Army Medical Center. While a revkw of the literature would suggest a very poor prognosk for these patients, we obtafned a 695% 5 year absdute survival. Tbe combination of surgery and radiatkm therapy appeared to be the most e&ctive approach. Survival and disease-free interval were inRuenced by clinical stage and level of lymph node invdvement. Recommendations and our current program of management are presented. Radiation
therapy,
Carcinoma
of the cervix, Lymph
INTRODUCTION The use of a clinical staging system for carcinoma of the cervix which is based on physically examinable criteria reflects both the need for readily defined stages for comparison and communication, as well as the tendency of the disease to remain locally confined, recur locally and cause death locally. However, as regional surgical and radiation therapy become applied more effectively and more aggressively, non-local failure pathways are being identified. The recognition of significant numbers of lymph node failures has stimulated the use of investigative procedures to find the patients with this pattern of spread in the hope that improved staging will increase the accuracy of treatment applied, and that this, in turn, will improve survival. Studies are underway currently to compare the accuracy of lymphangiographic and surgical staging of lymphatic metastases. The accuracy of the information that is obtained by these procedures must be weighted against the overall effect of more aggressive treatment on survival and compli-
tpresented at the Annual Meeting, American Society of Therapeutic Radiologists, San Francisco, California, October 1975. *Formerly, Chief, Radiation Therapy Service, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. Presently, Division of Radiation
node metastases.
cation rates of those patients with positive lymph nodes. If, in fact, lymph node metastases indicate incurability because of dissemination, then agressive procedures to identify and treat such metastases clearly are not justified.
METHODS
AND MATERIALS
Patient series
The present paper reports on 39 patients who were treated at Walter Reed Army Medical Center from 1962 to 1973 for carcinoma of the cervix with lymph node disease in a program that was directed initially by Drs. Edward Zimmermann and John Maier. Table 1 shows the patient material by stage and nodal station. During that interval, a total of 532 patients with invasive cervical carcinoma were treated; they have been reported previously.2~3~‘During 3 those 12 years, the treatment policy for carcinoma of the cervix remained basically constant at Walter Reed. Patients with Stage I carcinomas who were medically fit were treated by primary surgery with radical Wertheim-Taussig hysterectomy and
Oncology, University of Rochester Cancer Center, Strong Memorial Hospital, Rochester, NY 14642, U.S.A. Khief, Gynecologic Oncology Service, Walter Reed Army Medical Center, Washington, DC 20012, U.S.A. 1091
1092
Radiation Oncology 0 Biology 0 Physics
November-December
1976, Vol. 1, No. 11 and No. 12
Table 1. Cervix cancer: highest node and clinical stage Clinical stage
Pelvic
I-B II-A II-B III
17 2 6 0
1 0 1 1
4 1 4 2
22 3
zs
3
-11
-39
Common
pelvic lymphadenectomy. Patients with Stage II disease and beyond were treated with radiation therapy only. In 1971, we began to examine patients in the more advanced stages by lymphangiography to help outline treatment portals. Since 1973, a program of lymphangiography has been underway for all Stage I and II patients, followed by exploratory laparotomy to confirm lymphangiographic findings.” These patients are not included in this report. The patients were staged by the staffs of Gynecology and Radiation Therapy Departments at a joint conference. Staging examination was done in the Clinic without anesthesia. All patients had a standard neoplastic work-up including admission chest X-ray, barium enema, intravenous pyelogram (IVP) and cystoscopy. Routine blood chemistries and complete blood counts were obtained on all patients. Some patients had isotope scans, metastatic bone surveys and sigmoidoscopy, but these were not a consistent feature. These 39 patients represent all cases with known nodal disease and are derived from several treatment series at Walter Reed: 1. There were 14 patients with Stage I-B disease who underwent radical WertheimTaussig hysterectomy and pelvic lymphadenectomy, and in whom pelvic lymph nodes disease was discovered pathologically. 2. There were 5 patients with Stage I-B disease who were to undergo WertheimTaussig hysterectomy and lymphadenectomy, but in whom this procedure was not performed because of abnormal nodes with frozen section confirmation of metastatic carcinoma. 3. There were 12 patients (Stages II and III)
iliac
Para aortic
Total
11
3
who had grossly abnormal lymphangiograms without surgical confirmation. 4. There were 8 patients with Stages I and II disease who had abnormal lymphangiograms with surgical confirmation. Undoubtedly, more Stage II and III patients had node metastases than were recognized, but these later stages were not investigated routinely until the last three years of the study period. No intentional bias in selection exists, except that the series is heavily weighted with Stage I-B patients, because of the surgical management of these patients.
