The oncologic management of carcinoma cervix after primary treatment failure
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0973-1075.19184
Source of Support: None, Conflict of Interest: None
Keywords: cervical cancer, palliative care, re-treatment, palliative care, surgery, radiotherapy, chemotherapy
Cervical cancer is a serious health problem, with nearly 5,00,000 women developing the disease each year worldwide. Incidence is particularly high in developing countries such as India, Latin America, Southern and Eastern Africa where the majority of the patients present at late stages. In developed nations, effective screening with cervical cytology and yearly pelvic examinations has led to a greater than 70% decrease in the mortality rate since the 1940s., This has been attributed mainly to detection of early stage diseases where effective cure is possible. Risk factors for cervical cancer are young age at first coitus and childbirth, multiple sexual partners, promiscuous behaviour of the male partner, exposure to human papillomavirus, poor hygienic conditions, poor nutritional status, sexually transmitted diseases and immune-deficiency. The disease is generally radioresponsive and highly curable in the early stages. Either surgery or radiotherapy alone for stage IB and IIA tumors has resulted in 5-year survival rates of 75% to 90%. In India most patients present with locally advanced stage III disease where cure rates decline to 45-65%. For patients who present with stage IV disease or for those with recurrent disease after radiotherapy, no consistent improvement in survival has been observed over the last 30 years. Treatment of recurrent cervical cancer remains largely ineffective. Quality of life and supportive care are of paramount importance in helping such patients. This article reviews the palliative; and in selected situations, curative role of oncologic interventions in relapsed cervical cancer.
Nearly 1/3rd patients with carcinoma cervix will develop recurrence.,, Patients with local disease recurrence or with disease extension to lateral pelvic wall may present with bleeding, discharge per vaginum, severe backache radiating to thighs and pelvic pain. The incidence of locally recurrent disease after radical radiotherapy increases with increasing stage of the primary disease: stage IA-4.6%; stage IB-11.2%; stage IIA-10-20%; stage IIB-17-30%; stage IIIA-28-30%; stage IIIB-45-50%.,, The primary echelon of spread of carcinoma cervix is to the obturator lymph nodes (a medial group of the external iliac nodes), to other external iliac nodes,and to the hypogastric nodes. From here, metastasis spreads to the pelvic or paraaortic lymph nodes. Recurrent tumours of the cervix and enlarged pelvic nodes can infiltrate or compress the sciatic nerve, sacral plexus and the lumbosacral nerve trunks. Patients can also present with symptoms secondary to metastatic disease outside the pelvis i.e. paraaortic nodes, lung, liver, bone or brain.
The incidence of para-aortic lymph nodal metastasis is 5%, 16% and 25% respectively, for stages IB, II and III with a median survival of about 15.2 months and a survival probability of 25% at 3 years., In an analysis of 322 patients in whom distant metastases developed, the most frequently occurring metastatic site were the paraaortic lymph nodes (11%) causing radiating pain in lumbosacral area due to involvement of nerve roots and occasional epigastric pain due to metastases to high paraaortic lymph nodes. Other sites of metastases were the abdominal cavity (8%), and supraclavicular lymph nodes (7%). Hematogenous dissemination through the venous plexus and paracervical veins occurs more commonly in advanced stages. Bone metastasis is encountered in about 16% patients, most commonly in the lumbar and thoracic spine. Metastasis to the brain occurs rarely. In 1,279 patients with cervical carcinoma treated at the Cleveland Clinic, only 6 had brain metastases.
The management and prognosis of disease recurrence depends on the extent of disease, primary treatment, performance status, and associated comorbidities. Salvage surgery is applicable to a small number of patients with post radiation therapy failures as discussed later. Patients with pelvic recurrences after primary radical hysterectomy or isolated recurrence in the paraaortic lymphnodes have a significantly better 5 year survival rate with concurrent chemoradiation., There are very limited treatment options for other patients with recurrent or metastatic cervical carcinoma. Because of the low response rates and negligible impact on long-term survival, the use of either radiotherapy (RT) or chemotherapy (CCT) in these latter subgroups should be considered palliative.