Method of treatment
Radiation therapy was used as primary management in 25 of the 39 patients, all of whom received a combination of external plus intracavitary radiation. The remaining 14 patients had radical hysterectomies as previously mentioned. External pelvic radiation therapy was delivered using parallel opposed, three field cross-fire, or four field cross-fire techniques. Occasionally, rotational boosts were used. Whole pelvis field sizes were 15 x 15 cm to 15 x 19 cm., depending on the site of the positive lymph nodes. The whole pelvic dose maximums ranged from 4600 to 6200 rad, usually given at 200 rad per day. In order to raise the dose for the cervix and Point A to a minimum of 75OO-M)O rad in each case, one or two intracavitary applications were done with Ernst or Fletcher-Suit applicators. Para aortic fields were treated when there were positive nodes in the common iliac or para aortic region, usually the para aortic area was treated through parallel opposed fields and ocasionally with a rotational boost to
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. PARK
doses ranging imum.
from
1093
Patients with Stage I-B disease had 77% survival, Stage II, 57%, and Stage III, 33%. Table 3 shows the relation of survival to level of lymph node involvement. Of those patients with pelvic nodal disease 76% survived, but of those with common iliac or para aortic disease, only 50% survived. Those patients in whom all gross nodal disease was resected, had improved survival when compared to those who had gross residual disease (75% vs 53%) (Table 4). The 12 patients who had lymphangiogram diagnosis of lymph node metastasis survived equally well as those with surgical diagnosis (67% for each) (Table 5).
4600 to 6OOOrad max-
RESULTS Survival data presented here represent absolute survival 2-13 years after treatment. Those patients who were eligible for 5 year or longer follow-up had a 69% survival (9/13). Survival and disease-free survival were identical since all of the patients with recurrence had died. The time to recurrence (or persistence) ranged from 0 to 60 months; most often recurrence was noted in the first 2 years. Clinical stage (or “T” stage) is strongly correlated with survival as shown in Table 2.
Table 2. Cervix cancer with involved lymph nodes
*Clinical stage
Patients with positive nodes (No.)
Primary radiotherapy (No.)
Alive (No.)
Alive (%) 77 100 45 33 67
I-B II-A II-B III
22 3 11 3
8 3 11 3
17 3 5 1
Total
39
25
26139
*F.I.G.O. News Report presented by the Cancer Committee to the General Assembly of F.I.G.O., New York, April 1970. Classification of Malignant Tumors in the Female Pelvis. Am. College of Obstet. Gynecol. Tech. Bull., No. 23, August 1973.’ Table 3. Cervix cancer: highest lymph node station involved
Pelvic No. of patients No. alive Survival (%)
25 19 76
Cammon iliac
Para aortic
Common plus para aortic
Total
3 1 33
11 7 64
14 8 50
39 27 69
Table 4. Cervix cancer: influence of unresected disease on survival Patients (No.)