(I) After radical surgery
Recurrent disease after radical surgery may present with pelvic pain or bleeding. The diagnosis must be confirmed with local examination, tissue biopsy, and the extent of disease must be evaluated with biochemical parameters, radiographic studies, cystoscopy, proctoscopy. For patients who develop recurrent disease after definitive surgery and who have not received prior radiation therapy, radical chemoradiotherapy is the treatment of choice. Grigsby administered radiotherapy and 3 cycles of concurrent cisplatin and 5-fluorouracil to 22 patients with post radical hysterectomy pelvic recurrence. They achieved a 35% 10 year overall survival with an acute toxicity rate of 27%.
Patients maybe treated with external-beam radiotherapy with or without brachytherapy. In general, external radiation for recurrent tumor is given to limited volumes (preferentially using parallel opposed portals). Survival rates for patients treated with radical radiotherapy range between 20- 40%., Patients with central recurrence usually have a better prognosis than those with pelvic wall recurrence. reported a survival rate of 69% at 5 years after radical radiotherapy for central recurrences versus 18% survival at 5 years for disease involving pelvic sidewalls.
(II) After definitive radiation
Clinical features that suggest a post radiotherapy recurrence are local pain, bleeding, a bulky or nodular cervix, cervical cytologic findings abnormal at 6 months, or the presence of a new lesion on pelvic examination.
A small number of patients with limited pelvic recurrences not fixed to pelvic wall and without any evidence of extrapelvic metastases can be considered for salvage by radical hysterectomy. As the extent of disease maybe difficult to evaluate and the risk of serious urinary tract complications from pelvic surgery is high after high dose radiotherapy, surgical salvage treatment will usually require a total pelvic exenteration. Prior to attempting this major procedure, the patient needs thorough evaluation for any intraperitoneal or lymph nodal spread. Despite careful preoperative workup, 30% - 60% of operations are abandoned intraoperatively., Sommers et al attempted pelvic exenteration in 23 patients but only 10 were found to be operable. The 5-year survival in patients who underwent pelvic exenteration was 16%.
Good prognostic factors for surgical salvage are tumours less than 2cm, confined to the cervix without parametrial, nodal or pelvic wall involvement.,
In a study of 50 patients who underwent radical hysterectomy after primary radiation therapy, the 10-year survival was 80% in 12 patients with tumors < 2cm versus 48% in those with larger lesions (p < .01). Complications of surgery developed in 32 patients (64%) which was in the form of thromboembolic events, bowel and bladder obstruction, cellulites and leg edema. Twenty eight percent of patients developed fistulae. The authors suggested that a radical hysterectomy should be attempted only in patients with tumors < 2cm size with normal results on the preoperative intravenous pyelogram.
Ji et al undertook salvage surgery in 47 of 162 patients who had local failure. Patients were subclassified into three groups: tumours confined to cervix; tumours extending to adjacent tissue (parametria, uterus, vagina) but not beyond; and tumour extending beyond adjacent tissue but confined to the pelvis. The corresponding 5-year survival rates were 22% vs. 9% vs. 4% for the three groups ( p = 0.005). The 5-year overall survival rate was 29% vs. 3% ( p = 0.0001) for surgery versus no surgery. Their results implied that early detection of cervical relapse and performing salvage surgery for recurrence confined to the cervix could result in a survival benefit. In a Memorial Sloan Kettering Cancer Centre study of 65 patients treated with pelvic exenteration, the 5-year survival was 23%. The operative mortality was 9.2%. The authors stressed upon the significant mortality and morbidity associated with this procedure not recommending its use as a purely palliative procedure.
Thus, before planning any surgery, careful patient selection is of utmost importance. In all cases, preparation for pelvic exenteration involves careful counselling of the patient and the caregivers regarding the extent of surgery and postoperative expectations.
b) Reirradiation for pelvic recurrence
Pelvic reirradiation is generally not possible because of potential radiation damage to the bladder and rectum. Palliative chemotherapy may be tried, but previously irradiated pelvic disease is likely to respond poorly. Suzworo et al, delivered brachytherapy to central and parametrial post RT recurrences using a specialized Martinez Universal Perineal Interstitial Template (MUPIT) and Iridium high dose rate brachytherapy. Doses ranged from 6-16 Gy over 1-2 days. All four tumours were locally controlled with minimal morbidity at 15 months.
c) Palliative pelvic irradiation
Radiation therapy can provide palliative benefit in patients who are symptomatic because of extensive loco-regional disease. Two radiation schedules have been reported for the treatment of advanced pelvic disease including cervical cancer. The large single-dose schedule consisted of 10-Gy fractions repeated at monthly intervals to a maximum of 30 Gy. This schedule has produced good palliative results with symptomatic improvement in approximately 50% of patients and objective response in 35%-80%. However, severe late GI toxicity was shown to be as high as 49%. RTOG 85-02 tested a rapid fractionation approach using 3.7 Gy twice daily for two days to a total dose of 14.8 Gy. This schedule was repeated after a 2 to 4 week break, with fields reduced to exclude all small bowel third session of four treatments could be administered for a total dose of 44.4 Gy. A tumor response of 42% was seen after completion of all three courses with response rates (complete and partial) of 75% for pain, 98% for bleeding, and 83% for tenesmus. The treatment course was well tolerated with a severe complication rate of only 5/132 (4%). There were 284 patients accrued, and the subgroup of 61 cervical cancer patients was analyzed in this article. The subjective response (50%-100% complete response) and objective response (53%) were similar to those observed with the large single-fraction schedule. The late toxicity was significantly lower (7%). For patients who may survive 6 months or longer, this second schedule is preferable.
Isolated paraaortic lymph node recurrence
Chemoradiation is the treatment of choice for relapse limited to the paraaortic nodes, provided the general condition and performance status of the patient validates its use. Ji et al found that of the total 375 patients with local or distant relapse, 46 (22%) had isolated PALN recurrence of which 27% survived more than 5 years. The 5-year survival rate was 40%, 30% and 0%, respectively, for those undergoing concurrent chemoradiation (CCRT), radiation therapy or palliative chemotherapy, or no treatment(p < 0.0001). They concluded that with isolated para-aortic nodal metastases, patients can achieve long term survival when appropriately treated.
In a study by Chou et al isolated PALN recurrence as first site of metastasis was found in 26 patients of which 14 underwent cisplatin based CCRT, 1 received RT alone and 4 received chemotherapy alone. The 5-year survival rate of the 14 patients receiving CCRT was 51.2% with associated mild gastrointestinal toxicity. None of the patients receiving RT or chemotherapy alone achieved long-term disease free survival.
In our institution, PALN recurrence in the absence of pelvic disease is managed by radiation of the paraaortic area to a dose of 35-40 Gy/15-20#/3-4wks which is delivered using either 6 MV or 15 MV photons. We use a field 8-10 cm wide with a 2cm margin around the gross disease. The superior border is matched at the T10-11 intervertebral space. The lower border is matched to the superior edge of previous pelvic portal with a 1-1.5 cm gap. Nowadays, 3-D conformal or intensity-modulated radiation therapy are being considered to reduce small bowel toxicity. In one study, hyperfractionated (twice daily) radiotherapy to the nodal areas resulted in a late complications rate of 27% at 5 years without a significant improvement in the survival rate.
Paraaortic relapse associated with post radiotherapy pelvic recurrence
If there is associated pelvic recurrence along with PALN, then the intention of management is palliative. The treatment options are palliative radiotherapy to the PALN for pain relief, palliative chemotherapy, and supportive care. The decision would depend on symptoms, patient choice and performance status.
Early detection of paraaortic nodes
A study from Mallinckrod Institute of Radiology by Singh et al, found that 7/14 patients who were symptomatic for their PALN recurrence died within 1.5 yrs of diagnosis and none could complete the salvage therapy offered to them. The other 7 asymptomatic patients treated with concurrent chemo radiotherapy had a 100% 5 year survival. This single institution experience seems to suggest that it may be worthwhile imaging for paraaortic nodes while following up treated carcinoma cervix patients.