Alive (No.)
nodal
% survival
Gross residual nodal disease No gross residual nodal disease
I5
8
53
24
Total
39
18 26
75 67
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November-December
1976. Vol. 1, No. 11 and No. 12
Table 5. Cervix cancer:
comparison of survival of lymphangiogram surgically diagnosed patients
Patients Lymphangiogram positive + radiation Surgically positive nodes + radiation Total
Recurrences within the treated area were relatively uncommon, 9 of 13 patients had part or all of their recurrent disease beyond the irradiated volume (Table 6). There were four significant complications: two cases of small bowel injury occurred in patients who were treated with combined surgery and radiation therapy (one, with pelvic portals only, and one with pelvic and para aortic portals). Two cases of proctitis occurred in patients whose primary cervical cancer was treated with radiation therapy after lymph node biopsy (one case) or abnormal lymphangiogram (one case). Table
6. Cervix cancer: site of recurrence patients with positive nodes
Recurrence volume
in
within treated 4
Recurrence outside treated volume Recurrence both in and out of treated volume Total
6 3 13
DISCUSSION
The ability of clinical stage alone, determined in the absence of any knowledge of lymph node status, to predict survival in a group of patients, all of whom had lymph node metastasis, lends support to the prognostic value of the stage system. It suggests either that more advanced “T” stage disease is associated with more advanced lymph node disease, or that the larger primary tumors are more difficult to control with or without nodal metastases. The numbers in this study are too small for statistical analysis but probably both
(No.)
Alive (No.)
and
% survival
12
8
67
27 39
18 26
67 67
factors contribute to the “T” stage dependence of survival here. As would be expected. the more proximal the lymph nodes disease, the less favorable the prognosis. Patients with positive lymph nodes within the pelvis (and hence within the usual radiation portal arrangements) survived almost as well as patients without lymph node disease. However, these patients were treated more aggressively in terms of dose and size of radiation fields than would have been done routinely in the absence of known nodal disease. The salvage of the patients with high common iliac and para aortic node metastases was poorer (50%), but still better than anticipated.3.7.19 Fletcher,6 among others, has reported on the radiation curability of carcinomas in terms of the dose required for various tumor sizes. The limitations of normal tissue tolerance determined the dose to be delivered to areas of lymph node disease (4600-6200rad). In our series, 24 patients had no evidence of gross disease after surgery, although some (if not most) undoubtedly had significant microscopic tumor remaining. Their survival as a group (75%) corroborates the favorable results of treatment of small amounts of disease with moderate radiation doses. It is unlikely that any of these patients had as large as 2 cm aggregates of tumor, whereas in patients with gross residual disease, almost certainly the diameter of the disease in nodes was 2 cm or greater. The 53% survival of the latter group reflects the higher dose tolerance of pelvic structures, since they were treated to larger total doses in areas of known disease. The three patients with surgically unresectable nodal disease all have died. The survival in the lymphangiogram and
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. Pm
radiation therapy group (67%) is surprisingly good as it equals that of the group having surgery followed by post-operative irradiation. Although the numbers are small, they are even more interesting because these patients had more advanced disease and by definition had gross residual disease present at the time of irradiation. Most (24/27) of the surgical series had no gross residual disease. One fault with this analysis is that some incidence of false positivity of the lymphangiogram cannot be excluded without surgical confirmation. Data in the literature are sparse concerning the accuracy of lymphangiograms in detecting nodal disease in cervical cancer. Piver and Bar10w’~ have published impressive results which have not yet been reproduced by others. They suggest that false positive diagnoses can all but be eliminated if adherence to strict criteria is maintained. This is satisfactory if all patients are to have surgery, but false negative interpretations would prevent adequate radiation therapy from being given to some patients. Clearly, more lymphangiogram-exploratory surgical correlation is needed before the adequacy of lymphangiographic staging alone can be determined. This may have particular importance if, as suggested here, many patients, especially those with less bulky nodal disease, can be treated effectively by irradiation alone with improved survival. In our series, scalene node biopsies were
not done consistently for patients with positive nodes, However, data- from Ketcham et al.” suggests that this procedure is worthwhile even in the absence of palpable abnormality. In patients with lymphangiographic evidence of lymph node metastases a positive scalene node biopsy could greatly alter the proposed treatment. The opposing view is expressed by Delgado eC al.“ who found only one patient with a positive scalene biopsy in a series of 18 patients with positive pelvic and/or para aortic node biopsies. About 50% of the time, recurrences appeared only outside the area treated, suggesting that more distant dissemination had occurred at the time of treatment. However, 4 patients remained uncontrolled clearly within the treated volume and 3 others had both forms of recurrence. These last three may be local failures with further spread after treatment or simultaneous occurrence of local recurrence/persistence with the appearance of pre-existing distant disease. In either case, the control of tumor at the primary site and in involved nodes was quite good. Scattered throughout many papers7-9.1k’9are data on the management of patients with lymph node disease in cancer of the cervix. Several approaches have been used and selected results are pooled and summarized in Table 7. Surgery alone appears less effective in these patients than some combination of surgery and irradiation. The series reporting
Table 7. Cervix cancer: results of treatment of patients positive lymph nodes by stage and treatment modality
with
Treatment/stage
No.
%
No.
%
III No. %
Surgeryt Pre-Op irradiation + surgery+ Pre-Op Irradiation + surgery and Post-Op§
39
384
49
26.5
N/A
25
56
44
20
54
42
26
32
55
55
63
40
II
I-B
2
50
N/A
Surgery + Post-Op Irradiation
1095
4
50
tFrom Brunschwig (1968)’ SFrom Brunschwig (1%8),’ Parker et al. ( 1%7)14and Rousseau et al. (1972).” §From Brunschwig (1%8),’ Nieminen et al:(l974),” Pilleron et al. (1972).” (From Brunschwig (1968)’ Guttman (1970): Kelso (1959)9 and Rousseau et al. (1972).”
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Radiation Oncology 0 Biology 0 Physics
the results of pre-operative irradiation followed by surgery, with or without postoperative irradiation may give artefactually poor results, because those patients with the most minimal nodal disease may be cured prior to surgery and not appear in the positive node category at all. A randomized study at M.D. Anderson Hospital” compared curative radiation therapy with the same treatment followed by pelvic lymphadenectomy at 3 months post irradiation; there was no improvement in survival even though 8 of 142 patients (5.7%) were found to have resectable nodal disease within the previously irradiated field. Parenthetically, the complication rate was quite high when these radical treatments were combined in this sequence. While our survival rates are better than the pooled data for surgery and post-operative irradiation, Guttman’ and Kelso9 show almost as good survival with all patients followed for 5 years. No reports of irradiation only for nodal metastases were found, but our small numbers suggest that it may be a viable alternative, especially for patients who are poor surgical candidates. Reliable lymphangiographic diagnosis is a pre-requisitive to this form of management.
RECOMMENDATIONS As aggressive treatment is effective in controlling significant numbers of patients who have lymph node metastases from cancer of the cervix; such treatment requires radia-
November-December
1976. Vol. 1, No. 11 and No. 12
tion therapy to higher doses and larger fields than is given customarily in the absence of known nodal disease. These results appear to more than offset the small increase in morbidity resulting from more aggressive diagnosis and treatment techniques. Therefore it appears warranted to propose the following program for patients with cervical carcinoma, Stages I-B and above: 1. Bipedal lymphangiogram be performed on all patients. 2. At least until further data become available, staging laparotomy should be used in each institution to establish reliability of lymphangiography, as used in their own hands. 3. Limited “debulking” lymphadenectomy should be done for diagnosis and to reduce the volume of tumor to be treated by irradiation. 4. Should lymphangiograms prove adequate, then this debulking procedure should be reserved for those patients with a greater than 2 cm bulk of disease. 5. Curative dose (cu. 6000 rad) radiation therapy should be delivered to all known areas of nodal disease and next higher nodal station should be treated to elective dose levels (4500-5000 i-ad). 6. Scalene node biopsies should be considered for patients with positive lymphangiograms prior to exploratory laparotomy or curative radiotherapy. 7. Further exploration of combined chemotherapy, radiotherapy and/or surgery is needed, since no effective systemic treatment exists now for patients with disseminated or locally unmanageable disease.
REFERENCES Brunschwig, A.: Treatment of cancer of the cervix, all stages, by surgical excision. In Proc. 6th Nat1 Cancer Conf. 1970, Lippincott, Philadelphia, sponsored by American Cancer Society and National Cancer Institute, pp. 353-360.