If the supraclavicular region is the first site of relapse, fine-needle aspiration should be carried out to confirm metastatic disease. The radiotherapy field extends from the upper neck to the subclavicular region. An anteroposterior oblique field, is with the patient in a supine position and the head turned to the contralateral side. The spinal cord should be kept away from the field by giving a 10-15 degree angulation. Doses of nearly 30-40 Gy in 4 weeks calculated at a depth of 3 to 4 cm should be delivered. In cases of advanced disease, 20 Gy in 5 fractions or even 800c Gy in a single fraction is given at our institution. Ji et al 2004 found an overall 3 year survival rate of 28% and 5 year survival of 17% in patients with positive supraclavicular lymphadenopathy with or without paraaortic lymphadenopathy. They concluded that in patients with supraclavicular lymphadenopathy, radiotherapy is beneficial and these patients showed a longer survival as compared to those with metastasis to other sites except paraaortic lymph nodes.
Pain is the most frequent symptom (96%) in patients with bone metastasis %).,, Pain and impaired mobility occurs in 65-75%. Bone pain maybe nociceptive or neuropathic., Fracture of weight bearing long bone occurs in 10-20% of patients. This occurs especially in lytic bone metastases.
In carcinoma cervix patients, the most common form of bone involvement is extension to the lumbar spine from secondary deposits in the paraaortic nodes. Tumor cells in bone cause reaction of both destruction and new bone formation.,,,
Bone resorption occurs by two factors:
a) osteoclast -mediated osteolysis
b) tumor-mediated osteolysis.
The primary treatment option is radiation therapy. External radiation produces some healing and re-ossification in 65-85% of lytic lesions in unfractured bone., Traditionally, local-field radiation therapy has been used for patients with symptomatic bone metastases. There is a wide variation in the pain relief rates reported both in clinical reports and in randomized clinical trials. In a trial by Gaze et al, 280 patients were randomized to either 10 Gy/1# or a protracted course of 22.5 Gy/5#. Overall response rates for both schedules were similar, 83.7% and 89.2%. Complete response rates were 38.8% and 42.3%; and the median duration of pain control was 13.5 weeks and 14 weeks, respectively.
In a Dutch trial,  1171 patients were randomized to receive 8 Gy/1# or 24 Gy/6#/1wk. They found overall response rates to be similar but re-treatment rates were four times higher in the single fraction group (25% vs 7%, respectively). Similarly, in another study of 765 patients who were randomized to receive either 8 Gy/1# or 20-30 Gy/5-10#/1-2wks, there was no difference in the time to improvement in pain, time to complete pain relief or time to first increase in pain at any time upto 12 months. Re-treatment was twice as common after single fraction than after multifraction radiotherapy. In a randomized trial by Cole et al 1989, comparing 24 Gy/6#/2-3wks and single 8 Gy fraction found that, 25% patients in the single fraction group required re-irradiation. In a meta-analysis of 7 studies including 3260 patients with painful bone metastases comparing single fraction of 8 Gy to multiple fraction regimens, overall response rates were in favour of single fraction RT, 62.1% vs 58.7%, for multifraction doses). However, the re-irradiation rate is consistently higher in the single fraction groups (20-25% vs 7-12%). It is unclear if this is because radiotherapists are more willing to consider reirradiation after single fraction radiotherapy, or because troublesome pain recurs more frequently in the single fraction group. The multiple fractionation regimens used varied from 20 Gy/5#/1wk to 30 Gy/10#/2wk.
Koswig et al compared 8 Gy/1# to 30 Gy/10#/2wks. They found a significantly different re-calcification rates in both groups (120% vs 173% for multiple fractions, p < 0.0001).
In choosing between single fraction radiotherapy and a protracted course, one must bear in mind the location, extent of tumour mass and the patient's probable life expectancy. Patients with carcinoma cervix having bone pain due to metastatic nodes infiltrating the vertebrae may need fractionated radiotherapy as discussed in the section on paraaortic nodes. For others with bone metastases, single large dose fraction may be given when pain relief is the main aim. A longer fractionated course may be considered in patients with a longer life expectancy or those with pathologic fractures.
Brain metastases arise from hematogenous spread to the white matter of the watershed area of the brain at the junction of the gray and white matter. Patients may present with headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%) or seizures (18%).