4. Delgado, G., Smith, J.P., Ballantyne, A.J.: Scalene node biopsy in carcinoma of the cervix. Cancer 35: 784-786, Mar. 1975.
2. Chism, S.E., Keys, H.M., Gillin, M.T.: Carcinema of the cervix: a time dose analysis of control and complications. Am. J. Roentgenol. 123: &t-90, 1975. 3. Chism, S.E.. Park, R-C., Keys, H.M.: Prospects for para-aortic irradiation in treatment of cancer of the cervix. Cancer 35: 1505-1509, 1975.
malignant tumors in the female pelvis. Am. Coll. Obstet. & Gynecol. Tech. Bull. No. 23, Aug. 1973. 6. Fletcher, G.H.: Clinical dose response curves of human malignant epithelial tumors. Br. I. Radiol. 46: 1-12, 1973. 7. Guthrie, R.T., Buchsbaum, H.J., White, A.J., Latourette, H.B.: Para-aortic lymph node ir-
1.
5. F.I.G.O. News Report presented by the Cancer Committee to the %eneral Assembly of F.I.G.O., New York, Apr. 1970. Classification of
Cancer of the cervix and nodal metastases 0 H. KEYS and R. C. PARK
radiation in carcinoma of the uterine cervix. Cancer 34: 160-168, 1974. 8. Guttman, R.: Significance of postoperative irradiation in carcinoma of the cervix: a ten year survey. Am. J. Roentgenol. 108: 102-108, Jan. 1970. 9. Kelso, J.W.: Surgical management of carcinoma of the cervix. Southern Med. J. 52: 681-687, June 1959. 10. Ketcham, A.S., Chretien, P.B., Hoye, R.C., Harrah, J.D., Dickers, P.J., Sugarbaker, E.V., Taylor, P.T., Robson, A.S.: Occult metastases to the scalene lymph nodes in patients with clinically operable carcinoma of the cervix. Cancer 31: 180-183, Jan. 1973. 11. Leman, M.H., Park, R.C.. Bacham, E,D., Chism, S.E., Petty, W.M., Patow, W.E.: Pretreatment lymphangiography in patients with Stage I and II carcinoma of the uterine cervix. Gynecol. Oncol. 3: 354-360, 1975. 12. Nieminen, U., Mattsson, T., Widholm, 0.: Radical surgery combined with radiotherapy in the treatment of cervical carcinoma. Ann. Chir. Gynecol. Feminae 63: 134-140, 1974. 13. Park, R.C., Patow, W.E., Rogers, R-E., Zimmermann, E.A.: Treatment of Stage I carcinoma of the cervix. Obstet. & Gynecol. 41: 117-122, 1973.
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14. Parker, R.T., Wilbanks, G.E., Yowell, R.K., Carter, F.B.: Radical hysterectomy and pelvic lymphadenectomy with and without preoperative radiotherapy for cervical cancer. Am. J. Obstet. & Gynecol. 99: 933-943, Dec. 1%7. 15. Pilleron, J.P., Durand, J.C., Lenoble, J.C.: Carcinoma of the uterine cervix, Stages I and II, treated by radiation therapy and extensive surgery (1000 cases). Cancer 29: 593-5%, Mar. 1972. 16. Piver, M.S., Barlow, J.J.: Para-aortic lymphadenectomy, aortic node biopsy, and aortic lymphangiography in staging patients with advanced cervical cancer. Cancer 32: 367-370, 1973. 17. Rousseau, J., Fenton, J., Debertrand, P.H., Mathieu, G.: Carcinoma of the cervix: a 7-year study of 1,212 cases treated at Foundation Curie, Paris. Radiology 103: 412-418, May 1972. 18. Rutledge, F.N., Fletcher, G., McDonald, E.A.: Pelvic lymphadenectomy as adjuvant to radiotherapy in cancer of the cervix. Am. J. Roentgen. 93: 607-614, 1%5. 19. Vongrama, V., Piver, S.M., Tsukada, Y., Barlow, J.J., Webster, J.H.: Para-aortic node irradiation in carcinomas. Cancer 34: 169-174, 1974.