Most metastases are found between the supratentorial and infratentorial compartments in proportion to the relative weight and blood supply to these structures (85% in the cerebral hemisphere, 10-15% in the cerebellum, and 1-3% in the brain stem. Gynaecologic tumors have a predilection to the cerebellum. Most brain metastases grow as spherical, well demarcated, solid masses that displace rather than destroy adjacent tissue. They may be surrounded by minimal to extensive oedema. The microscopic appearance of the brain metastases resembles the tissue that they arise from.
I) Medical Management
The majority of patients with metastatic brain lesions have or will soon develop widely disseminated disease. Median survival of patients with symptomatic brain metastases is approximately 1 month without treatment, and 2 months with corticosteroid administration.
Rarely, surgery maybe used to establish the diagnosis of malignant disease or as treatment for single metastases. Patients with a single accessible lesion with controlled or absent extracranial disease, Karnofskhy performance status of at least 70, age less than 60, and a life expectancy of at least 2 months are most likely to benefit from any form of surgical intervention.
Palliative radiotherapy is appropriate for patients with multiple brain metastases and those with single metastases who are not candidates for surgery. Patients who are receiving whole brain radiotherapy should also receive steroids for at least 48 hours before starting treatment, which should subsequently be tapered during the second week of radiotherapy. The standard approach is to treat the whole brain to 30 Gy/10#/2wks. Depending on the symptoms, the response rate varies from 70% to 90%. Neurologic function is improved in 50% of patients. The durability of response is low, as the median time to progression is only 2 to 3 months. Overall, 75% to 80% of remaining life can be spent in improved or stable neurologic state. RTOG has tried 5 schedules of fractionation varying from 20 Gy/5#/1 week to 40 Gy/20#/4 weeks in three randomized trials. All the regimens were similar in improvement in neurological function (50%), duration of improvement (9 to 12 weeks), time to progression (10 weeks), survival (15 to 18 weeks), or improvement in quality of life palliation.
Encouraged by the apparent success of accelerated hyperfractionated radiotherapy in brain metastases in various phase I/II trials,, the RTOG designed a phase III trial comparing AH radiotherapy 54.4 Gy/34#/2wks (1.6 Gy twice daily) to accelerated fractionated (AF) radiotherapy 30 Gy/10#/2wks in 445 patients. Of the 429 patients analyzed, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm which was not statistically significant. Thus the study did not reveal any advantage of an accelerated hyperfractionated regime in patients with brain metastasis.
Chemotherapy has a limited role in the treatment of relapsed cervical cancer. The most active single agent, cisplatin is associated with clinical complete response rates ranging from 18-50% in previously untreated patients.,, No other single agent has shown objective response rates in excess of 25%. in randomized phase II or phase III trials.
Even responses to cisplatin are generally partial and of short duration and the impact of treatment with single-agent cisplatin on survival has been minimal.,,, There are many explanations for this poor response:
1)Following definitive surgery or radiotherapy, or both, pelvic anatomy is distorted and the vascular supply to residual tumour areas maybe compromised hence, inadequate anticancer drug concentrations are likely to reach these tumour masses.
2)Tumour clones that have persisted following high doses of radiotherapy may develop resistance to various cytotoxic agents. It was found that such drug resistance is amenable to high drug concentrations administered intraarterially, directly into the tumour bed in the pelvis.,
3)Most patients have already received high doses of radiotherapy to the large bone marrow reserves in the pelvis, lumbosacral vertebrae, and the femoral heads which compromises the further administration of myelotoxic agents resulting in low doses and further decrease in the response rates.
[Table - 1] below tabulates the response rates, median survival, toxicities and costs for different chemotherapy regimens.
The lack of success with single-agent therapy has led investigators to explore the use of combination chemotherapy. The most widely studied combination chemotherapy regimen has been cisplatin and ifosfamide . Several phase II trials have demonstrated response rates in the range of 30% to 60% using either ifosfamide alone or in combination with carboplatin and/or cisplatin.,,,
The Gynecologic Oncology Group protocol 110 in a prospective, randomized, three-arm phase III trial including 454 patients compared cisplatin alone versus cisplatin and ifosfamide versus cisplatin and dibromodulcitol. Results from this trial revealed that the combination of cisplatin and ifosfamide was superior to cisplatin alone with regard to response rates (31.1% vs 17.8%) and progression-free survival (4.6 vs 3.2 months). However, there were no differences among the three arms with regards to overall survival. Cisplatin and ifosfamide improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in overall survival.
This led investigators to evaluate three-drug regimens incorporating the cisplatin -ifosfamide combination. One such regimen is the combination of cisplatin or carboplatin with ifosfamide and bleomycin. Several phase II trials using this regimen have documented response rates ranging from as low as 13% to as high as 100%.,,, However a randomized trial of 287 patients found that addition of bleomycin did not improve the response rate, PFS, survival, and toxicity profile compared to cisplatin and ifosfamide [Table - 1].
In a Phase II trial Rose et al tried prolonged single daily dose of oral etoposide at 50 mg/m2/day (40 mg/m2/day for patients who had prior radiotherapy) for 21 days repeated after every 28 days. Based on toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed. In 25 patients studied, oral etoposide was not well tolerated, with grade 4 neutropenia occurring in 33.3% and grade 4 thrombocytopenia occurring in 15% patients. Seven patients were unable to complete their first cycle due to toxicity and 8 patients received only one course of therapy. Two responses (11.8%) were observed, one complete response and one partial response, both of these patients had disease in nonirradiated sites and one was chemotherapy-naive. Based on an intent-to-treat analysis, the response rate was 8.3%. The authors concluded that prior radiation therapy limited the ability to deliver prolonged oral etoposide. At the maximum tolerated dose, this regimen is not significantly active as second-line chemotherapy in squamous cell carcinoma of the cervix.
Paclitaxel i s a newer anticancer agent with a novel mechanism of action that involves stabilization of the mitotic spindle's microtubular polymer complex [Schiff 1979]. Paclitaxel has been studied in squamous cell carcinoma of the cervix in two prior studies., Rose et al found a 12.2% CR rate and 34.1% PR rates with cisplatin- paclitaxel in recurrent cervical carcinoma. However, this has been associated with significant toxicity. Neutropenia grade 3 (15.9%) and 4 (61.4%) was the most frequent severe adverse effect, which was associated with fever in 13 patients (27.7%). The median progression-free interval was 5.4+ months (range, 0.3 to 22+ months) with a median survival of 10.0+ months (range, 0.9 to 22.2 months). Response was more frequent in patients with disease in nonirradiated sites (70% v 23%, p =.008)
Tinker et al used a combination of carboplatin-paclitaxel repeated 4 weekly. Of the 25 women treated, 23 (92%) had prior pelvic radiotherapy and 14 (56%) had had concurrent radiosensitizing cisplatin. Fifty six percent patients died due to disease progression, 5/25 (20%) had a partial response and 5/25 (20%) had a complete response. The median progression free survival for the entire group was 3 months. Responders had a median PFS of 16 months. Median overall survival (OS) was 21 months. Grade 3 or 4 haematologic toxicity was seen in 32% patients.
Newer investigational agents used are vinorelbine showing a 18% response rate, while irinotecan and topotecan have shown response rates upto 24%. Single agent capecitabine in patients with recurrent cervical carcinoma did not show any objective responses at all.
In the light of these findings any form of chemotherapy in this setting must be tried only after proper counseling about the cost and toxicities involved. When a patient is willing for palliative chemotherapy, cisplatin and ifosfamide is a relatively cost effective combination in a developing country.
Radiation therapy has a clear role in surgical failures, and for palliation of metastatic disease. Only a small subset of radiation therapy failures are suitable for major pelvic exenteration. The benefit from chemotherapy is measurable in months, and is particularly limited when patients relapse in previously irradiated sites.
A cautious approach must be adopted by all treating physicians in the selection of treatment options for patients with recurrent carcinoma cervix. This must be done in an individualized and comprehensive manner taking into account the previous treatment received as well as the cost benefit ratio, toxicity, duration of benefit, social factors and patient choice. The morbidity associated with retreatment should not be worse than the symptoms due to the recurrence. Recurrent cervical cancer is a distressing disease for the patients, caregivers and the physicians involved. Good palliative care combined with a judicious use of oncologic interventions is necessary to address the patient's suffering.
[Table - 1]